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Marianne C. KASTRUP, MD, PhD
Head, Center of Transcultural Psychiatry, Psychiatric Center Copenhagen
Copenhagen, DENMARK

Globalization and increasing pluralism require psychiatrists to evaluate the impact of cultural factors on depressive disorders. Modern classification systems should pay due attention to culture-specific factors, and systematic, operationalized appraisals are needed in order to assess cultural elements. In the Diagnostic and Statistical Manual of Mental Disorders IVth Edition (DSM-IV), the Cultural Formulation was introduced, in order to provide an operational approach of the cultural perspective and allow patients to reflect cultural elements in their narratives. Prevailing classification systems are still criticized as reflecting Western concepts and not paying sufficient attention to the symptomatology of patients of non-Western backgrounds. Depression has a multifaceted etiology, and migrants run a particular risk, in part due to the migratory process itself. One should therefore distinguish culture-specific issues and migration-specific issues. The lifetime risk for a major depression is as high as 12% to 16%. The World Health Organization has predicted that in 2020 depression will be the second most important cause of disability. Culture influences depressive symptomatology, explanatory models, help-seeking behavior, and societal response. Furthermore, treatment tends to differ according to culture and so does the treatment gap.

With increasing globalization, mental health professionals are being confronted with decisions related to culture-specific aspects of diagnosis, validity of diagnostic entities, and variability of symptoms.¹ It is important to be able to evaluate the role of culture in explaining differences in symptom manifestation and to be aware of the interaction between culture and depressive symptomatology when assessing a depressed patient.² Assessing depressive disorders in persons from a variety of cultural backgrounds is becoming part of routine clinical work in many mental health settings. This paper examines issues related to cultural aspects of depression, with particular focus on diagnosis.

Table I. “Cultural Formulation” and depression.

Diagnostic considerations

Classification systems are affected by changes in our professional knowledge and orientation, by the actual situation in society, and even by political ideologies.³ Tseng further points out that hitherto it has been easier for Western psychiatrists to adapt to classification systems developed in the West than it is for non-Western psychiatrists, who experience a disparity between their actual practice of psychiatry and international classification systems. The diagnosis of depression has undergone major changes over time. In spite of the fact that melancholia and depression have been described for many centuries, the classification of depression has given rise to extensive debate. The very concept of depression is not universally accepted and, historically, many non-Western societies have consistently reported lower prevalences of depression than Western societies.³ Variations in diagnostic categories over time—including entities like endogenous versus reactive depression; psychotic versus neurotic depression; depression versus dysthymia—have also made comparisons across cultures or time difficult. From the point of view of research, the classification of depression is controversial. In many non-Western languages, there is no corresponding word for “depression” in spite of the fact that lowered mood is a universally encountered phenomenon.⁴ Furthermore, methodological differences, such as variations in study samples; differences in methodologies in clinical assessments, or lack of culturally validated assessment instruments, contribute to transcultural variability in depression.⁵

Confronted with a depressive patient of similar cultural background as their own, many clinicians may fail to recognize the prominent role of the cultural element and tend to underestimate its importance. In contrast, when dealing with a depressed patient from another cultural background, cultural differences may become obstacles for the clinician and thus mask the depressive process.⁶

The concept “category fallacy”⁷ was introduced to illustrate a fundamental error in transcultural diagnostics. When psychiatrists reject “non-Western” disease categories as being culture-specific, they so-to-speak impose their own cultural categories on the “non-Western” categories in the false conviction that these are neutral and culture-independent.

Several proposals have been made to overcome these diagnostic difficulties. One would be to introduce an independent cultural axis in the diagnostic systems; another would be to include culture-bound syndromes as part of the nosological entities.

As a result of expanding migratory population movements, it is increasingly recognized that culture-specific factors related to modern societal realities should be taken into account by international classification systems. Yet, culture does not have a prominent explicit place in the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10), even though the development of ICD-10 did include field trials in a number of countries worldwide.

In the Diagnostic and Statistical Manual of Mental Disorders IVth Edition (DSM-IV),Cultural Formulation was introduced to apply a cultural perspective to the clinical evaluation and to allow an operational approach and an individual assessment. This can be seen as a significant step toward a cultural-competent and cultural-sensitive assessment of mental disorders Table I.⁸ Using the Cultural Formulation to assess a depressive episode enables the patient to provide a narrative of all components reflecting cultural elements. It offers a larger scope than purely diagnostic evaluation by encompassing aspects of the patients’ social universe, personal interpretations, explanatory reflections, and attitudes toward help-seeking.⁹ A comprehensive biographical history, taking into account the patient’s cultural reference group and identity, as well as stressors related to migration and acculturation, enables better understanding of the depressive disease process and of its impact on patients and their relatives. Yet despite this innovation, objections are raised that classification systems nevertheless continue to reflect Western concepts and values and cannot be used uncritically in patients of other cultural backgrounds.¹⁰

Table II. Guidelines for diagnosis of depression by a clinician from
another culture than the patient’s.

Clinicians and researchers must find ways to carry out transcultural comparisons. Bhugra and Mastrogianni¹¹ suggest that when categorizing depression across cultures, the prevailing psychiatric model, the cultural context, and indigenous beliefs should be considered. It should be kept in mind that the pathogenetic and pathoreactive influence of culture may result in different clinical pictures, making differential diagnosis difficult for clinicians from other cultures Table II.^11,12

Epidemiology

Historically, it has been a frequently held belief that depression, in developing countries, in particular in Africa and Asia, is an infrequent illness compared withWestern countries, and suicides due to depressive illness were thought to be extremely rare in non-Western countries.² Investigations carried out by the World Health Organization (WHO) have demonstrated today that depressive disorders occur in all cultures.¹³ Cross-cultural comparisons of depressive disorders, eg, the WHO study following a cohort with standardized assessments in 5 different countries, show similarities in symptoms, such as lowered mood, sleep disorders, lack of energy, and concentration difficulties.^13,14 Depression today is a huge and increasing public health concern on a global level. Neuropsychiatric disorders contribute 31.7% of all YLDs (years lived with disability) according to WHO,¹⁵ with unipolar depression ranking highest (11.8%). Among the ten most important diseases measured by YLDs, psychiatric conditions make up four, among which unipolar depression.¹⁶

Around 360 million persons throughout the world suffer from mood disorders.¹⁶ Furthermore, depressive disorders are the fourth most important contributor to the global burden of disease, and in adults aged 15 to 44 years, they are the leading cause of DALYs (disability-adjusted life years) lost worldwide. As persons under 45 years run a greater risk of depression, persons are affected during their most productive years of life, in all cultural settings. About 5% to 10% of persons at any given time are suffering from identifiable depression that requires psychiatric/psychosocial intervention, while the lifetime risk for major depression is 12% to 16 %. WHO has predicted that in 2020 depression will be the second most important cause of disability. In the European Region, the prevalence of major depression and bipolar disorders totals 21 million.¹⁷

It is well documented that women run a greater risk in most cultures: overall, women have a 1.5- to 2-times higher risk of suffering from depression compared with men. In the Cross- National Collaborative Group, women in all countries had a higher prevalence with a female:male ratio varying from 1.6 in Lebanon to 3.1 in West Germany.¹⁸ Possible explanations for these differences include the multiple roles women have as homemakers, professionals, wives, and mothers.

The rate of depression does not vary significantly with ethnicity. Socioeconomic or educational differences may contribute to differences between ethnic groups, but the differences disappear to a large extent when controlled for these.¹⁹

The burden of depression (Figure 1, page 122)²⁰ is relatively smaller in poorer regions of the world, eg, depression represents 1.2% of the disease burden in Africa compared with 8.9% in high-income countries, but depression is predicted to become a leading cause of disease burden in developing countries as well.²¹ It has been suggested that differences in the prevalence of depression may reflect dysfunctionality of a changing culture.²²

Primary health care

General practitioners often diagnose depressive disorders. A WHO study of 15 primary care centers reported that 11.7% of patients presenting in a primary health care (PHC) setting had depression, but the fact that the psychiatric problem was generally not the presenting complaint meant that the depression risked going unidentified.²³

The frequency of depression in the community was measured by the WHO in its General Health Care Study including 14 countries around the world. The prevalence of current depression was found to vary from 2.6% in Nagasaki to 16.9% in Manchester and 29.5%in Santiago.²⁴ The range in frequency was interpreted as: (i) reflecting true differences in prevalence; (ii) cultural variations in disease concept; (iii) differences in help-seeking behavior; (iv) or differences in demographic characteristics.²⁴

Figure 1. The burden of depression.

Provoking factors

Depression is acknowledged to be a disorder with a multifaceted etiology. Depressive syndromes are very common in migrants, and up to half of all migrants in the US may have clinical depression.²⁵ The very process of migration itself may be partly responsible for the risk of emergence of stress-related disorders. A wide range of provoking factors may contribute to an episode in minority ethnic groups. These include: premigratory stressors; personality; physical health problems; as well as postmigratory stressful living conditions; discrimination; socioeconomic adversities; cultural conflicts; personal losses related to migration, etc (Table III).^2,26 In addition, persons coming from traditional, sociocentric, societies, who migrate to a Western country with a more egocentric type of society, may feel alienated, which makes adjustment more difficult and results in an increased risk of mental health problems.²⁷

Table III. Diagnosis of depression in migrants.

Migration is thus a highly complex experience comprising a range of processes, influences, and conditions that may affect health and illness.²⁸ At the same time, migration and the cultural change from a traditional, more community-centered, society to a modern, individualistic society, can lead to decompensation of coping mechanisms and emergence of depression. As the above shows, migration can trigger mental disorders when the protective function of the original culture is missing.²⁹

Cultural dimensions

WHO reports indicate considerable cross-cultural similarities in depressive symptomatology, with symptoms such as low mood, lack of joy, anxiety, lack of energy and interest in surroundings evidenced in most cultures.³⁰ However, crosscultural differences do exist: for example, feelings of guilt are one of the major symptoms of depression in Western countries even though they are not specific and can be observed in many other cultures, albeit with far lesser frequency. Thus, a WHO study reported the highest frequency of feelings of guilt in Swiss patients and the lowest in Iranian patients, while somatic complaints were more common in the latter.³¹

In non-Western patients delusions often have themes like physical health, or religion, and are not, as in Western patients, constructed around guilt and inferiority.² Due to the absence of the dualistic body-soul distinction prevalent in Western cultures, patients in some non-Western countries often have narratives that contain metaphors of body functions when describing their emotional state rather than psycho- logical terms.² Nevertheless, somatization as a sense of bodily discomfort, or vegetative symptoms without any demonstrable organic cause, are part of depressive symptomatology in all cultures.

Culture may also influence the expression of depressive thoughts. The question of whether suicide is considered an acceptable strategy for solving conflicts in a seemingly hopeless situation is very culture-dependent, and vast differences in the traditions of suicide exist depending on which culture is considered. Depressive reactions following bereavements or as part of old age are in many cultures not seen as conditions requiring an intervention, but rather as part of normal life. Western psychiatrists should, however, also be aware of the fact that more severe depressive symptoms may be interpreted as normal reactions, thereby preventing the afflicted person from receiving adequate treatment.³²

Thus, the interaction between culture and depression should be borne in mind whenever interviewing a patient in whom a depressive episode is suspected.³² When diagnosing depression in persons of another ethnic origin it is important to distinguish culture-specific issues and migration-specific issues, as they may have a different impact on the intrapsychic conflict forming part of the migration process. The literature often fails to distinguish between the two²⁹ and to indicate whether the increased vulnerability to depression is associated with the fact of being a migrant per se or with problems encountered in the host country due to cultural differences, or whether it is due to a combination of both (Table IV).^10,28

Therapeutic aspects

When assessing the impact of culture on the treatment of depression, attention should be paid to the specific context. Clinicians trained in Western countries tend to focus only on the individual. But in many instances it may be of benefit to consider the depressed patient in a social context and take into account social values and role expectations.² Clinicians from Western individualistic cultures sometimes falsely assume that cohesive family structures prevent personal growth and do not allow individualization, whereas in fact cohesive social patterns foster the development of a self-contained identity in accordance with one’s role within a social hierarchical structure.³³ Attitudes toward treatment tend to differ according to cultural context when comparing persons in their home country with the same ethnic groups having migrated to a Western country.

Table IV. Interaction between culture and depression.

Treatment gap

Overall, the increased focus on depression has failed to translate into a better situation for depressed persons, and there is still a significant lack of correlation between the disease’s extent and the availability of adequate treatment (the so called treatment gap). This gap is highest in low-and middle-income countries,³⁴ but even in Western Europe, the European Ministerial Report³⁵ estimates the treatment gap at 45.4% for severe depression, while in low-income and middle-income countries only a small proportion of treated depressed patients are in fact adequately treated.³⁶ Reasons for this treatment gap in many countries comprise the lack of trained staff, lack of resources, and stigma toward depression. Even in the US, it has been shown that the treatment gap varied considerably between ethnic groups.³⁷

In order to minimize the gap between the consequences of depression and the availability of treatment, research should focus on therapies that are practical and allow for the needs of the population in question.³⁸ With the current focus on prevention, a cost-effective decrease in the current burden of depression is possible. _

References

1. Minas H. Service responses to cultural diversity. In: Thornicroft G, Szmukler G, eds. Textbook of Community Psychiatry. Oxford, UK: Oxford University Press; 2001:192-206.
2. Kastrup M, Machleidt W, Behrens K, Calliess I. Cultural aspects of depression. In: Maj M et al, eds. The WPA Educational Series on Depressive Disorders. Volume 4: Depression in Population Groups. Geneva, Switzerland:WPA; 2009; 4:208-237
3. TsengWS. Handbook of Cultural Psychiatry. San Diego, Calif: Academic Press: 2001:335, 464.
4. Patel V. Cultural factors and international epidemiology. Br Med Bull. 2001; 57:33-45.
5. Ballenger JC, Davidson JRT, Lecrubier Y, et al. Consensus statement on transcultural issues in depression and anxiety from the International Consensus Group on Depression and Anxiety. J Clin Psychiatry. 2001;62:47-55.
6. Littlewood R. From categories to contexts: a decade of “new cross-cultural psychiatry.” Br J Psychiatry. 1990;156:308-327.
7. Kleinman A. Depression, somatization and the ”New cross-cultural psychiatry.” Soc Sci Med. 1977:11:3-10.
8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th ed.) Washington, DC: APA; 1994.
9. Lewis-Fernandez R, Diaz N. Cultural Formulation: a method for assessing cultural factors affecting the clinical encounter. Psychiatr Quart. 2002;73:271-295.
10. Kirmayer LJ. Cultural variations in the clinical presentation of depression and anxiety: implications for diagnosis and treatment. J Clin Psychiatry. 2001;62 (suppl 13):22-28.
11. Bhugra D, Mastrogianni A. Globalisation and mental disorders. Overview with relation to depression. Br J Psychiatry. 2004;184:10-20.
12. Pfeiffer W. Transkulturelle Psychiatrie. Stuttgart, Germany: Thieme; 1994.
13. Jablensky A, Sartorius N, Bulbinat W, Ernberg G. Characteristics of depressive patients contacting psychiatric services in four cultures. Acta Psychiatr Scand. 1981;63:367-383.
14. Thornicroft G, Sartorius N. The course and outcome of depressive disorders in different cultures: 10 year follow-up of the WHO collaborative study on the assessment of depressive disorders. Psychol Med. 1993;23:1023-1032.
15. World Health Organization (WHO). World Mental Health Atlas. Geneva, Switzerland: WHO; 2005.
16. World Health Organization (WHO). World Health Report. Geneva, Switzerland: WHO; 2001.
17. Olesen J, Baker M, Freund T, et al. Consensus document on European brain research. J Neurol Neurosurg Psychiatry. 2006;77(suppl 1):1-49.
18. Weismann MM, Bland RC, Canino GJ, et al. Cross-national epidemiology of major depression and bipolar disorder. JAMA. 1996;276:293-299.
19. World Health Organization (WHO). (http://www.searo.who.int/en/Section1174/ Section1199/Section1567/Section1826_8101.htm) 8.1. 2008.
20. Prince M, Patel V, Saxena S, et al. No health without mental health. Lancet. 2007;370:859-877.
21. Murray CJ, Lopez AD Alternative projections of mortality and disability by cause. 1990-2020. Global Burden of Disease Study. Lancet. 1997;349:1498-1504.
22. Bebbington P, Cooper C. Affective disorders. In: Bhugra D, Bhui K, eds. Textbook of Cultural Psychiatry. Cambridge, UK: Cambridge University Press; 2007: 224-241.
23. Wittchen HU, Lieb R, Wunderlich U, Schuster P. Comorbidity in primary care: presentation and consequences. Clin Psychiatry. 1999;60(suppl 7):29-36.
24. Goldberg D, Lecrubier Y. Form and frequency of mental disorders across centres. In: Ûstun TB, Sartorius N, eds. Mental Illness in General Health Care. Chichester, UK: Wiley; 1995.
25. Kleinman A. Culture and depression. N Engl J Med. 2004;351:951-953.
26. Bhugra D Ahmad K. Depression across ethnic minority cultures: diagnostic issues. World Cult Psychiatry Res Rev. 2007;2:47-56.
27. Bhugra D, Becker M. Migration, cultural bereavement and cultural identity. World Psychiatry. 2005;4:18-24.
28. Bhugra D. Cultural identities and cultural congruency: a new model for evaluating mental distress in immigrants. Acta Psychiatr Scand. 2005;111:84-93.
29. Cantor-Graae E, Selten J. Schizophrenia and migration: a meta-analysis and review. Am J Psychiatry. 2005;162:12-24.
30. Jablensky A, Sartorius N, Ernberg G, et al. Schizophrenia: manifestations, incidence and course in different cultures. A WHO ten-country study. Psychol Med. 1992; Monograph suppl 20.
31. Sartorius N, Davidian H, Ehrenberg G, et al. Depressive Disorders in Different Cultures: Report on the WHO-Collaborative-Study on Standardized Assessment of Depressive Disorders. Geneva, Switzerland: WHO; 1983.
32. Kastrup M. Global burden of mental health. In: Preedy VR, Watson RR, eds. Handbook of Disease Burdens and Quality of Life Measurements. New Yoirk, NY: Springer; 2009:1474-1491.
33. Fisek GO. Cultural Context. Migration and health risks—A multilevel analysis. In:Marschalck P,Wiedl KH , eds. Migration und Krankheit. IMIS-Schriften, Vol 10. Osnabrück, Germany: Universitätsverlag Rasch; 2001:113-122.
34. WHO; Mental Health Consortium. Prevalence, severity and unmet need for treatment of mental disorders in the World Health Organization. JAMA. 2004;291: 2581-2590.
35. WHO. Mental Health: Facing the challenges, Building Solutions. Report From the WHO European Ministerial Conference. Copenhagen Denmark: WHO Regional Office; 2005.
36. Lancet Global Mental Health Group. Scale up services for mental disorders: a call for action. Lancet. 2007;370:2241-2252.
37. Williams DR, Gonzales HM, Neighbors H, et al. Prevalence and distribution of major depressive disorder in African American, Caribbean Blacks, and non-Hispanic whites: results from the National Survey of American life. Arch Gen Psychiatry. 2007;64:305-315.
38. Desjarlais R, Eisenberg L, Good B, Kleinman A. World Mental Health. Problems and Priorities in Low-Income Countries. New York, NY: Oxford University Press; 1995.

Keywords: diagnosis; depression; culture; epidemiology; migration; globalization; gender

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Hans-Jürgen MÖLLER, MD, PhD
Michael RIEDEL, MD
Florian SEEMÜLLER, MD
Department of Psychiatry and Psychotherapy
Ludwig-Maximilian-University
Munich, GERMANY

Classification into relapse or recurrence of a newly occurring depressive episode has important therapeutic implications. In the past, diverse outcome measures with arbitrary definitions have been used in antidepressant treatment trials. In an attempt to harmonize and standardize these definitions, a task force was set up by the MacArthur Foundation. This article summarizes the currently used definitions for response, remission, relapse, recurrence, continuation, and maintenance treatment, and discusses whether relapse is the consequence of incomplete remission. The two most important outcomes that are important in order to distinguish relapse from recurrence are the threshold for remission and the time spent in remission before recovery can be ascribed to a patient. For remission a 17-item Hamilton Depression Rating Scale (HAMD-17) threshold of below 7, and for recovery a time span of 6 months in remission seem to be now accepted by the research community. Recent research on remission thresholds, together with the role of unrecognized residual symptoms in the development of depressive disorder, are discussed. The “6-month” period for determining the end of an episode is explained and justified by two different approaches involving the length of the depressive episode and data from antidepressant discontinuation trials. To conclude, the limitations and pitfalls of both methods are discussed.

Defining relapse or recurrence is directly dependent on the definition of the healthy, illness-free state commonly referred to as remission or recovery. Remission derives from the Latin word remittere (remisi, remissum), which literally translates as “to abate” or “to remit,” “to send back.” Clearly, in medical terms, the term remission relates to the former meaning, describing the “abatement” or the “decrease” of symptoms.

So from a linguistic point of view this would not necessarily imply absolute freeness of symptoms, but would rather describe an improvement in the course of illness. In the early days of depression research this has contributed to quite a few difficulties and much confusion regarding definitions of outcome terms like response, remission, and partial remission. This ultimately led to the paradox that one researcher’s definition of “remission” equaled another researcher’s definition of “response.”¹ In 1988, in an attempt to overcome these controversies, the MacArthur Foundation set up a task force led by Ellen Frank with the goal of achieving a con- sensus in defining outcomes of clinical studies.² This led to the current definition of “remission,” which, in its narrow medical sense, refers to the virtual absence of depressive symptoms. Terms like “recovery,” “relapse,” and “recurrence” were also precisely defined. Important therapeutic concepts relating to these outcomes, are “response,” and “acute, continuation, and maintenance therapy.” These terms have often been used quite arbitrarily in the past. After the publication of the consensus paper by Ellen Frank in 1991,² the American College of Neuropsychopharmacology (ACNP) updated these recommendations by introducing small changes.³ In the wake of the MacArthur Foundation, several other groups were set up to standardize the definition of psychiatric terms such as bipolar disorder⁴ or schizophrenia.^5,6 In the following, we briefly summarize the current concepts underlying the terms response, remission, recovery, relapse, and maintenance, before discussing in more detail some important aspects closely related to relapse and recurrence, as well as the why the time span of 6 months was agreed upon. Figure 1^2,4 shows the important periods in depression treatment and the corresponding terminology for the illness phases in relation to these treatment periods.

Response

Response describes a gradual improvement during depression treatment and usually implies a treatment effect.⁷ Response is usually defined as a 50% improvement from baseline to end point on depression rating scales such as the 17-item Hamilton Depression Rating Scale (HAMD-17) or the Montgomery-Åsberg Depression Rating Scale (MADRS). Response tends to occur early on during the course of treatment (eg, after 2 weeks⁸) and usually precedes remission as a precondition. It is the main categorical outcome parameter of short-term antidepressant trials. Thus, response occurs during the acute treatment phase of major depression.

Figure 1. Overview of response, remission, recurrence, and relapse in relation to the
treatment phase.

Remission

As stated before, remission refers to a relatively short symptom- free period.⁷ Usually, remission is defined by a threshold on a depression rating scale. In contrast to response, remission is not necessarily related to any treatment. It can also occur spontaneously in patients without treatment. Michael Thase has shown that a threshold of equal to or below 7 on the HAMD-17 best distinguished healthy control persons from patients with major depression (Figure 2).⁹ Recently, this threshold was replicated in a large sample of naturalistically treated patients with major depression.¹⁰ In contrast to response, remission can occur with or without treatment. From a therapist’s perspective, remission is the starting point of continuation therapy with the primary goal of sustaining remission until recovery is achieved.

Recovery

The concept of recovery implies a prolonged period of remission. This period should be long enough so that a major depressive episode (MDE) is unlikely to occur in the near future.³ In other words, once a patient achieves recovery, many months of remission can be anticipated.³ In accordance with remission, recovery can be ascribed while the patient is either on or off treatment. From a theoretical point of view, recovery implies that the illness activity of the MDE is no longer present, but it is important to keep in mind that the underlying vulnerability may still be present. This also means that recovery refers only to the last episode and not to the affective disorder as a whole.

Thus, recovery is only lost if recurrence occurs. The ACNP Task Force recommends a time span of 4 months, while others have repeatedly used a 6-month duration to define recovery.¹¹ The fact that a patient has recovered also raises the possibility for the treating clinician to consider discontinuing treatment, which is of course one of the most important clinical implications of recovery.

Relapse and recurrence

Both terms refer to the reappearance of a full-blown MDE. The essential distinction between both terms is the time at which each event occurs. According to the description by Frank et al, “relapse” is “a return of symptoms satisfying full syndrome criteria for an episode that occurs during a period of remission, but before recovery.”² This again points to how critical the time criterion of recovery and the symptomatic threshold of remission are, as all other definitions are based upon them. As for “recurrence,” this is defined as “the appearance of a new episode of MDE, occurring during recovery.”²

In summary, we not only discriminate remission and recovery, but also relapse as an early return or “fall back” into the initial MDE, and recurrence as a late return of the illness and as a development of a new depressive episode, unrelated to the prior, “cured” episode, respectively.

Continuation and maintenance therapy

These terms are closely connected with the terms relapse and recurrence. The goal of continuation therapy is to preserve the therapeutic success of the acute phase until recovery is achieved (Figure 1). In addition, clinicians should try to eliminate residual symptoms, restore social functioning, and prevent relapse of depression during continuation. The time span of the continuation therapy should have the length of the “natural course” of an MDE and is exactly the same time span that is used to define recovery.

In practice, patients mostly stay on the same medication regimen that led to the remitted state with only small changes in dosage, mostly to optimize tolerability. Once recovery is achieved, maintenance therapy starts, with the primary goal of prevention of recurrences. Clearly, the indication of maintenance therapy has to be reviewed for each single patient based on individual factors.

With respect to the above-described concepts relative to outcomes in major depression and corresponding therapeutic phases, it is obvious that two variables are crucial for longterm outcome:
- The threshold and definition of remission.
- Determining when recovery has set in, ie, the 6-month cutoff period.

Threshold and definition of remission

There is still no consensus regarding the best way of determining when the remitted state has been reached. As explained above, the HAMD rating scale, now in use for almost 50 years,¹² has been widely used to assess symptomatic severity, response, and remission in clinical trials. Despite recent criticism,¹³ it remains the “gold standard” in academic and regulatory clinical trials.¹⁴ Other depression rating scales include the MADRS¹⁵ with its hypothesized better sensitivity to change, or the Inventory of Depressive Symptomatology (IDS),^16,17 which reflect more contemporary definitions of depression, and are also used to define remission.

Figure 2. HAMD severity distribution for healthy controls (blue shade, left) and depressed outpatients (orange shade, right).

Postgraduate Press, Inc.

The most widely used criterion for remission is a HAMD-17 score of ≤7, which corresponds to a HAMD-7 score of ≤3.¹⁸ The recommendation of the ACNP Task Force is to use a score of ≤7 or even ≤5 on the HAMD-17 scale as criterion for remission.³ For the MADRS, scale cutoff scores of ≤8 or ≤9,¹⁹ <10,²⁰ ≤10,²¹ ≤11,²² were suggested. However, there is recent evidence to support the use of more stringent scores on both the HAMD and MADRS scales. Patients with HAMD-17 scores ≤2 (or MADRS scores ≤4) show better psychosocial functioning than those with scores of 3 to 7 (or MADRS scores of 5 to 9).²¹ On the other hand, a problem with the use of very stringent definitions of remission is that healthy, nondepressed individuals may be labeled depressive. A literature review of control groups in clinical depression trials reported a mean HAMD-17 score of 3.2±3.2 (SD) among healthy control individuals. ²¹ As already noted above, Michael Thase was able to separate depressed subjects form healthy controls and thus validate the HAMD-17 threshold of below 7 (Figure 2).⁹ In addition, in an analysis by our own group, a Hamilton-17 score ≤7 best corresponded to a Clinical Global Impression (CGI) score of 1 (corresponding to “normal, not ill”) in a large sample of naturalistically treated inpatients with MDE.¹⁰ However, Nierenbergvery recentlydemonstrated for theSequenced Treatment Alternatives to Relieve Depression (STAR*D) study sample that the number of residual symptom domains was significantly associated with relapse even in patients meeting criteria for full remission (Figure 3).²² This is of high clinical relevance as recent clinical studies indicate that 21% to 35% of patients in remission from an MDE had residual symptoms.^24,25 In a recent analysis by our own group on 1014 naturalistically treated inpatients with MDE, patients meeting symptomatic criteria for full remission still showed an identical symptom pattern to that of patients meeting criteria for response, only at a much lower degree of severity.²⁶

Figure 3. STAR*D sample: Kaplan-Meier survival curve of major depressive disorder relapse with the number of residual symptom domains in the year following acute remission with citalopram.

Both analyses indicate that residual symptoms in remitted patients resemble still-present illness activity more than anything else (eg, personality traits) and that the definitions we use are still in need of improvement. Two major options are currently under discussion. The first is to expand symptomatic remission criteria to areas of psychosocial functioning. The second option would be to also add a short time criterion for “sustained remission” as proposed by the ACNP Task Force (eg, 3 consecutive weeks). Clearly, a combination of both would probably be the most stringent and accurate method for defining remission. How long the time period of remission should last in order to declare a patient recovered will be reviewed in the next paragraph.

Why has the cutoff for recovery been set at 6 months?

_ Approach based on estimation of the duration of an MDE
The crucial question is: what is the mean duration of an MDE? So far there are only few long-term observational studies available. Based on data from a 10-year follow-up study, Solomon et al calculated an average duration of depressive episodes of 20 weeks, with a median duration of 5 consecutive episodes of 22, 20, 21, 19, and 19 weeks.²⁷ Similarly, Angst et al reported a median length of depressive episodes of 5.4 months in a 5-year follow-up of hospitalized patients with major depressive disorder.²⁸

The sampling method used in these studies has been much criticized, and the recruitment of more chronic and more severe patient samples in such clinical follow-up studies has been dubbed “clinician’s illusion” or “Neyman bias.”^29,30 Many individuals do not experience recurrences, and only those who do end up in clinical trials and thus represent the more chronic and severe cases. In other words, hospital-based clinical samples tend to be mostly “prevalence samples,” whereas epidemiological prospective follow-ups of patients with a first episode tend to be mostly “incidence samples.” This is why the natural history of major depressive disorder is usually best studied in prospective follow-up studies of individuals from their first lifetime episode onward,³⁰ such as the NEtherlands MEntal health Survey and Incidence Study (NEMESIS)³¹ and the Baltimore Epidemiologic Catchment Area (ECA) Follow-up Study.³⁰

The NEMESIS study followed a sample of 273 individuals with first lifetime major depressive episode over a period of more than 2 years.³¹ The approximated duration of depressive episodes was 3 months. The methodologically most elaborate trial was the ECA, reported on by Eaton et al in 2008.³⁰ Starting with a probability sample of 3481 household residents in 1981, 92 patients with a first lifetime episode of major depression were followed-up for at least 13 years. In this study, the median length of the depressive episode was also 3 months. Of note, about 50% of first-episode patients did not experience a second episode during follow up.

An important finding of this study was that there seemed to be a relationship between the total number of experienced episodes and the median episode duration. The first episode had a median duration of 20 weeks, patients with 3 or more episodes also had a median episode duration of 20 weeks, patients with 4 or more episodes had a median duration of 24 weeks, patients with 5 or more episodes had a median episode duration of 12 weeks, and patients with 9 or more episodes had a median duration of 6 weeks. Interestingly, once the total number of episodes was adjusted, there was neither a strong nor even a significant tendency for episodes earlier in the course to be shorter or longer than the episode occurring later in the course. In summary, this signals a preexisting heterogeneity among patients with major depressive disorder with respect to the duration of episodes.³⁰

_Approach based on discontinuation trials
Beyond the abovementioned descriptive pragmatic definition of recovery based on estimations of median episode duration, is an approach that is based on discontinuation trials. The theoretical backbone here is the assumption that once a patient has recovered, the underlying biological illness activity has stopped and hence treatment can be safely discontinued. Probably one of the best prospective discontinuation studies from a methodological point of view addressing this question was published by Reimherr et al in 1998.³² In this prospective double-blind, controlled, four-arm crossover design trial, 395 patients meeting criteria for remission after 12 or 14 weeks of open-label acute fluoxetine therapy were randomized to either: (i) receive 50 weeks of placebo; (ii) 14 weeks of continuation fluoxetine and then 36 weeks placebo; (iii) 32 weeks fluoxetine continuation and then 12 weeks of placebo; or (iv) 50 weeks of fluoxetine continuation. Relapse rates were lower for patients who continued fluoxetine treatment (FLU) compared with placebo (PLA) for the first interval after 24 weeks of total treatment (FLU: 26%, PLA 49%) and the second interval after 38 total weeks of fluoxetine treatment (FLU: 9%, PLA 23%), but there was no difference for the third time interval after 62 total weeks of fluoxetine treatment (FLU: 11%, PLA 16%). In summary, this report suggests that continuation treatment should be expanded to at least an additional 26 weeks to minimize the risk for relapse.³²

A very recent trial on continuation and maintenance treatment giving an estimate of outcome of 6-month continuation is the Prevention of Recurrent Episodes with VENlafaxine for Two years (PREVENT) study. In this trial, 1096 outpatients with recurrent unipolar depression were randomly assigned in a 1:3 ratio to 10 weeks of treatment with venlafaxine ER or fluoxetine. All responders on the HAMD-17 scale (>50% baseline reduction) entered a 6-month double blind continuation phase on the same medication. Continuation phase responders were then enrolled into maintenance treatment consisting of 2 consecutive 12-month phases. At the start of each maintenance phase, venlafaxine ER responders were randomly assigned to receive double-blind treatment with either placebo or venlafaxine, whereas fluoxetine responders continued treatment.

Among remitters of the acute phase, 81% in the venlafaxine and 81%in the fluoxetine group remained remitters at the end of continuation treatment.³³ Among patients who were remitters at maintenance baseline, 69% of those taking venlafaxine and 55% of those taking placebo were still remitters after 1 year.³⁴ Certainly it has to be kept in mind that the patient sample suffered from recurrent depression with a mean current episode duration of 6 to 7 months, thus representing a more chronic study population.³⁴ Nevertheless, this study gives fresh evidence for the efficacy of antidepressants during continuation over 6 months and during maintenance.

_ Limitations and pitfalls of these two approaches
Using discontinuation data to estimate the duration of time in remission for a patient to be declared as recovered has 3 important pitfalls:
_ Despite having achieved recovery after a period of 6 months in remission, patients can still experience a new MDE immediately thereafter.
_ Achievement of recovery after 6 months does not necessarily exclude still-present biological illness activity of the affective disorder.
_ Our knowledge of specific antidepressant action is still limited. So far we cannot distinguish whether symptoms are only “suppressed” by the medication or whether the MDE has really abated.

However, to sum up, most data suggest a median duration of depressive episodes varying between 12 and 20 months. But since it can nowadays be assumed that at least a substantial proportion of depressive episodes are under treatment, we currently have no clear idea of how long episodes would last without treatment. Posternak et al have tried to address this issue and estimate the duration of MDEs in the absence of any somatic treatment.³⁵ Out of 318 patients enrolled in the collaborative depression study, 130 patients experienced a recurrence over a 15-year follow-up period that initially went untreated for at least 4 weeks. Of those, 46 subjects received treatment, whereas the other 84 remained entirely untreated. In this study, recovery was defined as time to the first of 8 consecutive weeks with no or minimal symptoms. The total sample consisting of the 130 patients had a median time to recovery of 23 weeks. But surprisingly the subgroup of untreated patients had a much shorter median time to recovery of 13 weeks.³⁵ This example nicely illustrates the methodological difficulties in that research area. As the authors correctly state, the major reason for the shorter time period to recovery in the untreated sample is most probably the general difference between a treatment-seeking and a nontreatment-seeking depressed patient sample.³⁵ As this was a nonrandomized trial, the results rather support prior studies showing that nontreatment-seeking patients have an inherently better prognosis than treatment-seeking patients.³⁶ One possible methodological approach could be to meta-analyze placebo arms of controlled antidepressant trials in order to estimate the median time of a depressive episode in a treatment-seeking patient sample.

So far, we must assume, at least in case of treatment-seeking patients, that the depressive episode without treatment would last longer as discussed in the above-cited trials. In addition, since we have only one prospective study regarding the optimum length of continuation treatment, the 6-month duration still seems defensible. It could also well turn out that recovery should only be ascribed after 1 year, as suggested by Reimherr et al.³² With that definition it might also take longer to reach recovery. Reimherr et al showed that the mean time to recovery (defined as a 1-year period free of any episode) was 2 or 3 years for both men and women. However, periods of 4 months as suggested by the ACNP task force seem to be far too short.³ The main argument used here were reports that demonstrate that the highest chance for any relapse is within the first 4 months. But considering a wider range of trials on relapse rates, the highest risk indeed seems to be in the first or even 2 years after acute treatment.^27-30

Summary

To conclude, we should constantly remember the high heterogeneity of the disease major depressive disorder. With that in mind, an individualized approach is always preferable in good daily clinical practice. In this respect we should try to give the best estimate possible of each individual’s mean episode duration. Often patients remember earlier episodes, free of any treatment. With that information clinicians have a perfect estimate of how long continuation treatment should at least last in the individual patient. For research purposes and rougher guideline recommendations the 6-month threshold is still justifiable. Remission should still remain the main treatment goal in treating major depression. However, current criteria maybe need reconsideration, as residual symptoms, even in remitted patients, still seem to be associated with relapse. _

References
1. Nierenberg AA, Wright EC. Evolution of remission as the new standard in the treatment of depression. J Clin Psychiatry. 1999;6(suppl 22):7-11.
2. Frank E, Prien RF, Jarrett RB, et al. Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse, and recurrence. ^{Arch Gen Psychiatry}. 1991;48:851-855.
3. Rush AJ, Kraemer HC, Sackeim HA, et al. Report by the ACNP Task Force on response and remission in major depressive disorder. Neuropsychopharmacology. 2006;31:1841-1853.
4. Tohen M, Frank E, Bowden CL, et al. The International Society for Bipolar Disorders (ISBD) Task Force report on the nomenclature of course and outcome in bipolar disorders. Bipolar Disord. 2009;11:453-473.
5. Andreasen NC, Carpenter WT Jr, Kane JM, et al. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry. 2005;162:441- 449.
6. Andreasen NC. Standardized remission criteria in schizophrenia. Acta Psychiatr Scand. 2006;113:81.
7. Möller HJ. Outcomes inmajor depressive disorder: the evolving concept of remission and its implications for treatment. World J Biol Psychiatry. 2008;9:102-114.
8. Henkel V, Seemüller F, Obermeier M, et al. Does early improvement triggered by antidepressants predict response/remission? Analysis of data from a naturalistic study on a large sample of inpatients with major depression. J Affect Disord. 2009;115:439-449.
9. Thase ME. Evaluating antidepressant therapies: remission as the optimal outcome. J Clin Psychiatry. 2003;64(suppl 13):18-25.
10. Riedel M, Möller HJ, Obermeier M, et al. Response and remission criteria in major depression—a validation of current practice. J Psychiatr Res. 2010;44: 1063-1068.
11. Riso LP, Thase ME, Howland RH, et al. A prospective test of criteria for response, remission, relapse, recovery, and recurrence in depressed patients treated with cognitive behavior therapy. J Affect Disord. 1997;43:131-142.
12. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960; 23:56-62:56-62.
13. Bagby RM, Ryder AG, Schuller DR, et al. The Hamilton Depression Rating Scale: has the gold standard become a lead weight? Am J Psychiatry. 2004;161: 2163-2177.
14. Carroll BJ. Why the Hamilton Depression Rating Scale endures. Am J Psychiatry. 2005;162:2395-2396.
15. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382-389.
16. Rush AJ, Giles DE, Schlesser MA, et al. The Inventory for Depressive Symptomatology (IDS): preliminary findings. Psychiatry Res. 1986;18:65-87.
17. Rush AJ, Gullion CM, Basco MR, et al. The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med. 1996;26:477-486.
18. McIntyre R, Kennedy S, Bagby RM, et al. Assessing full remission. J Psychiatry Neurosci. 2002;27:235-239.
19. Carmody TJ, Rush AJ, Bernstein I, et al. The Montgomery Asberg and the Hamilton ratings of depression: a comparison of measures. Eur Neuropsychopharmacol. 2006;16:601-611.
20. Hawley CJ, Gale TM, Sivakumaran T. Defining remission by cut off score on the MADRS: selecting the optimal value. J Affect Disord. 2002;72:177-184.
21. Zimmerman M, Chelminski I, Posternak M. A review of studies of the Montgomery- Asberg Depression Rating Scale in controls: implications for the definition of remission in treatment studies of depression. Int Clin Psychopharmacol. 2004;19:1-7.
22. Nierenberg AA, Husain MM, Trivedi MH, et al. Residual symptoms after remission of major depressive disorder with citalopram and risk of relapse: a STAR*D report. Psychol Med. 2010;40:41-50.
23. Bandelow B, Baldwin DS, Dolberg OT, et al. What is the threshold for symptomatic response and remission for major depressive disorder, panic disorder, social anxiety disorder, and generalized anxiety disorder? J Clin Psychiatry. 2006;67:1428-1434.
24. Judd LL, Akiskal HS, Paulus MP. The role and clinical significance of subsyndromal depressive symptoms (SSD) in unipolar major depressive disorder. J Affect Disord. 1997;45:5-17.
25. Paykel ES, Ramana R, Cooper Z, et al. Residual symptoms after partial remission: an important outcome in depression. Psychol Med. 1995;25:1171-1180.
26. Seemüller F, Riedel M, Obermeier M, et al. Clinical description and 1-year persistence of residual symptoms in a large naturalistic sample of remitted depressed inpatients. BMC Psychiatry. Submitted.
27. Solomon DA, Keller MB, Leon AC, et al. Recovery from major depression. A 10-year prospective follow-up across multiple episodes. Arch Gen Psychiatry. 1997;54:1001-1006.
28. Angst J, Gamma A, Sellaro R, et al. Recurrence of bipolar disorders and major depression. A life-long perspective. Eur Arch Psychiatry Clin Neurosci. 2003; 253:236-240.
29. Cohen P, Cohen J. The clinician’s illusion. Arch Gen Psychiatry. 1984;41:1178- 1182.
30. Eaton WW, Shao H, Nestadt G, et al. Population-based study of first onset and chronicity in major depressive disorder. Arch Gen Psychiatry. 2008;65: 513-520.
31. Spijker J, de Graaf R, Bijl RV, et al. Duration of major depressive episodes in the general population: results from The Netherlands Mental Health Survey and Incidence Study (NEMESIS). Br J Psychiatry. 2002;181:208-213.
32.Reimherr FW, Amsterdam JD, Quitkin FM, et al. Optimal length of continuation therapy in depression: a prospective assessment during long-term fluoxetine treatment. Am J Psychiatry. 1998;155:1247-1253.
33. Keller MB, Trivedi MH, Thase ME, et al. The Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) study: outcomes from the acute and continuation phases. Biol Psychiatry. 2007;62:1371-1379.
34. Keller MB, Trivedi MH, Thase ME, et al. The Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) Study: Outcomes from the 2-year and combined maintenance phases. J Clin Psychiatry. 2007;68: 1246-1256.
35. Posternak MA, Solomon DA, Leon AC, et al. The naturalistic course of unipolar major depression in the absence of somatic therapy. J Nerv Ment Dis. 2006; 194:324-329.
36. Coryell W, Endicott J, Winokur G, et al. Characteristics and significance of untreated major depressive disorder. Am J Psychiatry. 1995;152:1124-1129.

Keywords: depression; relapse; recurrence; response; remission; recovery; continuation treatment; maintenance treatment; antidepressant

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Stuart MONTGOMERY, MD
Emeritus Professor of Psychiatry
Imperial College University of London
London, UNITED KINGDOM


Gang WANG, MD
Beijing Anding Hospital Capital Medical University
Beijing, CHINA

Severe depression is themost challenging subgroup of depression to treat; it is associated with greater suffering, increased disability, and increased morbidity and mortality. Treatment studies have found that some antidepressants are significantly more effective in treating severe depression than other, more conventional, antidepressants. Significant advantages are reported with escitalopram and with agomelatine both in individual studies and in meta-analyses of the data that define these antidepressants as superior. The issue of poor compliance with treatment in depression highlights the need for antidepressants that are not just superior in efficacy, but also superior in tolerability. Severe depression appears to bemore prone to relapse and recurrence, and this finding emphasizes the need to prioritize the use of superior treatments in the long-term treatment of depression. The finding that severity of depression is one of the predictors of the development of resistant depression supports the view that severe depression should be aggressively treated with appropriate superior antidepressants to avoid the consequences of the depression becoming resistant.

Depression, or rather major depressive disorder (MDD), is a common disorder associated with a high level of morbidity and mortality. It is one of the commonest causes of disability worldwide and its impact is particularly striking in the West. Depression affects 1 in 4 women in their lifetime and 1 in 8 men. The onset of the disorder occurs in the late teens to early twenties; in almost all cases it is a chronic or recurring disorder that has major impact on work and productivity as well as the personal and social life of the sufferer. For these reasons effective treatment is a high priority.

The importance of severe depression

The diagnostic criteria used to define a number of psychiatric disorders, eg, the anxiety disorders, have changed substantially over the last 25 years. This draws attention to an underlying instability of the diagnostic process and raises concern that the diagnostic criteria may be imprecise. This is not, however, the case with the diagnostic criteria for MDD, which have hardly varied over the same period. There is substantial agreement on the defining features and core symptoms of the disorder, which are well defined in the widely used and recognized symptomatic diagnostic criteria. The same pivotal rating scales that were used 25 years ago to assess the efficacy of treatment are still in use today. What has changed is the recognitionof the importance of establishing the severity of depression in order to identify the risk of disability, the risk of relapse, and the risk of the high levels of morbidity of the disorder. Severe depression is associated with increased mortality, higher morbidity, and greater disability than moderate or mild depression; it is also the group where the relapse rate in responders or remitters is highest.¹ The treatment of severe depression is therefore one of the most challenging areas encountered by the physician. The assessment of severity also turns out to be a major tool in quantifying the proportion of individuals who respond well and achieve a reduction in symptom score to a low level in line with that when well. The concept of remission and the importance of remission as a target for treatment have been confirmed in recent studies.

Specific investigations of treatment and outcome in subgroups of patients with differing severity levels indicate that severe depression lies on a continuum of severity from mild and moderate depression with no obvious cutoff separating moderate from severe depression; rather there appears to be an increasing dimensional risk of disability with increasing severity of depression from moderate to severe illness. There is, however, no evidence to suggest that severe depression is a separate disorder although available treatments have been shown to have increased efficacy in the severe subgroup.

Definitions of severe depression

Severe depression is comparatively easy to recognize. Reasonable concordance between assessors can be achieved as to whether depression is mild, moderate, or severe, although this may be affected by the inherent variability due to differing levels of experience of the assessors. Quite marked cultural differences in assessment occur and these may be exacerbated by insensitive translation of global rating scales. A well-known example is the mismatch in meaning between the English word “moderate” and the French word “moderé,” which has led to difficulties in merging the data from studies carried out in different cultures when poorly translated global scales have been used.

Precise ratings of the severity of the individual symptoms of depression have helped to derive more easily defended definitions of severe depression identified by a score on an accepted depression rating scale. Currently, the most widely used criteria to define severe depression are a score of 30 or more on the Montgomery-Åsberg Depression Rating Scale (MADRS),^2,3 or a score of 25 or more on the 17-item Hamilton Depression Rating Scale (HAMD-17),^4,5 which are the two most widely used pivotal scales. These definitions used in clinical treatment studies have the advantage that they appear to be in accord with clinical judgment. Other definitions have been used, for example, hospitalization or suicidal risk, but they are less specific and vary widely in different treating settings. Other factors unrelated to severity can play a role, for example the availability of hospital beds varies widely from country to country and even within a country from one region to another. Similarly, the risk of suicide is not necessarily an accurate marker of the severity of depression since suicidality is substantially altered by personality factors, by concomitant drug or alcohol abuse, by concomitant physical illness, by religious conviction, and by family support. The concept of melancholia, used in some countries to indicate severity, has been found to represent a loosely defined diagnostic subgroup of depression with varying levels of severity. Although melancholia as currently defined appears more common in severe depression, it can be found also in those with mild depression, moderate depression, and severe depression, and therefore the use of this term to define severity is inappropriate.

Differential efficacy in severe depression

Recognition of the importance of severe depression, in terms of associated increased morbidity, disability, and increased mortality, has stimulated research into the possible differential efficacy of various antidepressants. Initially, the analyses carried out found that selective serotonin reuptake inhibitors (SSRIs) were effective in both moderate and severe depression with no obvious difference in efficacy between the two groups. For example, in an elegant analysis of the placebo controlled data with citalopram the treatment effect, that is, the difference in response between citalopram and placebo, was constant in moderate and severe depression and there was no signal of any change in efficacy with increasing severity.^6,7 In contrast, the treatment effect increased with increasing baseline severity with escitalopram and with agomelatine.8

The greatest response to placebo is observed in mild depression and the least in severe depression. Indeed, in mild depression the placebo response is so high that it is very difficult in clinical studies to identify a significant treatment effect of antidepressants. In the large placebo-controlled efficacy study of fluoxetine given in doses of 20, 40, or 60 mg in mild depression, defined by a baseline score of less than 20 on the HAMD, there was no perceptible difference between placebo and any dose of fluoxetine.⁹ It is probable that any pharmacological effect in thesemildly depressed patients wasmarginal and the close attention and concern to be expected in the conduct of a clinical treatment trial had the consequence of improving all groups during the short duration of the study and obscured any difference. Factors such as the careful assessment and rating of depression in the context of a clinical study carry a nonspecific benefit that appears to be more marked in mild depression and less in severe depression.

Some antidepressants that are effective in moderate-to-severe depression have, however, been shown to have increased efficacy in the severely depressed subgroup. Analyses of the escitalopram clinical trial data were carried out to examine the possible influence of severity at the start of treatment on patients’ outcomes.When patients were categorized into cohorts of severity, a clear increase in efficacy was observedwith increasing severity.^7,10 If some, but not all, antidepressants are associated with this important feature of extra response in severe depression it is of great interest for the clinician to clarify in direct comparisons whether a significant difference between antidepressants can be established. The most scientifically rigorous way to investigate potential differences between antidepressants is to conduct individual studies with random double-blind assignment to treatment to reduce the risk of bias in the population studied. Providing that the studies are carried out under conditions of fair comparison, the results can show whether there are differences in efficacy and whether there is clear-cut superiority for some antidepressants.

A number of antidepressants have been compared and significant differences reported. Escitalopram was found to be more effective than citalopram in treating severe depression defined as a baseline MADRS score of 30 or more^11,12 and also more effective than paroxetine.¹³ More recently, agomelatine was found to show increasing treatment effect (difference from placebo) with increasing severity of baseline depression in an analysis of the pivotal placebo-controlled studies.⁸ The greater treatment effect observed in the more severe patients suggested that agomelatine might also have advantages compared with other antidepressants in treating more severe depression. This has been confirmed on the pivotal efficacy measure in a prospective randomized double-blind study in severe depression comparing agomelatine with fluoxetine.

The severity of depression in this study was defined as having a baseline score 25 or more on the HAMD 17-item scale, and agomelatine was shown to be significantly superior to fluoxetine. Previous studies in moderate and severe depression have shown the superiority of agomelatine in comparison with sertraline¹⁴ and venlafaxine.¹⁵ Venlafaxine has itself a reputation of being more effective in severe depression¹⁶ though the evidence from formal studies is sparse. A large meta-analysis reported a modest, but significant, increase in the percentage of remissions (6%) with increasing baseline severity.¹⁷ This finding is supported by the superiority of venlafaxine demonstrated in a double-blind randomized comparison with fluoxetine in a largely severe depression population.¹⁸ Extra efficacy in severe depression is now regarded by many as the hallmark of the superior antidepressant.

The results from comparisons of individual antidepressants are supported by a retrospectivemeta-analysis of several studies, though in this analysis the agomelatine studies were excluded.¹⁹ The use of meta-analyses has its drawbacks since they are almost always conducted post hoc and they generally make the assumption that every study is equally fair, valid, and useful. Attempts to exclude biased or unfair comparison studies such as when the dose of one antidepressant can be raised to a maximum while the other remains low²⁰ or when the population is already resistant to one of the treatments²¹ are rare. Nevertheless, despite their weaknesses, meta-analyses can provide support for the findings from individual comparisons that antidepressants differ in efficacy and tolerability. Identifying the antidepressants that have superior efficacy is an important step in guiding treatment choice. We need to concentrate our treatment efforts, giving priority to the use of antidepressants that are superior, and also, since compliance with treatment is such a problem in depression, to those that additionally have a better tolerability profile close to that seen with placebo.

Discontinuation symptoms

Abrupt termination of antidepressant treatment is in almost all cases associated with the appearance of discontinuation symptoms.²² Discontinuation symptoms have been reported with all classes of antidepressants since the early studies with imipramine. In some cases, it appears that these discontinuation symptoms may destabilize the clinical status and induce relapses. The discontinuation symptoms, which usually appear in the first few days after stopping treatment and reach maximal severity in the first week, may well be mistaken for relapses. This phenomenon complicates the design of the relapse prevention studies, which require that responders or remitters to the treatment under investigation, for example an antidepressant, are then randomized to receive treatment with either the same antidepressant or placebo under double-blind randomized conditions.

Some antidepressants appear to be more prone to produce discontinuation symptoms than others, eg, paroxetine22 or venlafaxine.²³ Some antidepressants have a lower propensity to cause discontinuation symptoms, eg, fluoxetine²⁴ or escitalopram,²⁵ but only agomelatine has been found to be completely free of discontinuation symptoms. The clear difference between antidepressants in the rate of associated discontinuation symptoms is illustrated by a placebo-controlled discontinuation study that investigated rates in agomelatine and paroxetine. Stopping agomelatine treatment was associated with no signal of discontinuation symptoms compared with continuing agomelatine. In contrast, in the same study, after stopping paroxetine, given in a low dose of 20 mg, up to 45% of patients showed discontinuation symptoms.²⁶

Discontinuation symptoms and relapse

The need for long-term treatment of depression to prevent relapse following response to treatment and to reduce the risk of recurrence has long been established and is universally recommended. Improving long-term outcome is of particular concern for those who suffer severe depression, given the potential serious consequences. The clinically significant efficacy of antidepressants in long-term treatment is supported by an overwhelming weight of evidence in the literature. One example is the long-term placebo-controlled study of agomelatine, carried out largely in severe depression, which found that agomelatine has a powerful ability to reduce the risk of subsequent relapses or recurrences. This ability is reflected inthe strikingly low number of patients needed to treat (NNT) in order to show a significant advantage compared with placebo.²⁷ There is also some indication in the agomelatine database that the risk of relapse is low in the mild depression subgroup suggesting that mild depression may not be the target for long-term antidepressant treatment. In placebo-controlled studies mild depression has a high spontaneous response rate, and evidence to support the need for long-termtreatment would therefore be difficult to obtain. Mild depression might be a lower priority for both short- and long-term treatment.

We can have less confidence in the evidence of efficacy in relapse prevention derived from studies where the abruptly discontinued treatment is associated with frequent or troublesome discontinuation symptoms. For example, in the relapse prevention study of fluvoxamine there was a high and rapid relapse rate, which was associated with high levels of discontinuation symptoms.²⁸ To overcome the problem it is now routine procedure in a secondary analysis to exclude from the analysis data from the first month after stopping treatment to try to discount the discontinuation symptoms. A relapse prevention study with agomelatine is perhaps the first where the results are uncontaminated by a possible increase in the relapse rate associated with discontinuation symptoms, since such symptoms are not a problem with agomelatine. The efficacy of agomelatine in relapse prevention is therefore more securely based than other antidepressants that are prone to discontinuation symptoms and were tested using the same design.

Resistant depression

Nonresponse to antidepressants is common and is reported in between 30% and 50% of patients treated with antidepressants in randomized double-blind placebo-controlled clinical studies. Surprisingly few studies have investigated what happens to these patients and as a result the evidence base on which advice can be given is limited. The short duration of the acute studies, normally 6 to 8 weeks, leaves unanswered the question as to whether there may be a further response if treatment were contained longer. This could be the case, but the longer 12-week placebo-controlled studies, which also report similar high levels of nonresponse, suggest otherwise.

The treatment of resistant depression is a pressing clinical problem that dominates the practice of almost all specialists. In the US, a range of treatments are licensed as adjuncts in resistant depression, but, in the EU, regulatory recognition of the problem is more limited. This stems partly from the complicated definition of resistant depression used by the EU,²⁹ which requires both a prospective demonstration of resistance and demonstration that patients have not responded to two different antidepressants from different pharmacological classes, each given in an adequate dosage for sufficient duration. Moreover, a treatment proposed for resistant depression has to show persistence of efficacy compared with placebo for at least 6 months. The evidence supporting the validity of these complicated requirements is trivial and appears to be based on a single meta-analysis, which included unfair comparisons, that showed a modest advantage in remission, though not responders, using these criteria.³⁰

Other much larger studies have failed to find this advantage.^31,32 In a very large survey of resistant depression across Europe the Treatment Resistant Depression Group found that switching classes of antidepressants was not helpful and that continuing with the same antidepressant for longer was associated with a significantly better response. In a prospective study in resistant depression, switching nonresponders from citalopram (a SSRI), to desipramine (a tricyclic norepinephrine reuptake inhibitor) was associated with significantly fewer responders than staying on the same medication. The problem with switching antidepressants comes partly from the discontinuation symptoms on stopping the previous antidepressant and partly from the slow onset of action of the new antidepressant, normally around 6 weeks. The effect of these findings should be to encourage prescribers to use antidepressants that have low or no discontinuation symptoms and also to use antidepressants with superior antidepressant efficacy including a faster onset of antidepressant action.

The criteria for defining treatment resistance have led to studies that have shown that the key criterion is the failure to respond to a single course of treatment with an approved dose for adequate duration.^33,34 The extra requirement of demonstrating a failure to respond to a second treatment adds little and delays the diagnosis. The suggestion that an antidepressant from a different class must be tried to establish treatment- resistant depression is patently inaccurate and merely delays the correct diagnosis even further.

The predictors of resistant depression are well known.³⁵ Most of these factors relate to severity of depression and also include comorbidity with any anxiety disorder (which of course increases the severity), the presence of suicidality, which is frequently severity related, and failure to respond to treatment of the first episode of depression. This suggests that resistance to treatment is an enduring feature that persists from one episode of depression to the next and emphasizes the need to use the more effective, superior antidepressants early, before resistance becomes established.

The same finding provides a rationale for seeking a possible genetic basis for nonresponse and resistance. The finding that polymorphism of the short arm of the serotonin transporter increases vulnerability to stress and increases levels of nonresponse36 has been confirmed in a number of studies. It now appears from the studies of the Treatment-Resistant Depression Group and the STAR*D studies (Sequenced Treatment Alternatives to Relieve Depression) that a numberof other genetic factors such as COMT (catechol-O-methyltransferase) also are also associated with increased resistance.

The finding that severity of depression and associated features is a predictor of treatment-resistant depression is provocative, and this raises the uncomfortable question that initial treatment with weaker conventional antidepressants may in some way induce resistance. In this context, current guidelines that are influenced by economic considerations, such as those of the National Institute for Health and Clinical Excellence (NICE) committee, and suggest using the weakest treatments first and without discussion of the superior efficacy of some antidepressants, now appear unacceptable.

Severe depression is associated with increased morbidity and mortality as well as increased treatment resistance and should be prioritized for accurate diagnosis and special treatment. We need to rethink our treatment recommendations and treat severe depression aggressively to achieve response and remission with those antidepressants that have been shown to be particularly effective. _

References
1. Prien RF, Kupfer DJ, Manskey PA, et al. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders: Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine and a lithium carbonate-imipramine carbonate combination. Arch Gen Psychiatry. 1984;41: 1096-1104.
2. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382-389.
3. Burke WJ, Gergel I, Bose A. Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry. 2002;63:331-336.
4. Hamilton M. A rating scale for depression. J Neurolog Neurosurg Psychiatry. 1960;23:56-62.
5. Montgomery SA, Lecrubier Y. Is severe depression a separate indication? European Neuropsychopharmacology. 1999;9:259-264.
6. Montgomery SA, Moller HJ. Is the significant superiority of escitalopram compared with other antidepressants clinically relevant? Int Clin Psychopharmacol. 2009;24:111-118.
7. Lam RW, Andersen M. The influence of baseline severity on efficacy of escitalopram and citalopram in the treatment of major depressive disorder: an extended analysis. Pharmacopsychiatry. 2006;39:180-184.
8. Montgomery SA, Kasper S. Severe depression and antidepressants: focus on a pooled analysis of placebo-controlled studies on agomelatine. Int Clin Psychopharmacol. 2007;22:283-291.
9. Dunlop SR, Dornseif BE, Wernicke JF, Potvin JH. Pattern analysis shows beneficial effect of fluoxetine treatment in mild depression. Psychopharmacol Bull. 1990;26:173-180.
10. Kennedy SH, Andersen M, Thase ME. Escitalopram in the treatment of major depressive disorder: a meta-analysis. Curr Med Res Opin. 2009;25:161-175.
11. Moore N, Verdoux H, Fantino B. Prospective, multicentre, randomized, doubleblind study of the efficacy of escitalopram versus citalopram in outpatient treatment of major depressive disorder. Int Clin Psychopharmacol. 2005;20:131-137.
12. Yevtushenko VY, Belous AI, Yevtushenko YG, Gusinin SE, Buzik OJ, Agibalova TV. Efficacy and tolerability of escitalopram versus citalopram in major depressive disorder: a 6-week, multicenter, prospective, randomized, double-blind, active-controlled study in adult outpatients. Clin Ther. 2007;29:19-32.
13. Boulenger J-P, Huusom AKT, Florea I, Baekdal T, Sarchiapone M. A comparative study of the efficacy of long-term treatment with escitalopram and paroxetine in severely depressed patients. Curr Med Res Opin. 2006; 22:1331-1341.
14. Kasper S, Hajak G, Wullf K, et al. Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder: a randomized, double-blind comparison with sertraline. J Clin Psychiatry. 2010;71:109-120.
15. Lemoine P, Guilleminault C, Alvarez E. Improvement in subjective sleep in major depressive disorder with a novel antidepressant, agomelatine: randomized, double-blind comparison with venlafaxine. J Clin Psychiatry. 2007;68: 1723-1732.
16. Montgomery SA, Baldwin DS, Blier P, et al. Which antidepressants have demonstrated superior efficacy? A review of the evidence. Int Clin Psychopharmacol. 2007;22:323-329.
17. Nemeroff CB, Entsuah AR, Benattia I, Demitrack MA, Sloan DM, Thase ME. Comprehensive analysis of remission (COMPARE) with venlafaxine versus SSRIs. Biol Psychiatry. 2007;63:424-434.
18. Clerc GE, Ruimy P, Verdeau Pailles J. A double-blind comparison of venlafaxine and fluoxetine in patients hospitalized for major depression and melancholia. Int Clin Psychopharmacol. 1996;9:139-143.
19. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373:746-758.
20. Poirier MF, Boyer P. Venlafaxine and paroxetine in treatment-resistant depression. Double-blind, randomised comparison. Br J Psychiatry. 1999;175:12-16;
21. Hoehn-Saric R, Ninan PT, Black DW, Stahl S, Greist JH, Lydiard RB et al. Multicenter double-blind comparison of sertraline and desipramine for concurrent obsessive-compulsive and major depressive disorders. Arch Gen Psychiatry. 2000;57:76-82.
22. Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry. 1998;2:77-87.
23. Montgomery SA, Fava M, Padmanabhan SK, Guico-Pabia CJ, Tourian KA. Discontinuation symptoms and taper/poststudy-emergent adverse events with desvenlafaxine treatment for major depressive disorder. Int Clin Psychopharmacol. 2009;24:296-305.
24. Judge R, Parry MG, Quail D, Jacobson JG. Discontinuation symptoms: comparison of brief interruption in fluoxetine and paroxetine treatment. Int Clin Psychopharmacol. 2002;17:217-225.
25. Baldwin DS, Cooper JA, Huusom AK, Hindmarch I. A double-blind, randomized, parallel-group, flexible-dose study to evaluate the tolerability, efficacy and effects of treatment discontinuation with escitalopram and paroxetine in patients with major depressive disorder. Int Clin Psychopharmacol. 2006;21:159-169.
26. Montgomery SA, Kennedy SH, Burrows GD, Lejoyeux M, Hindmarch I. Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation symptoms with paroxetine: a randomized, double-blind, placebocontrolled discontinuation study. Int Clin Psychopharmacol. 2004;19:271-280.
27. Goodwin GM, Emsley R, Rembry S, Rouillon F. Agomelatine prevents relapse in patients with major depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70:1128-1137.
28. Terra JL, Montgomery SA. Fluvoxamine prevents recurrence of depression: results of a long-term, double-blind placebo-controlled study. Int Clin Psychopharmacol. 1998;13:55-62.
29. Committee for Proprietary Medicinal Products. Note for Guidance on Clinical Investigation of Medicinal Products in the Treatment of Depression. The European Agency for the Evaluation of Medicinal Products Evaluation of Medicines for Human Use, CPMP/EWP/518-97-Rev.1. 2002.
30. Papakostas GI, Fava M, Thase ME. Treatment of SSRI-resistant depression: a meta-analysis comparing within- versus across-class switches. Biol Psychiatry. 2008;63:699-704.
31. Bschor T, Baethge C. No evidence for switching the antidepressant: systematic review and meta-analysis of RCTs of a common therapeutic strategy. Acta Psychiatr Scand. 2010;121:174-179.
32. Ruhe HG, Huyser J, Swinkels JA, et al. Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review. J Clin Psychiatry. 2006;67:1836-1855.
33. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53:649-659.
34. Thase ME, Rush AJ. When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry Suppl. 1997;13:23-29.
35. Souery D, Oswald P, Massat I, et al. Clinical factors associated with treatment resistance in major depressive disorder: results from a European multicenter study. J Clin Psychiatry. 2007;68:1062-1070.
36. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:291-293.

Keywords: depression; relapse; recurrence; morbidity; mortality; antidepressant; treatment compliance; treatment resistance; escitalopram; agomelatine

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Silla M. CONSOLI, MD, PhD
Paris-Descartes University of Medicine, Department of Clinical Psychology and Consultation-Liaison Psychiatry
Assistance Publique-Hôpitaux de Paris, European Georges Pompidou Hospital
Paris, FRANCE

Anetwork of complex relationships exists between stress, depressive mood or the spectrum of depressive disorder, and cardiovascular disease, in particular coronary heart disease. Depressive mood and major depressive episodes can both be considered as risk factors for the development of cardiovascular disease, even after controlling for behaviors at risk for cardiovascular disease. Recurrent depression, but not single major depressive episode, is associated with the development of atherosclerosis and arterial calcifications. Type A behavior pattern and, more recently, work stress and cynical hostility, were also examined as predictors of cardiovascular disease. Incident post–myocardial infarction depression predicts cardiac mortality and new onset of cardiac events. Coronary heart disease and depression share common genetic vulnerabilities (eg, serotonin transporter [5-HTT] polymorphism), which interact with environmental factors and medical triggers, such as acute coronary syndrome. The continuum between depressive episode and depressive disorder, applied to cardiovascular patients, and the respective times of onset of cardiac events and depressive symptomatology, must be taken into account in order to determine the appropriate time and type of mood disorder treatment.

Avery large number of publications have been dedicated, during the past two decades, to the complex relationships between stress, depressive mood or the spectrum of depressive disorder, and cardiovascular disease, in particular coronary heart disease.^1-9

To disentangle these complex relationships, we will successively address the following issues, which are important to understand in order to make causal inferences and, consequently, design preventive interventions:
_ Depressive mood, major depressive episode (MDE), or recurrent depression as risk factors for cardiovascular disease.
_ Stress and coronary heart disease.
_ Prognostic value of depression following a coronary event, according to depression type.
_ Common genetic factors for cardiovascular disease, depression, and depression responsiveness to an antidepressant.
_ Stress and cardiovascular condition as risk factors for depressive recurrence.

Depressive mood, MDE, or recurrent depression as risk factors for cardiovascular disease

The possibility that depression has an impact on the development of coronary heart disease (CHD) or atherosclerotic lesions in initially healthy subjects has led to controversial findings. In 1987, Booth-Kewley and Friedman showed in ametaanalysis a strong association between depression and CHD, but most of the studies included in that review were crosssectional.¹⁰ Actually, in the late 80s, very few studies used a prospective cohort design. This situation changed in the next decade, but most of the studies assessed depressive symptomatology using self-administered questionnaires, without any standardized interview for performing Diagnostic and Statistical Manual of Mental Disorders, 3rd or 4th Editions (DSM-III or DSM-IV) diagnoses ofMDE or depressive disorder.

In a further meta-analysis based on 11 selected studies, clinical depression was assessed only in three of the studies, whereas in the remaining eight studies, depressive mood was measured alone.³ In this meta-analysis, pooling all the studies, overall relative risk (RR) for the development of CHD in depressed subjects was 1.64 (95% confidence interval [CI], 1.29-2.08), but clinical depression (RR, 2.69; 95% CI, 1.63- 4.43) was a stronger predictor than depressive mood (RR, 1.49, 95% CI: 1.16-1.92). Among the studies using a clinical diagnosis of depression, the nationally representative Mini- Finland Health Survey covered 8000 individuals and consisted of a 6.6-year follow-up: an increased risk of coronary death was found in clinically depressed persons, both with and without cardiovascular diseases at entry. The authors concluded that “the hypothesis that depression is a cause of cardiovascular diseases requires further study.”¹¹

In a study based on a follow-up of a survey of psychiatric disorders in the general population—the Baltimore cohort of the Epidemiologic Catchment Area (ECA) Study—a history of MDE or dysphoria (2 weeks of sadness) was assessed in 1981 using the Diagnostic Interview Schedule (DIS), a widely used tool in psychiatric epidemiology, and self-reported myocardial infarction (MI) was assessed in 1994.¹² The odds ratio (OR) for MI associated with a history of MDE was 4.54 (95% CI, 1.65-12.44), independent of coronary risk factors, whereas the OR for MI associated with a history of dysphoria was 2.07 (95% CI, 1.16-3.71). Moreover, the use of tricyclic antidepressants and benzodiazepines was not predictive of MI.

The Johns Hopkins Precursors Study was a prospective, observational study of 1190 male medical students who were enrolled between 1948 and 1964 and who continued to be followed up.¹³ During a median of 37 years follow-up, the incidence of clinical depression was measured by means of mailed surveys with direct questions concerning the occurrence of depression and associated treatment. Self-reports of depression were confirmed by a committee of physician reviewers who were unaware of the study hypothesis. The cumulative incidence of clinical depression was 12%. Subjects who developed clinical depression drank more coffee than those who did not, but did not differ in terms of cardiovascular risk factors (baseline blood pressure, serum cholesterol levels, smoking status, physical activity, obesity, or family history of coronary artery disease). Multivariate analysis showed that clinical depression was associated with greater risk for subsequent CHD (RR, 2.12; 95% CI, 1.24-3.63) or MI (RR, 2.12; 95% CI, 1.11-4.06), and was still an independent risk factor for CHD 10 years after the onset of depression (RR, 2.1; 95% CI, 1.1-4.0).

In another study, after controlling for known cardiovascular risk factors, a self-reported history of treatment for depression was also independently associated with subsequent MI in 5564 treated hypertensive patients without prior cardiovascular disease (hazard ratio [HR], 2.10; 95% CI: 1.04-4.23).¹⁴

None of these studies separately assessed the predictive value of single MDE vs recurrent MDE regarding the development of cardiovascular diseases. This was the purpose of a series of studies on female populations. In 336 healthy middleaged women from 1 of the 7 sites of the Study of Women’s Health Around the Nation, a prospective study of the perimenopausal transition, carotid plaque was assessed using a B-mode ultrasonography and psychiatric diagnoses were assessed using the Structured Clinical Interview for the DSM-IV Axis I Disorders–Non-Patient Edition (SCID-IV). The risk of plaque was twofold in women with a lifetime history of recurrent MDE relative to women with no history of depression (OR, 2.30; 95% CI, 1.10-4.82), whereas lifetime history of a single MDE was not associated with plaque.¹⁵ Similar findings were published regarding coronary and aortic calcifications in 58 African-American and 152 white healthy middle-aged women.¹⁶ This association was in part mediated by the waisthip ratio. A recent publication confirmed that among 149 middle- aged healthy women who reported no heart disease, stroke or diabetes at baseline, women with recurrent MDE (n=33) had greater progression of coronary artery calcification, assessed using computed tomography measures on two occasions, approximately 2¼ years apart, than did women with a single or no episodes.¹⁷

Other publications examined the role of depression timing as a risk factor for cardiovascular events, even if depressive mood was assessed using only self-administered questionnaires. In a prospective cohort of 4493 elderly Americans followed for 6 years, free of cardiovascular disease at baseline and enrolled in the Cardiovascular Health Study, the Center for Epidemiological Studies Depression Scale (CES-D) score was annually computed.¹⁸ The cumulative CES-Dmean at last visit before any cardiovascular event was associated with development of CHD and all-cause mortality, using time-dependent, proportional-hazards models. As expected, cumulative CES-D mean was higher in subjects with a history of depression at baseline and, interestingly, in women, but not in men with baseline hypertension or smoking.

In another prospective cohort study of 3701 men and women aged >70 years, CES-D depressive symptomatology was also measured on three occasions during a 6-year period to distinguish persons who were newly (depressed at baseline, but not at 3 and 6 years before baseline) and chronically depressed (depressed at baseline and at 3 or 6 years before baseline).¹⁹ Subjects were then followed for a median period of 4 years. Their risk of subsequent CVD events and all-cause mortality was compared with that of subjects who were never depressed during the 6-year period. In men, but not in women, newly depressed mood was associated with an increased risk of cardiovascular mortality, new cardiovascular events, and new CHD events, after adjustment for traditional cardiovascular risk factors. Chronic depressed mood was not associated with new cardiovascular events.

Similar results were published by Surtees et al regarding the recency of an MDE in the European Prospective Investigation of Cancer (EPIC)–Norfolk United Kingdom Prospective Cohort Study (median follow-up period of 8.5 year), consisting of 8261 men and 11 388 women 41 to 80 years of age, who were free of clinical manifestations of CHD at baseline: compared with never-depressed patients, subjects with an MDE within the last 12 months were at high risk for cardiovascular death, especially those with current MDE; no increased risk was associated with a history of lifetime depression, but not in last 12 months.²⁰ CES-D depression score was also assessed every 6 months in the 4367 participants of the Systolic Hypertension in the Elderly Program (SHEP) followed up for 5 years.²¹ Cox proportional hazards regression analyses, with the CES-D score as a time-dependent variable and controlling for multiple covariates, indicated an increased risk of stroke or myocardial infarction for 5-unit increase in the CES-D score (RR,1.18; 95% CI, 1.08-1.30).

Therefore, according to the studies, the role of depression as a risk factor for cardiovascular disease appears as a time-dependent or a dose-dependent effect.

Stress and coronary heart disease

Early in the 1980s, a stress-prone personality trait defined as Type A behavior pattern, characterized by hard driving, competitive behavior, and a potential for hostility, was found in several prospective studies as associated with an increased risk for fatal as well as nonfatal CHD.²² Stress may affect healthrelated behaviors such as smoking, diet, alcohol consumption, or physical activity, which in turn may influence the risk of coronary heart disease, but, generally, results are adjusted for these confounding variables, suggesting more direct pathophysiological mediations such as endothelial dysfunction, inflammation, increased blood clotting, and decreased fibrinolysis. In further studies, due to repeated negative findings, Type A as a cardiovascular risk factor was abandoned and replaced by a more specific component of type A, namely, hostility, and especially cognitive or cynical hostility.

Type A individuals are supposed to be focused on achievement by work and to actively seek out challenging situations. Two main models of work stress have been proposed. In a prospective cohort study with a mean follow up of 25.6 years on 812 employees free from any cardiovascular disease at baseline both Karasek’s and Siegrist’s models of work stress (respectively “job strain,” a combination of high demands at work and low job control, and “effort-reward imbalance”) predicted cardiovascular mortality: HR=2.2 (95% CI, 1.2-4.2) for high job strain and 2.4 (95% CI: 1.3-4.4) for effort-reward imbalance, after adjustment for age and sex. The association remained significant after additional adjustment for smoking, physical activity, systolic blood pressure, cholesterol concentration, and body mass index.²³

In the INTERHEART study (not an acronym), a case-control design on 11 119 patients with a first myocardial infarction compared with 13 648 age-matched and sex-matched controls, patients reported higher prevalence of stress at work and at home, financial stress, and major life events in the past year. The highest OR, adjusted for age, sex, geographic region and smoking, were found for permanent stress at work (OR, 2.14; 99% CI, 1.73-2.64) and permanent stress at home (OR, 2.12; 99% CI, 1.68-2.65).²⁴

In another case-control study, 97 consecutive patients with a first episode of coronary heart disease, interviewed with Paykel’s Interview for Recent Life Events, reported significantly more life events, as well as more mood disorders than matched controls. The difference regarding life events was similar in patients with and without mood disorders and concerned all the categories of events, excepted “entrances” (introduction of new people, such as marriage), eg, “exits” (departure of a person from the social field of the subject, such as the death of a close family member), socially desirable (promotion) as well as undesirable (major financial problems) events, and controlled (initiation under subject’s control or choice) as well as uncontrolled events.²⁵

Prognostic value of depression following a coronary event, according to depression type

About 1 in 5 acute coronary syndrome (ACS) patients meets criteria for MDE, and of these patients, 50%or more have had depression symptoms in the past. The prognostic value of depressive disorder, regarding cardiac outcome, in patients with already established CHD, is based on much more convergent findings than the role of depression as a cardiovascular risk factor in healthy individuals. As early as in late 1980s Carney et al showed in 52 patients undergoing cardiac catheterization and subsequently found to have significant CHD, that major depressive disorder was the best predictor of major cardiac events during the 12 months following catheterization. The predictive effect was independent of the severity of CHD, left ventricular ejection fraction, and smoking.²⁶

In 1993, Frasure-Smith et al showed that major depression in 222 patients hospitalized following a MI was as an independent risk factor for mortality at 6 months (adjusted HR, 4.29; 95% CI, 3.14-5.44).²⁷ In 1995, the same research team published its results relating to an extended follow-up period of 18 months, showing that both the Diagnostic Interview Schedule (DIS) diagnosis of MDE (OR, 3.64; 95% CI, 1.32- 10.05) and elevated Beck Depression Inventory (BDI) scores (OR, 7.82; 95% CI, 2.42-25.26) were significantly related to 18-month cardiac mortality.²⁸ Adjusting for clinical confounding variables did not change the results, but contrary to BDI, MDE was no still predictive of cardiovascular deaths in patients who survived to 6 months. Multivariate analyses showed that anxiety and history of major depression each had an impact independent of each other, as well as of measures of cardiac disease severity.²⁹

Many further studies replicated these first findings.^5,7 The question remains whether the association between depression and mortality in patients with ACS is confounded by incomplete adjustment formeasures of known prognosticmarkers. In a prospective survey on 457 ACS subjects, neither depression measure (MDE assessed using a standardized interview or BDI score) was associated with the Global Registry of Acute Coronary Events (GRACE) risk score, the most comprehensive empirically derived index of clinical mortality predictors. MDE and depressive symptom severity each predicted mortality after controlling for GRACE score and left ventricular dysfunction (HR [adjusted for MDE], 2.51; 95% CI, 1.45-4.37).³⁰ No significant differences were found in GRACE scores between participants with initial MDE, as compared with those with recurrent MDE.

A growing literature has recently been dedicated to the differential prognostic value of incident vs ongoing and recurrent depression in patients with ACS. De Jonge et al assessed a total of 468 MI patients for the presence of an International Classification of Diseases–10 (ICD-10) depressive disorder within the year after index MI. During the 2.5-year mean follow up period, compared with nondepressed patients, those with incident depression had an increased risk of cardiovascular events (adjusted HR, 1.76; 95% CI, 1.06 to 2.93), but not those with nonincident depression (adjusted HR, 1.39; 95% CI, 0.74 to 2.61).³¹ New-onset depression—but not isolated pre-MI depression—was also related to cardiac death in an 8-year follow up in 588 post-MI subjects; in the subgroup of subjects with post-MI depression, pre-MI depression did not convey any additional risk of cardiac mortality.³² Using the BDI in 750 patients who had unstable angina pectoris and myocardial infarction, 23.2% of the participants self-reported a history of depressed mood for >2 weeks, and 31.3% had elevated BDI scores at index hospitalization, with 14.0% reporting persistent depressive symptomatology with an onset before the index hospitalization. History of depressed mood was found in 44.7% of subjects with elevated BDI compared with 13.4% in the rest of the population studied. After controlling for prognostic indicators, such as cardiac disease severity, medical history, and smoking, depressive symptomatology during hospitalization was significantly predictive of mortality, but depressive history was not.³³

Similar findings were published by Parker et al,³⁴ who recently proposed a more sophisticated classification of depression in 489 patients experiencing an ACS and undergoing a standardized interview a few days following their admission, then 1 month later: the poorer cardiovascular prognosis was associated with “incident depression” (no depression at admission, but depressed at 1 month) and “recurrent depression” (history of depression prior to the admission, then new episode at 1 month assessment); the best with “no depression” (never depressed), “prior depression” and “noncontinuing depression” (depression at admission, whatever the history of depression, but no depression at 1 month); intermediate prognosis was associated with “continuing depression” (depression at admission and still depressed at 1 month).³⁵

In the Depression after Myocardial Infarction (DepreMI) study, a naturalistic follow-up study of 475 patients admitted for MI, BDI scores during hospitalization and at 3, 6, and 12 months post-MI were analyzed, using latent class analysis. One out of 5 classes was characterized by significant and increasing depressive symptoms (4.0%). Subjects in this class had a higher risk for a new cardiovascular event compared with subjects without depressive symptoms.³⁶

Controlled trials focused on psychosocial distress, and especially depressivemood in patients hospitalized for an ACS were rather disappointing, regarding cardiac outcomes. SADHART (Sertraline AntiDepressant Heart Attack Randomized Trial) was a double-blind, placebo controlled, randomized trial comparing the safety and antidepressant efficacy of sertraline vs placebo in 369 patients with ACS who met criteria for MDE. In this trial, baseline MDE severity and failure of MDE to improve substantially during treatment with either sertraline or placebo were strongly and independently associated with long-term mortality.³⁷ Fifty-three percent of MDEs began before hospitalization for the index episode of ACS: they responded more frequently to sertraline than to placebo (63% vs 46%, respectively; OR, 2.0; 95% CI, 1.13-3.55) whereas depression with onset beginning after hospitalization showed a high placebo response rate (69% vs 60%, respectively).³⁸ Multivariate analysis indicated that onset of the current episode before the index episode of ACS, history of MDE, and baseline severity independently predicted the sertraline– placebo response ratio.

In the multicenter randomized Myocardial INfarction and Depression– Intervention Trial (MIND-IT) on the effects of antidepressant treatment for post-MI depression, patients were enrolled in double-blind, placebo-controlled treatment with mirtazapine and, in the case of insufficient treatment response after 8 weeks, open treatment with citalopram. The 18-month event rate (cardiac mortality or cardiac-related hospital admission) was 25.6% among nonresponders, 11.2% among untreated control subjects, and 7.4% among responders.³⁹ Gender differences were also noted in Linden’s meta-analysis on 23 trials comparing a psychological treatment to a control group on a total of 9856 coronary patients: the mortality benefits appeared only in men, even after controlling for age differences.⁴⁰ Moreover, trials initiating treatment at least 2 months after a cardiac event showed greater mortality benefits than those initiating treatment right after the event.

Finally, a poorer cardiac outcome in patients presenting with CHD and a comorbid depressive disorder could also be explained by a suboptimal access to standard therapeutic procedures, as demonstrated by the publication of Druss et al. Compared with CHD patients with no mental disorder, the use of revascularization procedures in patients presenting with affective disorders was significantly lower (RR=0.51 for percutaneous transluminal coronary angioplasty, and RR=0.63 for coronary artery bypass graft surgery.⁴¹ The likelihood of undergoing catheterization (RR=0.65) was also lower, but among patients who underwent catheterization the reduction in the use of revascularization procedures was no longer significant (RR=0.75 for percutaneous transluminal coronary angioplasty, and RR=0.94 for coronary artery bypass graft surgery, respectively). Thus, access to and content of medical care, eg, catheterization in patients with CHD symptoms, may plausibly be influenced by depression history.

Common genetic factors for CVD, depression, and depression responsiveness to antidepressants

The association between cardiovascular disease, especially CHD, and depressive disorder, cannot be totally explained by reciprocal causal effects; common genetic factors to both vulnerabilities are also involved.

In twin studies, both depression and CHD appear heritable. In the only twin study to consider depression and CHD jointly, the correlation across heritabilities was 0.42, suggesting that nearly 20% of variability in depressive symptoms and CHD was attributable to common genetic factors.⁴² Genetic variation related to inflammation has been primarily examined in relation to CHD, whereas genetic variation of the serotonin system has been primarily examined in relation to depression, although both pathways are involved in CHD and depression. The S (short) allele of the serotonin transporter (5-HTT) gene was shown to reduce transcription of this gene and thus reduce serotonin reuptake. A gene-environment interaction was suggested, individuals with one or two copies of the S allele exhibiting more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the L (long) allele.⁴³ In 2509 genotyped patients with MI, depressive symptoms were more common in patients with the S allele. Cardiac post-MI events were also more frequent in patients with the S allele than in those without it, and the increased risk for cardiac events became insignificant after an adjustment for depressive symptoms, indicating a possible mediating role of post-MI depression.⁴⁴ CHD outpatients carrying an S allele have a higher mean score for perceived stress than L/L homozygotes45: genetic vulnerability to depression could thus interact with a physical stressing situation such a CHD condition.

Stress and cardiovascular condition as risk factors for depressive recurrence

Several characteristics have been described as contributing to depressive recurrence: age at onset/number of episodes, severity, psychiatric comorbidity, family history, internal attributions, neuroticism, poor social support, and stressful life events.⁴⁶ Comorbid somatic condition has been less examined as a risk factor for depressive recurrence.

In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study carried out in 1500 patients, subjects with recurrent depression were older, had an earlier age of onset, and were more likely to have a positive family history of depression than first-episode patients. Their mean score on the Cumulative Illness Rating Scale (CIRS)—a 14-item interview that gauges the severity/morbidity of general medical conditions relevant to different organ systems—was also higher, even though this difference was largely attributable to patients with 10 or more episodes, who reported the greatest number of comorbid medical illnesses.⁴⁷

In the late 80s, Schleifer et al had already noted that depression following myocardial infarction was not associated with the severity of cardiac illness, but with the presence of noncardiac medical illnesses.⁴⁸

In the Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial (2481 depressed or socially isolated patients with MI), the adjusted ORs for having an MDE increased linearly with medical comorbidity, as measured by a modified version of the Charlson Comorbidity Index. This relationship remained after adjusting for CHD severity. The relationship between severity of depression and medical comorbidity was also maintained after excluding somatic symptoms of depression.⁴⁹

In 88 patients suffering from an ACS, a clinical interview was performed to assess current and past diagnosis ofMDE. CHD severity was assessed in all patients by coronary angiography. Neither in-hospital MDE status nor history of depression were significant predictors of CHD severity, but the interaction term between both was (higher CHD severity in patients without any history of depression and with incident depression). Follow- up analyses showed that patients with first-time, incident MDE had significantly more severe CHD compared with patients with recurrent MDE.⁵⁰ Authors suggest that ACS patients without a history of depression have normal vulnerability to depression, but because their CHD is more severe than those patients with past episodes of depression, they experience a first-time reactive depression in response to the significant physiologic and psychological stress. In these patients, incident MDE can be triggered by underlying cardiac disease. Another tentative explanation is that ACS patients with incident depression appear to have more advanced coronary vascular disease and that these patients may be more vulnerable to a certain type of depression termed vascular depression. Recurrent depression in ACS patients more likely resembles depression seen in the general population. Common risk factors for depression in the general population such as lower educational level and higher neuroticism are also seen in nonincident post-MI depressed patients. For individuals with recurrent depression disease severity is not a trigger for MDE: they may experience an exacerbation of a previously existing vulnerability, which is triggered by the ACS. Time course of depression in CHD patients can thus be understood as a result of genetic vulnerability, history of mood disorders, personality, severity of CHD, and comorbid somatic factors. Such complexity likely accounts for specific difficulties in treating depression in cardiovascular patients, in addition to symptom overlap and all the other obstacles related to a condition that is associated with multiple diagnoses. _

References
1. Hemingway H, Marmot M. Psychosocial factors in the aetiology and prognosis of coronary heart disease: systematic review of prospective cohort studies. BMJ. 1999;318:1460-1467.
2. Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation. 1999;99;2192-221.
3. Rugulies R. Depression as a predictor for coronary heart disease. A review and meta-analysis. Am J Prev Med. 2002;23:51-61.
4. Wulsin LR, Singal BM. Do depressive symptoms increase the risk for the onset of coronary disease? A systematic quantitative review. Psychosom Med. 2003; 65:201-210.
5. Barth J, Schumacher M, Herrmann-Lingen C. Depression as a risk factor for mortality in patients with coronary heart disease: a metaanalysis. Psychosom Med. 2004;66:802-813.
6. Lett SH, Blumenthal JA, Babyak MA, et al. Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment. Psychosom Med. 2004;66:305-315.
7. Van Melle JP, De Jonge P, Spijkerman TA, et al. Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: a meta-analysis. Psychosom Med. 2004;66:814-822.
8. Nicholson A, Kuper H, Hemingway H. Depression as an aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6362 events among 146,538 participants in 54 observational studies. Eur Heart J. 2006;27:2763- 2774.
9. Pozuelo L, Tesar G, Zhang J, Penn M, Franco K, JiangW. Depression and heart disease: what do we know, and where are we headed? Cleve Clin J Med. 2009;76:59-70.
10. Booth-Kewley S, Friedman HS. Psychological predictors of heart disease: a quantitative review. Psychol Bull. 1987;101:343-362.
11. Aromaa A, Raitasalo R, Reunanen A, et al. Depression and cardiovascular diseases. Acta Psychiatr Scand Suppl. 1994;377:77-82.
12. Pratt LA, Ford DE, Crum RM, Armenian HK, Gallo JJ, Eaton WW. Depression, psychotropic medication, and risk of myocardial infarction: prospective data from the Baltimore ECA follow-up. Circulation. 1996;94:3123-3129.
13. Ford DE, Mead LA, Chang PP, Cooper-Patrick L, Wang NY, Klag MJ. Depression is a risk factor for coronary artery disease in men: the precursors study. Arch Intern Med. 1998;158:1422-1426.
14. Cohen HW, Madhavan S, Alderman MH. History of treatment for depression: risk factor for myocardial infarction in hypertensive patients. Psychosom Med. 2001;63:203-209.
15. Jones DJ, Bromberger JT, Sutton-Tyrrell K, Matthews KA. Lifetime history of depression and carotid atherosclerosis in middle-aged women. Arch Gen Psychiatry. 2003;60:153-160.
16. Agatisa PK, Matthews KA, Bromberger JT, Edmundowicz D, Chang YF, Sutton- Tyrrell K. Coronary and aortic calcification in women with a history of major depression. Arch Intern Med. 2005;165:1229-1236.
17. Matthews KA, Chang YF, Sutton-Tyrrell K, Edmundowicz D, Bromberger JT. Recurrent major depression predicts progression of coronary calcification in healthy women: study of women’s health across the nation. Psychosom Med. 2010;72:742-747.
18. Ariyo AA, Haan M, Tangen CM, et al. Depressive symptoms and risks of coronary heart disease and mortality in elderly Americans. Circulation. 2000;102: 1773-1779.
19. Penninx BW, Guralnik JM, Mendes de Leon CF, et al. Cardiovascular events and mortality in newly and chronically depressed persons > 70 years of age. Am J Cardiol. 1998;81:988-994.
20. Surtees PG, Wainwright NW, Luben RN, Wareham NJ, Bingham SA, Khaw KT. Depression and ischemic heart disease mortality: evidence from the EPIC-Norfolk United Kingdom prospective cohort study. Am J Psychiatry. 2008;165: 515-523.
21. Wassertheil-Smoller S, Applegate WB, Berge K, et al. Change in depression as a precursor of cardiovascular events. Arch Intern Med. 1996;156:553-561.
22. Haynes SG, Feinleib M, Kannel WB. The relationship of psychosocial factors to coronary heart disease in the Framingham study: 3. Eight year incidence of coronary heart disease. Am J Epidemiol. 1980;111:3758.
23. Kivimaki M, Leino-Arjas P, Luukkonen R, Riihimaki H, Vahtera J, Kirjonen J. Work stress and risk of cardiovascular mortality: prospective cohort study of industrial employees. BMJ. 2002; 325:857-861.
24. Rosengren A, Hawken S, Ounpuu S, Sliwa K, Zubaid M, Almahmeed WA, Blackett KN, Sitthi-amorn C, Sato H, Yusuf S; INTERHEART investigators. Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:953-962.
25. Rafanelli C, Roncuzzi R, Milaneschi Y, et al. Stressful life events, depression and demoralization as risk factors for acute coronary heart disease. Psychother Psychosom. 2005;74:179-184.
26. Carney RM, Rich MW, Freedland KE, et al. Major depressive disorder predicts cardiac events in patients with coronary artery disease. Psychosom Medw. 1988; 50:627-633.
27. Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction: impact on 6-month survival. JAMA. 1993;270:1819-1825.
28. Frasure-Smith N, Lesperance F, Talajic M. Depression and 18-month prognosis after myocardial infarction. Circulation. 1995;91:999-1005.
29. Frasure-Smith N, Lesperance F, Talajic M. The impact of negative emotions on prognosis following myocardial infarction: is it more than depression? Health Psychol. 1995;14:388-398.
30. Kronish IM, Rieckmann N, Schwartz JE, Schwartz DR, Davidson KW. Is depression after an acute coronary syndrome simply a marker of known prognostic factors for mortality? Psychosom Med. 2009;71:697-703.
31. de Jonge P, van den Brink RHS, Spijkerman TA, Ormel J. Only incident depressive episodes after myocardial infarction are associated with new cardiovascular events. J Am Coll Cardiol. 2006;48:2204-2208.
32. Dickens C, McGowan L, Percival C, et al. New onset depression following myocardial infarction predicts cardiac mortality. Psychosom Med. 2008;70:450- 455.
33. Grace SL, Abbey SE, Kapral MK, Fang J, Nolan RP, Stewart DE. Effect of depression on five-year mortality after an acute coronary syndrome. Am J Cardiol. 2005;96:1179-1185.
34. Parker GB, Hilton TM,WalshWF, et al. Timing is everything: the onset of depression and acute coronary syndrome outcome. Biol Psychiatry. 2008;64:660-666.
35. Parker G, Hyett M, Walsh W, Owen C, Brotchie H, Hadzi-Pavlovic D. Specificity of depression following an acute coronary syndrome to an adverse outcome extends over five years. Psychiatry Res. 2010. In press.
36. Kaptein KI, de Jonge P, van den Brink RH, Korf J. Course of depressive symptoms after myocardial infarction and cardiac prognosis: a latent class analysis. Psychosom Med. 2006;68:662-668.
37. Glassman AH, Bigger JT Jr, Gaffney M. Psychiatric characteristics associated with long-termmortality among 361 patients having an acute coronary syndrome and major depression: seven-year follow-up of SADHART participants. Arch Gen Psychiatry. 2009;66:1022-1029.
38. Glassman AH, Bigger JT, Gaffney M, Shapiro PA, Swenson JR. Onset of major depression associated with acute coronary syndromes: relationship of onset, major depressive disorder history, and episode severity to sertraline benefit. Arch Gen Psychiatry. 2006;63:283-288.
39. de Jonge P, Honig A, van Melle JP, et al; MIND-IT Investigators. Non response to treatment for depression following myocardial infarction: association with subsequent cardiac events. Am J Psychiatry. 2007;164:1371-1378.
40. Linden W, Phillips MJ, Leclerc J. Psychological treatment of cardiac patients: a meta-analysis. Eur Heart J. 2007;28:2972-2984.
41. Druss BG, Bradford DW, Rosenheck RA, Radford MJ, Krumholz HM. Mental disorders and use of cardiovascular procedures after myocardial infarction. JAMA. 2000;283:506-511.
42. McCaffery JM, Frasure-Smith N, Dubé MP, et al. Common genetic vulnerability to depressive symptoms and coronary artery disease: a review and development of candidate genes related to inflammation and serotonin. Psychosom Med. 2006;68:187-200.
43. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:386-389.
44. Nakatani D, Sato H, Sakata Y, et al; Osaka Acute Coronary Insufficiency Study Group. Influence of serotonin transporter gene polymorphism on depressive symptoms and new cardiac events after acute myocardial infarction. Am Heart J. 2005;150:652-658.
45. Otte C, McCaffery J, Ali S, Whooley MA. Association of a serotonin transporter polymorphism (5-HTTLPR) with depression, perceived stress, and norepinephrine in patients with coronary disease: the Heart and Soul Study. Am J Psychiatry. 2007;164:1379-1384.
46. Burcusa SL, Iacono WG. Risk for recurrence in depression. Clin Psychol Rev. 2007;27:959-985.
47. Hollon SD, Shelton RC, Wisniewski S, et al. Presenting characteristics of depressed outpatients as a function of recurrence: preliminary findings from the STAR*D clinical trial. J Psychiatr Res. 2006;40:59-69.
48. Schleifer SJ, Macari-Hinson MM, Coyle DA, et al. The nature and course of depression following myocardial infarction. Arch Intern Med. 1989;149:1785-1789.
49. Watkins LL, Schneiderman N, Blumenthal JA, et al; ENRICHD Investigators. Cognitive and somatic symptoms of depression are associated with medical comorbidity in patients after acute myocardial infarction. Am Heart J. 2003; 146:48-54.
50. Goodman J, Shimbo D, Haas DC, Davidson KW, Rieckmann N. Incident and recurrent major depressive disorder and coronary artery disease severity in acute coronary syndrome patients. J Psychiatr Res. 2008;42:670-675.

Keywords: depression; recurrence; incident episode; stress; coronary heart disease; risk factor; prognostic factor; genetic vulnerability; 5-HTT polymorphism

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Eduard Vieta, MD, PhD

Maria REINARES, PsyD, PhD
Bipolar Disorders Program
Institute of Neuroscience
Hospital Clinic
University of Barcelona
IDIBAPS, CIBERSAM
Barcelona, SPAIN

Depression is the most frequent presentation of bipolar disorder. Several studies have reported that the long-term course of the illness is dominated by depressive rather than manic symptoms, with a direct negative impact on patient functioning. Despite its high morbidity and mortality, it is a field of research that has been neglected until recent years. A high percentage of bipolar patients are initially misdiagnosed as having unipolar depressive disorder. This mistake carries significant negative consequences for the treatment of this population and for outcomes. Therefore, it is essential to establish an accurate distinction between bipolar and unipolar depression in order to make an accurate and early diagnosis, leading to improvements in treatment and course of illness. This could also help clarify whether bipolar depression and major depressive disorder are separate diagnostic entities or belong to the same illness spectrum. This review aims to analyze the differences between unipolar and bipolar depression and identify possible predictors that may influence the “conversion” from unipolar depression to bipolar disorder. New proposals and future challenges in this area will also be discussed.

Bipolar disorder is a high prevalent, chronic, recurrent illness with devastating consequences when untreated because of high rates of morbidity and mortality. About 15% of severe bipolar patients die by suicide¹ and the percentage of patients who attempt suicide more than once is even higher. These attempts mostly occur during depressive phases. The long-term course of the illness is dominated by depressive rather than manic symptoms.^2-5 Recent studies suggest that depression has a direct and negative impact on functioning and these deficits appear to persist even during remission.⁶ Furthermore, subsyndromal symptoms can not only impair psychosocial functioning,⁷ but can also lead to a recurrence.⁸ In spite of the deleterious consequences of bipolar depression, it has been a neglected field of research for a long time. All the risks mentioned could be lowered by means of an early diagnosis and prophylactic treatment.

To be able to distinguish between bipolar and unipolar depression is crucial, as the treatment of both conditions differs considerably. This distinction is necessary in order to ensure accurate and early diagnosis, and to improve the pharmacological treatment of depression and understand the biology involved in each condition. It would reduce the economic burden and improve the health and quality of life of these patients. It also could help clarify whether bipolar depression and major depressive disorder are separate diagnostic entities or whether they belong to the same illness spectrum as different manifestations of the same underlying disorder.

Diagnostic issues

Unipolar and bipolar depression were first described by Leonhard⁹ and this distinction was validated by Angst,¹⁰ Perris,¹¹ and Winokur and coworkers¹² who showed that clinical, familial, and course features supported the nosological differentiation between both forms. Officially recognized in 1980 by DSM-III (Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition), this subtyping of unipolar/bipolar was further established in DSM-IV (4th Edition) and DSM-IV-R (4th Edition, Text Revision), both of which distinguish between bipolar type I and type II. Although major depressive disorder is classified separately from bipolar disorder, the criteria for unipolar and bipolar depression are identical, and emphasis is placed upon the euphoric condition and not upon differences in the depressive episodes.¹³ However, the impact of antidepressant treatment is different, clear for unipolar patients, unclear and sometimes self-defeating for bipolar patients, increasing the risks of (hypo)manic switch or rapid cycling. Due tomisdiagnosis,many bipolar patients are less likely to receive mood stabilizer medications.¹⁴ Furthermore, some of the illness treatments might be less effective when they are introduced in patients who have had many previous episodes^15,16 and the impact of a late introduction of mood stabilizers on top of antidepressants may carry high switch rates and increased suicidality.¹⁷

It has been reported that about 7.5 years elapse from the first time the patients ask for medical help and the time an accurate diagnosis of bipolar disorder is made.¹⁸ A survey of bipolar patients involved with National Depressive and Manic-Depressive Association support groups pointed out that 69% of patients were initially misdiagnosed, on average four psychiatrists were consulted before an accurate diagnosis was made, and unipolar depression was the most frequent misdiagnosis.¹⁹ As suggested by Goodwin and Jamison,¹ there are five primary causes for misdiagnosis: (i) patients’ lack of insight with regard to manic as opposed to depressive symptoms; (ii) clinicians’ neglect of information available from family members or other third parties; (iii) clinicians’ relative focus on euphoric rather than dysphoric or irritable mood as a criterion for hypomania; (iv) the structure of DSM-IV, which by separating bipolar from all depressive disorders has obscured the close relationship between early-onset recurrent depression and bipolar disorder; and (v) widespread interest in and use of “second-generation” antidepressants.

It is difficult to establish a correct differential diagnosis based on cross-sectional information, without obtaining data about the patient’s course of illness. By definition, (hypo)mania plays an essential role in the understanding of the bipolar condition of a mood disorder. Sometimes, especially when dealing with a bipolar disorder type II, diagnosis can be difficult when hypomanic episodes are not clearly detected. Furthermore, some subjects have a hyperthymic or cyclothymic temperament with mood disturbances that can sometimes be seen as borderline personality traits. Hence, the bipolar nature of a depressive episode could be difficult to establish. In fact, it has been pointed out that depressive polarity was strongly associated with a higher number of years undiagnosed.²⁰ A recent study found that the delay to first treatment was associated with being depressed for longer, greater severity of depression, greater number of episodes, more days of ultradian cycling, and fewer days euthymic.²¹ Another confusion factor to take into account is comorbidity with other psychiatric disorders. The high prevalence of comorbidities in bipolar patients has a negative impact on prognosis and sometimes also makes an accurate diagnosis more difficult to establish. The most frequent misdiagnosis includes substance-use disorders, anxiety disorders, personality disorders, and attention deficit hyperactivity disorder.^22,23 To sum up, bipolar depression, which is often related to comorbidity, disability and mortality, is still largely unknown and frequently underestimated, which may engender a more severe course of the illness.

Clinical features of unipolar and bipolar depression

Several authors have tried to define the clinical specificity of bipolar depression. Unfortunately, some studies do not consider the distinction between bipolar subtypes. Although there are no pathognomonic characteristics specific to bipolar depression compared with unipolar depressive disorder, when both conditions have been analyzed, some clinical and epidemiological differences can be described (Table I).

Table I. Differences between bipolar and unipolar depression.

The age of onset of the first depressive episode in bipolar disorder has been found to be earlier than that observed in unipolar depression.^24,25 Regarding the course of the illness, it has been reported that bipolar depressed subjects are more likely to report more prior episodes²⁶ and shorter episode duration.²⁷ Other typical characteristics of bipolar depression are lability of mood and hypomanic symptoms during depression.^28,29 Goldberg et al³⁰ found that two thirds of the subjects with bipolar depressed episodes had concomitant manic symptoms, most often distractibility, flight of ideas or racing thoughts, and psychomotor agitation. They observed that manic symptoms during depression demarcated a more severe and psychopathologically complex clinical state. It has also been reported that the stronger the manic component, the higher the mean values for novelty seeking and reward dependence, but the lower they are for harm avoidance.³¹ Bipolar depression is more often related to a higher risk of psychotic symptoms,³² suicidal ideation,³³ postpartum episodes,³⁴ seasonal pattern,³⁵ fewer somatic symptoms,²⁶ less appetite loss,³⁶ hypersomnia,²⁷ and atypical depressive symptoms.³⁷ Most, but not all, investigations have reported higher levels of psychomotor retardation in bipolar patients.^38,39 Comorbid conditions such as anxiety disorders and substance abuse are also more frequent in bipolar depression than in unipolar depression.⁴⁰ Bipolar depression has also been more frequently related to a family history of bipolar disorder,^26,41 and with manic symptoms associated with antidepressants (Table I).⁴² A potential limitation of many cross-sectional studies is that some people diagnosed with major depressive disorder could develop bipolar disorder.

Predictors of bipolar outcome in depression

The percentage of patients initially identified with “unipolar” depression who experience manic episodes varies widely across studies, but may be as high as 50%.⁴³ To identify those unipolar patients who, in the long-term, “become” bipolar patients is another way of obtaining more information about bipolar depression. When the predictors are analyzed, they are quite similar to those aspects described in cross-sectional comparative studies between unipolar and bipolar depression. In a retrospective study published in 1976, Dunner and colleagues⁴⁴ found that up to 21% of type I and type II bipolar patients had previously been hospitalized due to “unipolar depression.” Akiskal et al⁴⁵ proposed eight criteria predictive of the “bipolarization” of a depression, and suggested calling “pseudounipolar depression” the episodes that will show its bipolarity afterwards. They found the following predictors: treatment-induced hypomania, family history of bipolar disorder, strong inheritability, depression with hypersomnia and motor retardation, psychotic depression, continuous multigenerational familial transmission, postpartum onset and early onset (before age 25). Long-term studies have shown that those patients who became bipolar were more likely to show psychosis at the index depressive episode.^32,46 Younger age at onset, chronicity of the index episode, and family history of mania have also been reported.⁴⁶ Some of these aspects have been included by Solomon et al⁴⁷ who suggested using three items of the Screening Assessment of Depression-Polarity (SAD-P) as a preliminary screen for bipolar disorder in patients who present with an active episode of major depression: presence of delusions during the current episode of major depression, number of prior episodes of major depression, and family history of major depression or mania.

In an 11-year follow-up study composed of 559 subjects with a major depressive episode, Akiskal and coworkers28 found that up to 12.5% later developed a manic or hypomanic episode, which confirms its inclusion in the so-called “bipolar spectrum.” Twenty-two patients (3.9%) had a full-blown manic episode, becoming bipolar type I, and 48 (8.6%) had at least one episode of hypomania, confirming its status as belonging to the bipolar II disorder. Except for greater acuteness, severity, and psychotic symptomatology, bipolar I converters were similar to major depressive disorder nonconverters. In contrast, bipolar II converters were robustly distinguished from those with major depressive disorder who remained unipolar on the basis of self-report measures of mood lability, energy/ activity, and daydreaming. This profile was associated with early age at onset of major depressive disorder and pleomorphic psychopathology beyond the usual affective realm, high rates of substance abuse, as well as educational, marital, and occupational disruption and minor antisocial acts prior to discrete hypomanic episodes. Bipolar II switchers had a more protracted and tempestuous course with shorter well intervals. Overall, descriptions of temperamental instability during major depressive disorder episodes provided useful clinical information for predicting which depressed patients will switch to bipolar II.

Recently, a 5-year prospective study showed that 2.8% and 8.9% of unipolar major depressive patients switched to bipolar I and II disorder, respectively. Together with severity, predictors for diagnostic switch included psychiatric comorbidity such as obsessive-compulsive disorder, social phobias, and symptoms of cluster B personality disorders.⁴⁸

A great number of individuals with the so-called soft or subsyndromal states belong to the bipolar spectrum by virtue of their positive family histories, their pharmacological response, and their tendency to progress to full clinical disorder.⁴⁹ Based on a sample of patients with bipolar II disorder and major depressive disorder, Benazzi and Akiskal²⁴ aimed to identify validated bipolar markers. Lower age at onset (before 21 years), higher major depressive episode recurrence, mixed depression, and bipolar family history were significantly more common in bipolar II disorder. Early onset was the most discriminative feature of this major depressive disorder subgroup at possible higher risk of shifting to bipolar disorder. The authors suggested that early age at onset of depression represents a marker of a genetically based recurrent or polyphasic mood disorder.

New proposals

Based on the fact that some clinical characteristics are more common in both bipolar depression andmajor depressive disorder, respectively, or are observed in unipolar depressed patients who “convert” to bipolar disorder over time, Mitchell et al⁵⁰ have suggested a probabilistic approach. Instead of proposing a categorical diagnostic distinction between bipolar and unipolar depressive disorder, they recommend a likelihood approach as follows (see Table II).

This approach uses a set of sociodemographic and clinical variables to establish which patients with depression are more or less likely to have an underlying bipolar disorder, and it is based on differences between subjects with bipolar disorder and major depressive disorder other than the presence or absence of manic symptoms.⁴¹ Therefore, the assessment of the presence of (hypo)manic symptoms would be complemented by other aspects related to the clinical history to make an accurate diagnosis. Although this approach should be carried out with new data and be further explored, the use of probabilistic models has been reinforced when the criteria of actual classifications systems have been discussed.⁵¹

As previously mentioned, Solomon et al⁴⁸ suggested a preliminary screen for bipolar disorder in patients with a depressive episode bymeans of assessing the presence of delusions during the current episode of major depression, the number of prior episodes of major depression, and a family history of major depression or mania.

The influence of subsyndromal depression on psychosocial functioning and on futuremood recurrences points to the need to introduce treatments with the aim of achieving full remission. Based on the fact that the risk of subsequent recurrence and impairment increases with each new episode and that there is a poorer response to treatment when it is implemented later in the course of the illness, recent proposals have been made regarding the application of clinical staging to bipolar disorder.^52,53 The staging model suggests a progression from prodromal tomore severe and refractory presentations.⁵⁴ However, early intervention in bipolar disorders depends on the ability to identify individuals at high risk of developing the illness. Failure to identify minor elated states leads to misdiagnosis of bipolar spectrum patients as unipolar. It is essential to strive to make appropriate distinctions among various forms of depression and differentiate them diagnostically, prognostically, and therapeutically from ordinary unipolar major depressive disorder.¹⁴

Table II. Likelihood of diagnosis of bipolar I depression and of
unipolar depression.

A better knowledge of the characteristics that permit discrimination between unipolar and bipolar disorder, together with a good anamnesis complemented with information from family members and a higher use of screening tools, could facilitate an increase in the detection of bipolar disorder in patients with depression. The Mood Disorder Questionnaire (MDQ) may help to increase recognition of bipolar disorder.55

A recent study56 showed that the MDQ yielded a positive screen rate of bipolar patients with a diagnosis of unipolar disorder and a current depressive episode. The Hypomania Checklist (HCL-32)⁵⁷ can also help to identify the hypomanic component of depressive episodes and increase the detec- tion rate of both bipolar disorder and minor bipolar disorders. Rating tools should be introduced systematically in primary care, paying special attention to young people.

A contentious issue is whether (hypo)mania that occurs during treatment of “unipolar” depression is, following DSM-IV, an antidepressant-induced mood disorder or, as suggested by some experts, the precipitation of an underlying bipolar disorder. A high increase in the number of patients who would be considered bipolar if the duration criteria of hypo(manic) symptoms were more flexible has also been reported.⁵⁸ Therefore, major depressive disorder seems to be overdiagnosed at the expense of bipolar disorder. Using a broader concept and a more comprehensive screening of bipolarity, Zimmermann et al31 have suggested that major depressive disorder is a heterogeneous concept including a large group with subthreshold bipolar disorder. In contrast to the dichotomicalmodels, the development of a validated bipolar spectrum concept has been introduced to assist in more differentiated research and provide a treatment model for affective disorders, which may help reduce the underrecognition of bipolarity.⁵⁹ Thismodel unifies categorical classification with a dimensional view, as some proposals for future diagnostic classification systems have suggested.⁶⁰

Conclusions

Despite depression being the most frequent presentation of bipolar disorder associated with high morbidity and mortality, it has been a neglected field of research. Fortunately, in recent years, a number of studies have shed some light on this topic. There are areas of overlap between both forms of depression, although some differences have also been found. The distinction between bipolar and unipolar depression would assist in making an accurate and early diagnosis, in improving treatment, and in reaching a better understanding of each condition which, in turn, would contribute to improving illness outcome. The new editions of the forthcoming diagnostic classifications will face the challenge of improving the discriminant validity of bipolar and unipolar depressions. New treatments will also need to be tested in the two indications, hopefully providing a final answer to the unsolved question of the efficacy and safety of antidepressants in bipolar depression. Meanwhile, the best way to discriminate between unipolar and bipolar depression is the course and outcome of the condition. To what extent both disorders are merely different course patterns of one condition is still a matter of debate. _

References
1. Goodwin FK, Jamison KR. Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression, Second Edition. New York, NY: Oxford University Press; 2007.
2. Judd LL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry. 2003;60:261-269.
3. Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002; 59:530-537.
4. Kupka RW, Altshuler LL, Nolen WA, et al. Three times more days depressed than manic or hypomanic in both bipolar I and bipolar II disorder. Bipolar Disord. 2007;9:531-535.
5. De Dios C, Ezquiaga E, Garcia A, Soler B, Vieta E. Time spent with symptoms in a cohort of bipolar disorder outpatients in Spain: a prospective, 18-month follow- up study. J Affect Disord. 2010;125:74-81.
6. Rosa AR, Reinares M, Michalak E, et al. Functional Impairment and disability across mood states in subjects with bipolar disorder. Value Health. 2010;13: 984-988.
7. Altshuler LL, Post RM, Black DO, et al. Subsyndromal depressive symptoms are associated with functional impairment in patients with bipolar disorder: results of a large, multsite study. J Clin Psychiatry. 2006;67:1551-1560.
8. Perlis RH, Ostacher MJ, Patel JK, et al. Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2006;163:217-224.
9. Leonhard K. In: Robins E, ed. The Classification of Endogenous Psychoses (5th Edition). (Translated by Russell Berman from: Aufteilung der Endogenen Psychosen. 1st ed. Berlin, Germany: Akademie-Verlag; 1957). New York, NY: Irvington Publishers; 1979.
10. Angst J. Zur Aetiologie und Nosologie Endogener Depressiver Psychosen. Berlin, Germany: Springer; 1966.
11. Perris C. A study of bipolar (manic-depressive) and unipolar recurrent depressive psychoses. Acta Psychiatr Scand. 1966;42:1-189.
12. Winokur G, Clayton P, Reich T. Manic-Depressive Illness. St Louis,Mo: C.V.Mosby Company; 1969.
13. Goodwin GM, Anderson I, Arango C, et al. ECNP Consensus Meeting. Bipolar depression. Nice, March 2007. Eur Neuropsychopharmacol. 2008;18:535-549.
14. Baldessarini RJ, Vieta E, Calabrese JR, Tohen M, Bowden CL. Bipolar depression: overview and commentary. Harv Rev Psychiatry. 2010;18:143-157.
15. Swann AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD. Differential effect of number of previous episodes of affective disorder on response to lithium or divalproex in acute mania. Am J Psychiatry. 1999;156:1264-1266.
16. Ketter TA, Houston JP, Adams DH, et al. Differential efficacy of olanzapine and lithium in preventing manic or mixed recurrence in patients with bipolar I disorder based on number of previous manic or mixed episodes. J Clin Psychiatry. 2006;67:95-101.
17. Pacchiarotti I, Valentí M, Colom F, et al. Differential outcome of bipolar patients receiving antidepressant monotherapy versus combination with an antimanic drug. J Affect Disord. 2010; Sep 2. Epub ahead of print.
18. Ghaemi SN, Sachs GS, Chiou AM, Pandurangi AK, Goodwin FK. Is bipolar disorder still underdiagnosed? Are antidepressants overutilized? J Affect Disord. 1999;52:135-144.
19. Hirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? Results of the national depressive and manicdepressive association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry. 2003;64:161-174.
20. Rosa AR, Andreazza AC, Kunz M, et al. Predominant polarity in bipolar disorder: diagnostic implications. J Affect Disord. 2008;107:45-51.
21. Post RM, Leverich GS, Kupka RW, et al. Early-onset bipolar disorder and treatment delay. Are risk factors for poor outcome adulthood. J Clin Psychiatry. 2010; 71:864-872.
22. Vieta E, Colom F, Martínez-Arán A, Benabarre A, Reinares M, Gastó C. Bipolar II disorder and comorbidity. Compr Psychiatry. 2000;41:339-343.
23. Vieta E, Colom F, Corbella B, et al. Clinical correlates of psychiatric comorbidity in bipolar I patients. Bipolar Disord. 2001;3:253-258.
24. Benazzi F, Akiskal HS. How best to identify a bipolar-related subtype among major depressive patients without spontaneous hypomania: superiority of age at onset criterion over recurrence and polarity? J Affect Disord. 2008;107:77-88.
25. Tondo L, Lepri B, Cruz N, Baldessarini RJ. Age at onset in 3014 Sardinian bipolar and major depressive disorder patients. Acta Psychiatr Scand. 2010;121: 446-452.
26. Perlis RH, Brown E, Baker RW, Nierenberg AA. Clinical features of bipolar depression versus major depressive disorder in large multicenter trials. Am J Psychiatry. 2006;163:225-231.
27. Forty L, Smith D, Jones L, et al. Clinical differences between bipolar and unipolar depression. Br J Psychiatry. 2008;192:388-389.
28. Akiskal HS, Maser JD, Zeller PJ, et al. Switching from “unipolar” to bipolar II. A 11-year prospective study of clinical and temperamental predictors in 559 patients. Arch Gen Psychiatry. 1995;52:114-123.
29. Benazzi F, Akiskal HS. Delineating bipolar II mixed states in the Ravenna-San Diego collaborative study: the relative prevalence and diagnostic significance of hypomanic features during major depressive episodes. J Affect Disord. 2001; 67:115-122.
30. Goldberg JF, Perlis RH, Bowden CL, et al. Manic symptoms during depressive episodes in 1,380 patients with bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2009;166:173-181.
31. Zimmermann P, Brückl T, Nocon A, et al. Heterogeneity of DSM-IV major depressive disorder as a consequence of subthreshold bipolarity. Arch Gen Psychiatr. 2009;66:1341-1352.
32. Goldberg JF, Harrow M, Whiteside JE. Risk for bipolar illness in patients initially hospitalized for unipolar depression. Am J Psychiatry. 2001;158:1265-1270.
33. Olfson M, Das AK, Gameroff MJ, et al. Bipolar depression in a low-income primary care clinic. Am J Psychiatry. 2005;162:2146-2151.
34. Sharma V, Khan M, Corpse C, et al. Missed bipolarity and psychiatric comorbidity in women with postpartum depression. Bipolar Disord. 2008;10:742-747.
35. Shin K, Schaffer A, Levitt AJ, Boyle MH. Seasonality in a community sample of bipolar, unipolar and control subjects. J Affect Disord. 2005;86:19-25.
36. Papadimitriou GN, Dikeos DG, Daskalopoulou EG, Soldatos CR. Co-occurrence of disturbed sleep and appetite loss differentiates between unipolar and bipolar depressive episodes. Prog Neuropsychopharmacol Biol Psychiatry. 2002; 26:1041-1045.
37. Benazzi F. Depression with DSM-IV atypical features: a marker for bipolar II disorder. Eur Arch Psychiatry Clin Neurosci. 2000;250:53-55.
38. Mitchell PB, Malhi GS. Bipolar depression: phenomenological overview and clinical characteristics. Bipolar Disord. 2004;6:530-539.
39. Parker G, Roy K, Wilhelm K, Mitchell P, Hadzi-Pavlovic D. The nature of bipolar depression: implications for the definition of melancholia. J Affect Disord. 2000; 59:217-224.
40. Schaffer A, Cairney J, Veldhuizen S, Kurdyak P, Cheung A, Levitt A. A population- based analysis of distinguishers of bipolar disorder from major depressive disorder. J Affect Disord. 2010;125:103-110.
41. Winokur G, Coryell W, Keller M, Endicott J, Leon A. A family study of manic-depressive (bipolar I) disease. Is it a distinct illness separable from primary unipolar depression? Arch Gen Psychiatry. 1995;52:367-373.
42. Wada K, Sasaki T, Jitsuiki H, et al. Manic/hypomanic switch during acute antidepressant treatment for unipolar depression. J Clin Psychopharmacol. 2006; 26:512-515.
43. Goldberg JF. Optimizing treatment outcomes in bipolar disorder under ordinary conditions. J Clin Psychiatry. 2008;69(suppl 3):11-19.
44. Dunner DL, Fleiss JL, Fieve RR. The course of development of mania in patients with recurrent depression. Am J Psychiatry. 1976;133:905-908.
45. Akiskal HS, Walker P, Puzantian VR, King D, Rosenthal TL, Dranon M. Bipolar outcome in the course of depressive illness. J Affect Disord. 1983;5:115-128.
46. Coryell W, Endicott J, Maser JD, Keller M, Leon AC, Akiskal HS. Long-term stability of polarity distinctions in the affective disorders. Am J Psychiatry. 1995; 152:385-390.
47. Solomon DA, Leon AC, Maser JD, et al. Distinguishing bipolar major depression from unipolar major depression with the screening assessment of depression- polarity (SAD-P). J Clin Psychiatry. 2006;67:434-442.
48. Holma KM, Melartin TK, Holma IA, Isometsä ET. Predictors for switch from unipolar major depressive disorder to bipolar disorder type I or II: a 5-year prospective study. J Clin Psychiatry. 2008;69:1267-1275.
49. Vieta E, Suppes T. Bipolar II disorder: arguments for and against a distinct diagnostic entity. Bipolar Disord. 2008;10:163-178.
50. Mitchell PB, Goodwin GM, Johnson GF, Hirschfeld RM. Diagnostic guidelines for bipolar depression: a probabilistic approach. Bipolar Disord. 2008;10:144-152.
51. Ghaemi SN, Bauer M, Cassidy F, et al. ISBD Diagnostic Guidelines Task Force. Diagnostic guidelines for bipolar disorder: a summary of the International Society for Bipolar Disorders Diagnostic Guidelines Task Force Report. Bipolar Disord. 2008;10:117-128.
52. Berk M, Conus P, Lucas N, et al. Setting the stage: from prodrome to treatment resistance in bipolar disorder. Bipolar Disord. 2007;9:671-678.
53. Kapczinski F, Vasco D, Kauer-Sant’Anna M, et al. Clinical implications of a staging model for bipolar disorders. Expert Rev Neurother. 2009;9:957-966.
54. Vieta E, Reinares M, Rosa AR. Staging bipolar disorder. Neurotox Res. 2011; 19:279-285.
55. Hirschfeld RM, Williams JB, Spitzer RL, et al. Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry. 2000;157:1873-1875.
56. Tafalla M, Sanchez-Moreno J, Diez T, Vieta E. Screening for bipolar disorder in a Spanish sample of outpatients with current major depressive episode. J Affect Disord. 2009;114:299-304.
57. Angst J, Adolfsson R, Benazzi F, et al. The HCL-32: towards a self-assessment tool for hypomanic symptoms in outpatients. J Affect Disord. 2005;88:217-233.
58. Angst J, Gamma A, Benazzi F, Ajdacic V, Eich D, Rössler W. Toward a re-definition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar- II,minor bipolar disorders and hypomania. J Affect Disord. 2003;73:133-146.
59. Angst J. The bipolar spectrum. Br J Psychiatry. 2007;190:189-191.
60. Vieta E, Phillips ML. Deconstructing bipolar disorder: a critical review of its diagnostic validity and a proposal for DSM-V and ICD-11. Schizophr Bull. 2007;33: 886-892.

Keywords: bipolar disorder; major depression; unipolar depressive disorder; switch; outcome; spectrum

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Eduard Vieta, MD, PhD

Michael BAUER, MD, PhD
Professor of Psychiatry
Department of Psychiatry and Psychotherapy, University
Hospital Carl Gustav Carus Technische Universität Dresden
Dresden, GERMANY

The long-term course of unipolar major depressive disorder (MDD) is characterized by high rates of recurrence and prolonged symptomatic chronicity. The primary goals of continuation andmaintenance treatment are to prevent a fast relapse into depression or new episode of depression (recurrence). Adverse prognostic indicators for recurrence include: high number of previous episodes; residual symptoms at remission; previous longer episodes and chronicity; more severe previous episodes; onset early in life; concurrent dysthymic disorder (“double depression”); concurrent substance abuse or anxiety disorders; and family history ofMDD in first-degree relatives. Key elements of long-term treatment include: pharmacotherapy; psychoeducation; and adherence monitoring. Extending treatment for an additional 6 months (continuation therapy) can reduce the likelihood of relapse by about 70%, and extending treatment for another 12 months or longer (maintenance therapy) can reduce the risk of recurrence. Most patients receive antidepressants during the acute and continuation phase, and the best treatment recommendation to prevent relapse and recurrence of depression is to continue the antidepressant medication at the same dose during these treatment phases as well. Randomized placebo-controlled efficacy studies (RCTs, usually conducted 1 or 2 years after remission) indicate that all major classes of antidepressants are effective in preventing recurrence of depression with about a twofold higher relapse rate with placebo treatment. Evidence suggests that the “newer” antidepressants have superior long-term efficacy and better tolerability compared with traditional antidepressants, eg, the tricyclics. Although concerns about the generalizability of results fromplacebo RCTs can be raised, RCTs testing the efficacy of a new antidepressant in comparison with placebo remain the gold standard for proof of efficacy requested by the regulatory authorities. Effectiveness trials studying patients in the “true world” provide additional important information, but due to methodological reasons they cannot replace placebo-controlled RCTs.

Major depressive disorder: a highly recurrent disease

Major depressive disorder (MDD) presents typically as a recurrent disorder. 50% to 85% of the patients who suffer a depressive episode will have another episode of major depression.¹ The likelihood of a recurrence increases with the number of previous depressive episodes and the severity of the current episode. Patients who have had three episodes of major depression have a 90% chance of having another.² Among other risk factors for recurrence of MDD, prior history of multiple episodes of MDD, early age at onset, persistence of dysthymic symptoms after recovery from an episode of MDD, presence of an additional, non-mood psychiatric diagnosis, and presence of a chronic physical disorder have been identified.³ Factors that have been associated with increased severity of subsequent depressive episodes include a history or a prior episode complicated by serious suicide attempts, psychotic features, or severe functional impairment.

Keeping these facts in mind, it is apparent that the primary goals of long-term, maintenance (prophylactic) treatment are to prevent a new episode of depression (a recurrence) and development of chronicity. A recurrence is an episode that appears after a completely asymptomatic period (remission) has been achieved for a 6-month period.^4,5 The consideration of the patient’s course of illness and treatment history is essential for the implementation ofmaintenance phase therapy. Even though no definite recommendation can be given as to when prophylactic therapy should be initiated, it is clearly indicated in situations associated with a high risk of recurrence (Table I). In addition to the risk factors shown in Table I, patient preference, severity of functional impairments, and side effects experienced during the continuation phase also play a role in determining whether or not maintenance treatment should be implemented.^6,7

Key elements of relapse prevention

Key elements of relapse/recurrence prevention treatment of recurrent depressive disorders include: (i) psychoeducation; (ii) pharmacotherapy; and (iii) adherence monitoring. Adjunctive depression-targeted psychotherapy may also be included in the treatment plan. Because maintenance treatment requires compliance with medication, education, and a close therapeutic alliance with patients and their families/friends are essential. Education does not only reduce treatment attrition, but also leads to a better outcome.⁸ Strategies to prepare patients and their families for maintenance treatment include education on the typical course of the illness, treatment options, medication effects and side effects, use of (daily) selfreport instruments to track mood and early warning signs of relapse or recurrence, long-term perspectives, and projected end of treatment. A relapse prevention program (a low intensity intervention including enhanced patient education, visits with a depression specialist, telephone calls, symptom monitoring) for depressed patients in primary care significantly improved antidepressant adherence and depressive symptoms outcome in a randomized controlled 12-month trial compared with usual primary care.⁹

Table I. Factors associated with increased risk for recurrence in
major depressive disorder.

Relapse prevention in depression with antidepressant medication

Pharmacotherapy is the most studied treatment modality in the long-term treatment of recurrent MDD. Among the therapeutic options available, antidepressant medications, and lithium have received the most study. The majority of controlled trials investigating these medications in maintenance treatment demonstrated efficacy for relapse prevention.^6,10-14 The medication of first choice is either the antidepressant with which remission was achieved in the acute/continuation phase or lithium.^2,6,7,15 Likely reasons why antidepressants may be preferred to lithium are that patients are usually treated with antidepressants during the acute/continuation phase and that patients usually prefer to use medication that does not require regular monitoring by blood tests. The final choice of prophylactic agent does depend on how individual patients respond to and tolerate treatment with antidepressants and lithium. Patients’ preference and their own or their family member’s experience with maintenance treatment are also helpful in the choice of the medication.

Antidepressants for relapse prevention

Randomized placebo-controlled studies (usually 1 or 2 years after remission) of antidepressants for relapse prevention treat- ment of depression indicate that literally all major available antidepressants are effective in preventing relapse of depression: tricyclic antidepressants (TCAs), eg, amitriptyline, imipramine, nortriptyline; irreversible monoamine oxidase inhibitors (MAOIs), eg, phenelzine;^10,11,13,16 selective serotonin reuptake inhibitors (SSRIs), eg, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline);^13,17-19 selective serotonin and norepinephrine reuptake inhibitors (SSNRIs), eg, duloxetine, venlafaxine;^20,21 bupropion;²² and agomelatine²³ have been tested with positive results by either indicating significant lower relapse rates (with placebo about twice as high as with active agents) or a longer time to relapse compared with placebo treatment. To give an example: in a most recent study, the cumulative relapse rate at 6 months for agomelatine-treated patients was 21.7% and for placebo-treated patients 46.6%.²³ The calculated effect sizes (and the active treatment– placebo differences) in these studies appear to be even higher compared with acute treatment studies. Relapse rates are high in the first months after remission in particular and decline with time. From naturalistic follow-up studies, the rates of relapse following remission have been estimated at 20% to 24% by 2 months, 28% to 44% by 4 months, 27% 50% by 6 months, and 37% 54% by 12 months.¹⁴

A meta-analysis of discontinuation randomized controlled trials (RCTs) in patients with MDD reported that 60% of patients on placebo relapsed in the year after randomization and 29% relapsed in months 12 to 36.²⁴ For clinical decision making it is also useful to express the relative benefit of an active treatment over placebo using the “number needed to treat” (NNT). The NNT concept represents one component of the complex benefit/risk estimation of antidepressant treatments. It represents the minimal number of patients who have to be treated to reach a benefit in one patient. In relapse prevention treatment studies, the active treatment–placebo difference seems to be even higher compared with acute treatment studies of antidepressants: in a pooled analysis of 31 RCTs in 4410 patients, a rounded NNT of 5 (4.34) for the relapse prevention during the first 12 months after successful acute treatment has been calculated.²⁴

In the majority of these relapse prevention trials, however, only responders to the drug tested during the acute phase were included in the continuation/maintenance randomized, double- blind treatment phase. This design has been described as introducing a potentially significant selection bias that limits the generalizability of results.²⁵ Strictly speaking, findings are only relevant to the population of patients who are responsive to study medication during the acute phase. To overcome this selection bias, continuation and maintenance medication should be assessed among patients achieving initial remission through other means and antidepressant medications besides the maintenance drug.¹⁸ The latter design, however, is more difficult to conduct for obvious reasons (and subsequently more expensive) and brings up the question why patients should be treated in the continuation/maintenance phase with a medication that they have not responded to in the acute phase.

Efficacy and effectiveness of antidepressants

_ Antidepressant efficacy
There is an ongoing debate as to whether randomized, placebo- controlled trials are the best and only way to test if a medication is effective in certain patient populations. There is one clear answer to that: to receive approval for a specific indication, regulatory authorities, eg, the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) request RCTs testing the efficacy of a new antidepressant in comparison with placebo or in comparison with placebo and a standard (comparator) drug.²⁶ The term “efficacy” is usually defined as the power of an antidepressant to produce antidepressant effects under “ideal” conditions. According to the British National Institute for Clinical Excellence (NICE) it is defined “as the extent to which a specific treatment or intervention, under ideally controlled conditions (eg, in a laboratory), has a beneficial effect on the course or outcome of disease compared with no treatment or other routine care.²⁷ The mean differences of scores on any applied depression rating scale (typically the Hamilton Rating Scale for Depression [HAM-D] or the Montgomery Åsberg Depression Rating Scale [MADRS]) between active antidepressant drugs and placebo shown in pivotal RCTs are used for decision making by the regulatory authorities to determine whether new antidepressants may receive approval or not. Unfortunately, placebo effect plays a significant role in clinical trials of MDD. Recent meta-analyses showed that the mean responder rate in placebo-treated groupswas 29.7%and that this rate had been growing over the past decades of drug development.²⁸ The further consideration of other additional efficacy indicators such as response and remission rates and the number needed to treat (NNT) is useful.

The efficacy of antidepressant medication in the acute treatment of MDD in adults is well proven by a large number of RCTs.^13,14 This has been investigated in many RCTs comparing active antidepressants with placebo treatment and with active comparators. Most publications are reporting responder and remitter rates together with end-point differences in depression rating scales such as different versions of the HAM-D or the MADRS scale using the “last observation carried forward” (LOCF) method, which follows all included patients. Usual responder rates vary between 32% and 70%,²⁸ HAM-D17 differences between active and placebo treatment after 6 to 8 weeks of treatment often reach only 3 to 4 absolute points, but represent mean reductions in comparison to the scores before treatment of about 50% to 60%.

_ Antidepressant effectiveness
In contrast, “effectiveness “of an antidepressant drug can be achieved during the use of the substance in typical clinical circumstances and in larger populations of patients in the real world. In most studies, responder and remitter rates are higher in effectiveness studies compared with RCTs.²⁹ Serious concerns about the generalizability of results from placebo RCTs have been raised in the literature. The standard exclusion criteria of most trials, which have become much more stringent over the past decade, do exclude a significant number of patients suffering from suicidality, comorbid axis I disorders, and medical illnesses. In the case of trials investigating the efficacy of antidepressants, patients with a history of treatment failures and long depressive index episodes are generally also excluded from participation. Furthermore, simply the use of placebo, randomization, and blinding procedures excludes many patients who refuse study participation because of these procedures that may in their view reduce the chances of improvement. Ghaemi³⁰ has estimated that fewer than 10% of depressed patients qualify for, and agree to, participate in available RCTs of antidepressants. Subsequently, the assumption in the world of clinical trials is that the research conducted on these 10% is generalizable to the other remaining 90% of patients. Although unproven, it may well be that results of a placebo-controlled RCT would be different if a significant proportion of these 90% were included in the trial. Nevertheless, according to NICE and regulatory authorities such as the EMA, RCTs remain the most important method for establishing treatment efficacy and estimating the clinical effectiveness of antidepressants. Approval based on effectiveness studies only would introduce other biases (eg, by unblinded ratings, no placebo as a comparator drug), resulting in false results.

Comparative efficacy of antidepressants

A relatively small number of studies have directly compared different medications for maintenance treatment in recurrent unipolar depression.¹⁰ A meta-analysis of studies comparing lithium with other antidepressants showed no conclusive advantage for lithium in the prophylaxis of unipolar illness.³¹ In one relatively small randomized, placebo-controlled 2-year maintenance study, lithium (serum level 0.8 to 1.2 mmol/L) was superior to imipramine (100 to 150 mg/day); the combination of lithium and imipramine was not superior to lithium alone.³² Another, larger randomized, placebo-controlled 2-year study reported better maintenance effects for imipramine (the mean daily dosage at the start of the maintenance phase was 137 mg, range 75 to 150 mg/day) than lithium (the mean serum lithium level at the start of the maintenance phase was 0.66 mmol/L, range 0.43 to 1.05 mmol/L).³³ In the latter study, the combination of imipramine and lithium did not provide any advantage over imipramine alone in preventing depressive recurrences.

However, in a later reanalysis of the data, the same authors concluded that the results of the latter study could be accounted for by alternative explanations that are a consequence of the study design.²⁵ One randomized, prospective, open, 2.5-year trial comparing lithium (average serum lithium level 0.59 mmol/L) with amitriptyline (average dosage 98 mg/day) found significantly better prophylactic efficacy for lithium.³⁴

The question of dosing and additional psychotherapy in relapse prevention

The majority of patients with a moderate/severe depressive episode receive antidepressants during the acute and continuation phase, and the best treatment recommendation to prevent recurrence of depression is to continue the antidepressant medication that was effective during the acute and continuation phase of treatment at the same dose during the maintenance phase.^35,36 In two studies, the group of patients who received only half of the acute-phase dose of imipramine³⁵ or paroxetine³⁶ rather than the full dose, showed a significantly higher recurrence rate. Of course, in case of intolerance or disturbing side effects, the dose needs adaptation (decrease) in the clinical setting.

In the largest and probably most influential study of the use of antidepressants in maintenance treatment, a randomized 3-year placebo-controlled trial, survival analysis showed fulldose imipramine (mean dose at randomization 215 mg/day) withor without Interpersonal Therapy (IPT;weekly for12weeks, then biweekly for 8 weeks, and then monthly) to be the best maintenance treatment, followed by IPT with or without placebo, and then placebo.³⁷ In this study of highly recurrent unipolar depression, all patients enrolled in the 3-year study, had remitted on the combination of imipramine and IPT, and all had remained well for 4 months of continuation therapy prior to randomization. A subsequent additional 2-year placebo- controlled study of the patients who completed the 3- year study³⁷ showed that imipramine (average dose of 200 mg/day) was significantly better than placebo in preventing recurrence.³⁸

Side effect profile: relevance for long-term treatment

Side effects and tolerability of medications are key considerations in maximizing adherence to treatment, and they should be as minimal as possible. Even mild-to-moderate side effects during maintenance treatment may lead to noncompliance with the consequence of symptom worsening and increased risk of recurrence. Using medications with a more favorable side effect profile than the TCAs may facilitate patient compliance with pharmacotherapy, as long as these agents are effective in the maintenance treatment of depression. A number of more recent studies suggest that the “newer” antidepressants have superior long-term efficacy and better tolerability compared with traditional TCAs and tetracyclics.^11,13,39 A randomized, placebo-controlled 2-year study comparing the efficacy of mirtazapine with that of amitriptyline found that the time to relapse was significantly longer in the mirtazapine group.⁴⁰ Similarly, a double-blind 1-year study reported significantly greater improvement in some of the out- come measures in the venlafaxine group compared with imipramine.⁴¹ Ideally, the rate and severity of side effects of the antidepressant medication should be at the level of placebo as demonstrated for agomelatine²³ and other “newer” antidepressants.

Figure 1. Therapeutic options for maintenance
treatment of major depressive disorder.

Maintenance treatment options

There is growing recognition that prophylactic treatment of depressive disorders may be inadequate in a substantial proportion of patients. The maintenance treatment of patients with recurrent depression who experience recurrences during prophylactic treatment with standard agents, eg, antidepressants and/or lithium, is one of the most challenging issues in the treatment of these disorders. However, little data from formal studies are available to guide physicians in the maintenance treatment of patients suffering from recurrences during standard prophylactic treatment.¹² Combination therapy administering two or even three antidepressants, maybe combined with lithium (or in case of refractoriness or intolerance lamotrigine or valproate), are treatment options for the clinician although there are little controlled data to support such polypharmacy. Figure 1 gives an algorithm for treatment options during the maintenance treatment phase.

Duration and discontinuation of maintenance treatment

The optimal moment to discontinue a longer- term medication is difficult to predict. Current evidence suggests that maintenance treatment should be continued as long as the risk of recurrence persists. That risk is often difficult to assess in the individual patient, particularly after a long period (years) of absence of symptoms/recurrence. It appears that the likelihood of a recurrence increases with the number of previous depressive episodes. However, some authors have argued that there is a similar risk of recurrence whether medication is discontinued after months or years of pharmacotherapy.⁴² There is good evidence from a controlled 5-year study that patients who benefited the most from continued prophylaxis were those receiving active full-dose medication for at least 5 years.³⁸ Thus, for some patients, maintenance treatment is required for very long periods (eg, a decade) and for others it is required indefinitely.⁴³ Three years maintenance therapy is appropriate almost as a routine for recurrent patients, particularly where an episode prior to the present one has occurred in the last 5 years or where remission has been difficult to achieve. Maintenance for 5 years or indefinitely is recommended for those patients at greater risk, particularly where two or three attempts to withdraw medication have been followed by another episode within 1 year. Only with long-term antidepressant treatment can the risk of development of serious depressive illness with a high relapse and suicide rate be stopped or at least reduced. _

References
1. Mueller TI, Leon AC, Keller MB, et al. Recurrence after recovery from major depressive disorder during 15 years of observational follow-up. Am J Psychiatry. 1999;156:1000-1006.
2. NIMH Consensus Development Conference Consensus Development Conference Statement. Mood disorders: pharmacologic prevention of recurrences. Am J Psychiatry. 1985;142:469-476.
3. Kovacs M, Devlin B, Pollock M, et al. A controlled family history study of childhood- onset depressive disorder. Arch Gen Psychiatry. 1997;54:613-623.
4. Frank E, Prien RF, Jarrett RB, et al. Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse, and recurrence. Arch Gen Psychiatry. 1991;48:851-855.
5. Kupfer DJ. Managment of recurrent depression. J Clin Psychiatry. 1993;54(2): 29-33.
6. AHCPR (Agency for Health Care Policy and Research). Depression Guidelines Panel. Depression in Primary Care: Clinical Practice Guideline No. 5. AHCPR pub. No. 93-0550. Rockville, Md; 1993.
7. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000;157(4):1-45.
8. Rush AJ. Strategies and tactics in the management of maintenance treatment for depressed patients. J Clin Psychiatry. 1999;60(14):21-26.
9. Katon W, Rutter C, Ludman EJ, et al. A randomized trial of relapse prevention of depression in primary care. Arch Gen Psychiatry. 2001;58:241-247.
10. Solomon DA, Bauer MS. Continuation and maintenance pharmacotherapy for unipolar and bipolarmood disorders. Psychiatr Clin North Am. 1993;16:515-540.
11. AHCPR (Agency for Health Care Policy and Research). Evidence Report on Treatment of Depression: Newer Pharmacotherapies. San Antonio Evidence- Based Practice Center. Washington, DC, AHCPR, Evidence-Based Practice Centers. AHCPR pub. No. 99-E014; 1999.
12. Bauer M, Whybrow PC, Angst J, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 2: Maintenance treatment of major depressive disorder and treatment of chronic depressive disorders and subthreshold depressions. World J Biol Psychiatry. 2002;3:69-86.
13. Bauer M, Bschor T, Pfennig A, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders in Primary Care. World J Biol Psychiatry. 2007;8:67-104.
14. Anderson IM, Ferrier IN, Baldwin RC, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. J Psychopharmacol. 2008;22 (4):343-396.
15. Paykel ES. Continuation and maintenance therapy in depression. Br Med Bull. 2001;57:145-59.
16. Bauer M, Whybrow PC, Angst J, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for biological treatment of unipolar depressive disorders, Part 1: Acute and continuation treatment of major depressive disorder. World J Biol Psychiatry. 2002;3:5-43.
17. Hochstrasser B, Isaksen PM, Koponen H, et al. Prophylactic effect of citalopram in unipolar, recurrent depression: placebo-controlled study of maintenance therapy. Br J Psychiatry. 2001;178:304-310.
18. Lépine JP, Caillard V, Bisserbe JC, et al. A randomized, placebo-controlled trial of sertraline for prophylactic treatment of highly recurrent major depressive disorder. Am J Psychiatry. 2004;161(5):836-842.
19. Kornstein SG, Bose A, Li D, et al. Escitalopram maintenance treatment for prevention of recurrent depression: a randomized, placebo-controlled trial. J Clin Psychiatry. 2006;67(11):1767-1775.
20. Kocsis JH, Thase ME, Trivedi MH, et al. Prevention of recurrent episodes of depression with venlafaxine ER in a 1-year maintenance phase from the PREVENT Study. J Clin Psychiatry. 2007;68:1014-1023.
21. Perahia DG, Maina G, Thase ME, et al. Duloxetine in the prevention of depressive recurrences: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70(5):706-716.
22. Weihs KL, Houser TL, Batey SR, et al. Continuation phase treatment with bupropion SR effectively decreases the risk for relapse of depression. Biol Psychiatry. 2002;51(9):753-761.
23. Goodwin GM, Emsley R, Rembry S, et al. Agomelatine prevents relapse in patients with major depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70(8):1128-1137.
24. Geddes JR, Carney SM, Davies C, et al. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet. 2003; 361:653-661.
25. Greenhouse JB, Stangl D, Kupfer DJ, et al. Methodologic issues in maintenance therapy clinical trials. Arch Gen Psychiatry. 1991;48:313-318.
26. Baldwin D, Broich K, Fritze J, et al. Placebo-controlled studies in depression: necessary, ethical and feasible. Eur Arch Psychiatry Clin Neurosci. 2003;253: 22-28.
27. National Institute for Clinical Excellence. Depression: management of depression in primary and secondary care. www.nice.org.uk/pdf/CG023quickrefguide.pdf Clinical Guideline 23. 2004.
28. Walsh BT, Seidman SN, Sysko R, et al. Placebo response in studies of major depression: variable, substantial, and growing. JAMA. 2002;287:1840-1847.
29. Hegerl U, Mergl R. The clinical significance of antidepressant treatment effects cannot be derived from placebo-verum response differences. J Psychopharmacol. 2010;24(4):445-448.
30. Ghaemi SN. A Clinician’s Guide to Statistics and Epidemiology in Mental Health. Cambridge, UK: Cambridge University Press; 2009.
31. Souza FGM, Goodwin GM. Lithium treatment and prophylaxis in unipolar depression: a meta-analysis. Br J Psychiatry. 1991;158:666-675.
32. Kane JM, Quitkin FM, Rifkin A, et al. Lithium carbonate and imipramine in the prophylaxis of unipolar and bipolar II illness: a prospective, placebo-controlled comparison. Arch Gen Psychiatry. 1982;39:1065-1069.
33. Prien RF, Kupfer DJ, Mansky PA, et al. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination. Arch Gen Psychiatry. 1984;41:1096-1104.
34. Greil W, Ludwig-Mayerhofer W, Erazo N, et al. Comparative efficacy of lithium and amitriptyline in the maintenance treatment of recurrent unipolar depression: a randomised study. J Affect Disord. 1996;40:179-190.
35. Frank E, Kupfer DJ, Perel JM, et al. Comparison of full-dose versus half-dose pharmacotherapy in the maintenance treatment of recurrent depression. J Affect Disord. 1993;27:139-145.
36. Franchini L, Gasperini M, Perez J, et al. Dose-response efficacy of paroxetine in preventing depressive recurrences: a randomized, double-blind study. J Clin Psychiatry. 1998;59:229-232.
37. Frank E, Kupfer DJ, Perel JM, et al. Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry. 1990;47:1093-1099.
38. Kupfer DJ, Frank E, Perel JM, et al. Five-year outcome for maintenance therapies in recurrent depression. Arch Gen Psychiatry. 1992;49:769-773.
39. Montgomery SA. New developments in the treatment of depression. J Clin Psychiatry. 1999;60(14):10-15.
40. Montgomery SA, Reimitz PE, Zivkov M. Mirtazapine versus amitriptyline in the long-term treatment of depression: a double-blind placebo-controlled study. Int Clin Psychopharmacol. 1998;13:63-73.
41. Shrivastava RK, Cohn C, Crowder J, et al. Long-term safety and clinical acceptability of venlafaxine and imipramine in outpatients with major depression. J Clin Psychopharmacol. 1994;14:322-329.
42. Thase ME. Long-term nature of depression. J Clin Psychiatry. 1999;60(14):3-9.
43. Rush AJ, Kupfer DJ. Strategies and tactics in the treatment of depression. In: Gabbard GO, ed. Treatment of Psychiatric Disorders. Third Edition. Washington, DC: American Psychiatric Publishing, Inc; 2001:1417-1439.

Keywords: depressive episode; depressive disorder; recurrence; relapse; antidepressant; prevention; tolerability

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Sidney H. KENNEDY, MD, FRCPC
Department of Psychiatry
University Health Network
Department of Psychiatry
University of Toronto
Toronto, Ontario, CANADA


Franca M. PLACENZA, PhD
Department of Psychiatry
University Health Network
Toronto, Ontario, CANADA

There is strong evidence to support relapse prevention strategies in the intermediate and long-termmanagement of patients with a history of recurrent Major Depressive Episodes. Most placebo-controlled relapse prevention trials have evaluated the benefits of different antidepressant therapies (tricyclic, selective serotonin reuptake inhibitor, serotonin and norepinephrine reuptake inhibitor, and agomelatine) over 6-month to 3-year durations. Evidence-based psychotherapy studies, mainly cognitive behavioral therapy (CBT), mindfulness-based cognitive therapy (MBCT), and interpersonal psychotherapy (IPT), with and without pharmacotherapy, have also been carried out. Although there are considerable variations inmethodologies,metaanalyses and guidelines support maintenance treatments with both antidepressants and psychotherapies. In general, patients with risk factors for recurrent episodes of depression should remain at the same dose of antidepressant medication for at least 2 years. Patients require frequent monitoring with an emphasis onmodifiable risk factors for relapse, including comorbid disorders and treatment adherence. Those who relapse despite adequate medication therapy may benefit from additional CBT or MBCT. Discontinuation of medications requires gradual tapering. It is important to address individual patient factors in the long-term management of Major Depressive Disorder.

Relapse and recurrence

The definitions of relapse and recurrence of a major depressive episode (MDE) proposed by the MacArthur Foundation Task Force¹ have been more or less universally accepted. Relapse implies the loss of either response or remission and may be operationalized as the return of sufficient symptoms to meet criteria for an MDE for at least 2 weeks² or an increase in Hamilton Rating Scale for Depression (HRSD) scores above a predetermined threshold for a minimum duration (eg, HRSD ≥16 for 2 weeks or more).³ Recurrence implies the emergence of a new episode of depression some time after the risk period for relapse within an identified episode, although the distinction between relapse and recurrence is probably more theoretical than pragmatic. These definitions provide a basis for comparative studies to examine relapse prevention across different treatment modalities (eg, pharmacotherapy, electroconvulsive therapy, or cognitive therapy) or within one modality (eg, selective serotonin reuptake inhibitor (SSRI) vs serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants).
Guideline recommendations for relapse prevention

The evidence to support continuation and maintenance antidepressant therapies in the long-term management of MDD is among the most robust in the mood disorders literature.⁴ Among guidelines developed for the treatment of Major Depressive Disorder (MDD), those of the British Association for Psychopharmacology (BAP),⁵ the Canadian Network for Mood and Anxiety Treatments (CANMAT),⁶ the National Institute for Health and Clinical Excellence (NICE),⁷ the Texas Medication Algorithm Project (TMAP),⁸ and the World Federation of Societies of Biological Psychiatry (WFSBP)⁹ are among the most current.¹⁰

There is a consensus that maintenance treatment should continue for a minimum of 6 months after achieving symptomatic remission and that the medication dose that was effective during acute treatment should not be reduced. Maintenance treatment for 6 to 9 months is acceptable for patients with one or two episodes who do not have additional risk factors for relapse.⁵ The presence of risk factors in patients who have had two episodes supports an extended period of maintenance therapy.⁸ These risk factors are summarized in the CANMAT guidelines (Table I).⁶ While the WFSBP guidelines concur with the general recommendations to maintain antidepressants at the same dose as the acute phase, these guidelines offer more support for lithium in preventing recurrence of unipolar depressive illness. They also emphasize the benefits of lithium prophylaxis in reducing the risk of suicide.⁹

Most guidelines also recommend that patients with three or more MDEs should be maintained on antidepressants for at least 1 year and up to lifetime, with duration of maintenance therapy depending upon risk factors for recurrence and patient preference.⁸ According to the NICE guidelines, patients should continue antidepressants for at least 2 years if they are at risk of relapse.⁷ Recommendations from the BAP guidelines are that, for patients with more than five lifetime episodes and/or two episodes in the last few years, medication should be continued for at least 2 years.⁵

Table I. Risk factors supporting long-term (2 years to lifetime) antidepressant
maintenance.

Maintenance treatment beyond 2 years should be considered when factors such as older age, comorbid conditions, and other risk factors are present.⁷ There is also agreement that when the decision is made to discontinue an antidepressant, it should be done gradually to avoid discontinuation emergent symptoms. High-risk patients should be monitored regularly for early signs of recurrence after discontinuation of antidepressants. According to the CANMAT guidelines, evidence to support maintenance therapy for longer than 2 years has a less established evidence base, but certain risk factors, including earlier onset of depression, continuing psychosocial adversity, older age, and comorbid medical or psychiatric conditions, are indicators for extended maintenance treatment.⁶ In the NICE guidelines, patients who have relapsed despite adequate antidepressant maintenance treatment are considered candidates for combined medication and psychological interventions, particularly cognitive behavioral therapy (CBT) or mindfulness-based cognitive therapy (MBCT). MBCT is also recommended for people who are currently well, but have experienced three or more prior episodes of depression.⁷ Similar conclusions are reached in the BAP guidelines, which suggest the addition of CBT to medication for patients with residual symptoms or those with additional risk factors for relapse. The same group also concludes that interpersonal therapy (IPT) is not recommended as a sole maintenance treatment, although it may be a useful adjunct to antidepressants in patients with recurrent depression.⁵ Psychotherapy is not recommended as a sole treatment to prevent recurrence in the WFSBP guidelines,⁹ although these guidelines are considerably older than others and did not have access to literature in the past decade. The same is true overall for the guidelines from the American Psychiatric Association (APA).¹¹

Evidence to support relapse prevention strategies in major depressive disorder

_ Pharmacotherapy studies
Support for these guidelines on relapse prevention has steadily emerged over several decades. In a landmark relapse prevention trial, the Pittsburgh group evaluated the benefits of a tricyclic antidepressant (TCA) or IPT alone or in various combinations.¹² Results of the survival analysis demonstrated a robust effect for imipramine at an average dose of 200 mg daily and a modest effect for IPT. The mean survival time for both imipramine-treated groups was approximately 2.5 years compared to 1.5 years for IPT and just under 1 year for the placebo control group.¹² In the final phase of this project, 20 subjects who had remained in recovery up to 3 years were randomized to continue on imipramine (n=11) or to receive placebo (n=9) for a further 2 years. At the end of 5 years, 5 out of 9 receiving placebo had a recurrence of depressive episodes with a mean survival time of 54 weeks, while only 1 out of 11 receiving imipramine had a recurrence and the mean survival time was 99 weeks.¹³

One of the first relapse prevention trials with a second-generation antidepressant compared responders to paroxetine who remained on the active treatment for 1 year to those who switched to placebo. There was a significantly lower rate of relapse and longer survival time in the paroxetine group.¹⁴ This was followed by a large systematic review of relapse prevention in which Geddes and colleagues (2003)⁴ identified 31 randomized trials (published or unpublished up to August 2000) involving patients who had responded to an antidepressant during acute treatment and were randomized to continue on the drug or switch to placebo. Although this analysis included trials out to 36 months, most (58%) lasted 6 or 12 months and the majority (81%) involved TCAs or SSRIs. The authors concluded that continuing treatment with an antidepressant reduced the odds of relapse by 70%, with an average of 41% of patients receiving placebo and 18% on antidepressant experiencing a relapse. The relative reduction in year 1 was 20%, corresponding to a number needed to treat of 5 patients.⁴

Prevention of Recurrent Episodes of depression with VENlafaxine for Two years (PREVENT) was the first large trial to assess relapse prevention with an SNRI in patients with recurrent depression (defined as three or more prior episodes, two occurring within the past 5 years).^15,16 The study employed a three-phase, double-blind, placebo-controlled methodology to examine two consecutive 1-year maintenance phases in which responders to venlafaxine ER were randomly assigned to remain on the medication or switch to placebo. At the end of each maintenance phase, patients receiving venlafaxine ER had a significantly longer time to recurrence and lower likelihood of recurrence compared with those who were switched to placebo (Year 1: 23% vs 42%; Year 2: 8% vs 45%).^15,16

In a subsequent meta-analysis involving SSRIs, SNRIs, and other second-generation antidepressants, Hansen and colleagues (2008) evaluated 23 placebo-controlled and 4 comparative trials. There were no differences in relapse and recurrence rates in the 4 head-to-head comparative trials. Among the placebo-controlled trials, the duration of randomized follow up in 12 studies was less than 1 year, and 1 year or longer in the remaining 11 trials. The number of patients needed to treat to prevent 1 additional relapse was 5.¹⁷ In a recent update on the long-termtreatment of depression with SSRIs and newer antidepressants, Reid and Barbui (2010) reaffirmed the benefit of continuing antidepressant treatment for at least 12 months following the treatment of an acute episode.¹⁸

Agomelatine is a new antidepressant with a novel mode of action¹⁹ that has also been evaluated under relapse prevention conditions. Like the trials previously reviewed, agomelatine demonstrated similar efficacy in relapse prevention with a cumulative relapse rate of 21.7% for agomelatine compared with 46.6% for placebo over 24 weeks of maintenance therapy.³

_ Psychotherapy studies
In parallel with the pharmacotherapy evidence for relapse prevention, a number of studies have demonstrated the benefits of evidence-based psychotherapies, particularly CBT²⁰ and MBCT.²¹ While there is some support for IPT as a maintenance therapy, the evidence is less robust. For example, Schramm and colleagues (2007) reported a short-term (3- month) advantage for IPT over clinical management for relapse prevention in hospitalized depressed patients with MDD. However, this difference was not maintained at 1 year.²² Frank and colleagues (2007) also evaluated the potential preventative role of IPT at different frequencies in a large sample of women with recurrent unipolar depression who achieved remission with either IPT alone or in combination with an SSRI. Oncemonthly IPT proved to be a good method of prophylaxis for the subpopulation of women who achieved remission with IPT alone, but was less helpful in the group who required SSRIs in the initial phase of treatment.²³ A summary of recommendations for evidence-based psychotherapies in maintenance treatment from the CANMAT guidelines are shown in Table II.²⁴

Despite the impressive evidence from these various controlled trials, adherence to relapse prevention strategies in natural practice trials is considerably less impressive.^25,26 The investigators monitored, but did not control, the use of antidepressants during a 2-year follow up of remitted patients who had a history of recurrent depression and were candidates for maintenance antidepressant therapy. Only 42% maintained continuous antidepressant treatment, 38% received antidepressants intermittently, and 20% were without maintenance antidepressant therapy throughout the trial. Overall, based on a standardized minimum effective dose criterion, only 26% of patients received an antidepressant at or above the recommended guideline doses. In this study, there was no difference in rates of relapse between intermittent and continuous antidepressant groups, but those patients who received additional preventive cognitive therapy had the lowest relapse rates.²⁵

Table II. Relapse prevention: recommendations for individual psychotherapies.

In a subsequent report involving the same cohort of patients, Bockting and colleagues (2009) compared relapse rates after 5.5 years in “treatment as usual” (TAU) versus TAU augmented with a course of modified cognitive therapy.While the overall relapse rate was high (79%), there was a significantly lower rate in the augmented group (75%) compared with the TAU group (95%).²⁶

_ Neurostimulation studies
Among the neurostimulation therapies, only electroconvulsive therapy (ECT) has an adequate evidence base to provide guidelines for its use in relapse prevention.²⁷ The main clinical dilemma following successful treatment of an acute depressive episode with ECT is the selection of optimal maintenance therapy. In general, antidepressant treatments that failed prior to the use of ECT are not effective in subsequent relapse prevention. However, results from two large collaborative studies, the Consortium for Research in ECT (CORE)²⁸ and the Columbia University Consortium,²⁹ support a combination of nortriptyline and lithium for relapse prevention. In the CORE study, maintenance ECT was as effective as the combination therapy during the first 6 months.²⁸ However, there is insufficient evidence to recommend an optimal frequency for maintenance ECT and only modest evidence to support continuation of ECT in the long term.³⁰

From guidelines to personalized medicine

There are several reasons why it is difficult to compare outcomes for individual antidepressants across the studies and meta-analyses discussed here. Aside from differences in duration of various studies, there is a lack of consensus on what constitutes a relapse. This is well illustrated in the systematic review of 31 trials reported by Geddes and others (2003)⁴ where virtually every trial employed different criteria for “relapse.” These varied from: (i) poorly defined clinical criteria such as “change in treatment is indicated” or “increase in symptoms sufficient to warrant admission to hospital”; to (ii) increased scores on various symptom scales (eg, Montgomery- Åsberg Depression Rating Scale (MADRS) ≥22; ≥25 or HRSD ≥16, ≥17, ≥18); to (iii) recurrence of a MDE; to (iv) several of these criteria combined.⁴

Apart from differences in trial methodology, patient variables have also been shown to influence relapse. These include the number of prior episodes, medical and psychiatric comorbidity, and the presence of residual symptoms.³¹ In addition to clinical and demographic factors, certain biological (eg, short allele of serotonin transporter gene promoter region polymorphism) and psychological (eg, neuroticism, cognitive vulnerability) markers have been identified as risk factors for recurrence of MDD in the context of stress.^32,33 Longitudinal controlled studies are needed to establish the role of these markers in optimizing the duration of antidepressant treatment and predicting relapse. _

References
1. Frank E, Prien RF, Jarrett RB, et al. Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse, and recurrence. Arch Gen Psychiatry. 1991;48(9):851-855.
2. Segal, ZV, Bieling, P, Young, T, et al. Antidepressant monotherapy versus sequential pharmacotherapy and mindfulness-based cognitive therapy, or placebo, for relapse prophylaxis in recurrent depression. Arch Gen Psychiatry. 2010; 67(12):1258-1264.
3. Goodwin GM, Emsley R, Rembry S, Rouillon F; Agomelatine Study Group. Agomelatine prevents relapse in patients with major depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized, doubleblind, placebo-controlled trial. J Clin Psychiatry. 2009;70:1128-1137.
4. Geddes JR, Carney SM, Davies C, et al. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet. 2003;361 (9358):653-661.
5. Anderson IM, Ferrier IN, Baldwin RC, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. J Psychopharmacol. 2008;22 (4):343-396.
6. Lam RW, Kennedy SH, Grigoriadis S, et al; Canadian Network for Mood and Anxiety Treatments (CANMAT). Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. III. Pharmacotherapy. J Affect Disord. 2009;117(suppl 1):S26- S43.
7. National Institute for Clinical Excellence. Depression: management of depression in adults. Clinical Practice Guideline No 90. Updated Edition. London, UK: National Institute for Clinical Excellence. 2010:580.
8. Suehs BT, Argo TR, Beudele SD, et al. Texas Medication Algorithm Project Procedure Manual. Major Depressive Disorder Algorithms. Austin, Tx. Texas Department of State Health Services: 2008.
9. Bauer M, Bschor T, Pfenning A, et al; Task Force on Unipolar Depressive Disorders. World Federation of Societies of Biological Psychiatry (WFSBP). Guidelines for Biological Treatment of Unipolar Depressive Disorders in Primary Care. World J Biol Psychiatry. 2007;8:67-104.
10. Davidson JRT. Major depressive disorder treatment guidelines in America and Europe. J Clin Psychiatry. 2010;71(suppl E1):e04.
11. American Psychiatric Association. Practice Guidelines for the Treatment of Patients with Major Depressive Disorder. 2nd ed. Arlington, VA: American Psychiatric Association; 2000.
12. Frank E, Kupfer DJ, Perel JM, et al. Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry. 1990;47(12):1093-1099.
13. Kupfer DJ, Frank E, Perel JM, et al. Five-year outcome for maintenance therapies in recurrent depression. Arch Gen Psychiatry. 1992;49(10):769-773.
14. Montgomery SA, Dunbar G. Paroxetine is better than placebo in relapse prevention and the prophylaxis of recurrent depression. Int Clin Psychopharmacol. 1993;8(3):189-195.
15. Kocsis JH, Thase ME, Trivedi MH, et al. Prevention of recurrent episodes of depression with venlafaxine ER in a 1-year maintenance phase from the PREVENT Study. J Clin Psychiatry. 2007;68(7):1014-1023.
16. Keller MB, Trivedi MH, Thase ME, et al. The Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) Study: outcomes from the 2-year and combined maintenance phases. J Clin Psychiatry. 2007;68(8): 1246-1256.
17. Hansen R, Gaynes B, Thieda P, et al. Meta-analysis of major depressive disorder relapse and recurrence with second-generation antidepressants. Psychiatr Serv. 2008;59(10):1121-1130.
18. Reid S, Barbui C. Long term treatment of depression with selective serotonin reuptake inhibitors and newer antidepressants. BMJ. 2010;340:c1468.
19. Millan MJ, Gobert A, Lejeune F, et al. The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine 2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. J Pharmacol Exp Ther. 2003;306(3):954-964.
20. Vittengl JR, Clark LA, Jarrett RB. Moderators of continuation phase cognitive therapy’s effects on relapse, recurrence, remission, and recovery from depression. Behav Res Ther. 2010;48(6):449-558.
21. Kuyken W, Byford S, Taylor RS, et al. Mindfulness-based cognitive therapy to prevent relapse in recurrent depression. J Consult Clin Psychol. 2008;76(6): 966-978.
22. Schramm E, van Calker D, Dykierek P, et al. An intensive treatment program of interpersonal psychotherapy plus pharmacotherapy for depressed inpatients: acute and long-term results. Am J Psychiatry. 2007;164(5):768-777.
23. Frank E, Kupfer DJ, Buysse DJ, et al. Randomized trial of weekly, twice-monthly, and monthly interpersonal psychotherapy as maintenance treatment for women with recurrent depression. Am J Psychiatry. 2007;164(5):761-767.
24. Parikh SV, Segal ZV, Grigoriadis S, et al; Canadian Network for Mood and Anxiety Treatments (CANMAT). Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. II. Psychotherapy alone or in combination with antidepressant medication. J Affect Disord. 2009;117(suppl 1):S15-S25.
25. Bockting CL, ten Doesschate MC, Spijker J, Spinhoven P, Koeter MW, Schene AH; DELTA study group. Continuation and maintenance use of antidepressants in recurrent depression. Psychother Psychosom. 2008;77(1):17-26.
26. Bockting CL, Spinhoven P, Wouters LF, Koeter MW, Schene AH; DELTA Study Group. Long-term effects of preventive cognitive therapy in recurrent depression: a 5.5-year follow-up study. J Clin Psychiatry. 2009;70(12):1621-1628.
27. Kennedy SH, Milev R, Giacobbe P, et al.; Canadian Network for Mood and Anxiety Treatments (CANMAT). Canadian Network for Mood and Anxiety Treatments (CANMAT) Clinical guidelines for the management of major depressive disorder in adults. IV. Neurostimulation therapies. J Affect Disord. 2009;117 (suppl 1):S44-S53.
28. Kellner CH, Knapp RG, Petrides G, et al. Continuation electroconvulsive therapy vs pharmacotherapy for relapse prevention in major depression: a multisite study from the Consortium for Research in Electroconvulsive Therapy (CORE). Arch Gen Psychiatry. 2006;63(12):1337-1344.
29. Sackeim HA, Dillingham EM, Prudic J, et al. Effect of concomitant pharmacotherapy on electroconvulsive therapy outcomes: short-term efficacy and adverse effects. Arch Gen Psychiatry. 2009;66(7):729-737.
30. Gagné GG Jr, Furman MJ, Carpenter LL, Price LH. Efficacy of continuation ECT and antidepressant drugs compared to long-term antidepressants alone in depressed patients. Am J Psychiatry. 2000;157(12):1960-1965.
31. Furukawa TA, Cipriani A, Barbui C, Geddes JR. Long-term treatment of depression with antidepressants: a systematic narrative review. Can J Psychiatry. 2007;52(9):545-552.
32. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301(5631):386- 389.
33. Mulder RT, Frampton CM, Luty SE, Joyce PR. Eighteen months of drug treatment for depression: predicting relapse and recovery. J Affect Disord. 2009;114 (1-3):263-270.

Keywords: serotonin reuptake inhibitor; serotonin and norepinephrine reuptake inhibitor; agomelatine; cognitive behavioral therapy; electroconvulsive therapy

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Korinna KARAMPAMPA, MSc
Fredrik BORGSTRÖM, PhD
i3 Innovus, Stockholm SWEDEN


Bengt JÖNSSON, PhD
Stockholm School of Economics
Stockholm, SWEDEN

Major depressive disorder (MDD) is a mental disorder that frequently affects individuals of all ages. Patients may experience a single episode or recurrent ones. The impact the disease has on an individual’s everyday life is important, resulting in a substantial economic burden imposed on society, with the majority of the costs being generated outside the health care systems. Several cost-of-illness studies onmajor depression focus on the direct medical, and in some cases, direct nonmedical costs. Indirect costs are not frequently assessed even if they impose a significant burden on society, particularly during the acute phases of the disease. Pharmacological treatment is an important component of direct medical costs, estimated to account for 6% to 29% of total direct health care costs. Major depressive episodes represent an additional burden for society due to increased costs imposed on the health care system and higher productivity losses when compared with MDD patients not currently experiencing an episode. Therefore, pharmacological or other types of interventions that are used to treat patients withMDD in order to decrease the number ofmajor depressive episodes or delay their occurrence have the potential to translate into large cost reductions.

Major depressive disorder (MDD) or major depression (MD) is a form of unipolar depressive disorder, with typical signs of the disease including depressive mood, loss of interest and enjoyment, reduced energy, and/or increased fatigability (Revision of the International Classification of Diseases – World Health Organization 1992 – ICD-10).¹ The symptoms that are present in major depression interfere with an individual’s everyday life, preventing a person from functioning normally.²

Depression is characterized by single or recurrent major depressive episodes (MDEs) that can be classified according to their severity as mild, moderate, and severe.¹ A prospective psychiatric epidemiological survey in the Dutch general population revealed that the median duration of an MDE was 3 months, with about 50% of patients experiencing a depressive episode reporting full recovery within this period.³ Individuals are considered to be in remission when they have been diagnosed with major depression, but do not experience episodes.

There is no known single cause of depression; it is a disorder of the brain that results from a combination of genetic and other (environmental) factors acting together.⁴ It is a severely disabling and frequent mood disorder that affects individuals of all ages and has a significant impact on everyday life, and imposes a substantial economic burden on society.

Costs related tomajor depression are substantial and are borne by both the health care sector and other sectors of society (eg, costs related to loss of productivity). The costs also vary between countries, due to differences in health care systems, and between studies, due to differences in methodological approaches. This review aims to provide a comprehensive summary of the literature assessing the cost of major depression. This review will also discuss the key drivers and the main differences in the total costing structure of major depression.

Figure 1. 12-Month prevalence estimates
of mental disorders in Europe.

Epidemiology

A review of epidemiological publications on mental disorders conducted by Wittchen and Jacobi5 showed that one of the three most prevalent diagnoses among subjects between 18 to 65 years of age in Europe was major depression (median 6.9%, 3.1%-10.1%). The disease had the highest prevalence among women aged 35 to 49 years, with a 12-month prevalence of 12.7%. For all European countries plus Iceland, Norway, and Switzerland, the total 12-month prevalence for both sexes was 8.3% (ranging between 7.4% and 9.2%). This estimation implies that there are 18.4 million people suffering from major depression⁵ in Europe every year. Figure 1 gives the 12-month prevalence estimated for all mental disorders.

In the United States (US), the lifetime prevalence estimated by the National Comorbidity Survey-Replication (NCS-R) study for major depression was 16.2%; the 12-month estimate was 6.6%.⁶ The findings of this study indicated that the majority of patients were moderately or severely affected by the disease (38.6% and 38% respectively), while 10.4% experienced mild depression, and 12.9% very severe depression.

The European Study of the Epidemiology of Mental Disorders (ESEMeD), a cross-sectional population-based study which included 21425 noninstitutionalized adults from Belgium, France, Germany, Italy, the Netherlands, and Spain, indicated that the 12-month prevalence of MDEs in the male population was 2.8% compared with 5.3% among women. The lifetime prevalence rates of MDEs were higher for women as well: 17.1% for the female vs 9.4% for the male population.⁷ A significant correlation of major depressive disorder exists with various sociodemographic factors. As suggested by the NCS-R study in the US,⁶ age, marital status, employment, and income of an individual were all correlated with 12-month and lifetime prevalence of major depression.

Unemployment was suggested to have a causal relationship with depression. The ESEMeD study revealed that unemployed subjects were particularly at risk of depression (odds ratio: 2.96) compared with jobholders.⁷

Economic burden

_ Cost-of-illness methodology
A cost-of-illness study estimates the costs related to a specific disease and is not a comparison between treatment strate- gies. In full-scale societal perspective, a cost-of-illness study should include direct costs (medical and nonmedical), informal care (ie, care by relatives), productivity losses due to sick leave (aka indirect costs), and intangible costs.

A cost-of-illness study is most often based on a top-down or a bottom-up approach. The top-down approach starts with the identification of total disease-related costs for a given perspective (eg, health care or societal). These costs are divided by the number of cases for the relevant time period to obtain the cost per incident case. The bottom-up approach starts at the other end with the estimation of the cost per case, which is multiplied by the number of relevant cases. The calculation of costs can either be prevalence-based (costs attributable to all cases in a given period of time) or incidence-based (lifetime costs of new cases which have their onset in a given period).

Bottom-up studies have the advantage of being comprehensive and can provide reliable information on utilization of health care resources and productivity losses; however, they require more time and resources, and often the sample of patients included in the study is not representative of the entire disease population. Top-down studies have the advantage of being less complicated and time consuming to conduct; however, cost estimations derived from these types of studies usually lack important components as not all cost categories (eg, nonmedical costs and productivity costs) are included in the aggregated information for health care expenditure.

_ Costs of major depression
The cost-of-illness studies formajor depression that this review has identified were conducted using different perspectives, study designs, and methodological approaches in different countries. These variations among the studies resulted in differences in the total cost estimates of depression. Below follows a short summary of the most relevant studies. All studies used the bottom-up approach to collect information related to the burden of major depression.

The Longitudinal Investigation of Depression Outcomes (LIDO) study,^8,9 was an international cross-sectional observational study that involved primary care patients with depression from six countries; Israel, Brazil, Australia, Spain, Russia, and the United States. Results confirmed that the economic burden of the disease can vary depending on the severity of major depression.⁸ For Spain (Barcelona), the mean annual health care costs for patients in remission were lower compared with the costs for patients who were partially in remission or those who were experiencing persistent depression or MDE (€ 334 vs € 874 vs €1335, respectively,⁹ original cost estimates were per month in Spanish prices in the year 2000; they were converted to annual cost estimates in euros (2009 prices) assuming equal resource use per month throughout the year).

Figure 2. Working days lost per month due to major depression.

Another finding of the study was the difference in costs across participating countries. In Australia, the mean annual health care cost estimates for all patient subgroups were two times higher than the equivalent estimates for Spain. In the US, annual health care costs were considerably higher compared with estimates for the other countries: € 2259 for patients in remission, € 2678 for those with partial remission, and € 3044 for patients with persistent depression, converted into annual cost estimates in euros (2009 prices).⁹

Differences in health care costs were observed for the indirect costs across disease severities and countries in this study.^8,9 The number of workdays lost per month due to the disease increased when compared with patients in remission, partially in remission, or currently experiencing a depressive episode: 0.3 days during the 1-month period compared with 0.6 days. Estimates also differed across countries: productivity losses of patients with depression across six countries (cities) are presented in Figure 2.

A cross-sectional, prospective study in the US that included patients with major depression from two large Health Maintenance Organizations (HMOs) estimated that total 6-month direct health care costs for patients with major depression were US$ 3113 (2003 prices).¹⁰ Costs attributed to hospitalization and long-term care represented 30% of the total direct costs.

The other 70% of total direct costs was accounted for by outpatient visits, consultations with physicians, emergency department visits, diagnostic tests, pharmacological treatment, and other outpatient costs.

According to a recent observational study in Germany, total annual unadjusted direct costs were € 4821 (2009 prices) for patients being treated for major depression. Inpatient costs (treatment in hospital and rehabilitation centers) accounted for 68% of total direct costs. Total annual indirect costs for the same group of patients were lower than direct costs (€1926, 2009 prices).¹

A study that was conducted for the European Brain Council in 2005¹² combined available published epidemiologic and economic data for European countries plus Iceland, Norway, and Switzerland in order to measure the total cost for different brain disorders. The study showed that the cost of affective disorders (bipolar and unipolar depression) was the highest among the mental disorders, with a total of € 106 billion for all Europe (2004 prices). The population-weighted European annual average cost per case of major depression was estimated at € 3826 (2004 prices), with Germany having the highest cost across all European countries (€ 7102, 2004 prices). For France, the annual average cost per case of depression, which was calculated based on information from the literature, was € 4702 (2004 prices), and for the UK was € 5088 (2004 prices).¹²

A review of the literature including all available economic evidence for major depressive disorder, conducted by Luppa and colleagues,¹³ suggestedthat the average annual direct cost due to major depression ranged between US$ 1000 and US$ 2500 (2003 prices), depending on the country in which this cost was measured. Indirect costs accounted mainly for days lost from work and were shown to be between US$ 2000 and US$ 3700 (2003 prices). Differences in all cost components of the direct health care costs can be observed in Figure 3, including the major cost-of-illness bottomup studies presented in the review of the literature conducted by Luppa et al.¹³ Estimates varied significantly across studies/ countries, mainly due to the differences in the characteristics of the study populations and the methodologies used in the studies to measure costs. The study by Hawthorne and colleagues¹³ measured the highest inpatient costs as a percentage of total direct medical costs when compared with the other studies. Pharmaceutical/treatment costs were shown to take almost 30% of total direct medical costs in the study by Trivedi and colleagues.¹³

In Sweden, a bottom-up cost-of-illness study was conducted by Sobocki and colleagues¹⁴ to determine the magnitude of the impact of treating depression to full remission. They showed that the total annual per-patient cost for patients with major depression in remission was significantly lower compared with patients on a depressive episode; € 8400 vs €13800 (2005 prices). Remitting patients had lower direct health care costs and productivity losses compared with those not in remission. For patients in remission, direct health care costs only made up 36%of total costs. Almost the same percentage was applicable for patients undergoing a depressive episode (34% of total costs).¹⁴ This indicates that the greatest contributor to the burden of disease is productivity losses (indirect costs).

Figure 3. Cost components of total direct health care costs (%).

_ Treatment cost
Patients diagnosed with major depression or experiencing a depressive episode are treated with antidepressants, in some cases combined with psychotherapy. Selective serotonin reuptake inhibitors (SSRIs), such as sertraline, escitalopram, fluoxetine, paroxetine, and citalopram, and serotonin norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, are new-generation antidepressants. They are highly prescribed due to their positive impact on the course of the disease and relatively mild safety profile. Nonresponders to one SSRI may continue treatment with another SSRI, with venlafaxine, or switch to the atypical antidepressant bupropion.^15,16

A review of the literature by Luppa and colleagues,¹³ showed that costs of pharmacological treatment made up 6% to 29% of total direct costs, depending on the methodology and the study population, as well as the year the study was conducted.

In the cost-of-illness study conducted by Sobocki and colleagues,¹⁴ the total 6-month per-patient cost for antidepressants was € 228 (2005 prices), 6% of the total direct health care costs.

An alternative treatment for patients with persistent major depression who do not respond to antidepressant medication, or for severe MDEs, is electroconvulsive therapy (ECT). Pulses of electricity are sent through the brain via two electrodes, usually one on each temple, to induce a seizure while the patient is under a brief period of general anesthesia.¹⁷ The safety of this procedure is controversial since it may cause shortand long-term memory loss, disorientation, headache, and other cognitive disturbances; therefore, it is used mainly for treatment resistant depression.

A Health Technology Assessment (HTA) conducted for the National Institute of Clinical Excellence (NICE) in the UK indicated that the 6-month average cost of treatment with ECT was GBP 1314 (2007 prices).¹⁸

Cognitive Behavioral Therapy (CBT) is another treatment alternative recommended by NICE for managing patients with depression and/or anxiety. It is as effective as pharmacological treatment for treating depression and anxiety, with more lasting effects.¹⁹

Discussion

Major depressive disorder (MDD) is a mental disorder with a high prevalence, particularly among women. It is characterized by periods when the individual has no/mild symptoms (remission), and by periods when patients experience an exacerbation of symptoms (relapse, MDE). Patients may experience a single episode or recurrent ones. Its impact on the individual’s everyday life due to cognitive dysfunction and fatigue is important, resulting in a substantial economic burden imposed on society.

The per capita direct medical cost of major depression (inpatient, outpatient, and pharmaceutical costs), has been shown to be higher compared with anxiety disorders, but lower than psychotic disorders (€ 7688, 2004 prices), or bipolar depression (€ 6081, 2004 prices).¹²

All of the cost-of-illness studies reviewed capture the direct medical costs of depression with varying methodological approaches. Nonmedical costs (eg, community services) were considered in a few studies, but there were even fewer studies that took a full societal perspective including informal care and indirect costs (eg, cost of days lost from work or early retirement due to the disease). Indirect costs account for more than half of the total burden of depression.¹⁴ Thus, any study failing to consider these costs will underestimate the true burden depression imposes on society. Working days lost, informal care, and, for more severe cases of depression, community care, are important drivers of the total burden of depression. Since these costs mainly occur outside the health care system, bottom-up cost-of-illness studies that prospectively or retrospectively collect patient-level data are the best approach to fully capture the total cost related to depression.

The pharmacological treatment cost is also an important component of the total costs and was estimated to account for 6% to 29% of total direct health care costs.¹³ The differences in health care systems and the year the study was conducted can influence this estimation.

There is also an apparent difference in costs due to whether the patient is in remission or in an acute phase of the disease (MDEs). During remission, direct medical and nonmedical costs, as well as productivity losses, were found to be lower (about 25% to 75% lower^9,14) compared with periods in which patients were partially or not in remission (depressive episode).

The costs related to depression also vary between countries, which is not that surprising and can mainly be explained by differences in health care systems and access to care. For example, the total health care costs for patients with an MDE were found to be twice higher in Australia compared with Spain (€ 2004 vs € 1335).⁹

Direct comparison of the findings from the different studies presented in this review is, for the reasons outlined above, not that straightforward. What can be concluded is that depression is a costly disease and that it is the acute phases of the disease that are the main driver of the total burden. Therefore, interventions liable to curb the number of MDEs can lead to a substantial reduction in the economic burden for both the health care system and society as a whole.

Consistent and robust evidence shows that the new-generation antidepressants have superior efficacy to the older ones and that they delay potential depressive relapses. It is therefore important for patients to receive antidepressant treatment at an early stage in order to avoid MDEs and reduce the economic burden of depression. However, it has been shown that only a small fraction of depressive patients receive appropriate treatment, while many receive no treatment at all.²⁰ A study conducted in Germany indicated that 40%of patients meeting Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-IV) diagnostic criteria for MDE were not treated at all or received inappropriate interventions.²⁰ Other treatment alternatives exist for managing the disease: NICE recommends cognitive behavioral therapy (CBT) for the treatment of depression and anxiety as being as efficacious as pharmacological treatments with the advantage of havingmore long-lasting effects. ECT is a procedure that is used mainly on patients with severe and persistent forms of the disease in which pharmacological interventions have failed to manage the symptoms.

Conclusion

Major depressive disorder is one of the most prevalent mental disorders among adults in Europe, with women being more frequently affected compared with men.⁵ Its economic burden is assessed by a number of cost-of-illness studies that show that the time patients with major depressive disorder have to spend off work is the greatest contributor to the burden this disorder imposes on society. Major depressive episodes have a higher economic burden compared with the remission phase of the disorder; therefore pharmacological or other types of interventions that decrease the frequency of depressive episodes have the potential to translate into large cost reductions. _

References
1. Bauer M, Whybrow PC, Angst J, Versiani M, Moller HJ. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1: Acute and continuation treatment of major depressive disorder. World J Biol Psychiatry. 2002;3:5-43.
2. National Institute of Mental Health. A detailed booklet that describes depression symptoms, causes, and treatments, with information on getting help and coping. www.nimh.nih.gov. Accessed on 19 Jan 2011.
3. Spijker J, de GR, Bijl RV, Beekman AT, Ormel J, Nolen WA. Duration of major depressive episodes in the general population: results from The Netherlands Mental Health Survey and Incidence Study (NEMESIS). Br J Psychiatry. 2002; 181:208-213.
4. Tsuang MT, Bar JL, Stone WS, Faraone SV. Gene-environment interactions in mental disorders. World Psychiatry. 2004;3:73-83.
5. Wittchen HU, Jacobi F. Size and burden of mental disorders in Europe—a critical review and appraisal of 27 studies. Eur Neuropsychopharmacol. 2005;15: 357-376.
6. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289:3095-3105.
7. Alonso J, Lepine JP. Overview of key data from the European Study of the Epidemiology of Mental Disorders (ESEMeD). J Clin Psychiatry. 2007;68(suppl 2): 3-9.
8. Herrman H, Patrick DL, Diehr P et al. Longitudinal investigation of depression outcomes in primary care in six countries: the LIDO study. Functional status, health service use and treatment of people with depressive symptoms. Psychol Med. 2002;32:889-902.
9. Simon GE, Chisholm D, Treglia M, Bushnell D. Course of depression, health services costs, and work productivity in an international primary care study. Gen Hosp Psychiatry. 2002;24:328-335.
10. Katon WJ, Lin E, Russo J, Unutzer J. Increased medical costs of a populationbased sample of depressed elderly patients. Arch Gen Psychiatry. 2003;60: 897-903.
11. Hamre HJ, Witt CM, Glockmann A, et al. Health costs in patients treated for depression, in patients with depressive symptoms treated for another chronic disorder, and in non-depressed patients: a two-year prospective cohort study in anthroposophic outpatient settings. Eur J Health Econ. 2010;11:77-94.
12. Andlin-Sobocki P, Jonsson B, Wittchen HU, Olesen J. Cost of disorders of the brain in Europe. Eur J Neurol. 2005;12(suppl 1):1-27.
13. Luppa M, Heinrich S, Angermeyer MC, Konig HH, Riedel-Heller SG. Cost-ofillness studies of depression: a systematic review. J Affect Disord. 2007;98: 29-43.
14. Sobocki P, Ekman M, Agren H, Runeson B, Jonsson B. The mission is remission: health economic consequences of achieving full remission with antidepressant treatment for depression. Int J Clin Pract. 2006;60:791-798.
15. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354:1243-1252.
16. Zisook S, Rush AJ, Haight BR, Clines DC, Rockett CB. Use of bupropion in combination with serotonin reuptake inhibitors. Biol Psychiatry. 2006;59:203- 210.
17. American Psychiatric Association. Practice guideline for the treatment of patients withmajor depressive disorder (revision). Am J Psychiatry. 2000;157:1-45.
18. McLoughlin DM, Mogg A, Eranti S, et al. The clinical effectiveness and cost of repetitive transcranial magnetic stimulation versus electroconvulsive therapy in severe depression: a multicentre pragmatic randomised controlled trial and economic analysis. Health Technol Assess. 2007;11:1-54.
19. Layard R. The case for psychological treatment centres. BMJ. 2006;332:1030- 1032.
20. Wittchen HU, Holsboer F, Jacobi F. Met and unmet needs in the management of depressive disorder in the community and primary care: the size and breadth of the problem. J Clin Psychiatry. 2001;62(suppl 26):23-28.

Keywords: depression; cost; burden; review; antidepressant; treatment

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Luis AGÜERA-ORTIZ, MD
Associated Professor of Psychiatry
Universidad Complutense
Geriatric Psychiatry and Consultation Liaison Unit
Psychiatry Department University Hospital 12 de Octubre
Madrid, SPAIN

Geriatric depression is a cause of concern to psychiatrists for several reasons. Longer life expectancy has increased the potential for late-life depression, be it late-onset or recurrent. The elderly are also prey to frequent physical comorbidity requiring treatment in its own right. Such factors clearly influence the choice of antidepressant.

In conclusion, treatment choice for recurrent depression in the elderly is often limited by comorbidity and comedication precluding the use of an antidepressant that may have been effective at a younger age. Such factors need to be carefully weighed when selecting treatment for a new episode. _

References
1. Guerra Cazorla LM, Sánchez Pastor L, Navío Acosta M, Agüera-Ortiz L. Antidepresivos y deterioro cognitivo en el anciano. Psicogeriatria. 2010;2(3).
2. Menza M, Dobkin RD, Marin H, et al. A controlled trial of antidepressants in patients with Parkinson disease and depression. Neurology. 2009;72:886-892.
3. Agüera L, Failde I, Cervilla JA, Diaz-Fernandez P, Mico JA. Medically unexplained pain complaints are associated with underlying unrecognized mood disorders in primary care. BMC Fam Pract. 2010;11:17.
4. Montejo AL, Prieto N, Terleira A, et al. Better sexual acceptability of agomelatine (25 and 50 mg) compared with paroxetine (20 mg) in healthy male volunteers. An 8-week, placebo-controlled study using the PRSEXDQ-SALSEX scale. J Psychopharmacol. 2010;24:111-120.
5. Kasper S, Hajak G, Wulff K, et al. Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder: a randomized, double-blind comparison with sertraline. J Clin Psychiatry. 2010;71:109-120.

Eric CONSTANT, MD, PhD
Professor of Psychiatry
Université Catholique de Louvain
and Cliniques Universitaires Saint-Luc
Service de Psychiatrie Adulte
Avenue Hippocrate 10
1200 Brussels, BELGIUM

An important factor governing the choice of antidepressant is “past response to a given antidepressant.”¹ At first glance one would assume that, if a patient had achieved complete remission from a first depressive episode with a given antidepressant, it makes sense to use the same antidepressant for a new depressive episode. However, there can be several reasons for not doing so.

A third reason for using a different antidepressant may be that response to the previous antidepressant was only partial. If achieving and sustaining symptomatic remission is an essential first step toward functional recovery, naturalistic treatment studies show that up to two thirds of patients fail to achieve complete remission with the first antidepressant.⁶ In such cases, some clinicians employ a number of strategies to optimize treatment: increasing the dosage of antidepressant, switching to another antidepressant, adding a second nonantidepressant agent to augment the effect of the antidepressant, or adding a second antidepressant, typically from another class. But too many patients are allowed to remain in partial remission on their original antidepressant. In this case, it makes sense to change the antidepressant in a recurrence, given that the effect of the original antidepressant was only partial. A drug from a different class may be chosen or another drug from the same class: either choice is legitimate.² There is no unequivocal evidence to show the superiority of switching to a different class. _

References
1. Lam RW, Kennedy SH, Grigoriadis S, et al. Canadian network for mood and anxiety treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. III. Pharmacotherapy. J Affect Disord. 2009;117:S26-S43.
2. Ruhé HG, Huyser J, Swinkels JA, Schene AH. Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review. J Clin Psychiatry. 2006;67:1836-1855.
3. Anderson IM. Meta-analytical studies on new antidepressants. Br Med Bull. 2001;57:161-178.
4. Brambilla P, Cipriani A, Hotopf M, Barbui C. Side-effect profile of fluoxetine in comparison with other SSRIs, tricyclics and newer antidepressants: a metaanalysis of clinical trial data. Pharmacopsychiatry. 2005;38:69-77.
5. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373:746-758.
6. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28-40.

Massimo DI GIANNANTONIO, MD
Chair of Psychiatry
Department of Neuroscience and
Imaging, Università “G. d’Annunzio”
66100 Chieti, ITALY

In psychiatric clinical practice, the choice of suitable antidepressant medication for the treatment of recurrent depressive episodes is an important and controversial topic. Recurrence is generally defined as the appearance of a new depressive episode after at least 6 symptom-free months (remission). However, the clinical definition of remission differs somewhat from that used in therapeutic trials, in which treatment response is usually defined as a decrease in Hamilton or Montgomery-Åsberg Depression Rating Scale scores of at least 50% from baseline. The proportion of trial patients who, displaying significant residual symptomatology after treatment, are considered responders, but not remitters, can be as high as 30%. Incomplete remission of depressive symptoms is associated with increased risk of recurrence and relapse.

In short, before deciding whether or not to introduce an alternative drug belonging to the same or to a different class, recurrence requires a careful disease history and a thorough assessment of the patient’s medical and psychiatric state. The patient should be restarted on the same drug only if there are no relevant changes in these parameters and if previous medication had led to complete remission. _

References
1. Fava M, Schmidt ME, Zhang S, Gonzales J, Raute NJ, Judge R. Treatment approaches to major depressive disorder relapse. Part 2: reinitiation of antidepressant treatment. Psychother Psychosom. 2002;71:195-199.
2. Fava M, Detke MJ, Balestrieri M, Wang F, Raskin J, Perahia D. Management of depression relapse: re-initiation of duloxetine treatment or dose increase. J Psychiatric Res. 2006;40:328-336.
3. Friedman RA, Mitchell J, Kocsis JH. Retreatment for relapse following desipramine discontinuation in dysthymia. Am J Psychiatry. 1995;152:926-928.
4. Bauer M, Bschor T, Pfennig A, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders in primary care. World J Biol Psychiatry. 2007;8:67-104.
5. Judd LL, Akiskal HS, Paulus MP. The role and clinical significance of subsyndromal depressive symptoms (SSD) in unipolar major depressive disorder. J Affect Disord. 1997;45:5-17.
6. Bauer M, Whybrow PC, Angst J, Versiani M, Moller HJ. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for biological treatment of unipolar depressive disorders, part 1: acute and continuation treatment of major depressive disorder. World J Biol Psychiatry. 20023;3:5-43.

Stanislav IVANOV, PhD
Head of the Department of
Somatogenic Psychiatric Disorders
National Mental Health Research Center
Kachirskoe shosse 34
Moscow, RUSSIA

Choosing drug treatment for amajor depressive episode remains a serious problem in modern psychiatry because no single antidepressant currently available ensures successful treatment in 100% of cases. The problem is at its most difficult when dealing with a first depressive episode. It is comparatively easier to choose the most appropriate antidepressant for a recurrent episode because of the guidance afforded by the response to previous therapy.

Thus, in most cases of recurrent depressive disorder, especially those that are clinically indistinguishable from their predecessor, the most reasonable and useful approach is to choose the previously effective antidepressant. However, in terms of clinical practice it would be interesting and valuable to undertake specific studies designed to test this empirical approach to the treatment of patients with recurrent episodes of depression. _

Selcuk KIRLI, MD
Professor, Uludag University
Medical School
President of Psychiatry Department
Bursa, TURKEY

Despite the satisfactory results of drug treatment for major depressive episode, themost appropriate strategy for preventing and treating recurrence remains an important and unresolved clinical issue.

In conclusion, drugs that have proved safe and effective in previous episodes have long been advocated as the treatment of choice for recurrent depressive episode. But other dimensions should be taken into account for preventing relapse and improving posttreatment quality of life. The very fact that a drug failed to prevent recurrence despite its apparent success in treating the original episode suggests that a different drug may prove a more appropriate option in the longer run. _

References
1. Kennedy S, McIntyre R, Fallu A, Lam R. Pharmacotherapy to sustain the fully remitted state. J Psychiatry Neurosci. 2002;27:269-280.
2. Rush AJ, Thase ME. Psychotherapies for depressive disorders: a review. In: Sartorius N, ed. WPA Series, Evidence and Experience in Psychiatry. Vol 1: Depressive Disorders. Chichester, UK: John Wiley & Sons, Ltd; 1999:161-206.
3. Fava M, Thase ME, DeBattista C. A multicenter, placebo controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry. 2005;66:85-93.
4. Olié PJ, Kasper S. Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5HT2C antagonistic properties, in major depressive disorder. Int J Neuropsychopharmacol. 2007;10:661-673.
5. Eser D, Baghai TC, Möller HJ. Agomelatine: the evidence for its place in the treatment of depression. Core Evidence. 2008;3:109-116.
6. Dubovsky SL, Warren C. Agomelatine, a melatonin agonist with antidepressant properties. Expert Opin Investig Drugs. 2009;18:1533-1540.

Dusica LECIC-TOSEVSKI, MD, PhD
Professor of Psychiatry, Belgrade University
School of Medicine, Corresponding member,
Serbian Academy of Sciences and Arts
Director, Institute of Mental Health

Cedo D. MILJEVIC, MD, PhD
Head, Department for Clinical Trials
Institute of Mental Health
Palmoticeva 37, 11000 Belgrade
SERBIA


To change or not to change medication is a frequent question in clinical practice. Here we shall discuss two sides of this challenging dilemma. At first glance there is no logical reason not to prescribe the same antidepressant when a new depressive episode occurs in a patient who was a good responder the first time. There are two major reasons in favor of such an attitude. The first is proof of efficacy: the antidepressant that achieved remission the first time has an advantage over any other antidepressant that needs to prove its efficacy. The second is a proof of tolerability: in order to achieve remission the patient needs to take medication for some time, which indirectly points toward absence of significant side effects of the drug. Moreover, clinicians should be aware of patients’ psychological expectations. Patients expect the same drug to work well again and do not understand why they would need a different drug.

In conclusion, optimized management of depression should be individualized and patient-centered. All relapse risk factors— such as personality vulnerability, type of remission (full, partial), residual symptoms, and psychosocial stressors— should be assessed before deciding to administer a new and different drug or sometimes a combination of drugs. The combination of medication with psychotherapy is a sine qua non as is also the building of a treatment alliance. _

References
1. Parker G, Roy K, Mitchell P, Wilhelm K, Malhi G, Hadzi-Pavlovic D. Atypical depression: a reappraisal. Am J Psychiatry. 2002;159:1470-1479.
2. Fava M, Rush JA, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008;165:342-351.
3. Rush JA, Wisniewski SR, Warden D, et al. Selecting among second-step antidepressant medication monotherapies. Arch Gen Psychiatry. 2008;65:870-881.
4. Lam RW, Kennedy SH, Grigoriadis S, et al. Canadian network for mood and anxiety treatments (CANMAT)—Clinical guidelines for the management of major depressive disorder in adults. III. Pharmacotherapy. J Affect Disord. 2009;117: S26-S43.
5. Stahl SM, Nierenberg AA, Gorman JM. Evidence of early onset of antidepressant effect in randomized controlled trials. J Clin Psychiatry. 2001;62 (suppl l 4): 17-23.
6. Rogers MA, Kasai K, Koji M, et al. Executive and prefrontal dysfunction in unipolar depression: a review of neuropsychological and imaging evidence. Neurosci Res. 2004;50:1-11.

Kyung Jun MIN, PhD, MD
Chung-Ang University Medical Center
Yongsan Hospital
65-207 Hangangro 3 Ga, Yongsan-gu
Seoul, 140-757, KOREA

Over half of patients experiencing an initial episode of major depression will eventually suffer a second. About 75% of those who have had two depressive episodes will have a third. In addition, the more the episodes increase, the shorter the symptom-free interval becomes. Maintenance treatment to prevent further relapse or recurrence is therefore crucial in the management of major depressive disorder. Various treatment guidelines or algorithms recommend maintenance treatment for one or more years to recover full function. Longer-term or even indefinite lifelong prevention may be required.

However, some strategies may be more effective than others in individual patients. Clinicians therefore need to approach the problem on a patient-by-patient basis, considering individual factors, such as depression subtype, past and present episode severity, previous response to an antidepressant, number of episodes, family history, psychosocial stressors, comorbidities, bipolarities, treatment adherence, and other recurrence risk factors. _

Further reading
– Bschor T, Baethge C. No evidence for switching the antidepressant: systematic review and meta-analysis of RCTs of a common therapeutic strategy. Acta Psychiatr Scand. 2010;121:174-179.
– Franchini L, Rossini D, Bongiorno F, Spagnolo C, Smeraldi E, Zanardi R. Will a second prophylactic treatment with a higher dosage of the same antidepressant either prevent or delay new depressive episodes? Psychiatry Res. 2000;96:81-85.

Zoltán RIHMER, MD, PhD, DSc
Semmelweis University
Faculty of Medicine
1125 Budapest, Kútvölgyi út 4
HUNGARY

Owing to the biochemical heterogeneity of depressive disorders, groups of depressed patients respond differently to the various antidepressants available. Only about 50% to 60% respond to their first-line antidepressant. However, the differing response patterns to the various drugs are not an exclusive phenomenon since most selective serotonin reuptake inhibitor (SSRI) responders also respond to dual-action (serotonergic and noradrenergic) antidepressants while many depressed patients who fail to respond to their first SSRI respond well to their second.

On this basis, all major depressives, particularly those experiencing their third ormore depressive episode, should be carefully screened for bipolarity. If present, it should be managed with a mood stabilizer or mood stabilizer-antidepressant combination. As for antidepressants, the recommended agent is one such as agomelatine or escitalopram associated with more rapid onset of action, a higher response/remission rate, and fewer hypomanic/manic mood switches. _

References
1. Goodwin FK, Jamison KR. Manic-Depressive Illness. Bipolar Disorders and Recurrent Depression. New York, NY: Oxford University Press; 2007.
2. O’Donovan C, Garnham JC, Hajek T, Alda M. Antidepressant monotherapy in pre-bipolar depression: Predictive value and inherent risk. J Affect Disord. 2008; 107:2993-298.
3. Woo YS, Chae JH, Jun TY, Kim KS, Bahk WM. The bipolar diathesis of treatment- resistant major depressive disorder. Int J Psychiat Clin Pract. 2008;12: 142-146.
4. Amsterdam JD, Shults J. Does tachyphylaxis occur after repeated antidepressant exposure in patients with bipolar depressive episode? J Affect Disord. 2009; 115:234-240.
5. Rihmer Z, Akiskal HS. Do antidepressants t(h)reat(en) depressives? Toward a clinically judicious formulation of the antidepressant-suicidality FDA advisory in light of declining national suicide statistics from many countries. J Affect Disord. 2006;94:3-13.
6. El-Mallakh RS, Ghaemi NS, Sagduyu K, et al; STEP-BD Investigators. Antidepressant- associated irritable dysphoria (ACID) in STEP-BD patients. J Affect Disord. 2008;111:372-377.

Manit SRISURAPANONT, MD
Professor of Psychiatry
Department of Psychiatry
Faculty of Medicine
Chiang Mai University
Muang, Chiang Mai
50200 THAILAND

Depression is a clinical syndrome consisting of a lowering of mood tone, loss of interest or pleasure, neurovegetative symptoms, feelings of worthlessness or guilt, and recurrent thoughts of death. This syndrome can be a part of many psychiatric disorders.

In conclusion, the continuity of depression may be viewed in terms of two concepts. From the depressive symptom perspective, clinical depression is a disease with isolated episodes. However, from the standpoint of neurobiological abnormality, major depression, especially the chronic and recurrent form, should be considered as a lifelong disorder. Growing evidence tends to support the latter concept and is leading to wide acceptance of long-term prophylaxis of major depression. _

References
1. Kraepelin E. Manic-Depressive Insanity and Paranoia. Edinburgh, UK: Livingstone; 1921.
2. Solomon DA, Keller MB, Leon AC, et al. Recovery from major depression: a 10-year prospective follow-up across multiple episodes. Arch Gen Psychiatry. 1997;54:1001-1006.
3. Kupfer DJ, Frank E, Peral JM, et al. Five-year outcome for maintenance therapies in recurrent depression. Arch Gen Psychiatry. 1992;49:769-773.
4. aan het Rot M, Mathew SJ, Charney DS. Neurobiological mechanisms in major depressive disorder. CMAJ. 2009;180:305-313.
5. Kim JM, Stewart R, Kim SW, et al. Interactions between life stressors and susceptibility genes (5-HTTLPR and BDNF) on depression in Korean elders. Biol Psychiatry. 2007;62:423-428.
6. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008; 455:894-902.

Jogin THAKORE, PhD, MRCPI, MRCPsych
Clinical Director (Adult Psychiatry)
Dublin North Central
Senior Lecturer in Psychiatry,
St Vincent’s Hospital Fairview
Richmond Rd
Dublin 3, IRELAND.

The average patient with depression can expect to experience at least four separate episodes each lasting approximately 20 weeks during their lifetime.¹ Or, according to another statistic, 85% of all patients with depression will have a further episode of depression.² Recurrence is therefore the norm.

What therefore should we do? We only have clinical practice to guide us and this suggests that provided the subtype of depression is the same as before (eg, unipolar vs bipolar, melancholic vs atypical) and there are no comorbid physical conditions to contend with (eg, cardiovascular disease), then it is best to use the antidepressant the patient responded to in the past. _

References
^1. Judd LL. The clinical course of unipolar major depressive disorders. Arch Gen Psychiatry. 1997;54:989-991.
^2. Mueller TI, Leon AC, Keller MB, et al. Recurrence after recovery from major depressive disorder during 15 years of observational follow-up. Am J Psychiatry. 1999;156:1000-1006.
^3. Bertschy G. Severe depression: recurrence and chronicity. Encephale. 2009; 35(suppl 7):S257-S260.
4. Penninx BW, Beekman AT, Honig A, et al. Depression and cardiac mortality: results from a community-based longitudinal study. Arch Gen Psychiatry. 2001; 58:221-227.
5. Oquendo MA, Barrera A, Ellis SP, et al. Instability of symptoms in recurrent major depression: a prospective study. Am J Psychiatry. 2004;161:255-261.
6. Nivoli AM, Colom F, Murru A, et al. New treatment guidelines for acute bipolar depression: a systematic review. J Affect Disord. 2011;129:14-26.