What is Major Depressive Disorder (MDD)?

Major Depressive Disorder (MDD)

Major Depressive Disorder is a clinical syndrome characterized by depressed mood or anhedonia plus at least 5 specific symptoms persisting for at least 2 weeks that significantly impair normal functioning, representing one of the leading causes of disability worldwide.

Definition and Diagnostic Criteria

Major Depressive Disorder requires the presence of at least 5 of the following symptoms during the same 2-week period, with at least one symptom being either depressed mood or loss of interest/pleasure:

• Depressed mood most of the day, nearly every day
• Markedly diminished interest or pleasure in most activities (anhedonia)
• Significant weight loss/gain or appetite disturbance
• Insomnia or hypersomnia
• Psychomotor agitation or retardation
• Fatigue or loss of energy
• Feelings of worthlessness or excessive/inappropriate guilt
• Diminished ability to think/concentrate or indecisiveness
• Recurrent thoughts of death or suicidal ideation 1, 2

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

Epidemiology and Impact

• Lifetime prevalence of approximately 16% in the United States 1
• Affects women approximately twice as often as men 3
• Generates approximately 8 million ambulatory care visits annually 1
• Ranked as the fourth leading cause of disability worldwide by WHO, projected to rise to second by 2020 4
• Economic burden estimated at $83.1 billion in 2000 and likely higher today 1

Pathophysiology

MDD has a multifactorial etiology involving:

• Genetic factors (heritability estimated at approximately 35%)
• Environmental factors (particularly childhood trauma such as sexual, physical, or emotional abuse)
• Neurobiological alterations:
  • Changes in regional brain volumes (particularly hippocampus)
  • Functional changes in brain circuits (cognitive control network and affective-salience network)
  • Disturbances in stress-responsive systems (hypothalamic-pituitary-adrenal axis and immune system) 3

Clinical Course and Subtypes

The treatment of depression can be characterized by three phases:

1. Acute phase (6-12 weeks): Initial treatment period
2. Continuation phase (4-9 months): Preventing relapse
3. Maintenance phase (≥1 year): Preventing recurrence 1

Subtypes include:

• Dysthymia: Less severe but more chronic depressive symptoms lasting at least 2 years
• Subsyndromal depression (minor depression): Depressive symptoms that don't meet full criteria for MDD
• Melancholia: Severe form of MDD characterized by profound anhedonia, lack of reactivity to pleasurable stimuli, early morning awakening, marked psychomotor changes, and significant anorexia/weight loss 1

Screening and Assessment

Screening for MDD is recommended in the general adult population when resources are available for diagnosis, management, and follow-up. Validated screening tools include:

• Patient Health Questionnaire-9 (PHQ-9)
• Beck Depression Inventory for Primary Care (BDI-PC) 2

Laboratory tests may be considered to assess for comorbidities, rule out differential diagnoses, or identify contraindications to treatment.

Treatment Approaches

Pharmacotherapy

Second-generation antidepressants (SGAs) are commonly used first-line medications:

• Selective Serotonin Reuptake Inhibitors (SSRIs):

  • Examples: fluoxetine, sertraline, citalopram, escitalopram, paroxetine
  • Fluoxetine FDA indication: "Treatment of major depressive disorder in adults" 5
  • Sertraline FDA indication: "Treatment of major depressive disorder in adults" 6
  • Response rate: Approximately 60-70% of patients 7

• Other SGAs:

  • Serotonin-norepinephrine reuptake inhibitors (SNRIs)
  • Bupropion (associated with lower rates of sexual side effects) 7

Psychotherapy

• Cognitive Behavioral Therapy (CBT): Recommended as a first-line treatment with efficacy comparable to antidepressants 1, 7
• Other effective approaches: acceptance and commitment therapy, interpersonal therapy, and psychodynamic therapies 1

Treatment Selection and Algorithm

The American College of Physicians strongly recommends either cognitive behavioral therapy or second-generation antidepressants as first-line treatments for MDD, with selection based on discussion of treatment effects, adverse profiles, cost, accessibility, and patient preferences 1, 7.

Treatment considerations:

1. For mild to moderate MDD: Either CBT or SGAs are appropriate first-line options
2. For moderate to severe MDD: Combination of CBT and SGAs may provide additional benefits 7
3. For treatment-resistant depression: Consider electroconvulsive therapy (ECT), which has the best empirical evidence for non-responsive cases 3

Monitoring and Follow-up

• Start with low to moderate dose of SGA if pharmacotherapy is chosen
• Assess patient status within 1-2 weeks of starting therapy
• Evaluate treatment efficacy at approximately 6 weeks and 12 weeks
• Monitor for suicidal ideation, especially in the first weeks of treatment
• Use standardized measures (e.g., PHQ-9) for regular assessment
• If inadequate response after 6-8 weeks, consider:
  • Switching to a different SSRI
  • Adding CBT
  • Augmenting with a second pharmacologic agent 7

Treatment Duration

• Continue treatment for at least 4-9 months after satisfactory response for a first episode
• For maintenance, treatment should continue for at least 16-24 weeks to prevent recurrence 7, 2

Adverse Effects of Treatment

Pharmacotherapy Side Effects

• Over 60% of patients experience at least one adverse effect when taking SGAs
• Common side effects: constipation, diarrhea, dizziness, headache, insomnia, nausea, somnolence
• Major concerns: sexual dysfunction and suicidality
• Medication-specific considerations:
  • Bupropion: Lower rates of sexual adverse events
  • Paroxetine: Higher rates of sexual dysfunction 7

Special Considerations

• Elderly patients: Prefer sertraline, citalopram (maximum 20mg due to QT prolongation risk), or escitalopram due to favorable side effect profiles and lower risk of drug interactions
• Comorbid anxiety: Evaluate and treat possible comorbid anxiety disorders that frequently coexist with depression
• Drug interactions: Carefully evaluate potential interactions, especially in elderly patients taking multiple medications 7

Emerging Monitoring Approaches

Recent research suggests potential for using passive digital data (phone use, sleep data, step counts) with machine learning models to monitor mood stability in MDD patients, with promising accuracy that could help adjust treatment plans or warn of potential relapse 8.