CONTROVERSAL QUESTION – Is depression curable?



1. T. Alkin, Turkey
2. E. Allers, South Africa
3. C. M. Banki, Hungary
4. M. Bauer,Germany
5. R. Nel Córdoba Rojas, Colombia
6. M. R. El-Fiky,Saudi Arabia
7. E. A. de la Garza Velázquez, Mexico
8. R. W. Licht, Denmark
9.F. Lopes Rocha, Brazil
10. G. S. Malhi, Australia
11. N. O. Maruta, Ukraine
12. S. N. Mosolov, Russia
13. J. L. Pio-Abreu,Portugal
14. S. Smadja and R. Gaillard, France
15. C. Sukying,Thailand
16. S-J. Tsai, Taiwan
17. M. Yeghiyan, Armenia


1. T. Alkin, Turkey

Tunç ALKIN, MD
Professor
Dokuz Eylul University Medicine Faculty
İzmir, TURKEY
(e-mail: tunc.alkin@deu.edu.tr)



The word “cure” means permanently eliminating all the signs and symptoms of a given disease, by completely reversing the underlying pathogenetic mechanisms and thus restoring the patients’ premorbid health status and functioning. However, this is hardly true for depressive disorders. Residual symptoms are the rule after successful completion of pharmacological or psychotherapeutic treatment, and their presence has been correlated with poor outcome.1 The results of the STAR*D study (Sequenced Treatment Alternatives to Relieve Depression) showed that the overall cumulative remission rate is far from satisfactory, and that after 12 months the majority of patients had relapsed.2,3 Although various treatments exist for the symptoms of depression, there is no known “cure” as defined above. There are several reasons contributing to the absence of a real instrumental cure.

First, depression is an etiologically complex disorder. Although there are converging lines of evidence suggesting that patients’ susceptibilities shaped by neurobiological factors such as corticotropin-releasing factor system and HPA-axis abnormalities, elevated inflammation-related cytokines, and decreased neurogenesis, as indicated by low levels of brainderived neurotrophic factor (BDNF) may be associated with depression, the exact pathogenesis of depressive disorders is not fully understood.4 We are still awaiting biomarkers for depression to quantify the change in patients’ pathophysiological condition. Until validated and clinically interpretable biomarkers are available, no one will be able to conclude whether a depressive disorder is unequivocally “cured” or “not cured.” A patient who appears cured with ongoing treatment may still have an undetected, active, long-running illness. In contrast, in clinical studies some patients who do not meet the symptom- based definitions of remission nonetheless consider themselves in remission.5

Second, several “gene-environment (stress) interaction” processes are known to be involved in the pathophysiology of depression and further contribute to its heterogeneous nature. The disease is not only heterogeneous, but is also often complicated with other medical and psychiatric comorbidities.2,41 It is unrealistic to hope for a “cure,” if the sufferer’s chronic stress is not addressed with psychosocial interventions and relevant socio-political actions.

Third, current treatment options do not effectively relieve the symptoms of depression. As yet, alternative and causative psychopharmacological treatment strategies beyond monoamine reuptake inhibition are unavailable. Recent research has shown that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, leads to effects on the dysregulation of the glutamatergic system.6 Low-dose ketamine elicits an antidepressant effect in patients with major depression. These findings have fueled efforts to elucidate the mechanisms underlying ketamine’s antidepressant action as well as develop a new molecular understanding of depression. Thus, the development of novel, rapid-acting antidepressants yielding an outcome comparable to the definition of a “cure” must be a worldwide priority.

It is clear that we urgently need quantifiable biological markers to assess the underlying disease state and response to treatment and effective treatments that will bring a diseasefree wellness state. Until then, “cure-oriented attitudes” to depressive patients won’t make much sense. The main goal of treatment should be “a complete and sustained remission” or “recovery” as defined by several investigators.1 A definition of recovery based on symptoms and psychosocial functioning should be pursued. Furthermore, the concept of recovery should involve an active role of the patient, and take into account his/her psychological well-being.1 Whether “recovery” absolutely means “cure” in terms of psychosocial and neurobiological variables should be a major topic for psychiatric care in the future. ■
References
1. Fava GA, Ruini C, Belaise C. The concept of recovery in major depression. Psychol Med. 2007;37:307-317.
2. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcome with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28-40.
3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.
4. Lang UE, Borgwardt S. Molecular mechanisms of depression: perspectives on new treatment strategies. Cell Physiol Biochem. 2013;31:761-777.
5. Zimmerman M, Martinez J, Attiullah N, Friedman M, Toba C, Boerescu DA. Why do some depressed outpatients who are not in remission according to the Hamilton Depression Rating Scale nonetheless consider themselves to be in remission? Depress Anxiety. 2012;29:891-895.
6. Murrough JW. Ketamine as a novel antidepressant: from synapse to behavior. Clin Pharmacol Ther. 2012;91:303-309.

2. E. Allers, South Africa

Eugene ALLERS, MMed Psych
Consultant Psychiatrist
Glynnview Hospital
148 Cranbourne Avenue
Benoni, 1501
SOUTH AFRICA
(e-mail: allgrun@global.co.za)



Even though major depression ranks number one in years lost to disability (YLD) in the world, as defined by the World Health Organization, we have not yet established what we consider a cure; we treat until remission is reached.

The Oxford Dictionary defines cure and remission as follows:
Cure: “eliminate (a disease or condition) with medical treatment”
Remission: “a temporary diminution of the severity of disease or pain” In major depression, only a few attempts have been made to define what is meant by “cure” and most of the definitions are still only symptom-based and not related to functioning or subtle symptoms.

The “American College of Neuropsychopharmacology (ACNP) task force on response and remission in Major Depressive Disorder”1 recommended in 2006 that recovery in major depression should be ascribed only after patients have remitted for at least 4 months. Most patients relapse within the first 4 months of remission,2 hence the recommendation. Others recommend waiting for 6 months of remission before recovery can be declared.3,4 Twelve long-term outcome studies have been published to guide us.5

Major depression is a relapsing disorder, especially during the first few months following the onset of the disorder but it does not appear to be eventually chronic in the majority of patients. Approximately 75% of patients relapse at least once with 20% relapsing at least 4 times. Most relapses occur within the first 2 years of the disorder. Remission is achieved in 50% of patients in the first 6 months and between 80% and 90% of patients are in remission after 5 years.

The World Health Organization recommends that antidepressants should be given for 9 months, while others recommend that antidepressants be continued for 26 weeks after remission. Studies reveal that functional impairment can persist for some time after remission and this often goes unrecognized.

The objective of treating depression would be to relieve the symptoms, to minimize the risk of suicide, to reduce the number of relapses, to reduce the time spent in a relapse, and to improve functioning. The average duration of major depression, if relapses and subtle symptoms are included, is of several years. Most patients fortunately reach remission eventually. Treatment should be preventative, and should therefore continue for at least 2 years, the time frame in which most relapses usually occur. If a treatment and preventative approach were followed, the prospect of a cure would be much more within reach of most patients earlier, suicide could be better prevented, and suffering reduced. ■


References
1. 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.
2. 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.
3. Riso LP, Thase ME, Howland RH, Friedman ES, Simons AD, Tu XM. A prospective test of criteria for response remission relapse recovery and recurrence in patients treated with cognitive behavior therapy. J Affect Disord. 1997;43:131-142.
4. TA Furukawa, Fujita A, Harai H, Yoshimura R, Kitamura T, Takahashi K. Definitions of recovery and outcomes of major depression: results from a 10-year follow- up. Acta Psychiatr Scand. 2008;117(1):35-40.
5. Lehmann HE, Fenton FR, Deutsch M, Feldman S, Engelsmann F. An 11-year follow- up study of 110 depressed patients. Acta Psychiatr Scand. 1988;78(1):57-65.

3. C. M. Banki, Hungary

Csaba M. BANKI, MD, PhD
Professor of Psychiatry
Santha Kalman Mental Health Center
Nagykallo, HUNGARY
(e-mail: csamba7@gmail.com)



The answer depends on the definition of “cure.” Adisease, in the strict sense, is “cured” by eliminating its known primary pathology; this also implies no risk of recurrence and no need for further treatment. In most mental disorders— and indeed in most chronic medical conditions like hypertension, rheumatism, or diabetes—despite much promising research (eg, gene therapy) this is a future possibility rather than a clinical reality. On the other hand, a few loud critics regard depression as a mere social construct “medicalizing” a natural psychological response—sadness—to adverse life experiences in healthy individuals, not as a real disorder needing to be “cured” at all. Until clear identification of the primary brain pathology of depressive states is achieved, all current therapies will treat symptoms rather than cure the disease. From a practical perspective, however, the ability to achieve full and sustained symptomatic recovery and a low risk of recurrence even without long-term treatment can reasonably be considered as a proxy for “curability.” With this definition, about 50% of first-episode depressions appear to be “curable.”1 Unfortunately, in recurrent depression the chance of staying permanently well without maintenance treatment (ie, “remaining cured”) rapidly declines with the number of episodes, and hardly exceeds 10% during a 5-year follow-up.2

Acute response to current antidepressant pharmacotherapy is generally encouraging but far from satisfying. The commonly accepted goal in short-term treatment is remission (symptom reduction below diagnostic threshold, no more than “borderline ill”), not recovery (no depressive symptoms, full restoration of premorbid health, “not at all ill”). The much-quoted STAR*D data (Sequenced Treatment Alternatives to Relieve Depression) showed a remission rate of only 32% to 36% in the first 8 to 12 weeks, which further improved to 67% with subsequent treatment optimizations.3 Open, naturalistic studies sometimes report better outcomes, achieving remission rates above 80% during longer observation periods4; this coincides with the therapeutic experience of many clinicians. On the other hand, true recovery rates (using the strictest definition of HAM-D ≤3 [HAMilton Depression rating scale] for ≥120 days) are typically much lower, around 25% to 35% even after 2 years.5 The proverbially poor adherence in depression—less than 30% of the patients take their medication for at least 3 months6— also contributes to suboptimal response and apparent therapeutic failure. Incomplete therapeutic response with residual symptoms is common, and without further efforts to achieve full remission it usually predicts earlier relapses or more frequent recurrences. In contrast, proper continuation treatment in remitted patients may be able to keep the patient depression- free over several years, by reducing the “spontaneous” recurrence rate (about 80%) three to five times, down to 10%- 25% during follow-up.1,5,7 Moreover, the degree of the acute phase of recovery correlates strongly and almost linearly with the anticipated length of time without recurrence.5

The available evidence suggests that in some populations of depressed patients, psychotherapy may produce similar response and remission rates.1 Compared with drug treatment, most psychotherapy settings are inherently longer-term, allowing for stabilization and maintenance of early results. Some research data, including functional imaging studies of brain metabolism changes during and after psychotherapy and drug treatment, indicate more similarities than differences between the two modalities.8 However, no empirical data support the historical concept that psychotherapy is somehow “causal,” while pharmacotherapy is “only symptomatic.” Both can successfully treat, but neither appears to ultimately “cure” the clinical condition we currently call depression.

Is depression curable? The rigorous scientific answer must remain negative until we find the real “cause” and the means to eradicate it. The pragmatic answer for the clinicians is, however, more optimistic: with thoughtful and persistent use of our current therapeutic options most depressed patients respond to a meaningful extent; the majority achieve remission, and—with prophylactic treatment—many patients continue to experience long-lasting full recovery. ■


References
1. National Institute for Health & Clinical Excellence (NICE): The treatment and management of depression in adults. National Clinical Practice Guideline 90. (updated edition);2010:17-22.
2. Keller MB, Lavori PW, Mueller TI, et al. Time to recovery, chronicity, and levels of psychopathology in major depression: a 5-year follow-up of 431 subjects. Arch Gen Psychiatry. 1992;49:809-816.
3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.
4. Quitkin FM, Petkova E, McGrath PJ, et al. When should a trial of fluoxetine for major depression be declared failed? Am J Psychiatry. 2003;160:734-740.
5. Dunlop BW, Holland P, Bao W, Ninan PT, Keller MB. Recovery and subsequent recurrence in patients with recurrent major depressive disorder. J Psychiat Res. 2012;46:708-715.
6. Olfson M, Marcus SC, Tedeschi M, Wan GJ. Continuity of antidepressant treatment for adults with depression in the United States. Am J Psychiatry. 2006;163: 101-108.
7. Thase ME. Preventing relapse and recurrence of depression, a brief review of therapeutic options. CNS Forums. 2006;12(suppl 15):12-21.
8. Kennedy SH, Konarski JZ, Segal ZV, et al. Differences in brain glucose metabolism between responders to CBT and venlafaxine in a 16-week randomized controlled trial. Am J Psychiatry. 2007;164:778-788.

4. M. Bauer, Germany

Michael BAUER, MD, PhD
Professor and Chair of Psychiatry
Department of Psychiatry and Psychotherapy
University Hospital Carl Gustav Carus
Technische Universität Dresden
Dresden, GERMANY
(e-mail: michael.bauer@uniklinikum-dresden.de)



Major depressive disorder (MDD) is a severe mood disorder affecting individuals of all ages and races characterized by single or recurrent major depressive episodes of at least 2 weeks’ duration, although most episodes last considerably longer. MDD can begin at any age, even in childhood and adolescence, but the mean age of onset of MDD has been estimated around the age of 30, although it can sometimes begin late in life. It has been estimated that 50% to 85% of patients who have an episode will have another episode of major depression.1 So the question or concern is whether depression is curable.

The prognosis for a single depressive episode that is treated according to standard procedures (involving pharmacotherapy and psychotherapy) is generally good, and most patients return to normal functioning when the episode is over.2 However, MDD is associated with considerable morbidity and mortality when an initial episode of depression evolves into a recurrent and debilitating chronic illness with significant and pervasive impairments in psychosocial functioning. Studies on the effects of depression on health-related quality of life demonstrate detriments equal to or greater than those for patients with chronic medical illnesses such as ischemic heart disease or diabetes mellitus.

The likelihood of recurrence increases with the number of previous depressive episodes and the severity of the current episode.3,4 Patients who already have had three episodes of major depression have a very high risk (about 90%) of having another. Among other risk factors for recurrence of MDD are 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. Asymptomatic recovery from MDD is associated with significant delays in episode relapse and recurrence and a more benign course of illness. Unfortunately, it has become apparent in recent years that the long-term course of unipolar MDD is not only characterized by high rates of recurrence but also dominated by prolonged symptomatic chronicity.1 In approximately 30% of severely affected or hospitalized depressed patients, residual symptoms and social or occupational impairment persists. It is now well established that about onethird of patients suffering from severe major depression will have a chronic course marked by at least 2 years of illness.5 According to the new DSM-5,6 the group of depressive disorders encompasses the following subtypes of chronic depressive illness in adults:
◆ Major depressive disorder, single or recurrent episode, in partial remission (entitled chronic major depressive disorder in DSM-IV), and
◆ Persistent depressive disorder (dysthymia) (with an essential feature of depressed mood for more than 2 years).

Individuals suffering from either dysthymia alone or “double depression” (dysthymia plus major depressive episode) have significantly greater impairment in functioning than those with present major depression alone. According to epidemiological and prospective clinical follow-up studies the typical course of MDD involves fluctuating symptoms in which depressive subtypes included in official diagnostic systems do not represent discrete disorders but are stages along a dimensional continuum (spectrum) of symptomatic severity (subthreshold depression5). Residual subthreshold symptoms in the course of MDD are associated with a high risk for early episode relapse and a significantly more chronic future course of illness. Due to demographic changes it is of importance that patients with early-onset depression and older adults suffering from an initial depressive episode after the age of 60 appear to be at greater risk for the development of chronicity.

In conclusion, research data and reality in clinical practice teach us that quite a significant proportion of patients suffering from depression do not sufficiently improve over time despite receiving the best currently available treatments. This subgroup of chronically ill patients can be considered not curable (here being “cured” is defined as being permanently free of symptoms of depression) but all our therapeutic and research efforts should be aiming toward an improvement in their psychosocial functioning and quality of life. ■


References
1. 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.
2. Bauer M, Pfennig A, Severus E, et al; Task Force on Unipolar Depressive Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1: Update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry. 2013;14(5):334-385.
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. Angst J, Merikangas K. The depressive spectrum: diagnostic classification and course. J Affect Disord. 1997;45:31-39.
5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Washington, DC: American Psychiatric Publishing; 2013.
6. Judd LL, Akiskal HS, Zeller PJ, et al. Psychosocial disability during the long-term course of unipolar major depressive disorder. Arch Gen Psychiatry. 2000;57: 375-380.

5. R. Nel Córdoba Rojas, Colombia

Rodrigo NEL CÓRDOBA ROJAS, MD
Centro de Investigaciones del
Sistema Nervioso
Bogotá, COLOMBIA
(e-mail: rodrinel@yahoo.com)



“Nothing exposes the psychiatrist so much to discredit and failure as the treatment for melancholy, a syndrome which in many instances is most rebellious to therapy.” (Antonio Vallejo-Najera)

The clinical scope of sadness in humans has been debated for a long time. Following the development of modern psychiatric classifications in 1980, sadness in humans is now recognized as a clinical condition associated with other symptoms and changes in personal functioning, family, and social work, called major depressive disorder. But to consider it as a single entity that comprehends the whole concept of depression is difficult, and this has led to extensive clinical discussion, ranging from the different spectra or the distinction between unipolar/bipolar depression to the expression of anxiety. This heterogeneous clinical picture has prompted research to identify biomarkers and led to the development of diagnostic tests such as the dexamethasone suppression test or the thyroid hormone suppression test. Poor homogeneity, which is linked to the individual variability of human beings, is a major concern in psychiatric diagnoses.

Depression is a worldwide public health problem with a high prevalence rate, and has been identified as the fourth leading medical condition contributing to the global burden of disease.1 Major depressive disorder is also increasingly recognized as a recurrent and potentially chronic and disabling condition. A large USA study (STAR*D [Sequenced Treatment Alternatives to Relieve Depression]) reported response rates in terms of effectiveness of first treatment close to 40%,2 while follow-up studies in North America3 and Switzerland4 allow us to infer that up to 60% of all patients who suffer from one episode will have subsequent ones and experience a decrement in health and functioning. Each new depressive episode is associated with a renewed risk of future episodes and functional impairment. Each episode seems to increase the likelihood of subsequent recurrences. Published studies suggest that 30% to 50% of patients achieve only partial remission from a depressive episode. Even if there are some risk factors that can help us predict recurrence of the disorder—such as family history of affection disorders, female gender, onset before 25 years, previous recurrence, negative cognitive styles, exposure to stressful life events, absence of social support (especially in women), and comorbidity5—they also fail to predict with absolute certainty the recurrence of the disease.

It is likely, therefore, that between 30% and 50% of patients will only experience one episode in their lifetime. For this group of patients, depression is indeed curable. However, this statement is itself problematic, as there are no tests to identify who will recover and who will have to continue struggling with depression chronically or episodically. The concept of remission in the treatment of depressive patients has gained growing attention in the last decade and is now the accepted goal of the acute treatment of depression. With such a limitation, the current approach is based on phased managed intervention, where three phases are generally distinguished: acute management, continuation, and maintenance. Acute management focuses on the use of drug therapy, psychotherapy, electroconvulsive therapy, or a combination of them. The continuation phase aims to consolidate the response obtained and to achieve full symptom remission and relapse prevention, and normally takes between 4 and 6 months. Maintenance is aimed at those patients with three or more episodes of depression or two severe episodes that may need to be maintained on antidepressants for a long-term period or even indefinitely.6

Depression is treatable rather than curable. The responsible message to the patient and both the general and the medical community is to emphasize the importance of getting treatment and maintaining it over time as a means to full remission and personal, family, and social recovery. ■


References
1. Ferrari AJ, Charlson FJ, Norman RE, et al. Burden of Depressive Disorders by Country, Sex, Age, and Year: Findings from the Global Burden of Disease Study 2010. PLoS Med. 2013;10(11):1-12.
2. Gaynes BN, Dusetzina SB, Ellis AR, et al. Treating depression after initial treatment failure: Directly Comparing Switch and Augmenting Strategies in STAR*D. J Clin Psychopharmacol. 2012;32(1):114-119.
3. 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.
4. Angst J, Dobler-Mikola A. The Zurich Study – a prospective epidemiological study of depressive, neurotic and psychosomatic syndromes. IV. Recurrent and non-recurrent brief depression. Eur Arch Psychiatry Neurol Sci. 1985;234(6): 408-416.
5. 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(4):582-586.
6. Rapaport MH. Beyond acute treatment of depressive disorders. J Clin Psychiatry. 2009;70(7):e21.

6. M. R. El-Fiky, Saudi Arabia

Mohamed REFAAT EL-FIKY
MD, FRCPsych
Professor of Psychiatry and
Consultant Psychiatrist
Saad Specialist Hospital
Khobar, SAUDI ARABIA
(e-mail: mraselfiky@hotmail.com)



Owing to its different clinical presentations, degrees of severity, comorbidities, treatment responses, and outcomes, depression supports the notion of the “heterogeneity” of various mental disorders. Whether its forms arise as an illness remains a rather complex issue.

The hypothesized multifactorial etiology of depression, according to the “biopsychosocial” model, postulates disruptions at one or more of these spheres, or at different levels within each sphere, in an interactive way that adds to that complexity, as these factors might trigger the depressive illness or change its consequences.

At the biological sphere, the likely factors responsible for genetic, biochemical (within multiple extracellular, membranous, and intracellular stations), neurological, neuroendocrinological, neuroimmunological, and circadian rhythm may underlie depression, prolong its episodes, and alter response to treatment.

Thus, depression could be viewed as many disorders or different facets of the same highly heterogeneous disorder. Successful treatment of depressed subjects should regulate and normalize these underlying factors.

Agomelatine provides a means of resynchronizing the different biochemical and biological rhythms, giving a more valuable therapeutic intervention in managing major depressive disorder (MDD) and anxiety disorders by its direct antagonism of 5HT2c receptors, resulting in a consequent increase in dopaminergic and adrenergic neurotransmitter levels at the frontal cortex and a subsequent decrease in glutamate release and increase in brain-derived neurotrophic factor (BDNF) at the intracellular level. As a consequence, neurogenesis is increased and this effect is augmented by its chronobiotic effect on clock genes, which alleviates depressive symptoms related to the biological clock such as mood, energy, sleep, and appetite.

The extent of these actions incorporating dopamine and noradrenaline preserves emotional reactivity, cognition, and sexual function, combats anhedonia, and causes no discontinuation symptoms. All of this encourages adherence throughout the treatment period, strengthens durable improvement, lessens relapse risk, and helps depressed subjects to reach complete recovery and resume a normal life.

Other antidepressants may also have some effects on some of those parameters. However, their effect is not optimized as in the case of agomelatine, which is overall a positive good step forward on the path to real healing.
There is still considerable controversy regarding improvement in core and specific symptoms of depressive syndrome with antidepressant treatment, sustained response to treatment, and remission because of the limitation that antidepressants do not treat the underpinnings of the disease process. Comorbidities, which are the rule rather than the exception in psychiatry, add to this challenge as well. To appraise the benefits of antidepressant medications, they must be compared with the effects achieved by the most current medical and surgical interventions, and this confirms that they are never curative. Recovery-oriented medical practices that aim for the highest quality of life are still facing many challenges. The drugs currently available offer a glimmer of hope, but a glimmer only: they were developed based on what we know about depression. But what remains to be known is greater still. So “don’t blame the players, blame the game”: it’s not those who design the drugs who are at fault, it’s the premises they have been working on until now. Discovering the antidepressants of the future will require some serious thinking out of the box! ■



References
1. Wong, M, Licino J. From monoamines to genomic targets: a paradigm shift for drug discovery in depression. Nat Rev Drug Disovery. 2004;3(2):136-151.
2. Courtet P, Olie E. Circadian dimension and severity of depression. Eur Neuropsychopharmacology. 2012;22:3476-3481.
3. Kupfer D, Frank E, Philips, M. MDD: new clinical neurobiological, and treatment perspectives. Lancet. 2012;379 (9820):1045-1055.

7. E. A. de la Garza Velázquez, Mexico

Erick Alberto de la GARZA VELÁZQUEZ
MD, MB
Guadalajara, MEXICO
(e-mail: erickdelagarza@me.com)



Depression is a common mental disorder characterized by the presence of sadness, loss of interest or pleasure, feelings of guilt or worthlessness, disturbed sleep or appetite, tiredness, and lack of concentration. Depression is the most common mood disorder. It is a very common problem, affecting an estimated 350 million people worldwide, and is, according to the World Health Organization, the leading cause of disability worldwide. Some authorities estimate that at least 12% of the adult population has suffered or will suffer from a major depressive episode in the future. We know that depression is a serious medical illness that affects the brain and involves multiple causes, including genetic, environmental, psychological, and biochemical factors. Moreover, social conditions such as poverty, homelessness, and violence in the community can increase the chances that people become depressed. We also know that there are effective treatments for depression, including the use of antidepressants and psychotherapy—for which there are multiple options to choose from—and that most people get better faster if you use both. But is depression curable?

To establish a diagnosis of major depressive disorder, it is important to confirm the presence of multiple symptoms, each of which is associated with poor information processing in certain brain circuits. Pharmacotherapy should then be aimed at creating an effect on the neurotransmitters that are hypothetically involved—which could be achieved if they generate a single disorder—rather than symptom remission. One of the major unanswered questions about the natural history of the disease regards its progression. In adults experiencing a major depressive episode and responding well to initial treatment with antidepressants, treatment should not be suspended until 9 to 12 months of recovery have elapsed. Treatment— including adherence—must be monitored periodically. The frequency of monitoring should be determined by the compliance and severity of symptoms.

Statistics tell us that one of the features of this disease is a remission rate of approximately 65% with the use of pharmacotherapy and that out of the patients who go into remission a certain percentage will not relapse; this percentage may be increased by including some psychotherapy techniques in the treatment, including interpersonal psychotherapy, cognitive- behavioral, and problem-solving techniques, which have been shown to produce the best results.

The paradigm for the pharmacological treatment of depression has changed in recent years and is currently aiming for complete remission of symptoms and complete maintenance of remission—so that no relapses occur—as the final goal of treatment. This has led to a tendency to use multiple drug mechanisms and commonly using more than one drug, in addition to psychotherapy. However, the symptomatic manifestation of depression remains a very important and largely normative parameter for the choice of antidepressant use among clinicians.

Some of the major challenges facing clinicians who intend to carry out their work rationally, include how to properly master the mechanism of action of the various current drugs of choice and how to master the effective strategies for combining medication and clinical sensitivity to individualize treatment plans. On the other hand, it is unfortunate that around 30% of patients do not adequately take the drug they were prescribed, and that less than half of those who do complete their second month of treatment. So the shocking reality is that only a very small number of patients complete their prescribed treatment properly.

Other complications include the fact that current antidepressants are very effective in relieving symptoms such as depressed mood, suicidal ideation, and psychomotor retardation but are less effective on symptoms such as insomnia, fatigue, lack of interest or motivation and problems of concentration. In addition, response to antidepressants varies depending on the life cycle of patients.

Current evidence from the small number of patients who have achieved remission after a major depressive episode and kept it long term has forced a rethinking of pharmacological treatment schemes, giving preponderance to the goal of achieving remission versus the number of drugs used. ■

8. R. W. Licht, Denmark

Rasmus W. LICHT, MD, PhD
Professor of Psychiatry
Psychiatric Research Unit
Aalborg University Hospital
DENMARK
(e-mail: rasmus.licht@rn.dk)



Obviously, the answer to the question posed depends on the definition of “curable.” According to the Oxford dictionary a medical condition is curable if it can be relieved by a treatment. Or put in another way: even if the goal is full restoration to health, a treatment can be considered a cure as long as it improves the condition in question. To establish causality between a treatment and an improvement— a requirement inherent in the definition of a cure—evidence- based medicine relies on randomized clinical trials (RCTs).

Consequently, since a number of treatments have been demonstrated to improve the course of depression in RCTs, both under short-term and long-term conditions, as is the case for various antidepressants,1,2 we actually have cures for depression. By adopting RCTs as proof of causality, we accept that causality is determined on a group level and not on a case level, implying that an improvement in depression in a given patient may not be caused by the cure provided.

Depression is highly heterogeneous with multiple epidemiological features and etiologies.3 The condition comprises major depressive disorder (MDD), bipolar depression, and secondary depression. For some forms of depression, ie, certain types of organic depression, cures are scarce or even lacking. Even MDD, whether single-episode or recurrent, is considered heterogeneous, and a substantial proportion of MDD patients will remain depressed for a shorter or longer period of time no matter whether they have been treated sequentially with several treatments.4 Additionally, only a minority of patients whose symptoms have actually improved will experience full functional recovery. Finally, there are no reliable a priori characteristics indicating whether any given treatment will actually work for any given depressed patient. This unpredictability reflects the fact that we have no comprehensive full understanding of the various aspects of the pathogenesis of depression and how the various treatments may specifically influence the healing process.

As clinicians we can reliably communicate to our patients that we have evidence-based treatments—both psychotherapeutic and psychopharmacological—that overall may improve the prognosis of depression. However, due to the points raised above we may be reluctant to use the term cure for our treatments when introducing them to our patients even if they meet the definition. More precisely, we may instead specify that our treatments are cures simply because they increase the likelihood of a beneficial symptomatic course as compared with no treatment. In trials evaluating drugs for the acute treatment of depression, overall 21%-39% and 42%-70% of moderately to severely depressed patients responded in a placebo arm and in an active arm, respectively.5 Therefore, the likelihood will be increased roughly by a factor 2. When response (or better, remission) has been reached during drug treatment, we can also inform our patients that the risk of a subsequent reemergence of depressive symptoms within the first 12 months will increase by a factor 2 if they discontinue the given drug treatment, compared with continuing the treatment, ie, from 18% to 41%.6 Likewise, the risk of future recurrences, independent of a current episode can seemingly be reduced.2

Those patients that have had previous episodes and who, while being treated, experience long-term absence of episodes may be the group of patients that comes closest to having been cured. However, since a vulnerability to depression often remains, these patients need to continue taking the cure.

In conclusion, depression is curable, but unfortunately only a modest proportion of patients may actually feel cured by our treatments. ■


References
1. Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Moller HJ. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry. 2013;14(5):334-385.
2. Licht RW. Is it possible to evaluate true prophylactic efficacy of antidepressants in severely ill patients with recurrent depression? Lessons from a placebo-controlled trial. The fifth trial of the Danish University Antidepressant Group (DUAG-5). J Affect Disord. 2013;148(2-3):286-290.
3. Kupfer DJ, Frank E, Phillips ML. Major depressive disorder: new clinical, neurobiological, and treatment perspectives. Lancet. 2012;379(9820):1045-1055.
4. Rush AJ, Warden D, Wisniewski SR, et al. STAR*D: revising conventional wisdom. CNS Drugs. 2009;23(8):627-647.
5. Davis JM, Giakas WJ, Qu J, Prasad P, Leucht S. Should we treat depression with drugs or psychological interventions? A reply to Ioannidis. Philos Ethics Humanit Med. 2011;6:8.
6. 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.

9. F. Lopes Rocha, Brazil

Fábio LOPES ROCHA, MD, PhD
Chief – Psychiatric Clinic
Instituto de Previdência dos Servidores
do Estado de Minas Gerais
Belo Horizonte, BRAZIL
(e-mail: rochafl@uol.com.br)



Antidepressants are considered the cornerstone of depression treatment. However, their efficacy has been a source of debate in recent years. It is sometimes said that their effect is far from matching the criteria for clinical effectiveness or of questionable clinical significance. Sometimes, it is said that they can be useful only in the most severely depressed patients.1 Most authors agree that estimated rates of remission fall below 50%. That is, the majority of patients will benefit at most from an attenuation of their symptomatology, far from restoring previous functioning. Nevertheless, it is not reasonable to take this data at face value. Methodological limitations of clinical trials and meta-analyses, differences between trials and clinical practice, and results of other areas of medicine must be acknowledged.

Trials in depression have major drawbacks that hinder the detection of antidepressant efficacy. Our classification systems consist of a hodgepodge of different depressive disorders. Inclusion/exclusion criteria facilitate the enrollment of patients that are not representative of clinical practice. Some procedures favor the inclusion of inadequate patients. In fact, the response rates of placebo and antidepressants have been steadily increasing with consequently smaller effect sizes.2 Increasing the number of patients is a poor strategy, as larger trials inflate the statistical variance, decreasing study power. Failed or negative trials in depression are superior to 50%. Nevertheless, absence of evidence of a difference is not the same as evidence of absence. Moreover, clinical trials are designed to investigate the therapeutic potential of a drug under standardized conditions. They are not able to tell the extent of efficacy of an antidepressant in clinical practice.3

Theoretically, meta-analyses provide the best summary of the puzzling potpourri of trials assessing antidepressant efficacy. However, they are undermined by limitations related to the number and quality of individual clinical trials as well as variations in grouping and inclusion criteria. In addition, there is always a risk of flawed analysis and overinterpretation.4 These problems have brought an unfair pessimism regarding antidepressants. As a recent example of how meta-analyses can lead to equivocal assumptions, a study showing that the efficacy of antidepressants is limited to the most severe cases of depression1 was not supported by a patient-level data meta-analysis that found antidepressant efficacy to be independent of depression severity.5 Of course, antidepressants are not ideal drugs. They do not work for every patient and frequently do not alleviate all symptoms. They have side effects, pharmacological interactions, can have negative effects on other diseases, and they pose concerns during pregnancy and breastfeeding. Welcome to the real world of medicine! Most of these criticisms can be applied to clinical trials, meta-analyses, and pharmacological treatments in general medicine. In fact, the effect size of psychiatric drugs, including antidepressants, is in the same range as most general medical pharmacotherapeutics.6 Efforts to improve efficacy and methodologies are present in all fields. There is no reason to be particularly pessimistic about the treatment of depression.

Another frequently held assumption is that as clinical trials are very standardized, with highly selected populations of depressed patients, their results are far better than the results obtained in real-world settings. This is not necessarily true. From a clinical practice perspective, trials are like tailors who adapt the person rather than the clothing when the clothing does not fit their customer. In routine practice, psychiatrists do not roll dice; they choose what they judge to be the best treatment for a specific person considering the evidence, their expertise, and their patient’s preferences. Psychopharmacological history, type of depression, side effect profiles, and patient preferences are weighed. Dosages and timing are flexible and it is possible to adopt measures to attenuate side effects. In case of insufficient response or poor tolerability, changing the antidepressant, combination, and potentiation are optional methods. In addition, psychotherapeutic interventions should be considered. Taking everything in consideration, in clinical practice it is possible to help a significant number of patients to achieve remission, restoring quality of life and complete functioning. ■


References
1. Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS medicine. 2008;5(2):e45.
2. Khan A, Bhat A, Kolts R, Thase ME, Brown W. Why has the antidepressantplacebo difference in antidepressant clinical trials diminished over the past three decades? CNS Neurosci Ther. 2010;16(4):217-226.
3. Parker G, Anderson IM, Haddad P. Clinical trials of antidepressant medications are producing meaningless results. Br J Psychiatry. 2003;183:102-104.
4. Fountoulakis KN, Samara MT, Siamouli M. Burning issues in the meta-analysis of pharmaceutical trials for depression. J Psychopharmacol. 2014;28(2):106-117.
5. Gibbons RD, Hur K, Brown CH, Davis JM, Mann JJ. Benefits from antidepressants: synthesis of 6-week patient-level outcomes from double-blind placebocontrolled randomized trials of fluoxetine and venlafaxine. Arch Gen Psychiatry. 2012;69(6):572-579.
6. Leucht S, Hierl S, Kissling W, Dold M, Davis JM. Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses. Br J Psychiatry. 2012;200(2):97-106.

10. G. S. Malhi, Australia

Gin S. MALHI, MBChB (UK) BSc Pharmacol
(Hons) (UK); FRANZCP (Aus)
FRCPsych (UK); MD (Aus)
Professor and Head, CADE Clinic
Department of Psychiatry
University of Sydney
AUSTRALIA
(e-mail: gin.malhi@sydney.edu.au)



The concept of a cure seems alien to psychiatry and perhaps for some psychiatric disorders, such as neurodegenerative diseases, it is; but is it applicable to depression? It is important to understand that depression per se is not a single entity; it comprises multiple disorders and subtypes, resulting in its myriad presentations.1 This suggests that some kinds of depression may be the consequence of a disease process. If this is so, then there is a good possibility that we may be able to identify mechanisms, processes, and specific pathways that underpin these forms of depression, and so the idea of a cure for them is quite conceivable.

What would a cure for depression look like? At a molecular level, a cure could involve the replenishment of depleted or damaged proteins and the restoration of key neurochemical processes. At a functional level, a cure could involve reestablishing misfiring neural circuits. Clinically, these changes would ultimately modulate mood, drive, and cognition. But achieving such a cure, even in a subset of depression, requires detailed knowledge of the pathophysiology of established disease. In other words, we need to discover exactly “what is broken” and then know “how to fix it.” This kind of insight would also open the door to understanding how and why depression occurs in the first place, which in turn would provide an opportunity for preventing the disease. Hence it is important to investigate the onset of depression and the emergence of clinical symptoms, and also to examine the precursors to the clinical syndrome. In this vein, a recent study of adolescent girls has shown that the antecedents of depression are accompanied by discernible neural changes in the hippocampus and its emotion-processing interconnections.2 Though this is a step in the right direction, we are still a long way from finding a cure or preventing depression.

Clinically, a paradigm shift is long overdue. In recent years our frame for treatment outcome has moved from response to remission. This has been useful in emphasizing the importance of completely extinguishing the symptoms of depression with treatment, instead of simply achieving a measurable reduction. The next necessary step is to expand our frame further to encompass recovery; from here we can examine relapse and learn how to prevent further episodes of illness and maintain well-being. This is of utmost importance, because “recurrence” defines depressive disorders; indeed, it is the essence of depression. Therefore, in practice, treating depression properly and completely not only requires a thorough cross-sectional appraisal of depressive symptoms and their suitable treatment using antidepressants and psychological strategies, but it also requires a longitudinal perspective that identifies the psychosocial and lifestyle factors that contribute to the maintenance and recurrenceof depression, so that these too are adequately addressed.

The eventual aim of treatment is to achieve healthy emotional functioning. However, this does not mean the simple absence of negative emotions: positive emotions also need to be reinstated and engaged fully. The extent to which this is actually possible is unclear. For instance, it may be that depression compromises the brain’s ability to feel positive emotions in a normal healthy manner and that this alteration is irreversible. Furthermore, even with adequate treatment, it is conceivable that medications such as antidepressants restrict “normal” emotional functioning to the extent that full emotional recovery is simply not possible. Depression certainly alters brain structure and function, and it is no surprise that medications can do the same. The key question and concern is whether these changes are everlasting, or whether they can be reversed, or at least, limited. This is an area in urgent need of research and understanding. In the interim, it is important that we understand positive emotions and include these in our appraisal of depression and, in particular, recovery from depression. To this end, we need reliable standardized measures to capture positive feelings and to test these in depressed patients. In this regard, it is worth noting the recent interest in mixed features in depression3 and bipolar disorder,4 especially as it is becoming increasingly apparent that a considerable number of patients with depression have latent bipolar disorder and that, when they are depressed, they may also have mixed features that are likely to be overlooked if not targeted specifically. In other words, we will only find what we are looking for if we pose the correct questions. Relying purely on the phenomenology of mood disorders we have perhaps achieved as much as we can in terms of identifying and defining presentations that reflect underlying diseases. If we are to find a cure for depression, we must start to believe that this is a real possibility, and that depression, or at least some of it, can be conquered. ■
Acknowledgments: NHMRC competitive grant funding.


References
1. Malhi GS. Ordering Disorder. Malhi GS. DSM-5: Ordering disorder. Aus NZ J Psych. 2013;47:7-9.
2. Das P, Coulston CM, Bargh DM, et al. Neural antecedents of emotional disorders: An functional magnetic resonance imaging study of subsyndromal emotional symptoms in adolescent girls. Biol Psychiatry. 2013;74:265-272.
3. Malhi G, Lampe L, Coulston C, et al. Mixed state discrimination: a DSM problem that won’t go away? J Affect Disord. 2014;158:8-10.
4. Malhi GS. Diagnosis of bipolar disorder: who is in a mixed state? Lancet. 2013; 381:1599-1600.

11. N. O. Maruta, Ukraine

Nataliya O. MARUTA, MD, PhD
Institute of Neurology, Psychiatry, and
Narcology of the NAMS of Ukraine
Kharkiv, UKRAINE
(e-mail: mscience@ukr.net)



There has been an evolution of opinions concerning recovery in psychiatry following the transition of the paradigm of mental health care from an entirely medical one to a biopsychosocial one that takes into account not only the biological mechanisms of pathology formation, but also all the diversity of the determinants—including personality- environmental determinants—involved in the process. Contemporary conceptions of recovery are based on a dynamic approach that allows the assessment not only of outcomes of some pathological conditions in the form of a reduction or remission of symptoms, but also of the process of recovery per se when a patient is full of life and maintains his/ her social functioning despite the presence of symptoms.1,2

Evaluation of recovery in depression is complicated significantly by the fact that the essential manifestations of the pathological process (depressed mood, anhedonia, anxiety, etc) are very closely connected with patients’ social functioning and quality of life.

The only possible approach to such a situation is a personalization of diagnosis, therapy, and assessment of the further dynamics of the conditions with a detailed analysis of clinical and psychological components.

From a clinical point of view, the most important indicators of the process of recovery are therapeutic response and remission. Therapeutic response is a predictor of remission and has been shown to fluctuate within the range of 32% to 70% of patients.3 That is why the first antidepressant prescribed induces remission in only 33% of patients, and why after subsequent switches to four other antidepressants during a year, the total proportion of patients having achieved remission is only 67%.4

Problems in achieving remission are largely associated with the multifactorial nature of the neurobiological mechanisms of depression, including interactions between central neurotransmitters and endogenous opioid peptides providing emotional reactions. In addition, one cannot leave out mentioning the importance of motivation and psychological attitude as they both influence many clinical parameters, including onset of remission. This correlation is supported by data showing that in patients with a negative, neutral, or positive psychological attitude onset of remission is achieved in 51%, 56%, and 69% patients, respectively.5

When both biological and sociopsychological influences impact on the resulting recovery, the physician’s strategy and tactics should be fully oriented toward promoting treatment compliance and a therapeutic alliance. This will allow successful implementation of the numerous therapeutic options that contemporary science can offer. Such options include uptitration of the dose of antidepressant, switching to another antidepressant of the same class or of a different class, adding a medication (an antidepressant from another class, a neuroleptic drug, or a mood stabilizer), combination with psychotherapy, and using nonpharmacological methods such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), etc.

Taking into account that patients’ main motivations are to recover functioning and the positive mental health (optimism, energy, self-reliance, emotional control) they had before the disease, the choice of primary antidepressant should be based on the therapeutic properties of the medication regarding not only depressive symptoms, but also recovery of the richness and integrity of emotional reactions, cognitive functions, and social functioning.6,7

Finally, the importance of treatment personalization among the numerous factors influencing recovery in depression should be emphasized. This means using innovative medications that take into account the individual characteristics of the patient (clinical, gender, age, etc). ■


References
1. Leamy M, Bird V, Le Boutillier C, Williams J, Slade M. A conceptual framework for personal recovery in mental health: systematic review and narrative synthesis. Br J Psychiatry. 2011;199:445-452.
2. Slade M, Williams J, Bird V, Leamy M, Le Boutillier C. Recovery grows up. J Ment Health. 2012;21(2):99-104.
3. Bauer M. Depressive episode: does antidepressant treatment prevent the risk of depressive disorder? Medicographia. 2011;33(2):151-157.
4. Fava M, Rush AJ, Alpert JE, et al. Differences in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008;165(3):342-351.
5. Demyttenaere R. From sadness to depressed mood and from anhedonia to positive mood and well-being. Medicographia. 2013;35(3):287-291.
6. Munoz C. Valdoxan’s unique profile of antidepressant efficacy at the core of depression. Medicographia. 2013;35(3):327-333.
7. Zimmerman M, McGinchey JB, Postemar MA, Friedman M, Attiulalah N, Boerescu D. How should remission from depression be defined? The depressed patients perspective. Am J Psychiatry. 2006;163(1):148-150.

12. S. N. Mosolov, Russia

Sergey N. MOSOLOV, MD
Professor, Moscow Research
Institute of Psychiatry
Moscow, RUSSIA
(e-mail: profmosolov@mtu-net.ru)



Before speaking about the curability of depression, it is necessary to understand what we are treating and what is depression. The present-day definitions of depression are far from the scientific model and are usually defined by a purely descriptive (often based on subjective reports) and behavioral approach. This significantly complicates the search for biological markers and pathogenetically substantiated methods of therapy. It also cannot provide a satisfactory prognosis of the disease course or the therapeutic response. Under these conditions it is possible to speak about curability of depression only hypothetically, using futurological notions and terminology.

First of all, we should analyze and try to explain the major causes of the rapid growth of depression in the 21st century. I believe that this is related to certain contradictions with which Man has been confronted as a strictly determined biological species that was formed following a long evolutionary process, and the revolutionary technological changes occurring in the noosphere due to human activities. It is uncertain whether Homo sapiens will be able to cope with this global challenge or whether any qualitative leap or “phase transition” of Man’s psychophysiological and adaptational capabilities will take place. The prognosis for the epidemic growth of depression and its treatment is gloomy; however, there is a certain probability of achieving local success with the introduction of new treatment methods for the individual biological variants of depression. Additionally, a higher level of treatment personalization resulting from the progress made by genetic research may yield better results.

Another important question to ask is, “what therapeutic effect are we expecting to achieve?” Relieving the symptoms of depression and treating depression as a chronic disease while attempting to prevent relapses and preserving a high level of social adaptation and quality of life during remission are very different therapeutic tasks. We have become fairly successful at the first task; however, the solution to the second task does not seem to exist at the moment. The notion of recovery in depression should be comprehensive and cover not only complete reduction of the main symptoms, including residual subthreshold symptomatology (ie, achievement of remission), but also continued maintenance during remission, and complete restoration of cognitive, personal, and social functioning with preservation of an acceptable level of quality of life.

Neurotransmitters, chronobiological, neurotrophic (neuroplasticity), and stress-diathesis models of depression have become widely used; however, other mechanisms are also possible. Most mechanisms are described in both neurological and mental diseases; this is not surprising as the different spheres of cerebral activity are closely related to each other and integrated into the holistic system of the human “psyche.” Also, depression is probably not a homogenous disease, and its causes are varied. This heterogeneity is reflected in the modern diagnostic criteria for depression, which so far have been based to a greater extent on a phenomenological (symptomatic) approach than on a nosological (medical) model. This is in particular evidenced by the high comorbidity (up to 50%) of recurrent depression with anxiety disorders, a high placebo effect (up to 50%), and the heterogeneity of the effects of modern antidepressants. Uniting artificially under this diagnosis the fairly different clinical features, course, pathogenesis, and therapy response of conditions such as melancholic, atypical, and psychogenic (reactive) depressions or depressions in which psychomotor retardation, anxiety, anhedonia or psychic anesthesia, and cognitive disorders with depressive ruminations predominate makes the search for the biological basis of these conditions and more effective methods of therapy difficult. Evidently, when the disease develops at a young age, genetic factors and maybe early stress play a significant role. In mature and old age, chronic stress, chronobiological disturbances, and comorbid somatic diseases acquire greater importance. In addition, during the chronic course of depression, cognitive impairment and neurodegenerative changes develop. It is also evident that in most depressive patients sleep is altered and desynchronization of circadian rhythms and of rhythms that have another periodicity is observed, which may be the main pathophysiological link of depression. Although the causal relation between these disturbances and recurrent depression has not yet been established, a chronotherapeutic strategy should be taken into consideration in the complex therapy of depressive patients since it may provide a higher effectiveness not only in regard to adequate reduction of symptomatology, but also in providing prophylactic effect and in achieving a higher level of social functioning and quality of life.

The absence of a single harmonious theory of depression stimulates our research interest, which in recent years has been aimed at searching for reliable biological markers for the disease and new, more personalized, methods of treatment. ■

13. J. L. Pio-Abreu, Portugal

J. L. PIO-ABREU, MD, PhD
Clinical psychiatrist
Professor of Psychiatry
Faculty of Medicine, University of Coimbra
Center for Philosophy of Sciences of the
University of Lisbon
PORTUGAL
(e-mail: pioabreu@netcabo.pt)



Can depression be cured? May we cure human sadness? Can we speak about a cure when faced with an episodic disorder? Does the beginning of a manic episode represent a cure for depression? These questions may not make sense, but they frequently occur in the minds of clinical psychiatrists, and highlight the difficulty of dealing with such a fuzzy disorder.

Depression has been known since the Old Testament (the story of Job) and was described by Hippocrates. However, it defies clear definition and delimitation. Several authors agree that only the melancholic criteria may be considered as a pathological symptom of depression,1 but recent discussions about the inclusion of grief reactions in the DSM-5 criteria of major depression point to the difficulty in distinguishing between common human reactions and their pathological developments. Perhaps we are looking at similar phenomena, but from different angles. Can we link these different visions in order to understand the nature of the phenomenon?

From the pathology point of view, the main idea is that depression is a disorder of rhythms.2 Melancholic symptoms include early-morning waking, morning worsening of mood, weight loss, and loss of sexual desire. Depression occurs in episodes, with some seasonal incidence. The general picture is a loss of energy and slowing of all motor and cognitive activities. Sometimes, the episode remits spontaneously or switches to an episode of great energy and activity, which is called mania or hypomania. Sleep or light manipulation can modify the course of mood disorders, emphasizing their rhythmic nature.

Rhythms are universal features of life. Every organ, cell, neuron, gene, or body fluid pulses with a known rhythm, and life results from the harmonization of all these rhythms. External or internal events may disturb some rhythms, but homeostatic reactions tend to keep them in line. The diencephalon is the great synchronizer of vertebrate rhythms. Brain scars or genetic dysfunction of ionic channels (present in epilepsy and bipolar disorders)3 may desynchronize some neuronal rhythms. Thus, the thalamus recruits and distributes the neuronal impulses, producing a seizure and resynchronizing them. Hormonal rhythms are also regulated in the hypothalamus and pituitary gland. Furthermore, the diencephalon extends caudally to the pineal gland, another gland that produces melatonin in response to environmental light, thereby regulating the circadian rhythms.

However, in mammals, the hypothalamic suprachiasmatic nucleus takes over from the pineal gland as a circadian pacemaker. Mammals live in families, sometimes displaying nocturnal activity, and they need to be synchronized with each other more so than with the sun. Personal relationships imply a synchronization of activities and, even more, of physiological rhythms. When we lose a close person, we also lose an important source of synchronization and feel empty. Some complex feelings can then lead us to avoid other people and refuse other attachments and synchronizations. Furthermore, we can become desynchronized with the sun and all our rhythms may be disturbed.

Loss (of people, roles, and expectations)4 is a factor in depression, and mourning can be its model.5 Some authors also point to romantic passion as a model of mania.6 Passionate and manic people are very energetic, optimistic, and persuasive. In fact, passionate people try to synchronize with the person(s) they love, thus “rebuilding” what they have lost. Manic patients do so spontaneously.

So, should we cure depression? Yes and no. Life is made of changes where something is lost and something is gained. We may treat depression if patients are not able to regain something when they experience loss, if intense reactions, bad feelings, or previous conditioning lead them to add further losses to the original loss, and when these episodes are mere repetitions without sense. In every other circumstance, people should be allowed to grieve and to fall in love. ■


References
1. Wakefield JC, Schmitz MF. When does depression becomes a disorder? Using recurrence rates to evaluate the validity of proposed changes in major depression diagnostic thresholds. World Psychiatry. 2013;44(1):44-52.
2. Pio-Abreu JL. Elementos de Psicopatologia Explicativa. Lisboa: FundaçãoCalouste Gulbenkian. 2012: 167-231.
3. Craddock N, O’Donovan MC, Owen MJ. Psychosis genetics: modeling the relationship between schizophrenia, bipolar disorder and mixed (or “schizoaffective”) psychoses. Schizophrenia Bulletin. 2009; 35(3): 482-490.
4. Brown GW (1982). Social factors and affective disorders. Psiquiatria Clínica. 1982; 2(Suppl.2):19-23.
5. Freud S. Mourning and Melancholia. In: The Standard Edition of the Complete Psychological Works of Sigmund Freud, Volume XIV (1914-1916). London, UK: Hogarth Press; 1917.
6. Thase ME. Mood Disorders: neurobiology. In B Sadock and V Sadock (Eds.). Kaplan and Sadock’s Comprehensive Textbook of Psychiatry, 8th Ed. Philadelphia, PA: Lippincott, Williams & Willkins; 2004: 1594-1603.

14. S. Smadja and R. Gaillard, France

Sarah SMADJA, MD – Raphaël GAILLARD, MD, PhD
Laboratoire de Physiopathologie des Maladies Psychiatriques
Centre de Psychiatrie et Neurosciences
Université Paris Descartes, Sorbonne Paris Cité
FRANCE (e-mail: ssmadja1@gmail.com)



Major depressive disorder (MDD) is characterized by a combination of symptoms that interfere with a person’s ability to work, sleep, study, eat, and enjoy once-pleasurable activities. Major depression is disabling and prevents a person from functioning normally. According to this definition, we can consider recovery as a return to previous global functioning. Classically, recovery is defined by the persistence of complete remission for a period of 4 to 6 months. However, studies have found that about one-third (34% and 32%, respectively)1,2 of patients recover from major depressive episodes (MDEs) with residual subthreshold depressive symptoms (SSDs).

Judd et al have shown that residual SSD recovery is associated with very rapid episode relapse, which supports the idea that SSD is an active state of illness.2 Moreover, residual SSD recovery has a significantly stronger association with early depressive episode relapse than the recurrent MDE risk factor (OR, 3.65 vs 1.64, respectively). Asymptomatic recovery is associated with a prolonged delay in episode recurrence.

Over 80% of patients who have had a first episode will experience another one during their life. Consequently, unipolar depressive disorders are considered to be recurrent disorders. Kendler et al found strong evidence that the strength of the association between stressful life events and onset of depression declines with increasing number of previous depressive episodes, which supports the kindling hypothesis.3 These models predict that with recurrent episodes of major depression, the role of environmental stressors will progressively diminish. According to these models, each episode of depression leaves a “scar” that makes the subject more vulnerable to the onset of a new episode, and therefore a trigger of a lesser intensity is required to give rise to each event. In 1999, Sheline first exposed the notion of neurocognitive scars induced by the neurotoxicity of depressive episodes, by showing a correlation between the degree of hippocampal volume reduction and the total duration of a major depressive episode.4 Gorwood et al assessed the impact of depression on hippocampal function; their findings suggest that the intensity of past depression contributes to the impairment of memory performance when patients have recovered.5 Consequently, there may be advantages in early treatment, maintained for a sufficient period, and in not tolerating chronicity or even partial remission. Residual SSD is a treatment target to prevent a relapse. In a 3-year prospective study of 267 patients with MDD, Conradi et al found that on average three individual symptoms (cognitive problems, lack of energy, and sleeping problems) dominated the course of depression and were present 85% to 94% of the time during depressive episodes and persisted in 39% to 44% of remitted patients.6 Clinicians also need to distinguish persisting residual symptoms, newly emerging or re-emerging symptoms, and late-onset antidepressant side effects. Some patients with major depression report experiencing a narrow range of emotions, which may appear as a side effect of antidepressants. This phenomenon— also known as emotional blunting—can represent residual symptoms of depression or side effects of antidepressant treatment. C. J. Harmer has shown that treatment with selective serotonin reuptake inhibitors (SSRIs) can curb the neural processing of rewarding stimuli, an effect that may underlie the questioned effectiveness of SSRIs in depressive conditions characterized by decreased motivation and anhedonia, and could account for the experience of emotional blunting reported during SSRI treatment.7

Growing evidence suggests that some MDD symptoms (fatigue, cognitive symptoms, lack of motivation) may not respond to the conventional treatments that are effective in treating other core MDD symptoms. Early identification of these symptoms, combined with new treatment approaches, may restore optimal global functioning in our patients. ■


References
1. 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.
2. 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.
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. Sheline YI, Sanghavi M, Mintun 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.
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. Conradi HJ, OrmelJ, de Jonge P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011;41,1165-1174.
7. McCabe C, Mishor Z, Cowen PJ, Harmer CJ. Diminished neural processing of aversive and rewarding stimuli during selective serotonin reuptake inhibitor treatment. Biol Psychiatry. 2010;67:439-445.

15. C. Sukying, Thailand

Chakrit SUKYING, MD
Associate Professor Department of Psychiatry
Ramathibodi Hospital Mahidol University
Bangkok, THAILAND
(e-mail: chakrit.suk@mahidol.ac.th)



For the past two decades, researchers have been trying to better understand the nature of major depressive disorder in the hope that this deeper understanding will help those affected by the disease. Major depressive disorder, once manifested in a patient, inevitably not only affects the patient, but also the patient’s family and social circles. Naturally, these unfortunate victims desire an answer to the question: is depression curable?

The answer to this short and emotional question is surprisingly difficult to obtain. To be able to answer the question, one must look at information from research and from extensive clinical observations, both in the past and in the foreseeable future.

A key characteristic of major depressive disorder is the recurrence of episodic attacks. In 1989, the MacArthur Foundation launched an initiative to summarize and document the outcomes of this disease; and in 2006, the American College of Neuropsychopharmacology (ACNP) refined the criteria for remission to assist subsequent clinical studies.1,2 The result is an extensive documentation on five major areas: response, remission, recovery, relapse, and recurrence. The curability of depression then boils down to treating individual episodic attacks and lengthening the recovery periods between attacks. This implies that the process responsible for the ongoing episode has, at least, been arrested even though the underlying mechanism responsible for the recurrence may or may not be eradicated yet. However, if the ideal is to maintain the length of the recovery phase for as long as possible, we must understand what causes recurrences as well as what helps prevent recurrences. Evidence from previous studies strongly indicates that before a patient can be in recovery, the patient must first attain full remission, because one of the leading causes of recurrence is partial, or incomplete, remission. Exhibiting residual symptoms is a stronger factor in predicting chances of relapse than the severity of the condition and the number of previous depressive episodes. Studies have also shown that going into remission has a stronger positive impact on functioning, prognosis, and the maintenance of a stable enduring state than achieving a response. If the immediate goal for treating depression is for the patients to go into remission, a good benchmark is the remission rate. Efficacy studies in the past 10-20 years have shown a trend toward better and faster remission in patients treated with newer antidepressants relying on broad-spectrum mechanisms compared with patients taking older antidepressants. These new antidepressants, therefore, will potentially increase the remission rate. Another way to increase the remission rate is to eliminate factors that prevent patients from going into remission, for example, discontinuation of treatment due to adverse effects.

Aside from its severe mental toll, major depressive disorder can also lead to disabilities and is predicted to be the leading cause of disabilities worldwide by 2020. Fortunately, although patients are critically affected in their daily functions by depression, studies have shown that successful curing of the disease leads to a significant decrease in impairment in psychosocial functioning. Restoration of the patients’ global functioning will directly follow from the successful treatment of the disorder. The less affected the patients are by the episode, the more they can resume their previous level of functioning.

So, is depression curable? As of now, there is no clear answer to this question. However, with advances in different forms of treatments, organized research, and a clear goal for treatment, we will be able to further the understanding of the nature of this disease and its treatment. This will ultimately help us refine and improve our answer in the future. ■


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. Rush AJ, Kraemer HC, Sackeim HA, et al; ACNP Task Force. Report by the ACNP Task Force on response and remission in major depressive disorder. Neuropsychopharmacology. 2006;31(9):1841-1853.

16. S-J. Tsai, Taiwan

Shih-Jen TSAI, MD
Chief, Section of Adult Psychiatry
Taipei Veterans General Hospital
and Professor, National Yang-Ming University
Taipei, TAIWAN
(e-mail: tsai610913@gmail.com)



Depression is a common mental disorder, characterized by low mood and diminished interest or pleasure. Currently, the main medical treatment for depression is antidepressant medication. Is depression curable? Recovery is defined as a full remission with no symptoms for a certain length of time. However, many depressed patients fail to achieve remission after being placed on initial therapy with an antidepressant. In the STAR*D study (Sequenced Treatment Alternatives to Relieve Depression), which included nonpsychotic major depressive disorder outpatients, it was found that even with systematic measurement-based treatment, only approximately one-third of patients reached full remission after one treatment step, with two-thirds reaching remission after four treatment steps.1 This study clearly demonstrated that a large portion of depressed patients cannot achieve remission or recovery with initial antidepressant treatment. However, part of these nonremitted patients can achieve remission with other antidepressants.

Failure of depressed patients to achieve remission represents a major public health concern. Inadequately treated depression is associated with poorer quality of life, deleterious personal and societal economic ramifications, and increased mortality rates. Some of the primary challenges for the treatment of major depression are (i) how to increase the remission rate, and (ii) whether it is possible to subgroup depressed patients based on biological markers or clinical characteristics before treatment to predict remission rates.

How can we increase the remission rate? Even when an antidepressant is effective, lack of compliance can be a major problem in the treatment of depression. The ability of the depressed patient to tolerate a drug’s adverse effects greatly influences his or her treatment compliance, as well as the probability of relapse. For depressed patients who do not respond to initial antidepressant treatment, the next pharmacological treatment options include switching to another antidepressant with a different mechanism of action or augmenting the initial therapy with a second agent. Developing novel antidepressants with new therapeutic mechanisms and fewer adverse effects could improve adherence and increase remission rates. In addition to pharmacotherapy, psychotherapy shows promise in enhancing remission rates. It has been shown that the combination of pharmacotherapy and short-term psychotherapy is significantly more efficacious than either pharmacotherapy or psychotherapy alone. Various nonpharmacological, neuromodulatory strategies, such as electroconvulsive therapy (ECT), magnetic seizure therapy (MST), repetitive transcranial magnetic stimulation (rTMS), vagal nerve stimulation (VNS), and deep brain stimulation (DBS) have been used to treat treatment-resistant depressed patients.

Can we group depressed patients into subgroups based on biological markers or clinical characteristics at baseline to predict remission rates? Studies on this topic are still in the initial stages. A recent study suggested that using baseline evaluations of patients’ anguish/restlessness, reduced emotional reactivity, reduced attention, reduced motor response, feelings of worthlessness, and mood characteristics items, it was possible to correctly classify 88% of the sample group as remitters or nonremitters with a sensitivity of 0.77 and a specificity of 0.96.2 Other studies using neuroimaging, electroencephalograms, or genetic analysis have suggested that there are some biological biomarkers of remission in major depression patients, but these need further confirmation from replication studies. ■


References
1. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.
2. Navarro V, González A, Guarch J, et al. Association between symptomatic profile and remission following antidepressant treatment in unipolar major depression. J Affect Disord. 2013;150:209-215.

17. M. Yeghiyan, Armenia

Maruke YEGHIYAN, MD, PhD
Professor department of psychiatry
Yerevan State Medical University
Yerevan, ARMENIA
(e-mail: maruke@freenet.am)



In most societies the word depression has a colloquial connotation meaning “bad mood.” Mood variations throughout the day are within the norm and are an indicator of mental health rather than disturbance. A healthy person may experience daily combinations of different emotions such as joy, satisfaction, or irritation, which may contribute to them having a bad or a good day and may provide the feeling of having “a zest for life.” In medical terms, depression is a disease that can disrupt the emotional balance for a prolonged period of time and significantly debilitate a person.

Depression may occur as a result of a previous traumatic event, but often there are no apparent external triggers. In terms of the clinical picture, depression disrupts the plasticity, the dynamism, as well as the integrity of all emotional processes, and ultimately leads to a complete physical and mental collapse. Biologically the picture is vague; however, it is quite clear now that depression is an imbalance between receptors and neuromediators in brain tissue. Thus, the target organ is the brain itself.

The biggest improvement for the treatment of depression is the discovery of antidepressant medicine in the last century. There are continued efforts to develop new and improved antidepressant medications. With each new drug there are new hopes and new perspectives, and sometimes disappointments. However, advances in psychopharmacology have led to the development of various hypotheses on the pathogenesis of depressive disorders. Until the late 20th century the monoamine hypothesis was widely recognized as the fundamental cause of affective disorders.This hypothesisdetermined the development of the following types of antidepressants:
◆ Tricyclic antidepressants with nonselective effects on multiple receptor system
◆ Selective single-action antidepressants (eg, SSRIs, SNRIs)
◆ Multiple selective-action antidepressants (SSNRIs)

Over time, these drugs have become the standard in the treatment of depression; however, these treatments have numerous side effects such as sexual dysfunction, apathy, and changes in behavior and appetite. In my practice, patients treated with the standard SSRIs/SNRIs approach generally rated their condition as good but often noted a sense of “artificiality” (feeling robot-like) and a decrease in the intensity of their feelings. The 21st century brought about other therapeutic targets for depressive disorders beyond the monoamine hypothesis. This was due primarily to the inconsistency of the monoamine hypothesis and the empirical data on the efficacy of other treatments such as electroconvulsive therapy, phototherapy, and sleep deprivation.

The more immediate amelioration of depressive symptoms with electroconvulsive therapy or sleep deprivation1 provides an attractive alternative to the delayed onset of therapeutic action of monoamine antidepressants. There are also considerations regarding the cognitive components of depression and the role of glutamate and γ-aminobutyric acid (GABA) in neuroplasticity.2 The search for novel therapeutic agents continues. Currently, new therapeutic treatments in the pipeline include ketamine, a N-methyl-D-aspartate receptor antagonist,3 microRNAs, an entirely new class of therapeutic agent that mood stabilizers use as downstream effectors,4 circuitry based targets such as deep brain stimulation, vagus nerve stimulation, and magnetic stimulation.5 Another therapeutic target is inhibition of melatonin in the pineal gland, which causes a change in the concentration of cortisol and adrenocorticotropic hormone (ACTH) and regulates the balance of catecholamine synthesis, which in turn “resets” the circadian rhythm. This modality is by far the most reasonable since it mimics the natural mechanisms of mood regulation unlike monoaminergic antidepressants.

The answer to the controversial question of whether depressive disorders can be cured depends on the treatment goals chosen by physicians. Common sense, however, tells us that a physician should not focus solely on symptomatic targets, but rather on the restoration of the patient’s optimal global functioning. In other words, a person should not be free of “sadness” but truly happy, and experience the full range of feelings and social functioning that defines a healthy person. Such targets should include removal of symptoms of depressive disorders and restore to health the parts of human mental health that have been affected by the disease. ■


References
1. Black DW, Winokur G, Nasrallah A. The treatment of depression: Electroconvulsive therapy vs antidepressants: A naturalistic evaluation of 1,495 patients. Compr Psychiatry. 1987;28(2):169-182.
2. Gao SF, Bao AM. Corticotropin-releasing hormone, glutamate, and gammaaminobutyric acid in depression. Neuroscientist. 2011;17(1):124-144.
3. Duman RS, Aghajanian GK. Synaptic dysfunction in depression: Potential therapeutic targets. Science. 2012;338(6103):68-72.
4. O’Connor RM, Dinan, TG, Cryan JF. Little things on which happiness depends: MicroRNAs as novel therapeutic targets for the treatment of anxiety and depression. Mol Psychiatry. 2012;17(4):359-376.
5. Carlson PJ, Singh JB, Zarate CA Jr, Drevets WC, Manji HK. Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets. NeuroRX. 2006;3(1):22-41.