drug-induced parkinsonism

**Pathophysiology** - Blockade of postsynaptic D2 receptors in the striatum (nigrostriatal pathway) disrupts the direct/indirect basal ganglia circuitry. The result is decreased thalamocortical excitation and hypokinesia. - Unlike Parkinson disease (PD), there is no loss of dopaminergic neurons. The presynaptic terminals are intact, so the DaT-SPECT (ioflupane) scan is NORMAL. - Some drugs deplete presynaptic dopamine instead (reserpine, tetrabenazine, valbenazine, deutetrabenazine via VMAT inhibition). - Older patients, women, and those with subclinical PD are at higher risk. DIP can "unmask" underlying PD.

**Common culprit drugs** - Typical (first-generation) antipsychotics: haloperidol, fluphenazine, chlorpromazine. These have high D2 affinity and the highest risk. - Atypical antipsychotics: risperidone and paliperidone have the highest risk among atypicals. Quetiapine and clozapine have the lowest risk. - Antiemetics/prokinetics: metoclopramide, prochlorperazine, promethazine. - VMAT inhibitors: reserpine, tetrabenazine. - Others: valproate, lithium, amiodarone, calcium channel blockers (flunarizine, cinnarizine), and some SSRIs (less common).

**Clinical features** - Onset is usually within days to weeks, and almost always within 3 months, of starting the drug or raising the dose. - Classically **bilateral and symmetric**, in contrast to the asymmetric onset of idiopathic PD. Asymmetry doesn't completely rule out DIP. - Bradykinesia and rigidity are prominent. Tremor may be present (postural or rest tremor) but is often less prominent than in PD. - Anosmia and REM sleep behavior disorder are less typical, and a normal DaT scan supports DIP. - Extrapyramidal side effects (EPS) timeline for antipsychotics: - Acute dystonia: hours to days - Akathisia: days to weeks - Parkinsonism: weeks to months - Tardive dyskinesia: months to years - Neuroleptic malignant syndrome (NMS): can occur at any time (fever, "lead-pipe" rigidity, autonomic instability, elevated CK, altered mental status)

**Diagnosis** - Clinical: temporal relationship between drug exposure and symptom onset, plus improvement after withdrawal. - DaT-SPECT: normal in DIP and abnormal (reduced striatal uptake) in PD. It is used when the diagnosis is unclear.

**Management** - First step: discontinue or reduce the offending drug if possible. Symptoms typically resolve in weeks to months (sometimes up to 6 months or more). Persistent symptoms suggest underlying PD. - If an antipsychotic is required: switch to a lower-risk agent (quetiapine, clozapine, pimavanserin for PD psychosis). - Anticholinergics (benztropine, trihexyphenidyl) can be used for symptom relief when the drug can't be stopped. - Amantadine is an alternative. - Levodopa is generally NOT used. It is ineffective in most cases and may worsen psychosis.

**High-yield board points** - Antipsychotic + bilateral rigidity/bradykinesia/tremor → DIP. - Normal DaT scan distinguishes DIP from PD. - Treat with drug withdrawal first, then anticholinergics (benztropine) or amantadine. - Dopamine agonists and levodopa can worsen psychosis in these patients. - Metoclopramide is a classic non-psychiatric culprit (used for GERD or gastroparesis). - Differentiate from NMS (fever, high CK, autonomic instability), serotonin syndrome (clonus, hyperreflexia, diarrhea), and akathisia (inner restlessness).