Major depressive disorder

Major depressive disorder (MDD) is an episodic mood disorder primarily characterized by depressed mood and anhedonia lasting for at least 2 weeks. Women have a higher risk of developing MDD than men. The peak age of onset is the 3^rd decade. The etiology is multifactorial, including both biological and psychological factors. Reduced levels of neurotransmitters (serotonin, noradrenaline, dopamine) are believed to be the pathophysiological basis in most cases. Other symptoms of MDD include sleep disturbance, loss of appetite, and thoughts of suicide. There are various subtypes of MDD characterized by additional symptoms or occurrence in specific conditions, such as atypical depression (additionally characterized by, e.g., weight gain and increased appetite), psychotic depression (with additional psychotic features such as hallucinations and delusions), and peripartum depression (which occurs during or shortly after pregnancy). In elderly patients, MDD can also manifest with memory loss and other symptoms seen in dementia, referred to as pseudodementia. Treatment is multifaceted and often requires pharmacotherapy, psychotherapy, and lifestyle changes. First-line treatment mainly consists of SSRIs (e.g., citalopram) and SNRIs (e.g., venlafaxine).

• Sex: ♀ > ♂
• Lifetime prevalence: 10–20% ^[1]
• Age of onset: 3^rd decade of life

References: ^[2]

Epidemiological data refers to the US, unless otherwise specified.

• Biological factors
  • Monoamine hypothesis: Most antidepressants work by inhibiting the reuptake of monoamines (e.g., serotonin, noradrenaline, dopamine), indicating that a lack of monoamines plays a major role in the pathophysiology of depression (and other mood disorders).
  • Genetic factors
    • First-degree relatives of patients with depression are at increased risk of developing depression.
    • The concordance rate in identical twins is ∼ 50%.
  • Increased production of stress hormones (e.g., dysfunction of the hypothalamic-pituitary-adrenal axis)
• Psychological factors: traumatic and stressful experiences, behavioral factors (e.g., learned helplessness)
• Comorbidities: neurodegenerative diseases (e.g., Alzheimer disease), chronic inflammatory diseases (e.g., systemic lupus erythematosus or inflammatory bowel disease), and other psychiatric disorders (e.g., panic disorder)

References:^[3][4]

The presence of symptoms from criteria A to C constitutes a major depressive episode. For a diagnosis of major depressive disorder, the following two criteria must also be present: the symptoms are not due to another psychiatric disorder AND there is no history of a manic or hypomanic episode.

“DICES GAPS” (D or I must be present for diagnosis): Depressed mood (can present as irritability in children), Interest loss (anhedonia), Concentration (poor concentration or difficulty making decisions), Energy (low energy or fatigue), Sleep (insomnia or hypersomnia), Guilt (low self-esteem), Appetite (decreased appetite or overeating), Psychomotor agitation or retardation, and Suicidal ideation are the features of the major depressive disorder.

References:^[5]

Major depressive disorder with seasonal pattern (seasonal affective disorder, winter depression)

• Occurs in a yearly, season-specific pattern (commonly in fall or winter)
• Symptoms must be present for ≥ 2 consecutive years and for the majority of years in a lifetime.
• Patients present with typical symptoms of MDD alongside atypical ones, such as weight gain and requiring more sleep.
• Light therapy has been shown to improve symptoms.

Major depressive disorder with atypical features

• Most common variant of MDD
• Mood reactivity: brightening of mood in response to positive events, which is usually not the case in classical MDD
• Two or more of the following features are present:
  • Increased appetite or over-eating
  • Hypersomnia
  • Leaden paralysis (legs and arms feel heavy)
  • Interpersonal rejection sensitivity that leads to social and occupational impairment
• Treatment
  • 1^st line: CBT with or without SSRIs
  • MAO inhibitors can be effective although not commonly prescribed due to their side effects.

Major depressive disorder with psychotic features

• Major depression accompanied by psychotic symptoms
  • Features of MDD (see diagnostic criteria for major depressive disorder)
  • Psychotic features, such as delusions and hallucinations, which are usually mood-congruent (delusions and hallucinations are often about worthlessness, guilt, death, and hopelessness)
  • Psychotic features occur only alongside a major depressive episode.
• Overactivity of the hypothalamic-pituitary-adrenal axis (increased dopamine activity) is believed to play a major role.
• Treatment:
  • Antidepressants together with atypical antipsychotics
  • In severe cases, electroconvulsive therapy may be used.

Persistent depressive disorder (dysthymia) ^[6]

• Depressed mood in addition to ≥ 2 of the following symptoms
  • Poor appetite or overeating
  • Insomnia or hypersomnia
  • Low energy or fatigue
  • Low self-esteem
  • Poor concentration or difficulty making decisions
  • Feelings of hopelessness
• The symptoms are present for most of the day, and for the majority of days, for ≥ 2 years in adults.
• In children and adolescents, symptoms present for ≥ 1 year.
• Periods of remissions should not last more than 2 consecutive months.
• Unlike in MDD, thoughts of suicide, loss of interest, and psychomotor agitation or retardation are not typical features of persistent depressive disorder; therefore, dysthymia is often regarded as a milder form of MDD.
• In case all the criteria for MDD are met, the diagnosis should be changed to MDD.

HE'S 2 SAD: Hopelessness, Energy loss or fatigue, Self-esteem is low, 2 years minimum of depressed mood, Sleep is increased or decreased (insomnia or hypersomnia), Appetite is increased or decreased, Decision-making and/or concentration is impaired.

References:^{[5][6][7][8][9][10]}

• Clinical diagnosis
  • See diagnostic criteria for major depressive disorder.
  • Questionnaires can be used to help determine the features of depression:
    • Patient Health Questionnaire-9
    • Beck Depression Inventory
• Screening
  • Patient Health Questionnaire-2
  • Check for past episodes of mania and/or hypomania to rule out bipolar disorder.
• Assessment of suicide risk: indicated for all patients
• Laboratory evaluation: indicated to rule out organic disease
  • Thyroid function tests: to rule out hypothyroidism, which can manifest with lethargy, cognitive impairment (slowed mentation, poor concentration), psychomotor retardation, social withdrawal, and depressed mood
  • Urine toxicology: to screen for drug use causing depressive symptoms, such as benzodiazepine withdrawal, amphetamine use, and cocaine “crash”
• Neuroimaging: to evaluate for structural brain disease if suspected
• Polysomnography: not routinely performed; indicated in case a concurrent primary sleep disorder is suspected ^[11]
  • Decreased REM sleep latency
  • Increased total amount of REM sleep
  • Increased number of REM sleep episodes during the night

In pediatric patients, remember to first rule out organic causes, which are the most common cause of depression in this population.

References:^[12][13][14]

Overview ^[6]

Depressive disorder due to another medical condition ^[6]

• Depressed mood and/or anhedonia attributable to a general medical condition
• Conditions associated with depressive disorder include the following:
  • Hypothyroidism
  • Parkinson disease
  • CNS neoplasms
  • Other neoplasms (e.g., pancreatic cancer)
  • Stroke (especially ACA stroke)
  • Dementia
  • Parathyroid disorders

Substance/medication-induced depressive disorder ^[6]

• Depressed mood and/or anhedonia attributable to the use of, or withdrawal from, substances or medications
• Substances or medications associated with depressive disorder include the following:
  • Marijuana, γ-hydroxybutyric acid (GHB), flunitrazepam, ketamine
  • Alcohol
  • Corticosteroids
  • Oral contraceptive pill

Disruptive mood dysregulation disorder (DMDD)

• A disorder characterized by persistent irritability and episodes of extreme behavioral dyscontrol; in children under 18 years of age.
• Can manifest with severe temper outbursts (verbal or behavioral) ≥ 3 times/week, sometimes with severe, persistent irritability in between outbursts
• Duration of symptoms: ≥ 12 months
• Prognosis: Individuals with DMDD are at increased risk of developing major depressive disorder; or anxiety disorders in adulthood.

Burnout syndrome

• See “Burnout syndrome” for more information.

References: ^{[6][15][16][17][18][19]}

The differential diagnoses listed here are not exhaustive.

Approach ^[20]

• For initial treatment of adult patients, pharmacotherapy and psychotherapy can be used alone or in combination.
• For nonresponders to initial pharmacotherapy, consider one of the following:
  • Switching the modality to psychotherapy
  • Adding psychotherapy
  • Switching to another antidepressant
  • Adding an augmenting agent
• Therapy should be continued until the patient is in remission.
• Patients with ≥ 3 prior major depressive episodes or chronic MDD (≥ 2 years) should receive maintenance therapy (see below).

Pharmacotherapy

• Therapeutic principles
  • Most drugs have comparable efficacy but different side effects.
  • Most antidepressants require > 4 weeks to take effect.
  • Always start with the lowest dose and increase in small steps. ^[21]
    • Initial treatment: 6–12 weeks
    • If the patient is in remission, continue antidepressants for at least 4–9 months (continuation phase).
    • If the patient has had ≥ 3 prior major depressive episodes in total or severe episodes (e.g., including suicide attempt or psychosis) or has risk factors for recurrence , or chronic MDD, continue antidepressants for at least 1–3 years (maintenance phase).
  • Tapering off medications should be done over 6–8 weeks because this can help to:
    • Decrease the risk of relapse
    • Prevent antidepressant discontinuation syndrome: flu-like symptoms, nausea, insomnia, hyperarousal, and sensory disturbances
• First-line: : SSRIs
• Alternative options
  • SNRIs
  • Atypical antidepressants
    • Bupropion: lowers seizure threshold, results in less sexual dysfunction compared to SSRIs, and can also treat tobacco dependence
    • Mirtazapine: significant weight gain
    • Trazodone: used primarily for insomnia; higher dose is required when used as an antidepressant
  • TCA and MAO inhibitors: cause more side effects than SSRIs
  • Ketamine
• Augmenting agents: lithium, second-generation antipsychotics (e.g., aripiprazole), thyroid hormones ^[22][23]

MAO inhibitors should not be combined with SSRIs/SNRIs or tricyclic antidepressants, because this may lead to serotonin syndrome.

Psychotherapy

• Cognitive-behavioral therapy (CBT)
• Interpersonal therapy
• Psychodynamic psychotherapy
• Family and couples therapy

Other measures

• Lifestyle changes (aerobic exercise, nutrition, sleep hygiene, social support, stress reduction)
• Light therapy
• Repetitive transcranial magnetic stimulation (rTMS)
• Sleep deprivation therapy
  • Approach: complete or partial (second half of the night) sleep deprivation
  • Effect: A short-term antidepressive effect is achieved on the same day.
  • Goal: restoration of physiological sleep architecture
  • Implementation: 3 cycles/week as follows
    • Staying awake from 7 a.m. of day 1 to 7 p.m. of day 2
    • Recovery sleep from 7 p.m. of day 2 to 7 a.m. of day 3
    • Sleep deprivation should be repeated again as explained above
    • Short sleep phases in between diminish the antidepressive effect and hence should be avoided
    • Sleep-phase-advance (follows a sleep deprivation phase)
      • Changing the sleep phase to approximately 6 hours
      • In combination with sleep deprivation and antidepressants
  • Complications
    • Worsening of depressive symptoms
    • Sleep deprivation therapy should be carried out with caution in patients with bipolar disorders.
    • Proceed with extreme caution in patients with a history of convulsions!
• Electroconvulsive therapy: reserved for severe, refractory, and/or psychotic depression

References:^[24][25][26]

Peripartum mood disturbances

• Peripartum mood disturbances are mood disorders that commonly occur during pregnancy or within a month after delivery.
• Patients with a previous history of mood disorders are at increased risk of developing peripartum mood disorders.

Depression in palliative patients

• Definition: depressive symptoms or thoughts of suicide in patients with a limited life expectancy
• Treatment
  • Psychostimulants (e.g., methylphenidate) are effective for the urgent treatment of severe depressive symptoms or thoughts of suicide in terminally ill adults with a short life expectancy.
  • SSRIs can be introduced concurrently in patients with an anticipated life expectancy of several months.

Depression in children and adolescents

• Classical symptoms of major depressive disorder (e.g., depressed mood, loss of energy)
• Symptoms may be less marked than in adults.
• MDD in pediatric patients often resembles attention deficit hyperactivity disorder (difficulties concentrating, impaired memory, restlessness, aggression). ^[28]
• Treatment ^[29]
  • In children, psychotherapy (e.g., CBT, family therapy, play therapy) is the preferred initial treatment.
  • In adolescents, either psychotherapy or pharmacotherapy (fluoxetine) may be used as initial treatment.

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