Tardive dyskinesia is a late-onset extrapyramidal side effect most commonly associated with prolonged use of which class of antipsychotics?

Explanation

## Tardive Dyskinesia: Pathophysiology and Risk **Key Point:** Tardive dyskinesia (TD) is a hyperkinetic movement disorder that emerges after months to years of dopamine D2 receptor blockade, primarily with **first-generation (typical) antipsychotics**. ### Definition and Timeline - **Onset:** ≥3 months of antipsychotic exposure (or ≥1 month after dose increase) - **Characteristics:** Involuntary choreiform, athetoid, or rhythmic movements of face, tongue, lips, jaw, trunk, and limbs - **Persistence:** Often irreversible, even after drug discontinuation ### Pathophysiology 1. Chronic D2 blockade → denervation supersensitivity of dopamine receptors 2. Upregulation of postsynaptic D2 receptors in striatum 3. Relative dopaminergic hyperactivity → abnormal involuntary movements 4. Possible involvement of GABAergic and cholinergic dysfunction ### Risk by Antipsychotic Class | Class | TD Risk | Mechanism | Examples | | --- | --- | --- | --- | | **First-generation (Typical)** | **High (20–30% over 5 years)** | **Strong D2 blockade → supersensitivity** | Haloperidol, chlorpromazine, fluphenazine | | **Second-generation (Atypical)** | **Low (1–5% over 5 years)** | Weaker D2 affinity, faster dissociation | Risperidone, olanzapine, quetiapine, aripiprazole | | **Mood stabilizers** | Minimal | Not dopamine antagonists | Lithium, valproate | | **SSRIs** | Rare | Serotonergic, not dopaminergic | Fluoxetine, sertraline | **High-Yield:** **First-generation antipsychotics carry the highest risk of tardive dyskinesia** because of their high D2 receptor occupancy (>80%) and slow dissociation kinetics. Second-generation agents have lower occupancy and faster dissociation, reducing TD risk. **Mnemonic:** **TARD** = **T**ypical antipsychotics cause **A**cute and **R**ate-limiting **D**yskinesia (tardive). **Clinical Pearl:** Risk factors for TD include: - Age >40 years - Female sex - Affective disorders (bipolar, depression) - Longer duration of antipsychotic use - Higher cumulative doses - Presence of baseline movement disorders **Warning:** Abrupt discontinuation of antipsychotics can **unmask or worsen** tardive dyskinesia temporarily (withdrawal dyskinesia). Slow tapering is preferred.