What are potential alternative diagnoses for a patient with a history of psychiatric conditions, including major depressive disorder and anxiety disorder, who has discontinued multiple medications and is experiencing persistent symptoms?

Alternative Diagnoses to Consider

The most critical alternative diagnosis to evaluate in a patient with psychiatric history who has discontinued medications and continues to experience symptoms is antidepressant discontinuation syndrome, which can mimic or exacerbate the underlying psychiatric condition. 1

Primary Differential Considerations

Antidepressant Discontinuation Syndrome

• This is the most likely explanation for persistent symptoms following medication cessation, particularly if symptoms emerged within days to weeks after stopping treatment 2, 3
• Characterized by dizziness, fatigue, lethargy, general malaise, myalgias, chills, headaches, nausea, vomiting, diarrhea, insomnia, imbalance, vertigo, sensory disturbances, paresthesias, anxiety, irritability, and agitation 4
• Symptoms typically onset within 1-4 days of stopping shorter half-life SSRIs (particularly paroxetine, fluvoxamine, and sertraline) 4
• Can be mistaken for relapse of the underlying psychiatric disorder, physical illness, or even "addictive" behavior 2, 5

Relapse vs. Recurrence of Primary Psychiatric Disorder

• Relapse occurs during acute or continuation phases (within 4-9 months) and represents return of the same depressive episode 4
• Recurrence occurs during maintenance phase (≥1 year) and represents a new, distinct episode 4
• Distinguishing features: discontinuation symptoms emerge rapidly (hours to days), while true relapse typically develops more gradually over weeks 3, 6

Comorbid Psychiatric Conditions

• Anxiety disorders commonly co-occur with major depressive disorder and may become more prominent when antidepressant treatment is discontinued 4
• Bipolar disorder should be considered, as a major depressive episode may be the initial presentation of bipolar disorder 1
• Substance use disorders frequently co-occur with mood and anxiety disorders and can complicate the clinical picture 4

Medical Conditions That Can Mimic Psychiatric Symptoms

The following medical conditions must be ruled out, particularly if symptoms are atypical or treatment-resistant 4:

• Endocrine disorders: Hyperthyroidism, hypothyroidism, hypoglycemia, diabetes
• Cardiovascular: Cardiac arrhythmias, cardiac valvular disease
• Neurological: Central nervous system disorders, migraine, chronic pain
• Metabolic: Lead intoxication, pheochromocytoma
• Autoimmune: Systemic lupus erythematosus
• Other: Caffeinism, hypoxia, allergic reactions, dysmenorrhea (in females)

Substance-Induced Conditions

Evaluate for substance-induced anxiety or mood disorder, particularly given the high comorbidity between psychiatric conditions and substance use 4:

• Stimulant use (cocaine, methamphetamine, amphetamines)
• Alcohol or benzodiazepine withdrawal
• Opioid use or withdrawal
• Over-the-counter medications (dextromethorphan, diet pills, St. John's wort)

Serotonin Syndrome (If Recently on Multiple Serotonergic Agents)

Though less likely after discontinuation, consider if patient was recently on multiple serotonergic medications 4, 1:

• Mental status changes (confusion, agitation, anxiety)
• Neuromuscular hyperactivity (tremors, clonus, hyperreflexia, muscle rigidity)
• Autonomic hyperactivity (hypertension, tachycardia, diaphoresis)
• Typically occurs within 24-48 hours of combining serotonergic medications 4

Clinical Approach to Differentiation

Key Historical Features to Elicit:

• Exact timeline of symptom onset relative to medication discontinuation 3, 6
• Whether medications were tapered gradually or stopped abruptly 4, 2
• Which specific medications were discontinued (shorter half-life SSRIs like paroxetine, sertraline, fluvoxamine have higher discontinuation syndrome risk) 4
• Previous history of symptoms before medication initiation 4
• Presence of somatic symptoms (GI complaints, dizziness, flu-like symptoms, equilibrium disturbances) that suggest discontinuation rather than relapse 6

Diagnostic Strategy:

• If symptoms emerged within days of stopping medication and include prominent somatic features, discontinuation syndrome is most likely 3, 6
• If symptoms developed gradually over weeks to months, consider true relapse or recurrence 4
• Obtain collateral history from previous prescribers and review medical records to understand baseline symptomatology 4
• Consider laboratory testing (thyroid function, glucose, complete blood count) if clinical presentation suggests medical etiology 4

Management Implications:

• For discontinuation syndrome: reinstate the antidepressant at previous dose, which typically resolves symptoms within 24 hours, then taper very gradually 3
• For true relapse: reinitiate appropriate psychiatric treatment 4
• Some patients require extremely conservative tapering schedules over weeks to months to prevent symptom re-emergence 4, 3