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 or attempts may also occur during depressive episodes.

• 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.

• 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]

• MDD is associated with chronic medical conditions including heart disease, arthritis, back pain, chronic pulmonary disease, asthma, hypertension, and migraine.^[11]
  • Associated lifestyle risk factors include a more sedentary lifestyle, obesity, and cigarette smoking.
• Other comorbid psychiatric disorders include panic disorder, substance use disorders, obsessive compulsive disorder, anorexia nervosa, bulimia nervosa, and borderline personality disorder.^[12]

• 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]

• 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).

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

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

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.

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

• 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).

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.

Post-Stroke Depression (PSD) can develop acutely after a stroke, and associated with poorer functional outcomes.

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.

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]

• 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]

• When clinically indicated, bloodwork includes: complete blood count (BC), iron studies, liver function tests, TSH, vitamin B12, 25-OH Vitamin D, serum zinc, calcium, magnesium, phosphate
• The hypothalamic-pituitary-adrenal axis is associated with melancholia, psychotic features, and suicidality.
  • The dexamethasone suppression test has previously been used to identify the melancholic subtype of depression, but has fallen out of use.
• Polysomnography and EEG
  • 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]

• 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:^[49]
  • 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

• 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.^[51]
• 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.^[52]

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 or attempts may also occur during depressive episodes.

• In Canada, the annual prevalence of a depressive episode is 4.7%, and a lifetime prevalence is 11.3%.^[53]
• 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.^[54]
• 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.

• MDD can appear at any age, but the chance increases with the onset of puberty. The age of onset peaks in the mid-20s.^[55]
• 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.^[56]
• 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.^[57]
• The longer the period of full remission, the lower the chance of recurrence.^[58]
  • This means that the persistence of even mild depressive symptoms during a period of remission is a significant predictor for a future recurrence.^[59]
• Negative prognostic factors include having psychotic features, comorbid anxiety, personality disorders, and greater symptom severity.^[60]
• 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).^[61]
• The impairment from MDD can range from being mild to severe, depending on the individual, and depend on the symptom profile.^[62]

• MDD is associated with chronic medical conditions including heart disease, arthritis, back pain, chronic pulmonary disease, asthma, hypertension, and migraine.^[63]
  • Associated lifestyle risk factors include a more sedentary lifestyle, obesity, and cigarette smoking.
• Other comorbid psychiatric disorders include panic disorder, substance use disorders, obsessive compulsive disorder, anorexia nervosa, bulimia nervosa, and borderline personality disorder.^[64]

• 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.^[65]
• 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%.^[66]
• Medical conditions such as diabetes, obesity, and cardiovascular disease also increase the risk for depression.^[67]

• 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).

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

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

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.

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

• 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.^[69]

• 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).

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.

Post-Stroke Depression (PSD) can develop acutely after a stroke, and associated with poorer functional outcomes.

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^[73]). 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.^[74] 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.^[75] Bupropion has been shown to be effective in the prevention of SAD by starting treatment prior to the winter season.^[76]

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.

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.^[77]

• 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.^[78][79][80]
• 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.^[81]
• Functional magnetic resonance imaging (fMRI) studies also suggest functional abnormalities in specific neural networks involved in emotion processing, reward seeking, and emotion regulation.^[82]

• When clinically indicated, bloodwork includes: complete blood count (BC), iron studies, liver function tests, TSH, vitamin B12, 25-OH Vitamin D, serum zinc, calcium, magnesium, phosphate
• The hypothalamic-pituitary-adrenal axis is associated with melancholia, psychotic features, and suicidality.
  • The dexamethasone suppression test has previously been used to identify the melancholic subtype of depression, but has fallen out of use.
• Polysomnography and EEG
  • 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),^[84] and increased REM intensity.^[85]

• 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:^[101]
  • 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

• 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.^[103]
• 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.^[104]

• The decision to switch antidepressants or to add an adjunctive medication depends on patient preferences and factors. Increasingly, some meta-analyses have shown that dose increases and switching do not confer any additional benefits.^[105][106]
• The other issue to consider with antipsychotic augmentation is that although short-term studies have shown efficacy in improving depressive symptoms, clinically meaningful improvement (i.e., actual remission remains limited. Additionally, there are concerns about the side effects of antipsychotic medications including including weight gain, metabolic dysfunction and extrapyramidal symptoms with long-term use.^[107]

• 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.

• rTMS involves stimulation of cortical neurons using powerful, focused magnetic field pulses applied externally over the scalp. Unlike ECT, it does not require anaesthesia and has no cognitive side effects.
• rTMS shows efficacy for difficult-to-treat depression (DTD), with response rates of 40% to 50%.

• Digital health interventions (DHIs) are internet programs or mobile apps that deliver depression treatment. Many DHIs provide tools to promote depression self-management, drawing on evidence-based psychotherapies such as CBT, behavioural activation, and mindfulness.
• DHIs are potentially useful for individuals with mild to moderate severity of depressive symptoms. Guided DHIs (with a therapist, coach, or peer supporter) are generally more effective than self-directed DHIs.
• Clinicians should carefully evaluate any DHI for efficacy, privacy and security, risks, and accessibility before recommending it to patients.

• 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.

• Exercise has evidence as a treatment for mild to moderate depression and is recommended for all individuals.^[111]
• 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.^[112]

• Adhering to a healthy diet, especially a traditional Mediterranean diet or avoiding a pro-inflammatory diet, offers protection against depression in observational studies.^[113]
• Randomized controlled trials (RCTs) of dietary interventions suggest that a less sugar-sweetened drinks, reduced processed foods and meats, and higher vegetable, fruit and legume intake is associated with lower depressive symptoms.^[114]

• 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.

• rTMS involves stimulation of cortical neurons using powerful, focused magnetic field pulses applied externally over the scalp. Unlike ECT, it does not require anaesthesia and has no cognitive side effects.
• rTMS shows efficacy for difficult-to-treat depression (DTD), with response rates of 40% to 50%.

• Digital health interventions (DHIs) are internet programs or mobile apps that deliver depression treatment. Many DHIs provide tools to promote depression self-management, drawing on evidence-based psychotherapies such as CBT, behavioural activation, and mindfulness.
• DHIs are potentially useful for individuals with mild to moderate severity of depressive symptoms. Guided DHIs (with a therapist, coach, or peer supporter) are generally more effective than self-directed DHIs.
• Clinicians should carefully evaluate any DHI for efficacy, privacy and security, risks, and accessibility before recommending it to patients.

• 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.

• Exercise has evidence as a treatment for mild to moderate depression and is recommended for all individuals.^[115]
• 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.^[116]

• Adhering to a healthy diet, especially a traditional Mediterranean diet or avoiding a pro-inflammatory diet, offers protection against depression in observational studies.^[117]
• Randomized controlled trials (RCTs) of dietary interventions suggest that a less sugar-sweetened drinks, reduced processed foods and meats, and higher vegetable, fruit and legume intake is associated with lower depressive symptoms.^[118]