What are the key differentials and management strategies for a patient presenting with symptoms of Major Depressive Disorder (MDD) versus Generalized Anxiety Disorder (GAD)?

Differential Diagnosis of Major Depressive Disorder and Generalized Anxiety Disorder

When distinguishing MDD from GAD, use validated screening tools (PHQ-9 ≥8 for depression, GAD-7 ≥10 for anxiety) and recognize that the two conditions share four overlapping DSM-IV symptoms (restlessness/fatigue, difficulty concentrating, irritability, and sleep disturbance), which explains their high comorbidity rate of approximately 31%. 1, 2, 3

Core Distinguishing Features

Major Depressive Disorder

• Primary symptom: Anhedonia (loss of interest or pleasure in activities) with depressed mood for at least 2 weeks 4
• Unique symptoms not shared with GAD: Hopelessness, feelings of worthlessness or guilt, psychomotor agitation or retardation, and recurrent thoughts of death or suicide 1, 4
• PHQ-9 scoring thresholds: 8-14 indicates moderate depression, 15-19 indicates moderate-to-severe depression, and ≥20 indicates severe depression 2

Generalized Anxiety Disorder

• Primary symptom: Excessive, uncontrollable worry about multiple life domains (health, family, work, finances) persisting for at least 6 months 1
• Key distinguishing feature: The worry is disproportionate to actual circumstances and described as "uncontrollable" by patients 1
• Presentation caveat: GAD patients may not present with overt "anxiety" but rather with "concerns" or "fears" that are excessive relative to actual risk 5
• GAD-7 scoring thresholds: ≥5 indicates mild anxiety, ≥10 indicates moderate anxiety, and ≥15 indicates severe anxiety 2

Overlapping Symptoms (Diagnostic Pitfall)

• Four shared DSM-IV symptoms: Restlessness or feeling keyed up, fatigue, difficulty concentrating, irritability, muscle tension, and sleep disturbance 1, 3
• Clinical significance: The comorbid GAD/MDD group endorses these overlapping symptoms more than either disorder alone, which strongly influences the high comorbidity rate 3
• Temporal relationship: During treatment, changes in depressive symptoms lead to changes in anxiety symptoms more than the reverse, suggesting depression may be the primary driver when both are present 6

Structured Diagnostic Algorithm

Step 1: Initial Screening

• Administer both PHQ-9 and GAD-7 to all patients with suspected mood or anxiety symptoms 2
• Immediately assess suicide risk: Any positive response to PHQ-9 item 9 (thoughts of self-harm) requires immediate risk assessment and potential emergency referral 2

Step 2: Rule Out Medical and Substance-Induced Causes

• Before diagnosing primary MDD or GAD, obtain: Thyroid function tests, complete metabolic panel, complete blood count, vitamin B12 and folate levels, and toxicology screen 2
• Review current medications: Specifically check for interferon, corticosteroids, and beta-blockers, which can induce depressive and anxiety symptoms 2
• Assess for: Uncontrolled pain, delirium from infection or electrolyte imbalance, and substance use or withdrawal 2

Step 3: Determine Severity and Treatment Pathway

For PHQ-9 scores 1-7 (minimal depression) or GAD-7 scores 0-4 (minimal anxiety):

• Provide education about symptoms and natural course 4
• Implement watchful waiting with structured follow-up in 2-4 weeks 4
• Assess current coping strategies and social support systems 4

For PHQ-9 scores 8-14 (moderate depression) or GAD-7 scores 5-9 (moderate anxiety):

• Consider low-intensity interventions: guided self-help based on cognitive behavioral therapy or structured physical activity programs 2
• Reassess in 2-4 weeks to determine if symptoms progress or functional impairment worsens 4

For PHQ-9 scores ≥15 (severe depression) or GAD-7 scores ≥10 (moderate-to-severe anxiety):

• Refer to psychology and/or psychiatry for diagnosis and treatment 2
• Consider pharmacologic treatment with SSRIs (sertraline 50mg daily or fluoxetine 20mg daily), which have demonstrated efficacy for both MDD and GAD 2, 7, 8

Step 4: Screen for Bipolar Disorder

• Before initiating antidepressant therapy, conduct detailed psychiatric history including family history of suicide, bipolar disorder, and depression 7, 8
• Rationale: A major depressive episode may be the initial presentation of bipolar disorder, and treating with an antidepressant alone may precipitate a manic episode 7, 8

Management of Comorbid MDD and GAD

• When both conditions are present (31% of GAD cases), prioritize treatment for the condition causing the greatest functional impairment 1, 2
• Evidence suggests treating depressive symptoms may simultaneously improve anxiety symptoms, as depression appears to be the primary driver in comorbid presentations 6
• Use both PHQ-9 and GAD-7 at each visit to objectively track symptom changes in both domains 4

Critical Clinical Pitfalls to Avoid

• Do not miss substance use disorders: They require concurrent treatment and significantly complicate anxiety/depression management 4
• Do not omit PHQ-9 item 9 (self-harm assessment): This artificially lowers scores and misses critical suicide risk 2
• Do not fail to reassess suicide risk at every visit, especially when initiating or adjusting antidepressant medication 4, 7
• Do not overlook that GAD patients may present with "concerns" rather than overt anxiety symptoms, making the diagnosis easy to miss 5

Pharmacotherapy Considerations

• SSRIs are first-line for both MDD and GAD: Start sertraline 50mg daily or fluoxetine 20mg daily 7, 8
• Monitor closely during the first few months: Watch for clinical worsening, suicidality, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania 7, 8
• Dose adjustments should not occur more frequently than weekly given the 24-hour elimination half-life 7
• Maximum dose: Sertraline up to 200mg/day; patients not responding to 50mg may benefit from dose increases 7