Course, Natural History and Prognosis​

Presentation

Course, Natural History and Prognosis​

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Course, Natural History and Prognosis​
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Major depressive disorder​
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Recurrent major depression​
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Major depressive disorder: prognosis​
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Possible outcomes of a major depressive episode​
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Life course of recurrent major depressive disorder​
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Major depressive disorder with a seasonal pattern​
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Dysthymic disorder​
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Recurrent brief depressive disorder​
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Subsyndromal symptoms of unipolar depression and bipolar depression​
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Major depressive episode​
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Severity of major depressive episode​
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Acute treatment (continued)​
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Response, remission and relapse (continued 2)​
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Acute treatment (continued 3)​
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Continuation treatment (continued)​
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Recovery (continued 2)​
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Continuation treatment (continued 3)​
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Maintenance treatment (continued)​
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Recurrence (continued 2)​
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Maintenance treatment (continued 3)​
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Predictors of need for long-term, maintenance antidepressant therapy (continued 4)​
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Treatment resistant depression: non-response or partial response to antidepressant treatment​
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Functional recovery​
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Functional recovery – why is it important?​
References
  1. Borolato B et al. Cognitive Dysfunction in major depressive disorder: A state-of-the-art clinical review. CNS Neurol Disord Drug Targets 2014; 13: 1804-1818.​
  2. Greer TL, Kurian BT, Trivedi MH. Defining and measuring functional recovery from depression. CNS Drugs 2010; 24(4):267–284.​
  3. Stotland NL. Recovery from depression. Psychiatr Clin N Am 2012; 35: 37-49​
  4. Tranter RT et al. Prevalence and outcome of partial remission in depression. J Psychiatry Neurosci. 2002; 27(4): 241-7​
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What about the patients that don’t reach functional recovery?​
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References

The objectives for the treatment of depressed patients are to:​

  •  Achieve remission (acute treatment)​
  •  Prevent relapse (continuation treatment)​
  •  Prevent recurrence (maintenance treatment)1​

A response is defined as a 50% improvement in symptoms as measured by the HAM-D score5​

Remission is a virtually symptom-free state – the HAM-D score is ≤ 75​

Relapse is a worsening of symptoms after remission1​

Recurrence is the development of a new episode after initial recovery1​

The risk of relapse is significantly higher in patients that respond only partially to therapy compared with those who achieve remission (76% versus 25%)6​

 

  1. Kupfer DJ. Long-term treatment of depression. J Clin Psych 1991; 52 (5, suppl): 28–34 ​
  2. McClintock SM et al. Residual symptoms in depressed outpatients who respond by 50% but do not remit to antidepressant medication. J Clin Psychopharmacol. 2011; 31(2): 180-186 ​
  3. Trivedi MH et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice. Am J Psychiatry 2006; 163(1): 28–40 ​
  4. Borolato B et al. Cognitive dysfunction in major depressive disorder: A state-of-the-art clinical review. CNS Neurol Disord Drug Targets 2014; 13: 1804-181 ​
  5. Ballenger JC. Clinical guidelines for establishing remission in patients with depression and anxiety. J Clin Psych 1999; 60 (suppl 22): 29–34  ​
  6. Paykel ES et al. Residual symptoms after partial remission: an important outcome in depression. Psychological Medicine 1995; 25(6): 1171–1180​
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Depressive symptoms persist during periods of remission and subsequent depressive episodes​
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References

Key point: In depression, rates of overall residual symptomatology are high.1 Symptoms with high residual rates, such as cognitive problems, need continuous attention to prevent relapse.1​

​Residual depressive symptomatology constitutes a substantial risk for relapse in depression.3 Treatment until full remission is achieved is therefore needed.4

The presence of residual symptoms was studied in a 3-year follow-up of 267 initially depressed primary care patients.1 Patients received one of four treatment interventions:1

  • usual care by the GP (brief supportive counselling, possible antidepressant treatment, and/or referral according to clinical guidelines)​
  • psycho-educational prevention programme (low-intensity programme consisting of three face-to-face sessions, and short 3-monthly telephone contacts thereafter)​
  • psycho-educational prevention programme plus psychiatric consultation​
  • psycho-educational prevention programme brief cognitive behavioural therapy

The severity of the index depressive episode was moderate or severe in 70% of patients, and 74% of patients were receiving antidepressant medication at baseline.1​

The presence of individual DSM-IV depressive symptoms during subsequent depressive episodes and periods of partial remission were assessed by patient interviews at 3-monthly intervals to establish the presence/absence of individual DSM-IV criteria or symptom clusters per week during the past 3 months.1 ​

The slide illustrates the course of individual depressive symptoms during the 3-year follow-up.1 At study entry, nearly all of the patients were suffering from a major depressive episode – reflected in the high prevalence of most of the symptoms at baseline.1 During the entire 3-year follow-up, cognitive problems, lack of energy, sleeping problems, and depressed mood/diminished interest were present 58–66% of the time.1 During non-major depressive episodes, 21% of patients reported depressed mood/diminished interest, while 44% of patients reported cognitive problems, 39% reported sleeping problems, and 35% reported lack of energy.1 Thoughts of death were reported by 11% of patients.1​

Rates of overall residual symptomatology were fairly high.1 At any point during non-major depressive episodes, criteria for two DSM-IV depressive symptom clusters were met.1 Thus, as measured by presence of residual symptoms, depression is indeed a chronic disease.1 ​

Partial remission is very common and constitutes a challenge for clinical practice.1 Symptoms with high residual rates need continuous attention to prevent relapse.1 However, physicians also need to be alert to the less prevalent residual symptoms, such as thoughts of death, as these symptoms may constitute a higher risk of relapse.1​​

  1. Conradi HJ, Ormel J, de Jonge, P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychological Medicine 2011;41(6):1165–1174.​
  2. McClintock SM et al. Residual symptoms in depressed outpatients who respond by 50% but do not remit to antidepressant medication. J Clin Psychopharmacol. 2011; 31(2): 180-186​
  3. Judd LL, Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, Paulus MP et al. Major depressive disorder: A prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse.  Journal of Affective Disorders 1998;50(2–3):97–108.​
  4. American Psychiatric Association (APA). Practice guideline for the treatment of patients with major depressive disorder. Third edition. Arlington, VA, 2010.​
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Patients with residual symptoms relapse earlier ​ and at a greater rate than patients without residual symptoms​
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Key points
These data from Paykel and colleagues reinforce the importance of adequacy of treatment and the point that failure to achieve remission increases the risk of relapse.​

They found that patients with residual symptoms were 3 times more likely to relapse (76% vs 25%). ​​

Background
Paykel et al systematically followed 60 patients to the point of remission, or until 15 months without remission had elapsed. They specifically examined the outcomes of patients with and without residual symptoms of depression following partial or full remission (defined by improvement in the HAM-D17), and found that residual symptoms were a very strong predictor of subsequent early relapse.​

19 of the 60 patients (32%) were defined as having residual symptoms (defined as a score of 8 or more on the HAM-D17).  The remaining 41 patients reached remission according to the criterion of HAM-D17 < 7.  Patients were monitored for 15 months using the Beck Depression Inventory, as well as full psychiatric interviews in order to identify relapse, “defined as a return to Research Diagnostic Criteria definite major depression for at least 1 month, rated retrospectively.”​

The relationship between residual symptoms and subsequent relapse was analyzed using the Kaplan-Meier method.  They found a marked difference, with a very high relapse rate, in those patients with residual symptoms.  Overall, 76% (13/17) of those patients relapsed, as opposed to 25% (10/40) of those who had remitted (did not have residual symptoms).  The difference between the 2 survival curves was significant at P<0.001.​

  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(6): 1171-1180​
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Residual symptoms can lead to faster relapse​
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References

A 10-year, NIMH-sponsored study tested whether level of recovery from major depressive episodes (MDEs) predicts duration of recovery in 237 unipolar major depressive disorder (MDD) patients. ​

MDD patients seeking treatment at five academic centres were followed naturalistically for 10 years or longer. ​

Patients were divided on the basis of intake MDE recovery into residual mild depressive symptoms (SSD; n=82) and asymptomatic (n=155) recovery groups. ​

They were compared on time to first episode relapse/recurrence, antidepressant medication, and comorbid mental disorders. Recovery level was also compared to prior history of recurrent MDEs (>4 lifetime episodes) as a predictor of relapse/recurrence. ​

Residual SSD compared to asymptomatic recovery patients relapsed to their next MDE >3 times faster (median=68 vs 231 weeks) and to any depressive episode >5 times faster (median=33 vs 184 weeks). Residual SSD recovery status was significantly associated with early episode relapse (OR=3.68; 95% CI 2.64-5.12 vs asymptomatic) and was a stronger predictor of relapse than history of recurrent MDEs (OR=1.64; 95% CI 1.17-2.29; for >4 MDEs vs 1, 2 or 3 prior MDEs) in the asymptomatic group.​

  1. 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 (2-3): 97-108​
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More chronic course of illness​
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References

This study investigated the influence of incomplete recovery from first lifetime major depressive episodes on long-term outcome.​

After their first lifetime major depressive episode, patients were divided into asymptomatic (n=70) and residual subthreshold depressive symptom (n=26) recovery groups and compared on longitudinal course during up to 12 years of prospective naturalistic follow-up.​

Patients with residual subthreshold depressive symptoms during recovery had significantly more severe and chronic future courses. Those with residual symptoms relapsed to major and minor depressive episodes faster and had more recurrences, shorter well intervals, and fewer symptom-free weeks during follow-up than asymptomatic patients.​

Resolution of major depressive episodes with residual subthreshold depressive symptoms, even the first lifetime episode, appears to be the first step of a more severe, relapsing, and chronic future course. When ongoing subthreshold symptoms continue after major depressive episodes, the illness is still active, and continued treatment is strongly recommended.​

 

  1. Judd LL et al. Does incomplete recovery  from first lifetime major depressive episode herald a chronic course of illness? Am J Psych 2000; 157: 1501-1504​
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Chronic impairment in functioning​
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Background1​
Although residual symptoms after remission from depression are common and predict early relapse, little is known about the impact of residual symptoms on longer-term clinical course of depression or social functioning. ​

Methods1​
Sixty severe recurrent depressives, who remitted from an index episode of depression with residual symptoms or below residual symptomatology, were followed-up at 8–10 years​

Subjects underwent detailed longitudinal interviewing on course of depression, treatment and socioecomonic functioning over follow-up. ​

Results: Long-term follow-up data was obtained on all living subjects and 55 (95%) were interviewed. The residual symptoms group spent more time with depressive symptoms over follow-up but not at full criteria for major depression and showed greater impairment in longitudinal and follow-up social adjustment. ​

No significant differences were found between the two groups in percentage recurring long-term, mean number of recurrences, readmissions, chronic episodes or clinical global outcome criteria. ​

Limitations: Long-term clinical and social outcomes were assessed by a single retrospective longitudinal interview. Conclusions: ​

Patients who remit from depression with residual symptomatology continue to have more depressive symptoms and impaired social functioning long-term and may need more aggressive treatment​

  1. Kennedy N & Paykel ES. Residual symptoms at remission from depression: impact on long-term outcome. J Affect Disord 2004;80:135-14​
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Cognitive symptoms are among the most common residual symptoms in MDD​
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References

Key point: In the STAR*D trial, cognitive symptoms were among the most common residual symptoms experienced by patients who responded to treatment.​

Mid-nocturnal insomnia, decreased concentration/decision-making, suicidal ideation and negative self-view were all common residual symptoms.​1

 

  1. McClintock SM, et al. Residual symptoms in depressed outpatients who respond by 50% but do not remit to antidepressant medication.  Journal of Clinical Psychopharmacology 2011;31:180–186.​
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Cognitive symptoms persist when patients are in remission​
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A meta-analysis of 6 studies examining executive function, memory, and attention in 168 remitted depressed patients and 178 healthy control individuals revealed that significant impairments in cognitive function persist during remission.​

Cohen’s d is used to estimate the magnitude of an effect (ie, effect size). Cohen proposed benchmark values for what are considered to be “small” (0.2), “medium” (0.5), and “large” (0.8) effect sizes.​

Cognitive function was measured by tests within the Cambridge Neuropsychological Test Automated Battery, CANTAB:​

  • IED: Intra-Extra Dimensional Set-Shift (a test of cognitive flexibility)​
  • SWM: Spatial Working Memory (assesses working memory and strategy use)​
  • OTS/SOC: (One Touch) Stockings of Cambridge (assesses visual planning, reasoning, and impulsivity)​
  • PRM: Pattern Recognition Memory (assesses abstract visual pattern recognition memory)​
  • DMS: Delayed Matching to Sample (remember the visual features of a complex, abstract target)​
  • RVP: Rapid Visual Information Processing (assesses sustained attention, signal detection, and impulsivity)​

There was insufficient data to calculate weighted, pooled effect sizes for Spatial Span (SSP), Paired Associates Learning (PAL), Spatial Recognition Memory (SRM), and Reaction Time (RTI).​

 

  1. Rock PL, et al. Cognitive impairment in depression: a systematic review and meta-analysis. Psychol Med. 2014; 44: 2029-2040​
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Summary​
References
  1. McClintock SM et al. Residual symptoms in depressed outpatients who respond by 50% but do not remit to antidepressant medication. J Clin Psychopharmacol. 2011; 31(2): 180-186​
  2. Trivedi MH et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice. Am J Psychiatry 2006; 163(1): 28–40​
  3. Borolato B et al. Cognitive Dysfunction in major depressive disorder: A state-of-the-art clinical review. CNS Neurol Disord Drug Targets 2014; 13: 1804-181​
  4. Greer TL, Kurian BT, Trivedi MH. Defining and measuring functional recovery from depression. CNS Drugs 2010; 24(4):267–284.​
  5. Judd LL et al. Does incomplete recovery  from first lifetime major depressive episode herald a chronic course of illness? Am J Psych 2000; 157: 1501-1504​
  6. Conradi HJ, Ormel J, de Jonge, P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychological Medicine 2011;41(6):1165–1174.​
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Challenges in achieving functional recovery​
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Barriers to achieving functional recovery​
References
  1. Fournier JC et al. Prediction of response to medication and cognitive therapy in the treatment of moderate to severe depression. J Consult Clin Psychol 2009;77:775-787​
  2. Kendler KS et al. 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​
  3. Howland RH et al. Factors predicting reduced antidepressant response: experience with the SNRI duloxetine in patients with major depression. Ann Clin Psychiatry 2008;20:209-218​
  4. Fava M et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry 2008;165:342-351​
  5. Mulder RT. Personality pathology and treatment outcome in major depression: a review. Am J Psychiatry 2002;159:359-371​
  6. DeVeaugh-Geiss AM et al. The adverse effects of comorbid pain on depression outcomes in primary care patients: results from the ARTIST trial. Pain Medicine 2010;11:732-741​
  7. Nanni V et al. Childhood maltreatment predicts unfavorable course of illness and treatment outcome in depression: a meta-analysis. Am J Psychiatry 2012;169(2):141-51​
  8. Ostler K et al. Influence of socio-economic deprivation on the prevalence and outcome of depression in primary care: the Hampshire Depression Project. Br J Psychiatry 2001;178:12-17 ​
  9. Lamers F et al. One-year severity of depressive symptoms: results from the NESDA study. Psychiatry Res 2011;190(2-3):226-231  ​
  10. Watkins KE et al. Improving care for depression in patients with comorbid substance misuse. Am J Psychiatry 2006;163(1):125-132​
  11. Kendler KS et al. Toward a comprehensive developmental model for major depression in women. Am J Psychiatry 2002;159:1133-1145​
  12. Kendler KS et al. Toward a comprehensive developmental model for major depression in men. Am J Psychiatry 2006; 163:115-124​
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Inadequate or partial response to first line SSRI treatment​
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Key point: Inadequate or partial response to SSRI treatment increases the risk of relapse.1-3​

Recurrence rates range from 40–85%.2​

Few adults experience full symptomatic and functional remission between depressive episodes.2,3

  1. Rush AJ, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report.  American Journal of Psychiatry 2006;163(11):1905–1917. ​
  2. Kennedy SH. A review of antidepressant therapy in primary care: current practices and future directions. The Primary Care Companion for CNS Disorders 2013;15(2);3. ​
  3. Conradi HJ, Ormel J, de Jonge, P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychological Medicine 2011;41(6):1165–1174.​
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Treatment factors could lead to partial response​
References
  1. NICE (2009) Clinical Guideline 90. Depression in adults: The treatment and management of depression in adults (update): full guideline​

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Patients frequently discontinue treatment due to adverse events​
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Key point: Adverse events are a significant factor in the decision to discontinue antidepressant treatment, with as many as one quarter of patients discontinuing treatment due to difficult-to-tolerate side effects.1​

Others may continue on antidepressant therapy but experience diminished quality of life related to troublesome side effects.1​

The presence of multiple side effects or those deemed extremely bothersome significantly increased the odds of discontinuation.1,2 Side effects often create barriers to achieving remission, as well as preventing relapse and recurrence.1,2​

  1. Kelly K, Posternak M, Alpert JE. Toward achieving optimal response: understanding and managing antidepressant side effects. Dialogues in Clinical Neuroscience 2008;10(4):409–418. ​
  2. Hu X, Bull SA, Hunkeler EM, Ming E, Lee Jym Fireman B, Markson LE . Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate. Journal of Clinical Psychiatry 2004;65(7):959–965.​
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Antidepressants are associated with a range of side effects
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Key point: Antidepressants are associated with a range of side effects.1​

The side effects associated with antidepressants classes are summarised on this slide.​

  1. Taylor D, et al. The Maudsley prescribing guidelines in psychiatry, 12th Edition. Wiley Blackwell. 2015.​
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Decreased sexual drive and functioning is considered to be a bothersome adverse effect related to SSRI treatment​
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Key point: The most bothersome side effects reported by patients treated with SSRIs include decreased sexual drive and functioning.​

In an observational study of 406 patients, 1 in 4 discontinued the index antidepressant treatment after 3 months, and adverse events were the most common reason cited.1​

Decreased sexual drive and functioning was reported as being the most bothersome by 47% of the patients experiencing that adverse event, with over 30% of patients reporting gastrointestinal symptoms, weight changes, and insomnia finding those side effects most bothersome.1​

  1. Goethe JW, Woolley SB, Carodni AA, Woznicki BA, Piex DA. Selective serotonin reuptake inhibitor discontinuation side effects and other factors that influence medication adherence. Journal of Clinical Psychopharmacology 2007;27:451–458.​
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Long-term course of depression presents major clinical challenge​
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