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 also associated neurovegetative symptoms, such as a change in sleep, appetite, cognition, and energy levels. Suicidal ideation may also occur.


The one month prevalence is 1.3%, one year is 4.0%, and lifetime is 10.8%.[1] Women have a two times higher risk of developing MDD versus men. The reasons for the difference are hypothesized to involve hormonal differences, the effects of childbirth, differing psychosocial stressors for women and for men, and behavioural models of learned helplessness. The average age of onset is about 40 years old.

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 more slightly more common in rural areas than in urban areas.[2]

Criterion A

At least 5 out of 9 symptoms present in the same 2-week period and represent a change from previous functioning. 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
Do not include symptoms that are clearly attributable to another medical condition.
Criterion B

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


The mnemonic MSIGECAPS can be used to remember the criteria for major depressive disorder.[3]

  • M - Mood
  • S - Sleep
  • I - Interest
  • G - Guilt/Worthlessness
  • E - Energy
  • C - Concentration
  • A - Appetite
  • P - Psychomotor Slowing
  • S - Suicide
Criterion C

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

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.
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 depression 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.

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 subtyping followed by unified theories and back again.

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.

Atypical depression is also associated with conduct disorder, social phobia, interpersonal dependency, low self-esteem, and parental substance abuse.[4] Atypical depression has a poor response to TCAs and ECT, but excellent response to MAOis, due to suspected elevated MAO activity.[5][6] Atypical depression is also associated with higher rates of early childhood trauma, whereas melancholic depression is not.[7] This again suggests a difference in the etiology and pathophysiology of different depression subtypes.[8]

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.[9][10][11] Clinically, it can be challenging to distinguish between these disorders.

Melancholic Depression (sometimes known as “endogenous depression”) as a subtype of depression characterized by a profound sense of sadness, lack of mood reactivity (i.e. - absolutely nothing can brighten one's mood), and anhedonia. It is considered to be a biologically-based depression. Individuals often have hypercortisolemia and there is a strong genetic and familial association in melancholic depression. Theories on the pathophysiology of melancholic depression include disruption of the HPA axis.[12][13] Melancholic depression often progresses into psychotic depression (where delusions are usually nihilistic in nature). Females are less affected in melancholic depression, and there is typically an older age of onset. Melancholic depression is shorter in duration and more episodic. It also features diurnal variation (early-morning worsening of mood, with an afternoon slump or evening worsening).[14] There is concern from older clinicians that the proper diagnosis and treatment of melancholic depression has been overshadowed by the introduction of mass-marketed SSRIs.[15] There is evidence to suggest that melancholic depression responds better to TCAs and ECT.[16][17]

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.

In women with no lifetime history of depression, those who enter the menopausal transition earlier have a significant risk for first onset of depression. Since estrogen and serotonin may modulate hypothalamic thermoregulatory function, abrupt changes in neuromodulatory function and reproductive-hormone levels during menopause are thought to contribute to mood and vasomotor symptoms seen in menopause.[18] There is scant evidence to suggest that hormone replacement therapy should be used to prevent depressive symptoms during the menopause transition.[19] Additionally, the U.S. Preventive Services Task Force recently found “no net benefit” of hormone therapy for primary prevention of most chronic disorders related to menopause, but they did find “convincing evidence” of risks like breast cancer, thromboembolism, and cardiovascular disease.[20]

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]

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. BDI Download
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

Never, Ever, Forget This

“Major depressive disorder is a clinically heterogeneous group of conditions that respond variably to a diverse group of interventions.”[26]

The etiology of depression is heterogeneous and multifactorial, and also can be due to medical etiologies (“organic”). Often, subtyping the depression can be helpful in determing its etiology. Refer to the subtypes section for more information.

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.[27]

  • When clinically indicated, bloodwork includes:
    • Complete blood count (BC)
    • Iron studies
    • Liver function tests
    • 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),[29] and increased REM intensity.[30]

The following treatment recommendations are based on the Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder.[31] See also: Köhler-Forsberg, O., Cusin, C., & Nierenberg, A. A. Evolving Issues in the Treatment of Depression. JAMA.

Treatment with Medication or Psychotherapy?

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 (CBT) and Interpersonal Therapy (IPT) provides stronger protection from relapse following treatment discontinuation compared to medications.[32] Most patients also have a significantly higher preference for psychotherapy over medications.[33] CBT provides also provides stronger protection from relapse following treatment discontinuation compared to medications.[34] Unfortunately, psychological therapies can be very limited in availability, and sometimes medications are the only option.

First-line psychotherapy treatments include Cognitive Behavioural Therapy (CBT), Interpersonal Therapy (IPT), and behavioural activation.[35] Psychotherapy is effective for mild, moderate, and severe depression. For individuals with sub-threshold depression symptoms or mild depression, computerized CBT or guided self-help is recommended.[36]

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)
Recommended Reading

Buy on Amazon

PsychDB is an Amazon Associate and earns from qualifying purchases. Thank you for supporting our site!

Depression is a highly placebo-sensitive condition. Placebo response rates can be anywhere up to 30-40%.[37] If there is a poor response to the initial antidepressant, consider switching to another antidepressant when: 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 patient prefers to switch to another antidepressant.

Consider a adding an adjunctive medication when there have been 2 or more antidepressant trials, the initial antidepressant is well tolerated, there is partial response (>25% improvement) to the initial antidepressant, there are specific residual symptoms or side effects to the initial antidepressant that can be targeted, there is less time to wait for a response (more severe, more functional impairment), or the patient prefers to add on another medication.

Pharmacotherapy for major depressive disorder

1st line Agomelatine, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, mianserin, milnacipran, mirtazapine, paroxetine, sertraline, venlafaxine, vortioxetine
2nd line Amitriptyline, clomipramine, other tricyclics, levomilnacipran, moclobemide, quetiapine, selegiline (transdermal), trazodone, vilazodone
3rd line Phenelzine, tranylcypromine, reboxetine

Adjunctive pharmacotherapy for major depressive disorder

Adjunctive therapy (1st line) Aripiprazole, quetiapine, risperidone
Adjunctive therapy (2nd line) Brexpiprazole, bupropion, lithium, mirtazapine, mianserin, modafinil, olanzapine, triiodothyronine
Adjunctive therapy (3rd line) Other antidepressants, other stimulants (methylphenidate, lisdexamfetamine), tricyclic antidepressants, ziprasidone
Not recommended Pindolol

Phototherapy is indicated for treatment of depression with seasonal affective subtype.

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.[38]

Adhering to a healthy diet, especially a traditional Mediterranean diet or avoiding a pro-inflammatory diet, offers protection against depression in observational studies.[39] There is evidence to suggest that dietary changes can help elevate serotonin levels as well. Studies have shown that tryptophan can have anxiolytic effects.[40][41][42][43]

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[44]