Is the patient really the same after a major depressive episode?

1◆ M. Jarema, Poland

Professor and Chairman
3rd Department of Psychiatry
Institute of Psychiatry
and Neurology
Ul. Sobieskiego 9, 02-957
Warsaw, POLAND

Depression is a devastating disease for both the individual and his/her environment. The simple fact that someone suffers from depression constitutes a certain danger to the person in itself. The individual will experience bothersome symptoms such as lowered mood, loss of drive, anhedonia, pessimistic thoughts, overwhelming sadness, lack of perspective, low selfesteem, and many other symptoms, causing the patient’s life to become unbearable and useless. Clearly, there is an impact on the patient’s life and his/her family life. Therefore, depression is often considered as a disorder that affects the whole family. The most striking example may be the impact of a suicide attempt on family life. Thus, after a depressive episode, the patient themself, as well as the family, have experienced a very unpleasant mental condition that causes them to fear the next depressive episode. It is clear that everybody struggles to avoid the next episode or even the next hospitalization.1 The experience of a depressive episode seems also not to be neutral with regard to the patient’s environment. Those who have survived depression may recognize a change in the attitudes of other people toward them; depressive patients may be considered by others as strange, different, unpredictable, or individuals of a lower vital potential. Studies have revealed that patients with depression experience stigmatization like that of patients with schizophrenia.2 Another problematic consequence of a depressive episode is of a purely biological nature. Several neurobiological mechanisms underlay the pathology of depressive symptoms (eg, neuroanatomical and neuroendocrine alterations, changes in neurotransmitter systems, etc).3 One can presume that sequential depressive episodes may cause the hypothetical biological background of depression to become even more severe, and each depressive episode may have a certain consequence for the brain as far as biological damage may be concerned. The nature of such consequences may include not only the real “toxic” influence of the biological factors that presumably constitute the basis of depression, but also the impact of the biological treatment. Biological therapy is a first-choice treatment for depression, but one needs to realize that such a treatment is under no condition free of any unfavorable impact on the functioning of the brain. The question indeed may be raised as to why we insist on treating depressive patients with predominantly biological methods, if the expected remission rates after pharmacological interventions in depression are only about 50% to 55%?4 The issue of a negative impact of treatment methods on the patient’s brain should be given even more attention when dealing with patients who do not respond adequately to the treatment; the prevalence of “treatment- resistant” depression may constitute 50% of real-world patients.5 So-called “treatment-resistant patients” are usually subjected to numerous therapeutic attempts, and many such attempts are simply ineffective, necessitating introduction of the next treatment. Clinical experience tells us that such treatment-resistant patients are difficult to manage when the next depressive episode appears, because the previous treatment history causes both the patient and the clinician to develop treatment strategies that include more intensive methods of treatment (ie, higher doses, drug combinations, augmentation strategies, etc). Thus, in addition to biological treatment, psychosocial interventions (cognitive behavioral therapy, emotion-focused therapy, self esteem therapy)6 should be recommended. _

1. Harvey PD. Outcomes to monitor when treating bipolar disorder or schizophrenia.<.em> J Clin Psychiatry. 2006;67:e06.
2. Angermeyer MC, Beck M, Dietrich S, Holzinger A. The stigma of mental illness: patients’ anticipations and experiences. Int J Soc Psychiatry. 2004;50:153-162.
3. Foster JA, MacQueen G. Neurobiological factors linking personality traits and major depression. Can J Psychiatry. 2008; 53:6-11.
4. Huynh NN, McIntyre RS. What are the implications of the STAR*D trial for primary care? A review and synthesis. Prim Care Companion J Clin Psychiatry. 2008;10:91-96.
5. Kennedy SH, Giacobbe P. Treatment resistant depression— advances in somatic therapies. Ann Clin Psychiatry. 2007;19: 279-287.
6. Lau MA. New developments in psychosocial interventions for adults with unipolar depression. Curr Opin Psychiatry. 2008;21:30-36.

2◆ M. Bauer, Germany

Michael BAUER, MD, PhD
Professor of Psychiatry
Director, Department of Psychiatry and Psychotherapy
University Hospital
Carl Gustav Carus
Technische Universität
Dresden Fetscherstrasse 74
D-01307 Dresden

Major depressive disorder (MDD) is a severe mood disorder characterized by single or recurrent major depressive episodes. A total of 50% to 85% of patients who have a depressive episode will eventually go on to have at least one other episode. Between 9% and 24% of patients with the initial diagnosis of a major depressive episode will undergo a change in diagnosis over time, mostly to bipolar disorder.1 Several risk factors have been identified for depressive relapse. The more episodes that an individual has, the more likely it is that another will occur. Other important risk factors include preexisting dysthymia, a family history of mood disorders, concurrent anxiety or substance abuse, and long duration of severe index episode. In recent years it has become apparent that the longterm course of unipolar MDD is not only characterized by high rates of recurrence, but also dominated by prolonged symptomatic chronicity.2 Many patients with MDD return to their premorbid level of functioning between episodes of major depression. However, in approximately 30% of severe or hospitalized depressed patients, residual symptoms and social or occupational impairment persists. Having residual symptoms or subsyndromal depression after acute treatment is also an important risk factor for relapse and recurrence. About one third of patients suffering from severe major depression with residual symptoms will have a chronic course marked by at least 2 years of illness. Epidemiologic and prospective clinical follow-up studies have also documented that the typical course of unipolar MDD involves fluctuating symptoms, whereby depressive subtypes included in official diagnostic systems do not represent discrete disorders, but are stages along a dimensional continuum (spectrum) of symptomatic severity.3 The group of chronic depressive disorders encompasses four subtypes of depressive illness: (i) MDD, recurrent, without full inter-episodic recovery (incomplete remission); (ii) MDD, currently in a chronic (duration of _2 years) episode (chronic MDD); (iii) dysthymic disorder; and (iv) “double depression” (concurrent dysthymic disorder and major depression). The group of “subthreshold depressions” (depressive disorders not otherwise specified) includes depressive conditions in which the number, duration, or quality of symptoms is insufficient to meet the Diagnostic and Statistical Manual of Mental Disorders criteria for a diagnosis of major depression. Patients with an early onset and older adults suffering an initial depressive episode after the age of 60 years appear to be at greater risk for the development of chronicity. Individuals suffering from either dysthymia alone or “double depression” have significantly greater impairment in functioning than those who present with major depression alone, depressive symptoms, or past episodes of major depression. Residual (subthreshold) symptoms in the course of MDD are associated with high risk of an early episode relapse and a significantly more chronic future course of illness. Recovery from MDD with full resolution of symptoms is associated with significant delays in episode relapse and recurrence, and a more benign course of illness.4 MDD is also associated with considerable morbidity and mortality, and for many, an initial episode of depression evolves into a debilitating chronic illness with significant and pervasive impairments in psychosocial functioning.5 Chronic depression is characterized by the increased utilization of health care services, reduced employment, and greater economic costs associated with affected individuals. Studies investigating the effects of depression on health-related quality of life demonstrate decrements that equal or exceed those of patients with chronic medical illnesses such as ischemic heart disease or diabetes mellitus.6 Patients who have experienced major depressive episodes are less likely to sustain a demanding job or career or to achieve full intellectual potential. If the first depressive episodes arise during adolescence or early adulthood, diminished performance at school or during vocational training or university is a frequent negative outcome with lifelong consequences. With the information given here, it becomes clear that the patient is not the same after he or she has suffered a major depressive episode, because of the persistent (high) risk of relapse and recurrence and development of a chronic course of subthreshold depression. Therefore it is important to note that one of the most important goals in clinical practice is to start with effective treatment early on, to achieve remission in the acute phase of treatment, and to attempt as much as possible to remove all residual depressive symptoms.7 _

1. Angst J, Preisig M. Course of a clinical cohort of unipolar, bipolar and schizoaffective patients. Results of a prospective study from 1959 to 1985. Schweiz Arch Neurol Psychiatr. 1995; 146:5-16.
2. Judd LL, Akiskal HS, Maser JD, et al. A prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders. Arch Gen Psychiatry. 1998;55:694-700.
3. Angst J, Sellaro R, Merikangas KR. Depressive spectrum diagnoses. Compr Psychiatry. 2000;41(suppl 1):39-47.
4. Judd LL, Paulus MJ, Schettler PJ, et al. Does incomplete recovery from first lifetime major depressive episode herald a chronic course of illness? Am J Psychiatry. 2000;157:1501-1504.
5. Klerman GL, Weissman MM. The course, morbidity, and costs of depression. Arch Gen Psychiatry. 1992;49:831-834.
6. Wells KB, Stewart A, Hays RD, et al. The functioning and well-being of depressed patients. Results from the Medical Outcomes Study. JAMA. 1989;262:914-919.
7. 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.

3◆ E. Sacchetti, Italy

Professor of Psychiatry
Brescia University
School of Medicine
University Psychiatric Unit
Brescia Spedali Civili,
Piazza Spedali Civili 1
25123 Brescia, ITALY

The wide number of antidepressant drugs currently available to clinicians constitutes a valuable opportunity for an improved management of patients with depression. Nevertheless, the short-term and long-term prognosis for the disorder remains persistently far from good in a relevant proportion of patients. Indeed, among depressed patients, at least one third inadequately responds to the first antidepressant, and approximately 1 out of 10 remains depressed even after multiple interventions.1 Furthermore, residual depressive symptoms are common in patients who respond to antidepressants.2 Finally, syndromal and subsyndromal continued depression cause persistent disability and impose a substantial socioeconomic burden.3,4 Since the possibility of a true restitutio ad integrum after depression is nowadays precluded in many patients, the acquisition of new antidepressants with improved efficacy-safety profiles and mechanisms of action that are able to work in otherwise refractory patients is certainly welcome. Treatment response represents indeed the final phenotypic result of pharmacokinetic and pharmacodynamic interactions that are both drug- and patient-specific, and are moderated by several other superimposed modifiable and unmodifiable characteristics of the patient, the health care system, wider society, and/or the environment in general. Two examples may suffice to support this paradigm: the first example pertains to poor treatment adherence, a well-known, widespread phenomenon5 that plays a key influential role in the outcome of depression, because it exposes the individuals to “false” poor responses, relapses, recurrences, and, with between-drug differences, withdrawal symptoms. The individual’s propensity to adhere to therapies for depression is defined by, along with other variables, cultural and attitudinal factors in general, social stigma about depression and its treatment, frequent facilitation by the media of false conclusions about the utility of conventional antidepressants coupled with overemphasis on alternative remedies devoid of efficacy, patient health beliefs, mechanisms of illness denial, awareness of the need for treatment, decisions influenced by symptoms, knowledge about antidepressants, previous and current experience with antidepressants, concerns and aversion for adverse events, ease and convenience of drug regimens, cost of medications, and competence of the treating physician. The second example refers to the association of residual symptoms with a longer duration of depressive episode and increased risk of affective relapse and recurrence.6-10 The persistence of residual symptoms results not only from the inability of the available therapies to systematically promote a full recovery, but also on the inappropriate use of antidepressants and inherent limits in the current definitions of treatment success. Both these factors indeed promote a partial treatment response, even when the prescribed treatment has the potential for promoting complete symptom suppression with a return to normal functioning. Unfortunately, in clinical routine, it is common to face general practitioners and psychiatrists who prescribe antidepressants at lower doses and for shorter periods than are generally recommended by controlled clinical trials, panels of experts, and international guidelines. In turn, the conventional guidepost of treatment efficacy utilized in daily practice is grounded in the reduction of symptom severity at the expense of a full and sustained remission. Treatment adherence, appropriate prescription of antidepressants, and use of improved indicators of treatment success may be facilitated by dedicated informative campaigns, psychoeducational interventions, and continuous medical education: it seems therefore highly recommendable to spend more time and resources in these areas of intervention in order to promote a widespread dissemination of these proactive strategies that are able to moderate modifiable modulators of treatment response. _

1. Thase ME, Corya SA, Osuntokun O, et al. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder. J Clin Psychiatry. 2007;68:224-236.
2. Cuffel BJ, Azocar F, Tomlin M, Greenfield SF, Busch AB, Croghan TW. Remission, residual symptoms, and nonresponse in the usual treatment of major depression in managed clinical practice. J Clin Psychiatry. 2003;64:397-402.
3. Greden JF. The burden of disease for treatment-resistant depression. J Clin Psychiatry. 2001;62(suppl 16):26-31.
4. Pincus HA, Pettit AR. The societal costs of chronic major depression. J Clin Psychiatry. 2001;62(suppl 6):5-9.
5. Katon W, Robinson P, Von Korff M, et al. A multifaceted intervention to improve treatment of depression in primary care. Arch Gen Psychiatry. 1996,53:924-932.
6. Montgomery SA, Doogan DP, Burnside R. The influence of different relapse criteria on the assessment of long-term effi cacy of sertraline. Int Clin Psychopharmacol. 1991;6(suppl 2): 37-46.
7. Thase ME, Simons AD, McGeary J, et al. Relapse after cognitive behavior therapy of depression: potential implications for longer courses of treatment. Am J Psychiatry. 1992;149: 1046-1052.
8. Judd LL, Akiskal HS, Maser JD, et al. Major depressive disorder: a prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse. J Affect Disord. 1998; 50:97-108.
9. Pintor L, Gastó C, Navarro V, Torres X, Fañanas L. Relapse of major depression after complete and partial remission during a 2-year follow-up. J Affect Disord. 2003;73:237-244.
10. Kennedy N, Paykel ES. Residual symptoms at remission from depression: impact on long-term outcome. J Affect Disord. 2004;80:135-144.

4◆P. A. Schmidt do Prado-Lima, Brazil

Pedro Antonio SCHMIDT
Instituto de Pesquisas
Biomédicas Pontifícia
Universidade Católica do
Rio Grande do Sul (PUCRS)
Rua Alvares Machado, 33-305
Porto Alegre 90 630-010,

This is a very good question, with a very complex answer. From any angle that we examine this matter, it seems that the depressive experience changes the patient. The amount of information currently available on the neurobiological toxicity of depression is impressive. A simple search in PubMed using the key words “depression” and “brain derived neurotrophic factor (BDNF)” produces 517 articles, 89 of them published in the last 8 months, an example of the great interest that this topic arouses. The neurobiological approach, which is based mainly on the observation that patients undergo a decrease in BDNF and consequently neuronal atrophy and apoptosis—mostly of CA3 pyramidal hippocampus neurons1—establishes the concept of depression- induced brain damage. This brain damage leads to functional consequences that, for example, predispose the individual to other depressive reactions when he is facing an adverse environment.1 Depression is also associated with increased activity of the hippocampus-hypothalamus-pituitary- adrenal (HHPA) axis, due essentially to a diminished amount and/or sensitivity of glucocorticoid receptors in the hippocampus.2,3 This adjustment of the axis can persist after a single depressive episode and can also predispose the individual to other depressive reactions when he is confronted by a stressful situation. To illustrate how a hyperfunctioning HHPA axis can prompt depressive episodes, we should remember that very early diminishment of maternal care can lead to promoter-region methylation of the glucocorticoid receptor gene in the hippocampus, leading to a reduction in the expression of this gene and hyperfunctioning of the HHPA axis, which is associated with post-stress depressive reactions.4 Furthermore, epigenetic modulation through methylation in the hippocampus is associated with suicide.5 In an alternative view, using epidemiological data, we can observe that the occurrence of one depressive episode predisposes the individual to anoth- er.6 Although this could be due to a genetic predisposition, it is conceivable that the experience of depression could increase the risk of another episode.7 I would also like to argue in another way. Depression is a very intense experience. As an emotionally charged experience, it deeply influences memory acquisition.8 In other words, the depressive experience changes the meaning of many other experiences, since it will be strongly imprinted. Memory is a form of prolonging the past; in this way, the consequences of depression can persist for much longer than the depressive episode itself. Another memory mechanism can be influenced by depression. Traditionally, depression has been thought to reduce memory evocation. But is this true? Depressive people remember negative experiences very well, frequently better than nondepressive people. This may be explained by the state-dependent learning concept, proposed more than 20 years ago.9 To summarize this concept, the reproduction of the neurochemical scenario that occurred when the memory was consolidated facilitates its recall. Of course, during depression, the negative experiences are what will be remembered and used in the interpretation of facts. These negative memories color the daily events like a negative kaleidoscope. As almost every new experience is linked to a negative memory, there is a great possibility that they will be interpreted and stored as being aversive. So, depression leads to the consolidation of strong and abundant complexes of negative memories about the self and the environment, which will persist beyond the depressive episode itself. Interestingly, not every person uses this information in a negative way. Somehow, some people take advantage of this very aversive experience, using this negative information in a very positive way. I think this is the case with some writers and artists, who transform this overwhelming experience into a productive force.10 But in this case, depression also changes the person. _

1. Duman RS. The neurochemistry of depressive disorders: preclinical studies. In: Charney DS, Nestler EJ, eds. Neurobiology of Mental Illness. 2nd ed. Oxford, UK: Oxford University Press; 2004:421-439.
2. Juruena MF, Cleare AJ, Pariante CM. The hypothalamic pituitary adrenal axis, glucocorticoid receptor function and relevance to depression. Rev Bras Psiquiatr. 2004:26:189-201.
3. Shelton RC. The molecular neurobiology of depression. Psychiatr Clin North Am. 2007;30:1-11.
4. Fish EH, Shahrokh D, Bagot R, et al. Epigenetic programming of stress responses through variation in maternal care. Ann N Y Acad Sci. 2004;1036:167-180.
5. McGowan PO, Sasaki A, Huang TC, et al. Promoter-wide hypermethylation of the ribosomal RNA gene promoter in the suicide brain. PLoS ONE. 2008;3:e2085.
6. 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;56:1000-1006.
7. Beck AT. The evolution of the cognitive model of depression and its neurobiological correlates. Am J Psychiatry. 2008;165: 969-977.
8. Izquierdo I, Bevilaqua LRM, Rossato JI, Bonini JS, Medina JH, Cammarota M. Different molecular cascades in different sites of the brain control memory consolidation. Trends Neurosci. 2006;29:496-505.
9. Izquierdo I, Netto CA. Role of beta-endorphin in behavioral regulation. Ann N Y Acad Sci. 1985;444:162-177.
10. Schildkraut JJ, Otero A. Depression and The Spiritual in Modern Art: Homage to Miró. Chichester, UK: John Wiley & Sons; 1996.

5◆ H. Ågren, Sweden

Professor of Psychiatry
Sahlgrenska Academy,
University of Gothenburg
Institute for Neuroscience and Physiology
Department of Psychiatry and Neurochemistry
Sahlgrenska University
SE-416 85 Gothenburg

More than a century ago, Emil Kraepelin divided the major psychoses into dementia praecox (schizophrenia) and manicdepressive illness, using longitudinal progression and prognosis as major, but not exclusive, dichotomizing concepts. Nevertheless, both Kraepelin and we know that some schizophrenics get well, and some manic depressives never will. The concept that depression and mania “always” in time will heal, has, however, become rooted in clinical practice. Modern research has nevertheless concluded that if chronicity is defined as never getting out of an episode, then perhaps 1 out of 10 afflicted patients will remain ill for more than 2 years. If chronicity is defined as ever recurring episodes, then half of patients with an episode of unipolar depression will experience another episode, and almost all bipolar patients will continue shifting between mood states if left untreated. So, affective patients get better, but have a propensity to remain to some extent symptomatic and to suffer recurring episodes. Is major depression, once it has had its debut, a state or a trait? There is certainly evidence for increasingly severe episodes: Robert Post developed the kindling or sensitization hypothesis of mood disorders in the 1980s, stating that episodes tended to accelerate over time and be increasingly independent of a triggering event,1 and the validity of this concept has been replicated.2 The heavy toll on personal suffering and society has been investigated.3 There is also evidence for neurobiological consequences of mood swings: mood disorders have been associated with neurodegenerative changes within the central nervous system—the best researched area being enlarged lateral ventricles and smaller hippocampi. There is a negative correlation between hippocampal volume and duration of untreated depression.4 In a recent Anglo-French report on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) major depression, over 8000 outpatients were investigated on two occasions. Cognitive functioning was analyzed in terms of delayed recall, a memory function that is particularly related to hippocampal integrity. The study used a structural equation model (path analysis) in showing that the length of an episode of past depression is correlated with impaired memory performance when the patient is out of the recent depression, suggesting a toxic link between the burden of depression and cognition.5 There is new interest in connecting inflammation and oxidative stress within the central nervous system, not only with regard to dementia and the neurodegenerative disorders, but also the psychoses and mood disorders.6 Little is known about the temporal patterns of the central inflammatory process in patients with mood disorders. With regard to apoptotic cell death within the central nervous system, there is a large body of evidence for hippocampal neuronal apoptosis in depression7 and the importance of neurogenesis as a mechanism for the therapeutic effects of antidepressants8 and electroconvulsive treatment.9 The presence of neurogenesis in other areas of the brain, eg, the cortex, remains uncertain. There are steps toward counteracting the “pessimistic” evidence on depression: (i) there is general consensus among clinicians about the value of treating a patient with a mood disorder to full clinical remission, and the liberal use of long-term prophylactic treatment, especially (but not only) in bipolar disorder. Successful relapse prevention with the use of antidepressant medication is a robust finding—adding another year of treatment after the initial positive treatment effect on a depressive episode halves the risk of relapse.10 The major unresolved issue would rather be the question of when long-term medication is unnecessary; (ii) better identification of the origins of environmental risk factors would presumably reduce the risk of relapse or recurrence of depression.11 An important objective for future research will be to determine the changes in the organism that provide the basis for persistence of the environmental effects on psychopathology. The best known result of such studies to date has been the replicated demonstration that White carriers of two short arms in a polymorphism within the serotonin transporter gene are more susceptible to negative life events eliciting depressive episodes in adult life.12 In conclusion, if cerebral alterations in depression are viewed more as traits than states, then the line between mood disorders and, for example, schizophrenia would become blurred. Indeed, recently, genes have been found that are common to both bipolar disorder and schizophrenia.13 Few clinical psychiatrists, however, doubt that mood-stabilizing treatment helps. Most patients live almost comfortably with supportive medical and psychological help that hides their susceptibility to depression, making them resemble ordinary healthy individuals in tackling life’s vicissitudes. _

1. Post RM, Weiss SRB. Kindling and manic-depressive illness. In: Bolwig TG, Trimble MR, eds. The Clinical Relevance of Kindling. Chichester, UK: John Wiley & Sons Ltd; 1989:209-230.
2. Ehnvall A, Ågren H. Patterns of sensitisation in the course of affective illness. A life-charting study of treatment-refractory depressed patients. J Affect Disord. 2002;70:67-75.
3. Kocsis JH, Gelenberg AJ, Rothbaum B, et al. Chronic forms of major depression are still undertreated in the 21st century: systematic assessment of 801 patients presenting for treatment. J Affect Disord. 2008;110:55-61.
4. Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry. 2003;160: 1516-1518.
5. Gorwood P, Corruble E, Falissard B, Goodwin GM. Toxic effects of depression on brain function: impairment of delayed recall and the cumulative length of depressive disorder in a large sample of depressed outpatients. Am J Psychiatry. 2008; 165:731-739.
6. Maes M. The cytokine hypothesis of depression: inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression. Neuro Endocrinol Lett. 2008;29:287-291.
7. Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen Psychiatry. 1997;54: 597-606.
8. Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805-809.
9. Ekstrand J, Hellsten J, Wennström M, Tingström A. Differential inhibition of neurogenesis and angiogenesis by corticosterone in rats stimulated with electroconvulsive seizures. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:1466-1472.
10. 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.
11. Rutter M. How the environment affects mental health. Br J Psychiatry. 2005;186:4-6.
12. 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.
13. Craddock N, O’Donovan MC, Owen MJ. Genome-wide association studies in psychiatry: lessons from early studies of non-psychiatric and psychiatric phenotypes. Mol Psychiatry. 2008;13:649-653.

6◆ J. Pyo Hong, Korea

Associate Professor at Asan Medical Center
University of Ulsan
College of Medicine
388-1 Poonanap-dong
Songpa-gu, Seoul

Diverse adverse events such as separation, physical abuse, and traffic accidents can occur in everyone’s life and leave sequelae of variable intensity in many areas of human behavior. Major depressive disorder is a common but serious condition that causes distress to its victims, impairs family life, reduces social adjustment, and is a burden on the community.1 Depression is one of the most important public health problems in Korea: the prevalence of depressive disorders has increased 50% during the past 5 years according to a recent Korean national epidemiological study,2 and prescriptions of antidepressants have doubled in the last 5 years. In addition, the suicide rate in Korea is one of the highest among the Organization for Economic Co-operation and Development (OECD) countries. National depression initiatives from developed countries emphasize that awareness and recognition of depression is important, because depression is a treatable disease. There are many antidepressants that have proven efficacy and safety. However, the past two decades of research have shown that depression often runs a chronic, intermittent, lifelong course, although effective therapeutic approaches have been developed and provided.3 After acute episodes of illness, many patients do well for variable periods of time. However, more than half of patients have residual symptoms and impairment between episodes, despite ongoing therapy. Anxiety, sleep disturbance, somnolence/fatigue, apathy, and cognitive dysfunction are common residual symptoms and are associated with an increased risk of relapse and poor psychosocial functioning. Experience of major depressive episodes can lead to a change in psychological coping styles in patients. Many patients cope well with depression. They are able to escape negative thinking, and gain the capacity to be resilient. However, dynamic vulnerability theories suggest that consecutive depressive episodes cause biological and psychological changes that increase the vulnerability to subsequent depressive episodes. The experience of these episodes reduces the threshold for the individual’s mind/brain to enter into the depressive state, such that episodes can occur with little or no environmental precipitant.4 Disabilities related to depression affect work, family, and social aspects of a patient’s life. Many depressed patients choose to leave a job because of their depression and have difficulties in getting a new job. Due to the negative stigma related to depression, patients often choose not to disclose their condition at the workplace.5 Research shows that a significant proportion of men become depressed when their partners are depressed. There is an increase in marital conflict and discord within the families of depressed patients.6 Also, many patients with depression are unable to enjoy social and leisure activities. Alarmingly, many recovering depressive patients are often unaware of the long-term consequences of a maladaptive lifestyle, which include dysfunctional thought, chronic life stress, interpersonal friction, and inadequate rest.7 Major depressive episodes are believed to leave a substantial impact on many aspects of patients’ lives for a long time, even after an acute episode has passed. Development and delivery of innovative psychotherapeutic, psychoeducational, and family therapeutic programs, as well as novel antidepressants, are essential for the recovery of depressed patients. _

1. Klerman GL, Weissman MM. The course, morbidity, and costs of depression. Arch Gen Psychiatry. 1992;49:831-834.
2. Cho MJ, Hahm BJ, Hong JP, et al. The Epidemiological Survey of Psychiatric Illness in Korea. Seoul, Republic of Korea: Ministry of Health and Welfare; 2006.
3. Frank E, Kupfer DJ. Progress in the therapy of mood disorders: scientific support. Am J Psychiatry. 2003;160:1207-1208.
4. Kendler KS, Thornton LM, Gardner CO. Genetic risk, number of previous depressive episodes, and stressful life events in predicting onset of major depression. Am J Psychiatry. 2001; 158:582-586.
5. Depression Alliance. The Inside Story. The Impact of Depression on Daily Life. London, UK: Depression Alliance; 2008.
6. Burke L. The impact of maternal depression on familial relationships. Int Rev Psychiatry. 2003;15:243-255.
7. Fava GA, Ruini C, Rafanelli C, Finos L, Conti S, Grandi S. Six-year outcome of cognitive behavior therapy for prevention of recurrent depression. Am J Psychiatry. 2004;161:1872-1876.

7◆ R. Mahendran, Singapore

The treatment of depression improves a variety of aspects of the illness, such as its symptoms, the patient’s emotional well-being, and their occupational and social functioning. The conundrum as to whether the patient is really the same after a major depressive episode depends on whether remission or response is achieved. There are no biological markers for depression at present. Researchers in clinical trials utilize a 50% improvement on rating scales such as the Hamilton Rating Scale for Depression (HAM-D) and the Montgomery-Åsberg Depression Rating Scale (MADRS) as a guideline for treatment response.1 Although HAM-D is recognized as the gold standard in clinical trials for depression, it has been shown that subscales on HAM-D outperform the total scale in this respect. The available rating scales do not assess or reflect optimal functioning. In clinical trials, one-third of patients achieve full remission, one-third achieve a response, and one-third are nonresponders. Research has shown that early remission improves long-term wellbeing, and patients treated to remission have fewer missed workdays. But there are various obstacles to attaining remission in clinical practice, such as noncompliance, treatment discontinuation due to side effects, and failure to recognize residual symptoms. Many responders may still have a substantial degree of residual or subthreshold symptoms, leading to clinically significant negative and unfavorable outcomes.2,3 Paykel et al found that the rate of relapse in patients with a partial response was 76%, compared with 25% in patients achieving full remission.4 Even minimal levels of residual symptoms contribute to ongoing functional impairment and increase the risk of further depressive episodes to three to six times higher than in those with full remission. Additionally, treatment does not automatically improve social support outcomes. Residual symptoms are also associated with socioeconomic issues and help-seeking health care visits, chronicity, and the risk of suicidal thoughts and attempts.5 Unfortunately, whatever the improvement in mood symptoms, it is not synchronous with a full return of premorbid capabilities. Zimmerman et al showed that for patients, psychosocial functioning is of great importance, and positive features such as “optimism, vigor, and self-confidence” were crucial in their own assessments of whether they had returned to their normal selves.6 Patients who were more likely to view themselves as being in remission reported significantly less psychosocial impairment, and better quality of life.7 Yet findings from studies indicate that treatment does not ensure immediate and complete recovery of all aspects of the patient’s life. A recent study found that feelings of hopefulness did not improve until several weeks or even months after depressive symptoms were controlled.8 In another study of primary care patients treated with selective serotonin reuptake inhibitors for major depression, symptoms continued to improve over time, while painful physical symptoms persisted.9 In addition, neurobiological investigations of brain perfusion have shown that there can be a delay in perfusion normalization for up to 2 years into remission, with increases in the frontal regions and decreases in the parietocerebellar regions.10 From the clinician’s perspective, despite the heterogeneity of the etiologic mechanisms underlying depression such as the genetic antecedents, early trauma, and stress, and the various psychosocial factors such as coping styles, interpersonal events, and parental bonding experiences, which can impact recovery, the aim is to have very clear treatment goals for each patient, with detailed assessments and monitoring. Attention should be paid to underlying personality factors, comorbid psychiatric conditions, and co-existing medical conditions. The aim is for complete remission, not only through pharmacotherapy, but also a more holistic approach with the use of psychotherapeutic treatments and social interventions. _

1. Zajecka JM. Treating depression to remission. J Clin Psychiatry. 2003;64(suppl 15):7-12.
2. Casacalenda N, Perry C, Looper K. Remission in major depressive disorder: a comparison of pharmacotherapy, psychotherapy, and control conditions. Am J Psychiatry. 2002;159: 1354-1360.
3. Taylor WD, McQuoid DR, Steffens DC, Ranga Rama Krishnan K. Is there a definition of remission in late-life depression that predicts later relapse? Neuropsychopharmacology. 2004; 29:2272-2277.
4. Paykel ES, Ramana R, Cooper Z, Hayhurst H, Kerr J, Barocka A. Residual symptoms after partial remission: an important outcome in depression. Psychol Med. 1995;25:1171-1180.
5. Tranter R, O’Donovan C, Chandarana P, Kennedy S. Prevalence and outcome of partial remission in depression. J Psychiatry Neurosci. 2002;27:241-247.
6. Zimmerman M, McGlinchey JB, Posternak MA, Friedman M, Attiullah N, Boerescu D. How should remission from depression be defined? The depressed patient’s perspective. Am J Psychiatry. 2006;163:148-150.
7. Zimmerman M, Postemak MA, McGlinchey J, Friedman M, Attiullah N, Boerescu D. Validity of a self-report depression symptom scale for identifying remission in depressed outpatients. Compr Psychiatry. 2006;47:185-188.
8. Aikens JE, Kroenke K, Nease DE Jr, Klinkman MS, Sen A. Psychiatry and primary care. Trajectories of improvement for six depression-related outcomes. Gen Hosp Psychiatry. 2008;30:26-31.
9. Greco T, Eckert G, Kroenke K. The outcomes of physical symptoms with treatment of depression. J Gen Inter Med. 2004;19:813-818.
10. Kohn Y, Freedman N, Lester H, et al. Cerebral perfusion after a 2-year remission in major depression. Int J Neuropsychopharmacol. 2008;11:837-843.

8◆ A. Hatim Sulaiman, Malaysia

Associate Professor
Department of Psychological Medicine
Faculty of Medicine
University of Malaya
50603 Kuala Lumpur

Both biological and psychological factors are believed to play a role in the development of major depressive disorder (MDD). While the tendency to develop depression may be inherited or triggered by environmental stressors such as stressful life events, the traditional view is that depressive symptoms are a consequence of an imbalance in the neurotransmitters within the central nervous system1; namely, norepinephrine, serotonin, and dopamine, which are involved in the regulation of mood and emotion. It is well known that the risk of recurrence increases with each subsequent episode of depression.2 While the onset of depressive episodes becomes easily triggered over time, it is progressively less associated with environmental stressors.3 This phenomenon supports the “kindling hypothesis,” which proposes that psychosocial stressors play a greater role in the initial than in subsequent episodes of depressive disorders.4 Kendler and colleagues, in their study of white female-female twin pairs, further documented a threshold of approximately 9 episodes of depression at which the brain is no longer additionally sensitized to the depressive state.3 Their evidence suggests some neurobiological and neuroanatomical alterations that occur intensely in the brain during depression, even during the first few episodes of illness. Chronic activation of the stress-response system in MDD can cause a variety of adverse effects in the brain, and mediates many of the physiological and behavioral responses in depression.5 For example, an elevated level of corticotropin-releasing factor in depression is found to mediate some of the behavioral symptoms of depression involving sleep and appetite disturbances, reduced libido, and psychomotor changes. Current evidence has also shown the involvement of neurogenesis in depression, though its role has not been clearly elucidated yet.1 Neuronal atrophy and cell death occur as a result of hyperactivity of the stress-response system, in which adrenal glucocorticoid release is increased, while brain derived neurotrophic factor (BDNF) levels decline.6 More recent research suggests an association between depression and neurogenesis of the hippocampus, a structure essential to learning and memory, contextual fear conditioning, and neuroendocrine regulation.7 The damaging effects of prolonged stress could contribute to the selective loss of hippocampal volume. A number of neuroimaging studies have unanimously shown that patients with recurrent and/or severe depression tend to have smaller hippocampal volumes.8-11 These morphological changes were noted to persist long after depressive symptoms had resolved.7 Hippocampal volume reduction is also found to be greater in patients who have had a longer duration of illness and who went untreated,12-14 indicating that prolonged depression may result in progressive and cumulative damage to the brain. All these findings underscore the urgency for aggressive treatment early in the course of illness to achieve remission and to prevent a chronic, recurrent depressive course. It was demonstrated during a 2-year follow-up study that treatment to the point of symptom remission in the first 3 months significantly decreased the risk of relapse and recurrence.15 The therapeutic effects of antidepressants are believed to be the result of the drugs’ abilities to restore neurotransmitter imbalance at the synapses. However, most antidepressants appear to have a delayed onset of action. An experimental animal model study found that the onset of therapeutic effects following the initiation of antidepressant treatment neither coincides with the achievement of therapeutic serum concentrations nor with the inhibition of neurotransmitters.16 This raises questions about the traditional “chemical imbalance” hypotheses regarding the underlying pathophysiology of depression. Additionally, despite the fact that depression is traditionally viewed as a fully reversible disorder, accumulating evidence suggests otherwise. More recent evidence indicates that beyond restoring the chemical balance at the synapses, antidepressants may have effects associated with re-establishment of neurobiological activity in the brain. For example, antidepressant pharmacotherapy affects serotonin and/or norepinephrine activities, thereby affecting neuronal survival and growth by decreasing glucocorticoid levels and increasing BDNF levels.17 In fact, Malberg and colleagues have shown that chronic antidepressant treatment was able to increase neurogenesis in the adult rat hippocampus.18 In human subjects, it has been reported that patients with mood disorders who were receiving an antidepressant at their time of death, had greater hippocampal BDNF expression compared with untreated subjects.19 In essence, patients are unlikely to be the same after a major depressive episode, as neurobiological and neuroanatomical changes have taken place in the brain. Early and aggressive antidepressant therapy is hence imperative to achieve remission and prevent recurrence in the long term. _

1. Castren E. Is mood chemistry? Nat Rev Neurosci. 2005;6: 241-246.
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. Kendler KS, Thornton LM, Gardner CO. Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the “kindling” hypothesis. Am J Psychiatry. 2000;157:1243-1251.
4. Post RM. Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry. 1992;149:999-1010.
5. Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB. The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol. 1999;160:1-12.
6. Duman RS, Malberg J, Nakagawa, D’Sa C. Neuronal plasticity and survival in mood disorders. Biol Psychiatry. 2000;48: 732-739.
7. Sapolsky RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry. 2000;57: 925-935.
8. Bremner JD, Narayan M, Anderson ER, et al. Hippocampal volume reduction in major depression. Am J Psychiatry. 2000; 157:115-118.
9. Mervaala E, Fohr J, Kononen M, et al. Quantitative MRI of the hippocampus and amygdala in severe depression. Psychol Med. 2000;30:117-125.
10. Steffens DC, Byrum CE, McQuoid DR, et al. Hippocampal volume in geriatric depression. Biol Psychiatry. 2000;48:301-309.
11. Frodl T, Meisenzahl EM, Zetzsche T, et al. Hippocampal changes in patients with a first episode of major depression. Am J Psychiatry. 2002;159:1112-1118.
12. Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry. 2003;160: 1516-1518.
13. Sheline YI, Wang PW, Gado MH, et al. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U. S. A. 1996;93:3908-3913.
14. Sheline YI, Sanghavi M, Mintum MA, Gado MH. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci. 1999;19:5034-5043.
15. Simon GE. Long-term prognosis of depression in primary care. Bull World Health Organ. 2000;78:438-445.
16. Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805-809.
17. Gonul AS, Akdeniz F, Taneli F, et al. Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. Eur Arch Psychiatry Clin Neurosci. 2005;255:381-386.
18. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000;20:9104-9110.
19. Chen B, Dowlatshahi D, MacQueen GM, et al. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry. 2001;50:260-265.

9◆ F. Cañas, Spain

Fernando CAÑAS, MD
Head of Department
of Psychiatry, Hospital
Dr Rodríguez Lafora
Cra de Colmenar
Viejo Km 13.8
28049 Madrid, SPAIN

The spontaneous and first answer to this question should be a clear “no!!,” as any significant experience in life—and a major depressive episode undoubtedly is—has the effect of modifying the subject’s global perspective about himself and the world. This can be appraised through the vast literature produced on the matter, one such recent example being W. Styron’s first person account.1 But this answer probably fails to respond to the implicit insinuation that after having recovered from a major depressive episode, the patient has somehow permanently deteriorated in his functioning (what is known as the “scarring” effect of depression), and what may be a consequence of that is a high risk of subsequent episodes. It is well documented that depression frequently has a chronic course with recurrences2 and that the probability of presenting with a new episode increases with the number of previous ones.3 There are also numerous studies showing that individuals with a history of depressive episodes have higher scores in some pathological personality characteristics, such as interpersonal dependency, lack of social confidence, submissiveness, neuroticism or introversion.4 The role of these characteristics as being only state markers or acting as vulnerability factors has been largely discussed; but a third possibility has emerged that at least some of them could be a consequence of the depressive episode, thus producing a kind of “scar,” a relatively permanent residual deficit (by analogy with physical scars after an injury). This is known as the “scar hypothesis” of depression, first introduced as such in the early 1980s.5 Since then, there has been wide controversy around this possibility, with most published work on the issue showing results that did not support the scar hypothesis (it is not possible to quote them “in extenso,” but a representative sample may be Rohde et al,6 Shea et al,7 Ormel et al,8 and Kennedy et al.9 Taken as a whole, they indicate that postdepressive vulnerabilities correspond to the continuation of premorbid conditions. Nevertheless, some findings are still interpreted as being residual impairments—mostly in the realm of emotional reactivity—that last longer than the remission of symptoms and may even become “latent,”10 so as to mean that they would not appear except in emotionally charged situations. Almost in parallel to that, increasing attention has been devoted to the problem of residual symptoms after a depressive episode,11 a phenomenon whose clinical relevance relates to the dysfunction it can cause and also the risk of relapse that is significantly increased by its presence. In this case we will be facing a “badly cured” episode instead of a permanent scar, with “unresolved symptoms” that may be under the threshold of clinical diagnosis, but have a relevance that needs more detailed study. The prevalence and mechanisms involved in these subthreshold conditions are not well known,12 but they may force us to review some of the concepts involved (remission,13 recovery,14 euthymia15), as well as the difficulty in making prognostic and therapeutic decisions based upon a diagnostic category so heterogeneous as “major depression,” something that has already been pointed out.16,17 After more than 50 years of using antidepressant agents, we are still facing the complexities of the nosology of depression, as it requires an adequate coverage of a variety of different clinical presentations in terms of severity and chronicity. Going back to the initial question, it seems very clear that a major depressive episode will probably change the patient (although not necessarily for the bad18 if well treated) but an additional point should also be that we have to review our standards of treatment, looking for a more ambitious target and not merely remission of symptoms below the level of diagnosis.19 If we achieve that, patients will have a better chance of regaining a level of functioning that is at least as good as they previously had. _

1. Styron W. Darkness Visible: A Memoir of Madness. New York, NY: Vintage Books; 1992.
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. Gonzalez L, Lewinsohn PM, Clarke G. Longitudinal followup of unipolar depressives: an investigation of predictors of relapse. J Consult Clin Psychol. 1985;53:461-469.
4. Shea MT, Leon AC, Mueller TI, Solomon DA, Warshaw MG, Séller MB. Does major depression result in lasting personality change? Am J Psychiatry. 1996;153:1404-1410.
5. Lewinsohn PM, Steinmetz J, Larson D, Franklin J. Depression related cognitions: antecedents or consequences? J Abnorm Psychol. 1981;90:213-219.
6. Rohde P, Lewinsohn PM, Seeley JR. Are people changed by the experience of having an episode of depression? A further test of the scar hypothesis. J Abnorm Psychol. 1990;99:264-271.
7. Shea MT, Leon AC, Mueller TI, Solomon DA, Warshaw MG, Keller MB. Does major depression result in lasting personality change? Am J Psychiatry. 1996;153:1404-1410.
8. Ormel J, Oldehinkel AJ, Vollebergh W. Vulnerability before, during, and after a major depressive episode. Arch Gen Psychiatry. 2004;61:990-996.
9. Kennedy N, Foy K, Serráis R, McDonough M, McKeon P. Long-term social functioning after depression treated by psychiatrists: a review. Bipolar Disord. 2007;9:25-37.
10. Merens W, Booij L, Van der Does AJ. Residual cognitive impairments in remitted depressed patients. Depress Anxiety. 2008;25:E27-E36.
11. Paykel ES, Ramana R, Cooper Z, Haydurst H, Kerr J, Barroca A. Residual symptoms after partial remission: an important outcome in depression. Psychol Med. 1995;25:1171-1180.
12. Trivedi MH, Hollander E, Nutt D, Blier P. Clinical evidence and potential neurobiological underpinnings of unresolved symptoms of depression. J Clin Psychiatry. 2008;69:246-258.
13. Zimmerman M, Posternak MA, Chelminski I. Heterogeneity among depressed outpatients considered to be in remission. Compr Psychiatry. 2007;48:113-117.
14. Fava GA, Ruini C, Belaise C. The concept of recovery in major depression. Psychol Med. 2007;37:307-317.
15. Pizzagalli DA, Goetz E, Ostacher M, Iosifescu DV, Perlis RH. Euthymic patients with bipolar disorder show decreased reward learning in a probabilistic reward task. Biol Psychiatry. 2008;64:162-168.
16. Parker G. Beyond major depression. Psychol Med. 2005; 35:467-474.
17. Parker GB. Commentary on diagnosing major depressive disorder. Ask less that we embrace major depression and ask more what the concept does for us. J Nerv Ment Dis. 2006;194: 155-157.
18. Dahlberg KM, Waern M, Runeson B. Mental health literacy and attitudes in a Swedish community sample—investigating the role of personal experience of mental health care. BMC Public Health. 2008;8:8.
19. Koivumaa-Honkanen H, Tuovinen TK, Honkalampi K, et al. Mental health and well-being in a 6-year follow-up of patients with depression: assessments of patients and clinicians. Soc Psychiatry Psychiatr Epidemiol. 2008;43:688-696.

10◆ F. T. Antun, Lebanon

Fuad T. ANTUN, MD, PhD,
Professor of Psychiatry
Advisor on Mental Health & WHO Focal Point
Ministry of Health, Lebanon
Chairman, Scientific Council for the Arab
Board of Psychiatry
PO Box 135098

Major depressive illness is a chronic relapsing condition that sometimes warrants lifetime treatment. Studies on the long-term outcome of major depression have shown a significant difference between unipolar and bipolar types. More confusion is added when unipolar depression switches to bipolarity in later years, thus affecting the results of long-term outcome studies.1 Furthermore, the classification and diagnosis of depression is in effect that of a cluster or set of symptoms, or a syndrome. We therefore treat these symptoms, and not a diagnosis as such.2 Thus response and quality of life is measured by the response of these symptoms to treatment. The diagnostic categories of major depression and the presence of comorbidities affect the results of studies on the long-term outcome of depressive illness. Antidepressants have grown in number, as have their different mechanisms of action and molecular types. They all show varying degrees of ability to generate a response in comparison with placebo. Furthermore, short-term studies show that all antidepressants have a low advantage over placebo (15%- 20%) ie, 50% of depressed patients improve on placebo, although we are unable to know which patients do well on placebo.3 The duration of depression treatment in clinical practice varies, even though treatment algorithms do exist, and Isomesta et al4 showed that about 70% of patients receive subtherapeutic doses of antidepressant. Randomized controlled trials by Schulberg et al5 and Katon et al6 showed that adequate treatment according to the US Agency for Health Care Policy and Research guidelines gives a clinical outcome that is superior to that of usual treatment. Gender and the response to antidepressants has also been studied, and has shown that tricyclic antidepressants are more effective in males and that selective serotonin reuptake inhibitors are more effective in females.7 Compliance is difficult to study, and is a problem that is not resolved in assessing outcome.8 Last but not least, cure is a relative term whose definition varies from symptom relief, to social recovery, adaptive behavior, and remission. It is infrequently the case that a patient is cured of depression, in the sense that no further attacks of depression occur in the lifespan of the patient, and this is even less frequent with bipolar depression. Against the backdrop of all the above intricacies, controversies, and clinical variations, there is increasing literature on the unsatisfactory degree of remission achieved with current treatments in depression. A Medline review of relevant articles published from 1967 to 2006 showed that when psychotherapy and pharmacotherapy are used to treat depression, most patients report residual symptoms despite apparently successful treatment. These residual symptoms have strong prognostic value, as they have a relationship with prodromal symptoms that can lead to relapse.9 This subject has received inadequate attention. Review of the literature using Medline also showed that some clinical findings point toward: (i) unfavorable long-term outcomes in depression treated by available antidepressants (paradoxical depression-inducing effects), with anxiety and depressive symptoms; (ii) antidepressant- induced switching and cycle acceleration in bipolar disorders; (iii) occurrence of a tolerance to antidepressants in long-term treatment; and (iv) withdrawal effects after stopping treatment, with possible relapse.10 Residual symptoms are the rule in unipolar depression. The symptoms are related to the hypothalamic-pituitary-adrenal axis and to sleep architecture, and are predictors of relapse, as they progress to become prodromal symptoms of relapse upon recovery from the depressive episode. So antidepressants should not only be assessed on their differential remission rates, but also on the differential amount of residual symptomatology after response.11 Treatment of these residual symptoms may improve longterm outcome, so that recovery lies not exclusively in the alleviation of the negative, but also in engendering the positive. The above discussion focuses mainly on unipolar depression, in which there is growing controversy about the concept of “total cure.” The situation is no better in bipolar depression, where the spectrum of patients runs the full range from highly functional, welladjusted individuals who are almost completely symptom-free for decades, to socially dysfunctional, chronically ill patients with repeated relapses, who never recover.12 In general, in bipolar illness, depression has a more chronic natural course than the mania, with patients reporting chronic subsyndromal depression.13 In conclusion, unipolar depression, a chronic and relapsing illness, sometimes runs a course that is without full recovery, full recovery being a term that can be confused with remission or social recovery, meaning the patient is never really the same after a major depressive episode. There is more controversy with regard to bipolar depression, where it sometimes takes over 10 years for a diagnosis to be made, and where the progress toward recovery is often poor,14,15 with no remitting cyclical course. _

1. Akiskal HS, Maser JD, Zeller P, et al. Switching from unipolar to bipolar II. Arch Gen Psych. 1995;52:114-123.
2. Stefanis CN, Stephanis NC. Diagnosis of depression: a review. In: Maj M, Sartorius N, eds. Depressive Disorders. 2nd ed. West Sussex, UK: John Wiley & Sons; 2002: Chapter I (1-151).
3. Bech P. Pharmacological treatment of depressive disorders: a review. In: Maj M, Sartorius N, eds. Depressive Disorders. 2nd ed. West Sussex, UK: John Wiley & Sons; 2002: Chapter II (89-117).
4. Isometsa E, Seppala I, Henriksson M, et al. Inadequate dosaging in general practice of TCA vs other antidepressants for depression. Acta Psychiatr Scand. 1998:98:451-454.
5. Schulberg HC, Block MR, Madonia MJ, et al. Treating major depression in primary care practice, eight month clinical outcome. Arch Gen Psych. 1996;53:913-919.
6. Katon W, Robinson P, Vonkorff M, et al. A multifaceted intervention to improve treatment of depression in primary care. Arch Gen Psych. 1996;53:924-932.
7. Keller MB, Gelenberg AJ, Hirschfeld RMA, et al. The treatment of chronic depression, Part 2. A double-blind randomized trial of sertraline and imipramine. J Clin Psychiatry. 1998; 59:598-607.
8. Demyttenaere K. Compliance during treatment with antidepressants. J Affect Disord. 1997:43:27-39.
9. Fava GA, Ruini C, Belaise C. The concept of recovery in major depression. Psychol Med. 2007;37:307-317.
10. Fava GA. Can long-term treatment with antidepressant drugs worsen the course of depression? J Clin Psychiatry. 2003;64:123-133.
11. Fava GA, Fabbri S, Sonino N. Residual symptoms in depression: an emerging therapeutic target. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26:1019-1027.
12. Lerer B, Yakir A. Heterogeneity of course and outcome in bipolar disorder: can genetics help? In: Maj M, Akiskal HS, Lopez-Ibor JJ, Sartorius N, eds. Bipolar Disorder. New York, NY: John Wiley and Sons. 2002:178-181.
13. Coryell W, Turvey C, Endicott J, et al. Bipolar I affective disorder: predictors of outcome after 15 years. J Affect Disord. 1998:50:109-116.
14. Golderg JF, Harrow M, eds. Bipolar Disorders: Clinical Course and Outcome. Washington, DC: American Psychiatric Press; 1999.
15. Lish JD, Dime-Meenan S, Whybrow PC, et al. The National Depressive and Manic-Depressive Association (DMDA) survey of bipolar members. J Affect Disord. 1994;31:281-294.