What is the cause of anxiety, weight loss, paresthesias, and cognitive impairment in a patient with a history of treatment with fluoxetine, escitalopram, divalproex, buspirone, dextroamphetamine-amphetamine, and Lybalvi, with Cushing's syndrome ruled out?

Medication-Induced Adverse Effects as Primary Cause

The constellation of anxiety, weight loss, paresthesias, and cognitive impairment in this patient is most likely caused by adverse effects from the current polypharmacy regimen, particularly escitalopram discontinuation syndrome, amphetamine-related effects, and/or Lybalvi (olanzapine/samidorphan) complications, rather than an endocrine disorder given that Cushing's has been ruled out.

Primary Medication Culprits to Evaluate

SSRI Discontinuation Syndrome (Escitalopram)

• Paresthesias are a hallmark symptom of SSRI discontinuation, described specifically as "electric shock sensations" in the FDA labeling for escitalopram 1
• Additional discontinuation symptoms include anxiety, confusion, dizziness, sensory disturbances, and cognitive impairment—matching this patient's presentation 1
• Escitalopram requires gradual tapering rather than abrupt cessation to prevent these symptoms 1
• Critical pitfall: If escitalopram was recently stopped or dose-reduced without proper tapering, this is the most likely explanation for paresthesias and anxiety 1

Amphetamine Effects (Dextroamphetamine-Amphetamine)

• Amphetamines directly cause anxiety, weight loss, and cognitive impairment as documented adverse effects 2, 1
• The FDA labeling for escitalopram specifically warns about combining with amphetamines due to increased serotonin syndrome risk 1
• Weight loss is an expected pharmacologic effect of amphetamine therapy, not a pathologic finding 2
• Anxiety and agitation are common central nervous system effects of sympathomimetic amines 2

Antipsychotic Polypharmacy Effects (Lybalvi)

• Lybalvi contains olanzapine, which is associated with cognitive impairment and sedation 2
• Antipsychotic polypharmacy (this patient is on multiple psychotropic agents) increases risk of cognitive decline, though this may be dose-dependent rather than polypharmacy-specific 2
• Cognitive impairment from antipsychotics is well-documented, particularly with combinations 2

Algorithmic Approach to Diagnosis

Step 1: Medication Timeline Review

• Determine if escitalopram was recently discontinued or dose-reduced without proper taper 3, 1
• If yes, and symptoms began within days to weeks: SSRI discontinuation syndrome is the primary diagnosis
• Review amphetamine dosing and timing relative to symptom onset 2

Step 2: Symptom Pattern Analysis

• Paresthesias + anxiety + cognitive changes = SSRI discontinuation until proven otherwise 1
• Weight loss + anxiety without paresthesias = consider amphetamine dose too high 2
• Cognitive impairment predominant = evaluate antipsychotic burden and total medication load 2

Step 3: Rule Out Serotonin Syndrome

• This patient is on multiple serotonergic agents (escitalopram, buspirone, amphetamines) 1
• Monitor for confusion, agitation, tremors, hyperreflexia, muscle rigidity, autonomic instability 1
• Serotonin syndrome requires immediate medical attention and discontinuation of serotonergic agents 1
• The combination of SSRIs with amphetamines and buspirone increases this risk substantially 1

Management Recommendations

If SSRI Discontinuation Syndrome

• Resume escitalopram at previous dose, then taper gradually over 1-2 weeks 3, 1
• Monitor intensively for symptom resolution within 24-48 hours of resuming medication 3
• Symptoms are generally self-limiting but can be severe 1

If Amphetamine-Related

• Reduce dextroamphetamine-amphetamine dose or consider discontinuation 2
• Weight loss and anxiety should improve within days of dose reduction 2
• Avoid abrupt discontinuation due to potential withdrawal and rebound symptoms 2

If Polypharmacy-Related Cognitive Impairment

• Simplify medication regimen by discontinuing agents without demonstrated benefit 2
• Consider switching from olanzapine-containing Lybalvi to more weight-neutral antipsychotics like lurasidone or ziprasidone if antipsychotic is still needed 2
• Aripiprazole demonstrates lower risk for cognitive side effects compared to olanzapine 2

Critical Monitoring Parameters

First 48 Hours

• Vital signs every 4-6 hours for autonomic instability 1
• Mental status examination for confusion, agitation, or worsening symptoms 1
• Neuromuscular examination for tremor, rigidity, hyperreflexia, myoclonus 1

Ongoing Assessment

• Daily symptom diary tracking anxiety, paresthesias, cognitive function 1
• Weekly weight monitoring 2
• Suicidal ideation screening, as all antidepressants carry increased risk through age 24 1

Common Pitfalls to Avoid

• Never abruptly discontinue SSRIs without tapering—this dramatically increases discontinuation syndrome risk 3, 1
• Do not attribute all symptoms to psychiatric illness when medication effects are more likely 1
• Avoid adding more medications to treat medication-induced symptoms; instead, simplify the regimen 2
• Do not overlook drug-drug interactions, particularly with multiple serotonergic agents 1
• Paresthesias in a patient on SSRIs should trigger immediate evaluation for discontinuation syndrome, not neurologic workup 1

Why Cushing's Exclusion Matters

• While psychiatric symptoms (depression, anxiety, cognitive impairment) occur in Cushing's syndrome 2, 4, 5, weight loss is atypical—Cushing's typically causes weight gain with abnormal fat distribution 6, 7
• Paresthesias are not a recognized feature of Cushing's syndrome 4, 5, 6
• With Cushing's ruled out, medication effects become the most parsimonious explanation for this symptom cluster 1