Major Depressive Disorder

Major depressive disorder (MDD), commonly called depression, is a unipolar mood disorder characterized by persistent low mood and loss of interest in association with somatic symptoms for a duration of ≥ 2 weeks. Major depressive disorder has the highest lifetime prevalence among all psychiatric disorders. Biologic, psychosocial, and genetic factors contribute to depression. Treatment methods include pharmacotherapy, psychotherapy, and neuromodulation therapies such as electroconvulsive therapy (ECT). The leading cause of death associated with MDD is suicide, which is more common in the elderly population.

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  • Marked by episodes of low mood and loss of interest in association with somatic symptoms
  • Must present in episodes that last for ≥ 2 weeks
  • Causes significant decline in patient function


Major depressive disorder (MDD) can be classified on the basis of the severity and the course of the disease.

  • Severity: 
    • Mild, moderate, severe 
    • Depends on the number of diagnostic symptoms present 
  • Course: 
    • Single versus recurrent 
    • Depressive episodes may occur as a single event or may recur.
    • Recurrence requires some degree of resolution of symptoms as well as separation of the episodes by ≥ 2 months.


  • Highly prevalent, highly recurrent, disabling disease
  • Prevalence in adults: 
    • Lifetime prevalence: 12%–15%
    • Male-to-female ratio is 1:2.
    • 3 times more common from ages 18 to 29 years
    • Less common in elderly individuals (> 65 years old)
  • No ethnic or socioeconomic differences in incidence
  • Suicide:
    • ⅔ of all individuals with depression will contemplate suicide.
    • Up to 10%–15% actually commit suicide.
    • Highest rate in men > 65 years of age
  • Only half of patients with MDD will receive minimally sufficient treatment.


Risk factors

  • Genetics: more common among monozygotic twins (75%) than among dizygotic twins (14%–19%).
  • Neurotransmission: Decrease in neurotransmitters that control mood (such as serotonin) might lead to MDD.
  • Cognitive distortions: negative perception of self or the world shown to render susceptibility to MDD
  • Early childhood interpersonal losses: loss of parents before the age of 11 has been shown to be associated with MDD.

Catecholamine abnormalities

  • Levels of neurotransmitters such as serotonin, noradrenaline, and dopamine are ↓ in individuals with MDD. 
  • Elevation of these neurotransmitters results in relief of MDD symptoms.

Monoamine oxidase deficiency theory

  • Monoamine oxidase (MAO) is an enzyme responsible for degradation of monoamines (serotonin, norepinephrine, epinephrine, dopamine).
  • Abnormalities in amine neurotransmission (high or low) at nerve endings is thought to result in impaired neurotransmission → mediates depressive states
  • Monoamine oxidase inhibitors (MAOIs) are a class of medications used to treat depression.

Stress hormones

  • Stress hormones (cortisol, calcitonin) are increased in individuals with depression.
  • Increase assumed to be a result of a hyperactive hypothalamic-pituitary-adrenal axis

Neuroanatomic theory

  • Prefrontal cortex abnormalities are associated with depression.
  • Theory is supported by clinical improvement in patients who undergo deep brain stimulation.

Neurotrophic hypothesis

  • Untreated depression can damage vital brain structures (e.g., hippocampus).
  • This damage is mediated by glutamine and glucocorticoid toxicity.
  • The hippocampus is very sensitive to high levels of cortisol.


DSM-V diagnostic criteria

Symptoms cause significant decline in function in social, occupational/school setting, and persist for ≥ 2 weeks. Depressed mood or anhedonia must be among the symptoms.

Symptoms include:

  • Depressed mood, almost every day
  • Anhedonia (reduced pleasure from previously enjoyable habits)
  • Appetite/weight changes (increase or decrease)
  • Sleep disturbance (increase or decrease)
  • Psychomotor agitation or retardation (patient is anxious and moves a lot, or barely moves)
  • Loss of energy
  • Feeling worthless or excessively guilty
  • Trouble concentrating
  • Suicidal ideation and/or suicide attempts

Exclude a history of:

  • Other psychiatric disorders (especially bipolar disorder)
  • Substance use 
  • Medical conditions that cause depressive mood: hypothyroidism, nutritional deficiency, cerebrovascular disease

Other diagnostic factors

  • Screening:
    • There are self- and clinician-rated questionnaires to classify depression.
    • Commonly used: Beck Depression Inventory, Patient Health Questionnaire 9 
  • Assessment of suicide risk: If a patient appears suicidal, always inquire.
  • Laboratory evaluation 
    • There are no specific tests to screen for depression; however, several lab tests are used to rule out other causes. 
    • Thyroid function (thyroid-stimulating hormone (TSH), T3, T4)
    • Levels of vitamin B12, vitamin D, folic acid 
    • Urine drug screen 
  • Imaging: CT and MRI of brain may be indicated to rule out organic causes. 


To quickly recall the symptoms of depression, remember SIGECAPS:

  • Sleep disturbance
  • Interest loss
  • Guilty feelings 
  • Energy loss
  • Concentration problems
  • Appetite or weight change
  • Psychomotor retardation or agitation
  • Suicidal ideation

Classes of Major Depressive Disorder

Anxious depression

Symptoms include:

  • Tension
  • Restlessness
  • Impaired concentration due to worry
  • Fear that something awful might happen 
  • Fear of losing control

Melancholic depression

Symptoms include:

  • Loss of pleasure in most activities
  • Unreactive to pleasurable stimuli
  • Depressed mood that’s marked by profound despondency or despair
  • Early-morning awakening
  • Psychomotor retardation or agitation
  • Anorexia or weight loss
  • Excessive guilt


  • Can occur in different diseases (mood disorders, psychotic disorders, autism, medical conditions)
  • Symptoms include:
    • Very prominent psychomotor disturbances (increased or decreased movements)
    • Patient assumes a special posture and remains in it.
    • Examiner can change the patient’s posture, and the patient will maintain it.
    • Decreased response to external stimuli
    • Patients refuse to follow instructions.
    • Repeating words (echolalia) or movements (echopraxia) used or performed by the examiner

Psychotic depression

  • Psychotic features (hallucinations and delusions) occur only during mood symptoms. 
  • If they occur without mood symptoms, then this is most likely schizoaffective disorder.

Mixed depression

Describes a major depressive episode with subsyndromal manic symptoms.


  • Loss of pleasure in most activities
  • Elevated or expansive mood
  • Inflated self-esteem or grandiosity
  • Talkative or pressured speech
  • Flight of ideas/distractibility
  • Increased energy or goal-directed activity
  • Decreased need for sleep 
  • Excessive involvement in pleasurable activities that cause negative consequences

Atypical depression

Symptoms include:

  • Reactive to pleasurable stimuli (feels better in response to positive events)
  • Increased appetite or weight gain
  • Hypersomnia
  • Heavy feeling of limbs
  • Long-standing pattern of sensitivity to interpersonal rejection

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General approach

  • 1st-line treatment: a combination of psychotherapy and antidepressants
  • Severe cases: somatic therapies such as  electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS)


  • Effect size of psychotherapy alone is stronger than that of antidepressants alone. 
  • Requires time, financial, and emotional commitment
  • CBT: 
    • Usually the most recommended psychotherapy regimen for depression
    • Structured and shorter-length therapy 
    • Focuses on cognitive distortions 
    • Cognitive therapy alone is as effective as pharmacotherapy; however, the combination of the 2 is the most efficacious. 
  • Psychodynamic therapy 
    • More fluid and longer in duration 
    • Includes discussion of experiences as well as interpersonal relationships
    • Goal is to change a patient’s personality, character, and structure.


  • Oral antidepressant efficacy:
    • Typically takes 4–6 weeks to see the full benefit.
    • Physical symptoms improve in the first 1–2 weeks (energy, sleep, appetite) 
    • Affective symptoms (mood, concentration, self-esteem) improve after improvement in physical symptoms 
  • Initiation of medication:
    • It is crucial to address suicide risk for every patient before initiating treatment. 
    • Selective serotonin reuptake inhibitors (SSRIs) carry a black-box warning about increased suicidal ideation in the pediatric population.
    • Ask about any previous episodes of mania, as antidepressant medications increase the risk of manic episodes in patients with bipolar disorder. 
  • Treatment duration:
    • 1st episode → treat for 6 months
    • 2 episodes of MDD, dysthymic disorder, strong family history, or suicidal attempts: treat for 1–3 years
    • 3 episodes or more of MDD: lifelong treatment
    • Failure to respond to initial treatment (no improvement in 1 month): switch to another antidepressant with a different mechanism of action. 
Table: Comparison of 2nd-generation antidepressants
Class Mechanism of action Benefits Common side effects Examples
SSRIs Inhibit serotonin transporter → ↑ 5-HT levels in synaptic cleft
  • 1st-line AD
  • Wide therapeutic index
  • Effective for treatment of other conditions:
    • Anxiety disorders
    • OCD
    • Eating disorders
    • PTSD
  • Sexual dysfunction
  • Weight gain
  • Increased risk for suicide
  • Sertraline
  • Fluoxetine
  • Paroxetine
  • Citalopram
  • Escitalopram
SNRIs Inhibit NET and SERT in the presynaptic terminal → ↑ NE and 5-HT levels in synaptic cleft Effective for treatment of other conditions:
  • Anxiety and panic disorder
  • Chronic pain (especially neuropathic pain)
  • Higher rates of discontinuation symptoms
  • Sexual dysfunction
  • Venlafaxine
  • Duloxetine
Atypical ADs Inhibit norepinephrine, serotonin, or dopamine reuptake in the presynaptic terminal
  • Bupropion:
    • Little to no effect on weight
    • No sexual dysfunction
    • Activating effect may help with fatigue.
    • Helps with smoking cessation
  • Mirtazapine and trazodone:
    • Sedating properties may help with anxiety and insomnia.
    • Faster onset of action than SSRIs
  • Bupropion:
    • Insomnia
    • Tremor
    • Increases risk of seizures
  • Mirtazapine
    • Sleepiness
    • Drowsiness
    • Increased appetite
  • Trazodone:
    • Sedation
    • Priapism
  • Bupropion
  • Mirtazapine
  • Trazodone
AD: antidepressant
5-HT: 5-hydroxytryptamine (serotonin)
NET: norepinephrine transporter
OCD: obsessive-compulsive disorder
PTSD: posttraumatic stress disorder
SERT: serotonin transporter
SNRI: serotonin–norepinephrine reuptake inhibitor
SSRI: selective serotonin reuptake inhibitor
Table: Comparison of 1st-generation antidepressants
Class Mechanism of action Benefits Common side effects Examples
MAOIs Irreversibly inhibit the enzyme MAO in the nerve terminal to prevent degradation of monoamines (5-HT, NE, and DA)
  • Can be effective in treating depression refractory to other medications
  • Suited for bipolar depression, panic disorder and social phobia
  • Rarely used clinically
  • Numerours food and drug interactions → can cause hypertensive crisis or serotonin syndrome
  • Strong discontinuation symptoms
  • Phenelzine
  • Selegiline
TCAs Decrease the reuptake of 5-HT and norepinephrine via inhibition of the SERT and NET in the presynaptic membrane Effective for treatment of other conditions:
  • Chronic pain (esp. neuropathic pain, fibromyalgia)
  • Obsessive compulsive disorder (OCD)
  • PTSD
  • ADHD
  • Anorexia nervosa, bulimia nervosa
  • Anticholinergic side effects
  • Overdose leads to 3 Cs:
    • Convulsion
    • Cardiotoxicity (arrhythmia)
    • Coma
  • Nortriptyline
  • Amitriptyline
  • Doxepin
  • Clomipramine
DA: dopamine
5-HT: 5-hydroxytryptamin (serotonin)
MAO: monoamine oxidase
MAOI: monoamine oxidase inhibitor
NET: norepinephrine transporter
SERT: serotonin transporter
TCA:tricyclic antidepressant

Somatic therapies

Electroconvulsive therapy (ECT):

  • Indicated for: 
    • Cases not responding to multiple drug therapies
    • MDD with psychotic features
    • Catatonia
  • Procedure done under general anesthesia 
  • Brief seizures are intentionally induced with small electric currents. 
  • Seizures trigger the release of:
    • Neurotransmitters:
      • Dopamine 
      • Serotonin 
      • Norepinephrine 
    • Hormones: 
      • Prolactin 
      • TSH
      • Endorphins
  • Typical course administered during 12 sessions.
  • Side effects: complications from the general anesthesia, confusion, short-term memory problems 

Transcranial magnetic stimulation (TMS):

  • Uses short pulses of magnetic energy to stimulate specific regions in the brain
  • Does not require anesthesia 
  • Indicated for adults with no improvement with ≥ 1 medication 
  • Typical course: daily 40-minute procedure for 4–6 weeks
  • Side effects: scalp discomfort/pain 

Vagal nerve stimulation:

  • Stimulation of the left vagal nerve using electronic device implanted under the skin
  • Exact mechanism of action unknown 

Differential Diagnosis

MDD versus stress responses

It is important to differentiate MDD from normal responses to stress or other related mood disorders.

Table: Comparison of MDD to stress responses
Disorder Distinguishing features Duration 1st-line treatment
  • Patient must fulfill diagnostic criteria.
  • Marked distress
  • No lifetime history of bipolar episodes
≥ 2 weeks Antidepressants + psychotherapy (CBT)
Normal stress response
  • No marked distress
  • Patient is able to function and is simply sad.
Usually doesn’t last > 9 months Reassurance
Acute grief reaction
  • Normal response to loss
  • Most of the patient’s sadness is focused on the loss.
  • Symptoms come in waves.
  • Less decline in function than MDD
  • No feeling of hopelessness or worthlessness
  • Varies widely
  • Usually begins after the triggering event
  • Resolves or vastly improves within 6–12 months
Complicated grief
  • Similar symptoms to acute grief, but more intense and severe
  • Greater decline in function than MDD
  • No feeling of hopelessness or worthlessness
Symptoms last > 6–12 months Psychotherapy (CBT)

Other differential diagnoses

  • Seasonal affective disorder: regular temporal relationship between the onset of major depression and a particular time of year (usually winter) for the past 2 years. History taking can differentiate seasonal affective disorder from MDD, as remission also occurs at a specific time of the year. Similar to MDD, antidepressants such as SSRIs and CBT are effective treatment options. Light therapy (exposure to bright light) may also be used.
  • Persistent depressive disorder: also known as dysthymia. Persistent depressive disorder is the continued presence of depressed mood. Dysthymia has an earlier onset, as patients will often mention that they have been depressed “all their life.” This diagnosis is distinguished from MDD, as the depressive symptoms are usually less severe. If a patient meets the diagnostic criteria for MDD, dysthymia cannot be diagnosed simultaneously.
  • Adjustment disorder: psychologic response to an identifiable stressor. Adjustment disorder is marked by emotional or behavioral symptoms that develop ≤ 3 months after exposure and that do not last > 6 months. Adjustment disorder is a diagnosis of exclusion, and patients with this disorder do not meet criteria for other psychiatric conditions. The 1st line of treatment is psychotherapy.


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