Major Depressive Disorder (MDD)

Major Depressive Disorder (MDD) is a mental disorder characterized by persistent, often daily, low mood and/or decreased interest (anhedonia). There are also associated neurovegetative symptoms, such as a change in sleep, appetite, cognition, and energy levels. Suicidal ideation may also occur.

Epidemiology
  • In Canada, the annual prevalence of a depressive episode is 4.7%, and a lifetime prevalence is 11.3%.[1]
  • In the United States, the annual prevalence is 7%, with 18 to 29-year-olds having a three times higher prevalence than individuals 60 and older.[2]
  • Females have a 2 to 3 times higher rate of being diagnosed with depression than males.
    • The reasons for the difference are hypothesized to involve hormonal differences, the effects of childbirth, differing psychosocial stressors for women and for men, increased seeking of clinical care, and behavioural models of learned helplessness.
Prognosis
  • MDD can appear at any age, but the chance increases with the onset of puberty. The age of onset peaks in the mid-20s.[3]
  • The course of MDD can vary significantly between individuals, such that some individuals have a chronic illness course, while others can have years with few or no symptoms between depressive episodes. 50% of depressive episodes are brief and resolve within three months.[4]
  • Those with underlying personality, anxiety, and substance use disorders are most likely to have a chronic course of symptoms and lower likelihood of full symptom remission.
    • Other factors for chronic symptoms or recurrence include early age of onset, greater number of episodes, severity of the initial episode, disruption of the sleep-wake cycle, presence of comorbid psychopathology (particularly dysthymia), a family history of psychiatric illness, presence of negative cognitions, high neuroticism, poor social support, and stressful life events.[5]
  • The longer the period of full remission, the lower the chance of recurrence.[6]
    • This means that the persistence of even mild depressive symptoms during a period of remission is a significant predictor for a future recurrence.[7]
  • Negative prognostic factors include having psychotic features, comorbid anxiety, personality disorders, and greater symptom severity.[8]
  • Many individuals with bipolar disorders are initially misdiagnosed with a major depressive disorder, but over the course of the illness, will later be correctly diagnosed with bipolar disorder.
    • This is especially true for individuals who present with mixed features (i.e. - some symptoms of bipolar, but not full hypomanic or manic episodes).[9]
  • The impairment from MDD can range from being mild to severe, depending on the individual, and depend on the symptom profile.[10]
Comorbidity
Risk Factors
  • MDD occurs most often in persons without close interpersonal relationships or in those who are divorced or separated. There is no correlation between socioeconomic status. It is slightly more common in rural areas than in urban areas.[13]
  • High neuroticism, adverse childhood events are risk factors for depression.
  • First-degree family members of an individual with MDD have a 2 to 4 times higher risk for depression.
  • The heritability of MDD is estimated to be 40%.[14]
  • Medical conditions such as diabetes, obesity, and cardiovascular disease also increase the risk for depression.[15]
Criterion A
  • At least 5 out of 9 symptoms present in the same 2-week period and represent a change from previous functioning, AND
  • At least 1 of the 5 symptoms is either (1) depressed mood or (2) loss of interest or pleasure (anhedonia).
  1. Mood is depressed most of the day, nearly every day, as indicated by either subjective report (e.g. - feels sad, empty, hopeless) or observation made by others (e.g. - appears tearful)
    In children and adolescents, there can be irritable mood.
  2. Sleep changes: insomnia or hypersomnia nearly every day
  3. Interest or pleasure markedly diminished in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation)
  4. Guilt and/or worthlessness (excessive or inappropriate - which may be delusional) nearly every day (not merely self-reproach or guilt about being sick)
  5. Energy decreased or fatigue nearly every day
  6. Concentration diminished, or indecisiveness, nearly every day (either by subjective account or as observed by others)
  7. Appetite changes: significant weight loss when not dieting or weight gain (e.g. - a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day
    In children, consider failure to make expected weight gain.
  8. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down)
  9. Suicide, recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide
If there are symptoms that are clearly attributable to another medical condition (e.g. - insomnia from chemotherapy treatment), then they do not count as part of meeting the criterion for diagnosis!

Mnemonic

The mnemonic MSIGECAPS can be used to remember the criteria for major depressive disorder.[16]
  • M - Mood
  • S - Sleep
  • I - Interest
  • G - Guilt/Worthlessness
  • E - Energy
  • C - Concentration
  • A - Appetite
  • P - Psychomotor Slowing
  • S - Suicide
Criterion B

The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

Criterion C

The episode is not attributable to the physiological effects of a substance or to another medical condition.

Bereavement and Loss

Responses to a significant loss (e.g. - bereavement, financial ruin, losses from a natural disaster, a serious medical illness or disability) may include the feelings of intense sadness, rumination about the loss, insomnia, poor appetite, and weight loss noted in Criterion A, which may resemble a depressive episode. Although such symptoms may be understandable or considered appropriate to the loss, the presence of a major depressive episode in addition to the normal response to a significant loss should also be carefully considered. This decision inevitably requires the exercise of clinical judgment based on the individual’s history and the cultural norms for the expression of distress in the contest of loss. See the Differential Diagnosis section below for more details on differentiating between the two.
Criterion D

The occurrence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders.

Criterion E

There has never been a manic episode or a hypomanic episode. (i.e. - a bipolar diagnosis trumps a major depressive disorder diagnosis)

Episode Specifier

  • Single episode
  • Recurrent episode

Severity Specifier

  • Mild: Few, if any, symptoms in excess of those required to make the diagnosis are present, the intensity of the symptoms is distressing but manageable, and the symptoms result in minor impairment in social or occupational functioning.
  • Moderate: The number of symptoms, intensity of symptoms, and/or functional impairment are between those specified for “mild” and “severe.”
  • Severe: The number of symptoms is substantially in excess of that required to make the diagnosis, the intensity of the symptoms is seriously distressing and unmanageable, and the symptoms markedly interfere with social and occupational functioning.

Remission Specifier

  • In partial remission: Symptoms of the immediately previous major depressive episode are present, but full criteria are not met, or there is a period lasting less than 2 months without any significant symptoms of a major depressive episode following the end of such an episode.
  • In full remission: During the past 2 months, no significant signs or symptoms of the disturbance were present.

With anxious distress

  • Anxious distress is defined as the presence of at least 2 of the following symptoms during the majority of days of a major depressive episode or persistent depressive disorder (dysthymia):
    • (1) Feeling keyed up or tense
    • (2) Feeling unusually restless
    • (3) Difficulty concentrating because of worry
    • (4) Fear that something awful may happen
    • (5) Feeling that the individual might lose control of himself or herself
  • Severity:
    • Mild: 2 symptoms
    • Moderate: 3 symptoms
    • Moderate-severe: 4 or 5 symptoms
    • Severe: 4 or 5 symptoms and with motor agitation
Note: Anxious distress has been noted as a prominent feature of both bipolar and major depressive disorder in both primary care and specialty mental health settings. High levels of anxiety have been associated with higher suicide risk, longer duration of illness, and greater likelihood of treatment nonresponse. As a result, it is clinically useful to specify accurately the presence and severity levels of anxious distress for treatment planning and monitoring of response to treatment.

With mixed features

  • A. At least 3 of the following manic/hypomanic symptoms are present during the majority of days of a major depressive episode:
    • (1) Elevated, expansive mood
    • (2) Inflated self-esteem or grandiosity
    • (3) More talkative than usual or pressure to keep talking
    • (4) Flight of ideas or subjective experience that thoughts are racing.
    • (5) Increase in energy or goal-directed activity (either socially, at work or school, or sexually)
    • (6) Increased or excessive involvement in activities that have a high potential for painful consequences (e.g. - engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)
    • (7) Decreased need for sleep (feeling rested despite sleeping less than usual; to be contrasted with insomnia)
  • B. Mixed symptoms are observable by others and represent a change from the person’s usual behavior
  • C. For individuals whose symptoms meet full criteria for either mania or hypomania, the diagnosis should be bipolar I or bipolar II disorder.
  • D. The mixed symptoms are not attributable to the physiological effects of a substance (e.g. - a drug of abuse, a medication, other treatment)
Note: Mixed features associated with a major depressive episode have been found to be a significant risk factor for the development of bipolar I or bipolar II disorder. As a result, it is clinically useful to note the presence of this specifier for treatment planning and monitoring of response to treatment.

With melancholic features

  • A. 1 of the following is present during the most severe period of the current episode:
    • (1) Loss of pleasure in all, or almost all, activities
    • (2) Lack of reactivity to usually pleasurable stimuli (does not feel much better, even temporarily, when something good happens)
  • B. 3 or more of the following:
    • (1) A distinct quality of depressed mood characterized by profound despondency, despair, and/or moroseness or by so-called empty mood,
    • (2) Depression that is regularly worse in the morning
    • (3) Early-morning awakening (i.e. - at least 2 hours before usual awakening)
    • (4) Marked psychomotor agitation or retardation
    • (5) Significant anorexia or weight loss
    • (6) Excessive or inappropriate guilt

With atypical features

This specifier can be applied when these features predominate during the majority of days of the current or most recent major depressive episode or persistent depressive disorder.

  • A. Mood reactivity (i.e. - mood brightens in response to actual or potential positive events)
  • B. 2 or more of the following:
    • (1) Significant weight gain or increase in appetite
    • (2) Hypersomnia
    • (3) Leaden paralysis (i.e. - heavy, leaden feelings in arms or legs)
    • (4) A long-standing pattern of interpersonal rejection sensitivity (not limited to episodes of mood disturbance) that results in significant social or occupational impairment
  • C. Criteria are not met for “with melancholic features” or “with catatonia” during the same episode

With psychotic features

Delusions and/or hallucinations are present.

  • With mood-congruent psychotic features:
    • The content of all delusions and hallucinations is consistent with the typical depressive themes of personal inadequacy, guilt, disease, death, nihilism, or deserved punishment
  • With mood-incongruent psychotic features:
    • The content of the delusions or hallucinations does not involve typical depressive themes of personal inadequacy, guilt, disease, death, nihilism, or deserved punishment, or the content is a mixture of mood-incongruent and mood-congruent themes

With catatonia

This specifier can apply to an episode of depression if catatonic features are present during most of the episode.

With peripartum onset

This specifier can be applied to the current or, if full criteria are not currently met for a major depressive episode, most recent episode of major depression if onset of mood symptoms occurs during pregnancy or in the 4 weeks following delivery.

With seasonal pattern

This specifier applies to recurrent major depressive disorder.

  • A. There has been a regular temporal relationship between the onset of major depressive episodes in major depressive disorder and a particular time of the year (e.g. - in the fall or winter). Do not include cases in which there is an obvious effect of seasonally related psychosocial stressors (e.g. - regularly being unemployed every winter).
  • B. Full remissions also occur at a characteristic time of the year (e.g. - depression disappears in the spring)
  • C. In the last 2 years, 2 major depressive episodes have occurred that demonstrate the temporal seasonal relationships defined above and no nonseasonal major depressive episodes have occurred during that same period.
  • D. Seasonal major depressive episodes (as described above) substantially outnumber the nonseasonal major depressive episodes that may have occurred over the individual’s lifetime.
  • When inquiring about a history of depressive symptoms, it can be helpful to ask an individual when was the last time they had at least 2 months where they were entirely free of depressive symptoms.
  • Hypersomnia and hyperphagia are more likely in younger individuals, while melancholic symptoms (psychomotor disturbances, weight loss) are more common in geriatric depression.[17]
  • Various subtypes of depression have been identified. Clinically, it is important to ask the right questions to target the correct treatments to these subtypes.
  • The history of depression and melancholia has gone through various periods splitting and subtyping, followed by unifying theories of depression, and back again. Having an understanding of the history behind diagnostic classification of depression can be helpful (see above links).

Atypical Depression is a depression characterized by mood reactivity (moods that are strongly reactive to environmental circumstances, and feeling extremely sensitive - this is a must have feature), hypersomnia, carbohydrate craving/increased appetite, leaden paralysis (profound fatigue), and chronic rejection sensitivity. Atypical depression results in more disability than melancholic depression, because individuals often have more interpersonal difficulties. Atypical depression patients lack classic melancholic depression features such as insomnia, weight loss, loss of reactivity of mood.

Are atypical depression, borderline personality disorder, bipolar II disorder, and cyclothymic disorder overlapping conditions?

The common feature in all these diagnoses are emotional dysregulation and mood reactivity. The research hints that these disorders may all exist on a continuum.[18][19][20] Clinically, it can be challenging to distinguish between these disorders.

Childhood and Adolescent Depression is a subtype of depression characterized by low mood, anxiety, and irritability in children and youth.

Melancholic Depression (also known as Major Depressive Disorder with melancholic features in the DSM-5, and previously as “endogenous depression”) is a subtype of depression characterized by a severe loss of pleasure and prominent physical symptoms. Classic melancholic depression features include insomnia, weight loss, and psychomotor changes.

Geriatric Depression is one of the major geriatric giants (dementia, delirium, and depression). As a treatment population, special considerations need to be taken into account.

Postpartum Depression (PPD) (also known as Peripartum Depression, or Major Depressive Disorder with peripartum onset in the DSM-5) is a subtype of depression that occurs during pregnancy or in the first 4 weeks after delivery. However, women remain at risk for developing depression up to several months following delivery. PPD is the most common psychiatric complication related to child-bearing.

Psychotic Depression (also known as Major Depressive Disorder with psychotic features in the DSM-5) is a subtype of depression characterized by psychosis (delusions, hallucinations) in addition to mood changes. It requires the treatment of the underlying mood disorder first to resolve the psychosis.

Perimenopausal Depression (also known as Major Depressive Disorder with peripartum onset in the DSM-5) is a subtype of depression experienced by women during the perimenopausal period, defined as the interval when a women’s menstrual cycles become irregular, usually between ages of 45 and 49.

Seasonal Affective Disorder (SAD) is a subtype of depression with a usual annual onset between September-November with spontaneous remission in April-May. There is generally an increased prevalence in countries the father it is from the equator (interestingly, Iceland has low rates of SAD[21]). The development of SAD is thought to be due to dark/grey conditions in the winter season, and lack of light availability. Fluctuations in circadian rhythms and melatonin release also plays a role.[22] SAD can be considered as an evolutionary phenomenon and many individuals have non-clinical symptoms of SAD. Clinically symptomatic SAD can occur in up to 2.6% of the Canadian population, with premenopausal women most affected. Individuals with certain serotonin transporter genotypes may be more predisposed to SAD.[23] Bupropion has been shown to be effective in the prevention of SAD by starting treatment prior to the winter season.[24]

Situational Depression (also known as Reactive Depression, Exogenous Depression, and Adjustment Disorder) are depressive symptoms that occur when an individual is unable to adjust to or cope with a particular stress or a major life event. This was a previously historical diagnosis that has fallen out of clinical use. Its close counterpart is now called adjustment disorder, which reflects much of the same symptoms.

Suicide is the most serious consequence of a major depressive episode. Suicidal ideation, planning, and attempts are highly prevalent in depression. The risk for suicidal behaviour is present at all times during a depressive episode. Thus, a suicide risk assessment should be done as part of routine clinical care. Certain risk factors place an individual for higher risk of suicide, with a past history of suicide attempts or behaviours being the highest risk factor.

Risk Factors for Suicide During a Depressive Episode

Lam, Raymond W., et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 1. Disease burden and principles of care. The Canadian Journal of Psychiatry 61.9 (2016): 510-523.
Non-modifiable Risk Factors Modifiable Risk Factors Modifiable Risk Factors
• Older men
• Past suicide attempt
• History of self-harm behaviour
• Being a sexual minority
• Family history of suicide
• History of legal problems
Symptoms and life events
• Active suicidal ideation
• Hopelessness
• Psychotic symptoms
• Anxiety
• Impulsivity
• Stressful life events such as financial stress (e.g. - bankruptcy) and victimization
Comorbid conditions
• Substance use disorders (especially alcohol use disorder)
• Posttraumatic stress disorder
• Comorbid personality disorders (especially cluster B personality disorders)
• Chronic painful medical conditions (e.g. - migraine headaches, arthritis)
• Cancer

Various scales can be used to measure depression severity in an individual. Below are the most common ones, with an indication for each. Measurement based care with scales has been shown to lead to better recovery in depression.[25]

Psychometric Scales for Depression

Name Rater Description Download
Beck Depression Inventory (BDI) Patient A 21-question multiple-choice self-report inventory, one of the most widely used psychometric tests for measuring the severity of depression. Designed for individuals aged 13 and over. Not Available
Patient Health Questionnaire (PHQ-9) Patient A 9-question instrument given to patients in a primary care setting to screen for the presence and severity of depression. PHQ-9 Download
Hamilton Rating Scale for Depression (HAM-D/HDRS) Clinician Rates patient between 17 to 29 dimensions (depending on version) with a score on a 3 or 5 point scale. Max Hamilton maintained that his scale should not be used as a diagnostic instrument. HAM-D Download
Montgomery–Åsberg Depression Rating Scale (MADRS) Clinican 10-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. MADRS Download
Quick Inventory of Depressive Symptomatology (QIDS-C) Clinican A 16-item clinician rating of the patient's depressive symptoms QIDS-C Download
Quick Inventory of Depressive Symptomatology (QIDS-SR) Patient A 16-item patient's self-report of depressive symptoms QIDS-SR Download
  • The etiology of depression is heterogeneous and multifactorial, and also can be due to medical etiologies (“organic”).
    • As such, there cannot be a “single cause” or etiology for depression.
    • This similarly means there is no “single cure” for depression.
  • Sometimes, subtyping the depression can be helpful in determining its etiology.
  • Amygdala hyperactivity and volumetric changes are a well-replicated finding in major depressive disorder.[26][27][28]
  • Neuroimaging studies with diffusion tensor imaging (DTI) imaging have shown that the cingulum bundle microstructure is altered in people at risk for depression.
    • The uncinate fasciculus and medial forebrain bundle microstructures are also altered during acute depression in adults.[29]
  • Functional magnetic resonance imaging (fMRI) studies also suggest functional abnormalities in specific neural networks involved in emotion processing, reward seeking, and emotion regulation.[30]
    • Major depressive episodes with prominent irritable mood can be difficult to distinguish from manic episodes with irritable mood or from mixed episodes as seen in bipolar disorder.
  • Adjustment disorder with depressed mood
    • If the full criteria for a major depressive episode are not met, then an individual may meet criteria for an adjustment disorder.
    • A diagnosis of major depressive episode is only appropriate 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. - Parkinson's disease, vitamin B12 deficiency, Huntington's disease, multiple sclerosis, stroke, hypothyroidism).
    • There are many medical conditions that can masquerade as MDD, and it is important for the clinician to have a broad differential diagnosis at all times.
    • Sleep apnea is often missed and not diagnosed. Adequately treated sleep apnea reduces depressive symptoms significantly in the absence of antidepressant treatment.[31] Do not miss this!
    • This is distinguished from MDD by the fact that a substance (e.g. - a drug of abuse, a medication, a toxin) appears to be etiologically and temporally related to the mood disturbance. For example, a depressed mood that occurs only in the context of withdrawal from alcohol would be diagnosed as alcohol-induced depressive disorder.
    • Distractibility and poor frustration tolerance can occur in both ADHD and MDD. Thus, if the criteria are met for both, both can be diagnosed. However, the clinician must be cautious not to overdiagnose depression in children with ADHD whose disturbance in mood is characterized by irritability rather than by sadness or loss of interest.
  • Normal sadness!
    • Sadness is an inherent part of the human condition and should not be medicalized. Thus, a major depressive episode should only be diagnosed if there is significant severity (i.e. - five out of nine symptoms), an appropriate duration (i.e. - most of the day, nearly every day for at least 2 weeks), and also clinically significant distress or impairment.
    • These are situations or conditions that may be causing some “symptoms” but are not diagnosable mental disorders.

Grief/Loss vs. Depression

Adapted from: American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
Presentation Grief Major Depressive Episode
Predominant affect Emptiness, loss Persistent low mood, inability to feel happiness or pleasure
Course Decreases in intensity over days to weeks, and occurs in waves (“pangs of grief”) Persistent and not tied to specific thoughts
Thought Content Mostly preoccupied with thoughts and memories of the deceased Self-critical, pessimistic ruminations
Self-esteem Preserved* Worthlessness, self-loathing is common
Death thoughts/suicidal ideation Thoughts involve wanting to “join” the deceased Idea of ending one's life associated with feelings of worthlessness, pain of depression
  • When clinically indicated, bloodwork includes: complete blood count (BC), iron studies, liver function tests, TSH, vitamin B12
  • The hypothalamic-pituitary-adrenal axis is associated with melancholia, psychotic features, and suicidality.
    • Individuals with depression have decreased sleep efficiency, decreased slow-wave sleep (meaning decreased stage 3 and stage 4 sleep time), shorter/decreased REM latency (i.e. - shorter time between sleep onset and first REM period),[32] and increased REM intensity.[33]

Never, Ever, Forget This

“Major depressive disorder is a clinically heterogeneous group of conditions that respond variably to a diverse group of interventions.”[34]
  • It is important to remember that there is no one-size-fits-all treatment for individuals with depression.
  • Pharmacological, psychological, complementary and alternative medicine, neurostimulation, and exercise treatments can all play a role in the treatment of depression, and prevention of recurrence.[35]
  • Depression is a highly placebo-sensitive condition.[36][37]
    • Placebo response rates can be anywhere up to 30-40%.[38]
  • The following treatment recommendations are mostly based on the Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder, but there are various international treatment guidelines that are equally applicable (see guidelines section).[39]

Treatment with Medication or Psychotherapy? Both?

  • Whenever possible, psychotherapy should be offered to a patient first. Recovery rates from depression when treated with medication monotherapy is around 30%. Both cognitive behavioural therapy and interpersonal therapy provides stronger protection from relapse following treatment discontinuation compared to medications.[40]
    • Most patients also have a significantly higher preference for psychotherapy over medications.[41]
    • Unfortunately, psychological therapies can be very limited in availability, and sometimes medications are the only option.
  • However, there is also evidence that combination treatment with both medications and psychotherapy offers more benefit than psychological treatment alone or medication treatment alone.[42]
  • Psychotherapy is appropriate for both men and women, individuals of all ages, all levels of education, and all cultural and ethnic backgrounds.[43]
  • Psychotherapy is effective for mild, moderate, and severe depression.
  • First-line psychotherapy treatments for acute depression include cognitive behavioural therapy, interpersonal therapy, and behavioural activation.[45]
  • For individuals with sub-threshold depression symptoms or mild depression, computerized CBT or guided self-help is recommended.[46]
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Psychological Treatments

Adapted from: Parikh, S. V. et al (2016). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 2. Psychological treatments. The Canadian Journal of Psychiatry, 61(9), 524-539.
Acute Episode Maintenance
1st line Cognitive behavioural therapy (CBT)
Interpersonal therapy (IPT)
• Behavioural activation (BA)
Cognitive behavioural therapy (CBT)
Mindfulness-based cognitive therapy (MBCT)
2nd line Mindfulness-based cognitive therapy (MBCT)
• Cognitive-behavioural analysis system of psychotherapy (CBASP)
• Problem-solving therapy (PST)
Short-term psychodynamic therapy (STPP)
• Telephone-delivered CBT and IPT
• Internet + computer-assisted therapy
Interpersonal therapy (IPT)
• Behavioural activation (BA)
• Cognitive-behavioural analysis system of psychotherapy (CBASP)
3rd line Long-term psychodynamic psychotherapy (PDT)
• Videoconferenced psychotherapy
Motivational interviewing
• Long-term psychodynamic psychotherapy (PDT)
  • For individuals who do not improve at the 2 to 4 week mark, the dose should be optimized during this time (instead of switching antidepressants).
  • If there is a poor response to the initial antidepressant past the 4 week point, then consider switching to another antidepressant when:[47]
    • It is the first antidepressant trial
    • If there are poorly tolerated side effects to the initial antidepressant
    • If there is no response (<25% improvement) to the initial antidepressant
    • There is more time to wait for a response (less severe, less functional impairment), or
    • If the patient prefers to switch to another antidepressant

Which First-Line Antidepressant Do I Choose?

Based on the latest meta-analyses, several antidepressants have been found to be more efficacious and better tolerated, including: escitalopram, venlafaxine, mirtazapine, agomelatine + amitriptyline (combination), paroxetine, and vortioxetine.[48] Some clinical guidelines also recommend picking based on the specifier diagnosis and symptom profile, though this approach has not necessarily borne out in evidence.
  • Depression treatment guidelines recommend that patients remain on an antidepressant for another 6 to 9 months after they have achieved remission of symptoms.
  • For individuals with risk factors for recurrence, the CANMAT 2016 Depression guidelines recommend that treatment be extended to 2 years or more after achieving remission of symptoms.
    • These factors include: frequent and/or recurrent episodes, severe episodes (psychosis, severe impairment, suicidality), cronic episodes, presence of comorbid psychiatric or other medical conditions, presence of residual symptoms, and difficult-to-treat episodes.[49]
  • There is recent evidence to suggest that antidepressants can be successfully discontinued when concurrent preventive cognitive therapy (PCT) or mindfulness-based cognitive therapy (MBCT) is offered.[50]

Pharmacotherapy for major depressive disorder

Kennedy, S. H. et al. (2016). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3. Pharmacological treatments. The Canadian Journal of Psychiatry, 61(9), 540-560.
Adjunctive
  • The decision to switch antidepressants or to add an adjunctive medication depends on patient preferences and factors, there is no specific evidence that one option is better than the other.
  • Consider switching completely to another medication when:[51]
    • It is the first antidepressant trial
    • There are poorly tolerated side effects to the initial antidepressant
    • There is no response (<25% improvement) to the initial antidepressant
    • There is more time to wait for a response (less severe, less functional impairment)
    • Patient prefers to switch to another antidepressant
  • Consider adding an adjunctive medication when:[52]
    • There have been 2 or more antidepressant trials, with poor response
    • If the initial antidepressant is well tolerated
    • If there is partial response (>25% improvement) to the initial antidepressant
    • If there are specific residual symptoms or side effects to the initial antidepressant that can be targeted
    • If there is less time to wait for a response (more severe, more functional impairment)
    • Or if the patient prefers to add on another medication.

Adjunctive pharmacotherapy for major depressive disorder

Kennedy, S. H. et al. (2016). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3. Pharmacological treatments. The Canadian Journal of Psychiatry, 61(9), 540-560.
1st line Adjunctive therapy: aripiprazole, quetiapine, risperidone
2nd line Adjunctive therapy: brexpiprazole, bupropion, lithium, mirtazapine, mianserin, modafinil, olanzapine, triiodothyronine
3rd line Adjunctive therapy: other antidepressants, other stimulants (methylphenidate, lisdexamfetamine), tricyclic antidepressants, ziprasidone
Not recommended Pindolol

Selecting Antidepressants Based on Clinical Specifiers and Dimension of Depression

From: Kennedy, S. H. et al. (2016). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3. Pharmacological treatments. The Canadian Journal of Psychiatry, 61(9), 540-560.
Recommendations Notes
With anxious distress • Use an antidepressant with efficacy in generalized anxiety disorder (Level 4) • No differences in efficacy between SSRIs, SNRIs, and bupropion (Level 2)
With catatonic features • Benzodiazepines (Level 3) • No antidepressants have been studied
With melancholic features • No specific antidepressants have demonstrated superiority (Level 2) • TCAs and SNRIs have been studied
With atypical features • No specific antidepressants have demonstrated superiority (Level 2) • Older studies found MAO inhibitors superior to TCAs
With psychotic features • Use antipsychotic and antidepressant cotreatment (Level 1) • Few studies involved atypical antipsychotics
With mixed features • Lurasidone (Level 2)
• Ziprasidone (Level 3)
• No comparative studies
With seasonal pattern • No specific antidepressants have demonstrated superiority (Level 2 and 3) • SSRIs, agomelatine, bupropion, and moclobemide have been studied
With cognitive dysfunction • Vortioxetine (Level 1)
• Bupropion (Level 2)
• Duloxetine (Level 2)
• SSRIs (Level 2)
• Moclobemide (Level 3)
• Limited data available on cognitive effects of other antidepressants and on comparative differences in efficacy
With sleep disturbances • Agomelatine (Level 1)
• Mirtazapine (Level 2)
• Quetiapine (Level 2)
• Trazodone (Level 2)
• Beneficial effects on sleep must be balanced against potential for side effects (e.g., daytime sedation)
With somatic symptoms • Duloxetine (pain) (Level 1)
• Other SNRIs (pain) (Level 2)
• Bupropion (fatigue) (Level 1)
• SSRIs (fatigue) (Level 2)
• Duloxetine (energy) (Level 2)
• Few antidepressants have been studied for somatic symptoms other than pain
• Few comparative antidepressant studies for pain and other somatic symptoms

Natural Health Products in Major Depressive Disorder

Ravindran, A. V. et al. (2016). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 5. Complementary and alternative medicine treatments. The Canadian Journal of Psychiatry, 61(9), 576-587.
Product Indication Recommendation Monotherapy or Adjunctive Therapy
St. John’s wort • Mild to moderate MDD
• Moderate to severe MDD
• First line
• Second line
• Monotherapy
• Adjunctive
Omega-3 • Mild to moderate MDD
• Moderate to severe MDD
• Second line
• Second line
• Monotherapy or adjunctive
• Adjunctive
S-adenosyl-L-methionine (SAM-e) • Mild to moderate
• MDD Moderate to severe MDD
• Second line
• Second line
• Adjunctive
• Adjunctive
Acetyl-L-carnitine • Mild to moderate MDD • Third line • Monotherapy
Crocus sativus (saffron) • Mild to moderate MDD • Third line • Monotherapy or adjunctive
Dehydroepiandrosterone (DHEA) • Mild to moderate MDD • Third line • Monotherapy
Folate • Mild to moderate MDD • Third line • Adjunctive
Lavandula (lavender) • Mild to moderate MDD • Third line • Adjunctive
Inositol Not recommended Not recommended Not recommended
Tryptophan Not recommended Not recommended Not recommended
Rhodiola rosea (roseroot) Not recommended Not recommended Not recommended
  • In cases of severe, treatment-refractory depression, or in cases where there are significant safety concerns, electroconvulsive therapy (ECT) can be a safe and rapid treatment.
  • Light therapy is indicated for treatment of depression with seasonal affective subtype and can also be used in the treatment of mild to moderate depression.

Summary of Recommendations for Physical and Meditative Treatments

Ravindran, A. V. et al. (2016). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 5. Complementary and alternative medicine treatments. The Canadian Journal of Psychiatry, 61(9), 576-587.
Intervention Indication Recommendation Evidence Monotherapy or Adjunctive Therapy
Exercise • Mild to moderate MDD
• Moderate to severe MDD
• First line
• Second line
• Level 1
• Level 1
• Monotherapy
• Adjunctive
Light therapy • Seasonal (winter) MDD
• Mild to moderate nonseasonal MDD
• First line
• Second line
• Level 1
• Level 2
• Monotherapy
• Monotherapy and adjunctive
Yoga • Mild to moderate MDD • Second line • Level 2 • Adjunctive
Acupuncture • Mild to moderate MDD • Third line • Level 2 • Adjunctive
Sleep deprivation • Moderate to severe MDD • Third line • Level 2 • Adjunctive
  • Exercise has evidence as a treatment for mild to moderate depression and is recommended for all individuals.
  • Antidepressants and/or psychotherapy may not adequately treat all patients with depression. Combining these treatments with lifestyle changes through exercise is supported by well-designed studies.[53]
  • Adhering to a healthy diet, especially a traditional Mediterranean diet or avoiding a pro-inflammatory diet, offers protection against depression in observational studies.[54]

Depression Guidelines

Guideline Location Year PDF Website
Canadian Network for Mood and Anxiety Treatments (CANMAT) Canada 2016 PDF Link
American Psychiatric Association (APA) USA 2010 PDF Guideline (2010)
Quick Reference
National Institute for Health and Care Excellence (NICE) UK 2019 PDF (adults)
PDF (children and youth)
Link (adults)
Link (children and youth)
The Royal Australian and New Zealand College of Psychiatrists (RANZCP) AUS, NZ 2015 PDF Link
American Academy of Pediatrics (AAP) Guidelines for Adolescent Depression in Primary Care (GLAD-PC) USA 2018 PDF Link
“It’s so difficult to describe depression to someone who’s never been there, because it’s not sadness. I know sadness. Sadness is to cry and to feel. But it’s that cold absence of feeling — that really hollowed-out feeling.”

– J.K. Rowling
3) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
6) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
7) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
8) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
9) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
10) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
12) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
14) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
15) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
17) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
30) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.