Course, Natural History and Prognosis

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Course, Natural History and Prognosis

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Course, Natural History and Prognosis
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Depression I
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References

This slide shows core definitions for depression based on World Health Organization’s ICD-10 classification system or the American Psychiatric Association’s DSM-IV and DSM-5 system

1. NICE CG90. Depression in adults: recognition and management. 2009. Update April 2016 Available at: https://www.nice.org.uk/guidance/cg90 Accessed April 2016
2. WHO. ICD-10 Classification .1993. Available from: http://www.who.int/classifications/icd/en/GRNBOOK.pdf. Accessed April 2016
3. American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-IV. 4th edition:  American Psychiatric Association. 1994:866;
4. American Psychiatric Association. Diagnostic and statistical manual of mental disorders 5th edition:  American Psychiatric Association. 2013
 

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Depression II
References

1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders 5th edition:  American Psychiatric Association. 2013

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Depression is a clinically heterogeneous disorder
References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Health Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013;
2. Marazziti D et al. Eur J Pharmacol 2010;626(1):83–86;
3. Hammar A, Ardal G. Front Hum Neurosci 2009;3:26. doi: 10.3389/neuro.09.026.2009;
4. Fehnel SE et al. CNS Spectr 2013;21:43–52. 
5. Jaeger J et al. Psychiatry Res 2006;145:39–48
6. World Health Organization Depression Fact Sheet N369. http://www.who.int/mediacentre/factsheets/fs369/en/#. Accessed August 2015
 

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Cognitive symptoms of depression have a negative impact on many aspects of the patient’s life
References

1. McIntyre RS et al. Depress Anxiety 2013;30(6):515–527
2. Hammar A, Ardal G. Front Hum Neurosci 2009;3:26. doi: 10.3389/neuro.09.026.2009

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MDD symptoms – American Psychiatric Association
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References

The American Psychiatric Association (APA) describes nine depressive symptoms for diagnostic purposes.1

Depressed mood

• Patients may describe their mood as depressed, sad, hopeless, discouraged, or ‘down in the dumps’.1 Alternatively, the patient may describe having no feelings at all, or feeling anxious.1

• The lowered mood varies little from day to day, and is unresponsive to circumstances.1,2

• Many individuals will report or show increased irritability, e.g., persistent annoyance, hostility, or a tendency to respond to events with outwardly expressed anger, ranging from argumentativeness to rage.1,3

• At least one of ‘depressed mood’ or ‘loss of interest or pleasure’ is required for a diagnosis of MDD, according to APA criteria (see section on Diagnosis of MDD).1

Loss of interest or pleasure

• Loss of interest or pleasure (known as ‘anhedonia’) in all, or almost all, activities, is nearly always present.1,2

• Individuals may report feeling less interest in hobbies, ‘not caring anymore’, or not finding enjoyment in activities that were previously considered pleasurable.1

• Family members, rather than the patient, may be the ones who notice social withdrawal or neglect of pleasurable activities.1

• Some patients may experience a significant reduction in levels of sexual interest or desire (i.e., decreased libido).1,2

• At least one of ‘depressed mood’ or ‘loss of interest or pleasure’ is required for a diagnosis of MDD, according to APA criteria (see section on Diagnosis of MDD).1

Psychomotor agitation/retardation

• ‘Psychomotor agitation’ describes the inability to sit still; pacing or hand-wringing; or pulling/rubbing of skin, clothing, or other objects.1,2

• ‘Psychomotor retardation’ describes slowed speech, thinking, and body movements; increased pauses before answering; or speech that is decreased in volume, inflection, amount, or variety of content, or muteness.1,2

Worthlessness/guilt

• Self-esteem and self-confidence are almost always reduced; feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) may be present.1,2

• The sense of worthlessness or guilt may include unrealistic negative evaluations of one’s worth, or guilty preoccupations or ruminations over minor past failings.1

• Individuals often misinterpret neutral or trivial day-to-day events as evidence of personal defects.1

Cognitive dysfunction

• Many individuals report an impaired ability to think, concentrate, remember things, or make even minor decisions.1,2

• Patients engaged in cognitively-demanding pursuits are often unable to function.1

Fatigue

• Decreased energy, tiredness, and fatigue are common.1,2

• Even the smallest tasks seem to require substantial effort, and result in marked tiredness.1,2

• Patients may complain that, for example, washing and dressing in the morning are exhausting and take twice as long as usual.1

Thoughts of death/suicide

• Recurrent thoughts of death, suicidal ideation, or suicide attempts, are common.1

• The severity of suicidal thoughts ranges from a passive wish to not awaken in the morning or a belief that others would be better off if the individual were dead, to transient but recurrent thoughts of committing suicide, to a specific suicide plan.1

Weight/appetite change

• Patients may experience either a reduction or an increase in appetite, which can present as significant weight loss (without dieting) or weight gain.1

• Some patients report that they have to force themselves to eat; others report a craving for specific foods (e.g., sweets or other carbohydrates).1

Sleep disturbance

• Sleep is usually disturbed, and may take the form of either difficulty sleeping (insomnia), or sleeping excessively (hypersomnia).1,2

• ‘Initial insomnia’ is having difficulty falling asleep, ‘middle insomnia’ is waking up during the night and then having difficulty returning to sleep, and ‘terminal insomnia’ is waking too early and being unable to return to sleep.1

• Hypersomnia may take the form of prolonged sleep at night, or increased daytime sleep.1

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition (DSM-5™). © American Psychiatric Association, 2013.
2. World Health Organization (WHO). International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) Version for 2010. http://apps.who.int/classifications/icd10/browse/2010/en. Accessed 12th March 2014. 
3. Judd LL, Schettler PJ, Coryell W, et al. Overt irritability/anger in unipolar major depressive episodes: past and current characteristics and implications for long-term course. JAMA Psychiatry 2013; 70 (11): 1171–1180.

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MDD symptoms – The Montgomery–Åsberg Depression Rating Scale
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References

The Montgomery–Åsberg Depression Rating Scale (MADRS), which was designed to be sensitive to the effects of antidepressants, includes ten depressive symptoms, six of which are described as ‘core symptoms’.1,2

MADRS item 1. Apparent sadness
Representing despondency, gloom and despair (more than just ordinary transient low spirits), reflected in speech, facial expression, and posture.1
This item is a core symptom of the MADRS.2
 
MADRS item 2. Reported sadness
Representing reports of depressed mood, regardless of whether it is reflected in appearance or not.1 Includes low spirits, despondency or the feeling of being beyond help and without hope.1
This item is a core symptom of the MADRS.2

MADRS item 3. Inner tension
Representing feelings of ill-defined discomfort, edginess, inner turmoil, mental tension mounting to either panic, dread or anguish.1
This item is a core symptom of the MADRS.2
 
MADRS item 4. Reduced sleep
Representing the experience of reduced duration or depth of sleep compared to the subject’s own normal pattern when well.1
 
MADRS item 5. Reduced appetite
Representing the feeling of a loss of appetite compared with when well.1
 
MADRS item 6. Concentration difficulties
Representing difficulties in collecting one’s thoughts mounting to incapacitating lack of concentration.1
 
MADRS item 7. Lassitude
Representing a difficulty getting started or slowness initiating and performing everyday activities.1
Some elements also correspond to psychomotor retardation in the APA system.3
This item is a core symptom of the MADRS.2
 
MADRS item 8. Inability to feel
Representing the subjective experience of reduced interest in the surroundings, or activities that normally give pleasure.1 The ability to react with adequate emotion to circumstances or people is reduced.1
This item is a core symptom of the MADRS.2
 
MADRS item 9. Pessimistic thoughts
Representing thoughts of guilt, inferiority, self-reproach, sinfulness, remorse and ruin.1
This item is a core symptom of the MADRS.2
 
MADRS item 10. Suicidal thoughts
Representing the feeling that life is not worth living, that a natural death would be welcome, suicidal thoughts, and preparations for suicide.1
 

1. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382–389.
2. Bech P, Tanghøj P, Andersen HF, Overø K. Citalopram dose-response revisited using an alternative psychometric approach to evaluate clinical effects of four fixed citalopram doses compared to placebo in patients with major depression. Psychopharmacology (Berl) 2002; 163 (1): 20–25.
3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition (DSM-5™). © American Psychiatric Association, 2013.

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The course of MDD
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References

The optimal outcome for a patient with major depressive disorder (MDD) is a full recovery from the major depressive episode and to never become depressed again.1 Treatment of MDD is divided into three phases, corresponding to different stages of the illness.2 Each of these phases has a different treatment goal.2

Acute treatment phase
‘Acute phase treatment’ of MDD occurs during a major depressive episode; it runs from the initiation of treatment until remission is achieved.3,4 The goals of acute phase treatment are to achieve remission (removal of symptoms, such that the criteria for a major depressive episode are no longer met), and an improvement in functioning and quality of life.3,5 Remission is a clinically-meaningful endpoint: patients who achieve remission are less likely to relapse than those who do not achieve remission.6,7 Response, i.e., a 50% improvement from baseline in a depression rating scale score, is an intermediate treatment goal; it is used to evaluate whether or not a treatment is benefiting the patient.3

Continuation treatment phase
‘Continuation phase treatment’ of MDD follows on from acute phase treatment, i.e., it starts when remission is achieved.3,4 The goals of continuation phase treatment are to prevent a relapse (a return of symptoms sufficient to meet the criteria for a major depressive episode) in the vulnerable period immediately following remission, to eliminate any unresolved symptoms, and to restore the patient’s level of psychosocial and occupational functioning – at least to levels seen prior to the current episode and, if possible, to levels seen prior to the onset of MDD.3,5 Continuation phase treatment continues until recovery is achieved (the end of a major depressive episode).3 The moment of recovery is difficult to identify in clinical practice.3

Maintenance treatment phase
‘Maintenance phase treatment’ of MDD follows on from continuation phase treatment, provided the patient did not experience a relapse.3,4 The goals of maintenance phase treatment are to prevent a new episode of depression (recurrence), to prevent suicide, and to enable full and lasting functional recovery.3 Typically, maintenance treatment is indicated in patients with chronic/recurrent MDD (i.e., those susceptible to recurrence).5

1. Nierenberg AA, DeCecco LM. Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: a focus on treatment-resistant depression. J Clin Psychiatry 2001; 62 (Suppl 16): 5–9.
2. Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009.
3. Bauer M, Pfennig A, Severus E, et al.; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Unipolar Depressive Disorders. 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.
4. Kupfer DJ. Long-term treatment of depression. J Clin Psychiatry 1991; 52 (Suppl 5): 28–34.
5. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd Edition. © American Psychiatric Association, 2010. http://psychiatryonline.org/guidelines.aspx. Accessed November 2017.
6. Nelson JC, Pikalov A, Berman RM. Augmentation treatment in major depressive disorder: focus on aripiprazole. Neuropsychiatr Dis Treat 2008; 4 (5): 937–948.
7. 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 (11): 1905–1917.

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MDD is a complex, often recurrent and remitting disorder
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References

Previous slide illustrates the typical course of illness for patients with depression; either receiving only acute-phase treatment or receiving longer-term treatment designed to prevent relapse. It also highlights that long-term treatment of depression with antidepressants benefits many patients by1 reducing the likelihood of relapse or recurrence and2 increasing the amount of time spent asymptomatic between episodes. 

Discontinuing antidepressant treatment in the acute phase before full symptomatic remission drastically increases the likelihood of relapse of the original episode, and discontinuing treatment during the continuation phase after symptomatic remission likewise increases the risk of relapse. 

Discontinuing treatment during the maintenance phase, which begins after full recovery, increases the risk of developing a new depressive episode (i.e., recurrence).
 

1. Kupfer DJ. J Clin Psychiatry 1991;52(suppl):28–34. 
2. Eaton WW et al. Arch Gen Psychiatry 2008;65:513–520

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Definitions of Clinical Course and Treatment Outcomes I
References
  • 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.
  • Keller MB. Long-term treatment of recurrent and chronic depression. J Clin Psychiatry 2001; 62 Suppl 24: 3–5.
  • Lavori PW, Keller MB, Mueller TI, et al. Recurrence after recovery in unipolar MDD: an observational follow-up study of clinical predictors and somatic treatment as a mediating factor. Int J Methods Psychiatr Res 1994; 4 (4): 211–229.
  • Nierenberg AA, DeCecco LM. Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: a focus on treatment-resistant depression. J Clin Psychiatry 2001; 62 Suppl 16: 5–9.
  • Nierenberg AA, Petersen TJ, Alpert JE. Prevention of relapse and recurrence in depression: the role of long-term pharmacotherapy and psychotherapy. J Clin Psychiatry 2003; 64 Suppl 15: 13–17.
  • Riso LP, Thase ME, Howland RH, et al. A prospective test of criteria for response, remission, relapse, recovery, and recurrence in depressed patients treated with cognitive behavior therapy. J Affect Disord 1997; 43 (2): 131–142.
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Definitions of Clinical Course and Treatment Outcomes
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References

MDD is a chronic disorder, most frequently characterised by relapses and recurrences.(Nierenberg et al., 2003) Relapse can be defined as an episode of MDD that occurs within 6 months of response or remission;(Nierenberg et al., 2003; Riso et al., 1997) theoretically, relapse signifies the return of a major depressive episode, rather than a new episode.(Nierenberg & DeCecco, 2001; Frank et al., 1991) Recurrence can be defined as a depressive episode that occurs after 6 months following response or remission;(Nierenberg et al., 2003; Riso et al., 1997) theoretically, recurrence signifies the start of a new major depressive episode.(Nierenberg & DeCecco, 2001; Frank et al., 1991) Naturalistic studies have found that most patients will eventually experience either relapse or recurrence if followed for a long enough period without sustained treatment.(Nierenberg et al., 2003; Lavori et al., 1994) Following an acute depressive episode, almost 90% of patients could be expected to become depressed again in the next 15 years.(Nierenberg et al., 2003; Keller, 2001)
 

  1. Kupfer. J Clin Psychiatry 1991;52(Suppl 5):28–34.
  2. Nierenberg AA, Petersen TJ, Alpert JE. Prevention of relapse and recurrence in depression: the role of long-term pharmacotherapy and psychotherapy. J Clin Psychiatry 2003; 64 Suppl 15: 13–17.
  3. Riso LP, Thase ME, Howland RH, et al. A prospective test of criteria for response, remission, relapse, recovery, and recurrence in depressed patients treated with cognitive behavior therapy. J Affect Disord 1997; 43 (2): 131–142
  4. Nierenberg AA, DeCecco LM. Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: a focus on treatment-resistant depression. J Clin Psychiatry 2001; 62 Suppl 16: 5–9.
  5. 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.
  6. Keller MB. Long-term treatment of recurrent and chronic depression. J Clin Psychiatry 2001; 62 Suppl 24: 3–5.
  7. Lavori PW, Keller MB, Mueller TI, et al. Recurrence after recovery in unipolar MDD: an observational follow-up study of clinical predictors and somatic treatment as a mediating factor. Int J Methods Psychiatr Res 1994; 4 (4): 211–229.
     
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MDD specifiers – I
References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition (DSM-5™). © American Psychiatric Association, 2013.
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition, Text Revision (DSM-IV-TR®). © American Psychiatric Association, 2000.

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MDD specifiers - II
References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition (DSM-5™). © American Psychiatric Association, 2013.
2. Oxford Concise Medical Dictionary. Second Edition. © Oxford University Press, 1998.

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MDD specifiers – III
References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition (DSM-5™). © American Psychiatric Association, 2013.
2. Oxford Concise Medical Dictionary. Second Edition. © Oxford University Press, 1998.

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MDD specifiers – IV
References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition (DSM-5™). © American Psychiatric Association, 2013.
2. Oxford Concise Medical Dictionary. Second Edition. © Oxford University Press, 1998.

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MDD specifiers – V
References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition (DSM-5™). © American Psychiatric Association, 2013.
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition, Text Revision (DSM-IV-TR®). © American Psychiatric Association, 2000.

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Depression – DSM-5: Updates from DSM-IV
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References

Highlights of Changes from DSM-IV-TR to DSM-5. American Psychiatric Association 2013. Available from: http://www.psychiatry.org/dsm5  Accessed April 2016

While bereavement may precipitate major depression in people who are especially vulnerable (i.e. they have already suffered a significant loss or have other mental disorders), when grief and depression coexist, the grief is more severe and prolonged than grief without major depression. Despite some overlap between grief and MDD, they are different in important ways, and therefore they should be distinguished separately to enable people to benefit from the most appropriate treatment. 
American Psychiatric Association, Changes in the new edition: Depression Bereavement Exclusion, 
Source: American Psychiatric Association_DSM-5-Depression-Bereavement-Exclusion: https://www.psychiatry.org/File%20Library/Psychiatrists/Practice/DSM/APA..., last assessed April 2016

A more chronic form of depression, persistent depressive disorder (dysthymia), can be diagnosed when the mood disturbance continues for at least 2 years in adults or 1 year in children. This diagnosis, new in DSM-5, includes both the DSM-IV diagnostic categories of chronic major depression and dysthymia.
Source:(1) American Psychiatric Association (APA). Diagnostic and statistical manual of mental disorders 5th edition:  APA. 2013

In DSM-IV, a diagnosis of mixed episode required an individual to simultaneously meet all criteria for an episode of major depression and an episode of mania. During its review of the latest research, the DSM-5 Mood Disorders Work Group recognized that individuals rarely meet full criteria for both episode types at the same time. In order to be diagnosed with the new specifier in the case of major depression, the new DSM-5 specifier will require the presence of at least three manic/hypomanic symptoms that don’t overlap with symptoms of major depression. In the case of mania or hypomania, the specifier will require the presence of at least three symptoms of depression in concert with the episode of mania/hypomania. 
Source: American Psychiatric Association_DSM-5-Mixed-Features-Specifier, Changes in the new edition: Mixed features. Available: https://www.psychiatry.org/File%20Library/Psychiatrists/Practice/DSM/APA..., last assessed April 2016
 

1. American Psychiatric Association (APA). Diagnostic and statistical manual of mental disorders 5th edition:  APA. 2013;
2. APA_DSM-5-Depression-Bereavement-Exclusion, Availability see notes;
3. APA_DSM-5-Mixed-Features-Specifier.pdf Availability see notes
 

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Recurrent Brief Depressive Disorder
References
  • American Psychiatric Association (1994)
  • Angst et al (1990)
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Subsyndromal symptoms of Unipolar Depression and Bipolar Depression
References
  • Howarth et al (1992)
  • Johnson et al (1992)
  • Judd et al (1994)
     
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Differential diagnosis
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References

Differential diagnosis is the distinguishing of a disorder from others presenting with similar signs and symptoms.

Manic episodes with irritable mood; mixed episodes (bipolar disorder)
Major depressive episodes with prominent irritable mood may be difficult to distinguish from manic episodes with irritable mood, or from mixed episodes.1 This distinction requires a careful clinical evaluation of the presence of manic symptoms.1
 
Mood disorder due to another medical condition
A major depressive episode is the appropriate diagnosis if the mood disturbance is not judged, based on individual history, physical examination, and laboratory findings, to be the direct pathophysiological consequence of a specific medical condition (e.g., multiple sclerosis, stroke, or hyperthyroidism).1
 
Substance/medication-induced depressive or bipolar disorder
This disorder is distinguished from MDD by the fact that a substance (e.g., a drug of abuse, a medication, or a toxin) appears to be aetiologically related to the mood disturbance.1 For example, depressed mood that occurs only in the context of withdrawal from cocaine would be diagnosed as cocaine-induced depressive disorder.1
 
Attention-deficit/hyperactivity disorder
Distractibility and low frustration tolerance can occur in both attention-deficit/hyperactivity disorder and a major depressive episode; if the criteria are met for both, attention-deficit/hyperactivity disorder may be diagnosed in addition to the mood disorder.1 However, the clinician must be cautious not to over-diagnose a major depressive episode in children with attention-deficit/hyperactivity disorder whose disturbance in mood is characterised by irritability rather than sadness or loss of interest.1
 
Adjustment disorder with depressed mood
A major depressive episode that occurs in response to a psychosocial stressor (e.g., relationship breakup, work problems) is distinguished from adjustment disorder with depressed mood by the fact that the full criteria for a major depressive episode are not met in adjustment disorder.1
 
Sadness
Periods of sadness are inherent aspects of the human experience.1 These periods should not be diagnosed as a major depressive episode unless criteria are met for severity (i.e., five out of nine symptoms), duration (i.e., most of the day, nearly every day for at least 2 weeks), and clinically significant distress or impairment.1 The diagnosis ‘other specified depressive disorder’ may be appropriate for presentations of depressed mood with clinically significant impairment that do not meet criteria for duration or severity.1

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition (DSM-5™). © American Psychiatric Association, 2013.

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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

Speaker notes:

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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Patients with residual symptoms relapse earlier and at a greater rate than patients without residual symptoms
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References

Speaker notes1
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 analysed by 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

Speaker notes

  • 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.
  • 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

Speaker notes

  • 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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References

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 one of 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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References

Speaker notes

  • 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 (i.e., 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 aetiology 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 unfavourable 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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References

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
Slide information
References

Key point: Adverse events are 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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References

Key point: Antidepressants are associated with a range of side effects.1

  • The side effects associated with antidepressant 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
Slide information
References

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
References

1. Thapar A et al. Lancet 2012;379:1056-67 
2. Lewinsohn PM et al. Am J Psychiatry 2000;157:1584-91
3. Fava GA et al. Psychol Med 2007;37:307-17
4. Conradi HJ et al. Psychol Med 2011;41:1165-74
5. Sinyor M et al. Can J Psychiatry 2010;55:126-35
 

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