Clozapine-associated akathisia – Lessons learnt from case reports

The second-generation antipsychotic clozapine is considered the gold standard in patients with treatment-resistant schizophrenia. It is generally associated with a lower incidence of extrapyramidal side effects (EPS), including akathisia, compared to most other antipsychotics. In this review, we investigate quantitative and qualitative descriptions of clozapine-associated akathisia in published case reports, including time of onset, clozapine dose, and subjective descriptions. We only included case reports where onset of akathisia was during clozapine treatment. In total we identified 9 case reports (3 females and 6 males) with clozapine-associated akathisia (mean age: 34 years (range 8-43), all rated with clozapine cause as ‘probable’ on the Naranjo adverse drug reaction probability scale. Five of those cases had no reports of previous akathisia, despite previous treatment with potent dopamine antagonists, suggesting a non-dopamine mechanism. The akathisia occurred without any other extrapyramidal side-effects. In most cases the akathisia was manageable with dose adjustment and/or propranolol. In three case reports switching to a more a potent dopamine antagonist unexpectedly resolved the akathisia, which suggest a non-dopamine mechanism. Three cases had a nocturnal pattern, which may be the result of highest dose was administered nighttime due to the potent antihistamine effects. However, an overlap to restless leg syndrome cannot be ruled out.