What's the next step in evaluating a 37-year-old woman with persistent anxiety, significant unintentional weight loss, paresthesias, and cognitive impairment, after a negative Cushing's (Cushing's syndrome) workup and normal thyroid studies, vitamin B12 levels, and negative screens for pheochromocytoma and celiac disease, who is currently taking fluoxetine (fluoxetine), escitalopram (escitalopram), divalproex (valproate), buspirone (buspirone), and dextroamphetamine-amphetamine (amphetamine and dextroamphetamine)?

Medication-Induced Psychiatric and Neurological Symptoms: Next Diagnostic Step

The next step is a comprehensive medication review with systematic discontinuation or substitution of polypharmacy, particularly focusing on the amphetamine-dextroamphetamine and the overlapping SSRI regimen (fluoxetine and escitalopram), as this patient's symptom constellation—anxiety, weight loss, paresthesias, and cognitive impairment—is highly consistent with stimulant toxicity and serotonergic adverse effects rather than an undiagnosed endocrine disorder.

Critical Medication Analysis

This patient is taking a concerning combination of psychotropic medications that can fully explain her presenting symptoms:

• Amphetamine-dextroamphetamine causes anxiety, significant weight loss, paresthesias (from sympathetic overactivity), and cognitive impairment at therapeutic or supratherapeutic doses 1
• Dual SSRI therapy (fluoxetine + escitalopram) is non-standard and increases risk of serotonin syndrome, which presents with anxiety, cognitive changes, and neurological symptoms 2
• Polypharmacy burden with four psychotropic agents (two SSRIs, valproate, buspirone, plus stimulant) substantially increases adverse effect risk 1

Why Medication Effects Are the Most Likely Diagnosis

Symptom Pattern Matches Drug Effects

• Unintentional weight loss: Classic amphetamine effect through appetite suppression and increased metabolism 1
• Persistent anxiety: Both stimulant-induced and potentially from excessive serotonergic activity 2
• Paresthesias: Sympathomimetic effects from amphetamines causing peripheral vasoconstriction and altered sensation 1
• Cognitive impairment: Can result from chronic stimulant use, polypharmacy interactions, or serotonergic effects 1, 3

Negative Workup Supports Iatrogenic Cause

The extensive negative endocrine evaluation makes organic disease increasingly unlikely:

• Negative Cushing's workup rules out hypercortisolism 4, 5
• Normal thyroid studies exclude thyrotoxicosis 1
• Normal B12 excludes deficiency neuropathy 1
• Negative pheochromocytoma screen rules out catecholamine excess 1
• Negative celiac screen excludes malabsorption 6

Recommended Diagnostic and Management Algorithm

Step 1: Immediate Medication Assessment

• Measure amphetamine levels to assess for supratherapeutic dosing or accumulation 1
• Review dosing history and any recent dose escalations of all psychotropic medications 2
• Assess for drug-drug interactions, particularly between fluoxetine (strong CYP2D6 inhibitor) and other agents 1, 6

Step 2: Systematic Medication Rationalization

• Consolidate SSRI therapy: Discontinue either fluoxetine or escitalopram—there is no evidence supporting dual SSRI therapy and this increases adverse effect risk 2
• Consider stimulant holiday: Temporarily discontinue amphetamine-dextroamphetamine for 2-4 weeks to assess symptom resolution 1
• Simplify regimen: Evaluate whether all four psychotropic agents are necessary or if symptoms represent medication adverse effects rather than inadequately treated psychiatric disease 3, 2

Step 3: Monitor for Symptom Resolution

• Weight monitoring: Expect weight stabilization or gain within 2-4 weeks of stimulant discontinuation 1
• Anxiety assessment: Use standardized scales to track anxiety symptoms off stimulants 3
• Neurological symptoms: Paresthesias should improve within days to weeks of reducing sympathomimetic burden 1
• Cognitive function: May require longer (weeks to months) to fully recover from chronic polypharmacy effects 1

Additional Diagnostic Considerations

If Symptoms Persist After Medication Adjustment

Only if symptoms continue after appropriate medication rationalization should further workup be considered:

• Cognitive assessment: Formal neuropsychological testing to evaluate for primary cognitive disorder versus medication-induced impairment 1
• Neuroimaging: Brain MRI if cognitive impairment persists, though psychiatric medications can cause reversible cognitive changes 1
• Autonomic testing: If paresthesias persist, consider small fiber neuropathy evaluation, though this is less likely given the clinical context 1

Pseudo-Cushing's State Consideration

• Chronic psychiatric illness (depression, anxiety) can cause mild hypercortisolism that resolves with psychiatric treatment, known as pseudo-Cushing's state 1, 6, 7
• The negative Cushing's workup makes true Cushing's syndrome very unlikely, but the psychiatric medication burden itself may have contributed to initial screening test abnormalities if any were present 6, 7

Critical Pitfalls to Avoid

Do Not Continue Extensive Endocrine Workup

• Avoid over-investigation: With comprehensive negative endocrine screening, further endocrine testing has extremely low yield and risks false-positive results leading to unnecessary interventions 6, 7
• Recognize medication effects: Clinicians often under-recognize iatrogenic causes of symptoms, particularly with polypharmacy 1, 2

Do Not Add More Medications

• Resist polypharmacy escalation: Adding medications to treat symptoms caused by existing medications creates a harmful cascade 2
• Prioritize simplification: Medication reduction is therapeutic in polypharmacy-related adverse effects 3, 2

Address Underlying Psychiatric Management

• Psychiatric consultation: Involve psychiatry to optimize medication regimen and address whether current polypharmacy represents appropriate treatment or prescribing cascade 3, 2
• Non-pharmacological interventions: Cognitive-behavioral therapy and other psychotherapeutic approaches may allow medication reduction while maintaining psychiatric stability 2