In a patient with chronic inflammatory demyelinating polyneuropathy who has normal electrolytes and intermittent hand and foot spasms while taking clozapine 300 mg, Ativan (lorazepam) 1 mg, fluoxetine 30 mg, and trazodone 150 mg, could any of these psychotropic medications cause the spasms and should clozapine serum levels be checked?

Clozapine Is the Most Likely Culprit for Hand and Foot Spasms

Among the psychiatric medications your patient is taking, clozapine is the most likely cause of intermittent hand and foot spasms, and checking clozapine serum levels is warranted to rule out toxicity. Clozapine is well-documented to cause myoclonus and movement disorders, particularly at higher doses or toxic levels 1, 2, 3.

Medication-Specific Risk Assessment

Clozapine (300 mg) – Highest Suspicion

• Clozapine commonly causes myoclonus and asterixis, which can manifest as intermittent spasms of the hands and feet, particularly when serum levels approach or exceed therapeutic ranges 2.
• These movement disorders may occur even at therapeutic doses but are more frequent with higher concentrations 2.
• Check clozapine serum levels immediately—therapeutic range is typically 350-600 ng/mL, and levels above this increase the risk of movement disorders and seizures 2.
• Clozapine-induced movement disorders do not require dopamine receptor blockade to occur, distinguishing them from typical neuroleptic extrapyramidal symptoms 2.

Fluoxetine (30 mg) – Moderate Suspicion

• SSRIs including fluoxetine can cause tremor and, less commonly, myoclonus, particularly when combined with other serotonergic agents 2, 3.
• Fluoxetine is a potent CYP2D6 inhibitor and could theoretically increase levels of other medications metabolized by this pathway, though none of the other listed medications are significantly affected 4.
• The 30 mg dose is moderate and less likely to cause severe movement disorders as monotherapy 4.

Trazodone (150 mg) – Low Suspicion

• Trazodone at 150 mg is a moderate dose used primarily for sedation and is not prominently associated with movement disorders 5.
• While serotonergic, it has minimal propensity to cause spasms or myoclonus at this dose 5.

Lorazepam (Ativan 1 mg) – Unlikely

• Benzodiazepines like lorazepam typically suppress rather than cause movement disorders 6.
• Ataxia can occur with benzodiazepines but would present differently than intermittent spasms 2.

Recommended Diagnostic Approach

Immediate Actions

• Order clozapine serum trough level (drawn before morning dose) to assess for toxicity or supratherapeutic concentrations 2.
• Review timing of spasms relative to medication dosing—clozapine-induced myoclonus often worsens at peak serum concentrations (2-4 hours post-dose) 2.
• Assess for other signs of clozapine toxicity: sedation, confusion, seizure activity, or autonomic instability 2.

Clinical Examination

• Distinguish myoclonus from other movement disorders: myoclonic jerks are brief, shock-like movements that can affect distal extremities 2, 3.
• Evaluate for asterixis (negative myoclonus): have the patient extend arms and dorsiflex wrists—brief lapses in posture suggest metabolic or drug-induced etiology 2.
• Assess for features of CIDP progression: symmetric proximal and distal weakness, areflexia, sensory loss in glove-and-stocking distribution 7, 8.

Management Algorithm

If Clozapine Level Is Elevated (>600 ng/mL)

1. Reduce clozapine dose by 25-50% and recheck level in 5-7 days 2.
2. Monitor for improvement in spasms over 1-2 weeks as levels decline 2.
3. If spasms persist despite dose reduction, consider switching to an alternative antipsychotic with lower movement disorder risk 2.

If Clozapine Level Is Therapeutic (350-600 ng/mL)

1. Consider empiric dose reduction of 50-100 mg if spasms are disabling, as some patients develop movement disorders within the therapeutic range 2.
2. Evaluate for drug-drug interactions: although none of the listed medications significantly interact with clozapine, review for any recent additions 1.
3. If spasms continue, proceed to CIDP assessment below 7.

If Clozapine Level Is Subtherapeutic (<350 ng/mL)

• Clozapine is less likely the cause; prioritize evaluation for CIDP progression 7, 8.
• Consider fluoxetine as a secondary contributor and assess for serotonin excess (tremor, hyperreflexia, diaphoresis) 4, 2.

Distinguishing Drug-Induced Spasms from CIDP Progression

Features Favoring Drug-Induced Etiology (Clozapine)

• Intermittent, brief, shock-like movements (myoclonus) rather than sustained weakness 2, 3.
• Temporal relationship to medication changes or recent dose escalation 2.
• Distal predominance (hands and feet) without proximal weakness 2.
• Preserved reflexes—CIDP typically causes areflexia 7, 8.

Features Favoring CIDP Progression

• Progressive symmetric weakness affecting proximal and distal muscles 7, 8.
• Areflexia or hyporeflexia on examination 7, 8.
• Sensory loss in glove-and-stocking distribution 7, 8.
• Gait instability and falls due to weakness rather than involuntary movements 8.
• Nerve conduction studies showing demyelination: prolonged distal latencies, slowed conduction velocities, conduction block, or temporal dispersion 7.

Additional Considerations

Electrolyte Rechecking

• Although you report electrolytes are normal, verify that potassium is >4.5 mEq/L and magnesium is in the high-normal range, as borderline-low levels can exacerbate drug-induced movement disorders 1.
• Clozapine can cause SIADH and hyponatremia, which may contribute to neurological symptoms 2.

Serotonin Syndrome Risk

• The combination of fluoxetine and trazodone carries a theoretical risk of serotonin syndrome, though the doses are moderate 5.
• Monitor for agitation, tremor, hyperreflexia, diaphoresis, and hyperthermia—if present, discontinue all serotonergic agents immediately 5.

When to Attribute Spasms to CIDP

• If clozapine levels are normal or low, spasms persist after dose reduction, and neurological examination reveals new or worsening weakness, areflexia, or sensory deficits, repeat nerve conduction studies to assess for CIDP progression 7, 8.
• CIDP can cause fasciculations and cramps but typically presents with sustained weakness rather than intermittent spasms 7, 8.

Common Pitfalls

• Assuming all neurological symptoms in a CIDP patient are due to disease progression without considering medication effects 2, 7.
• Failing to check clozapine levels when movement disorders emerge—levels can drift into toxic range even on stable dosing due to pharmacokinetic variability 2.
• Overlooking the combination of multiple serotonergic agents (fluoxetine + trazodone) as a contributor to tremor or myoclonus 5, 2.
• Not recognizing that clozapine-induced movement disorders can occur without dopamine receptor blockade, unlike typical antipsychotic extrapyramidal symptoms 2.