Pathophysiology of Major Depressive Disorder
Neurobiological Basis
Major depressive disorder involves structural, functional, and molecular alterations in multiple brain regions, particularly the prefrontal cortex and limbic system, with progressive neuroanatomical changes that worsen without treatment. 1
Key Pathological Mechanisms
Neuroanatomical alterations: Patients with MDD demonstrate altered dynamic activity patterns among prefrontal and limbic structures involved in affective regulation, with particular vulnerability of the hippocampus to structural damage. 1
Hippocampal changes: The hippocampus shows progressive structural and functional deterioration in untreated depression, mediated by chronic stress and elevated glucocorticoid exposure. 1
Molecular mediators: Three primary systems drive pathological changes:
Monoamine dysfunction: While traditional models focused on serotonin and norepinephrine deficits, current understanding recognizes this as one component of a more complex pathophysiology involving multiple neurotransmitter systems. 2, 3
Clinical Manifestations
MDD is defined by depressed mood or anhedonia lasting at least 2 weeks, accompanied by at least 5 total symptoms including significant weight change, sleep disturbance, psychomotor changes, fatigue, worthlessness/guilt, concentration difficulties, and recurrent thoughts of death. 4, 5
Diagnostic Criteria
Core symptoms: Either depressed mood OR loss of pleasure/interest must be present, plus additional symptoms affecting normal functioning. 4, 5
Associated features: Significant appetite/weight changes, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, feelings of worthlessness or inappropriate guilt, indecisiveness, and suicidal ideation. 4
Duration requirement: Symptoms must persist for minimum 2 weeks and cause functional impairment. 4, 5
Treatment Approach
First-Line Treatment Selection
For moderate to severe MDD, initiate either cognitive behavioral therapy (CBT) or second-generation antidepressants (SSRIs/SNRIs), as both demonstrate equivalent effectiveness with moderate-quality evidence. 4, 5, 6
Mild depression: Start with CBT alone, which shows equivalent effectiveness to antidepressants without medication adverse effects. 5
Moderate to severe depression: Either CBT or second-generation antidepressants are appropriate first-line options, selected based on adverse effect profiles, cost, and patient preferences. 4, 5
Severe depression with high-risk features: Initiate antidepressants immediately with close monitoring, regardless of symptom count. 5
Pharmacotherapy Details
Select second-generation antidepressants based on adverse effect profiles rather than efficacy, as no SGA demonstrates superior effectiveness over others. 4, 5
Starting dose for fluoxetine: 20 mg daily in the morning is sufficient for most patients, with maximum dose of 80 mg/day if needed after several weeks. 7
Pediatric dosing: Start with 10 mg/day for one week, then increase to 20 mg/day (lower weight children may remain at 10 mg/day). 7
Time to effect: Full therapeutic response may require 4-6 weeks of treatment at adequate doses. 5, 7
Common adverse effects: Sexual dysfunction (lower with bupropion), gastrointestinal symptoms, sleep disturbances, with over 60% of patients experiencing at least one adverse effect. 4, 6
Psychotherapy Options
Cognitive behavioral therapy, interpersonal therapy, behavioral activation, problem-solving therapy, brief psychodynamic therapy, and mindfulness-based psychotherapy all demonstrate medium-sized effects (SMD 0.50-0.73) compared to usual care. 8
Combination Therapy
Combined psychotherapy plus antidepressant medication produces superior outcomes compared to either treatment alone, particularly for severe or chronic depression. 8
- Advantage over monotherapy: Combined treatment shows greater symptom improvement than psychotherapy alone (SMD 0.30) or medication alone (SMD 0.33). 8
Treatment Monitoring and Adjustment
Initial Monitoring
Assess patient status, therapeutic response, and adverse effects within 1-2 weeks of treatment initiation, with particular attention to suicidality risk. 4, 5
Suicide risk: Greatest during first 1-2 months of treatment, requiring close monitoring for agitation, irritability, or unusual behavioral changes. 4
SSRIs and suicide attempts: SSRIs carry increased risk for nonfatal suicide attempts compared to placebo, necessitating vigilant monitoring. 4
Treatment Modification
If inadequate response occurs by 6-8 weeks, modify treatment through dose adjustment, medication switching, or augmentation strategies. 4, 5
Second-line options: Changing antidepressants, adding a second antidepressant, or augmenting with atypical antipsychotics show approximately equal likelihood of success. 8
Treatment-resistant depression: Defined as failure to respond to two or more adequate trials (sufficient dose for minimum 4 weeks). 5
Treatment Duration
Continue treatment for 4-9 months after satisfactory response for first episodes; longer duration (≥1 year) is required for recurrent episodes. 5, 7
Three treatment phases: Acute phase (6-12 weeks), continuation phase (4-9 months), and maintenance phase (≥1 year for recurrent depression). 4, 5, 6
Relapse vs recurrence: Symptom return during acute/continuation phases represents relapse (same episode), while return during maintenance phase indicates recurrence (new episode). 4
Critical Pitfalls to Avoid
Inadequate dosing or duration: Premature discontinuation before 4-6 weeks prevents therapeutic effects from manifesting. 5
Insufficient monitoring: Failure to assess suicidality during initial treatment period when risk is highest. 4, 5
Premature discontinuation: Stopping treatment before completing minimum 4-9 month continuation phase increases relapse risk. 5
Ignoring treatment resistance: Not modifying approach after 6-8 weeks of inadequate response delays recovery. 4, 5