3.3.4.2 From specific pharmacology

Extrapyramidal side effects

Antipsychotics block dopamine D2 receptors in the nigrostriatal pathway, which upsets the striatal balance between dopamine and acetylcholine.

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• Risk is highest with potent first-generation drugs, high doses and rapid titration.

• One extrapyramidal effect predicts more: early dystonia or parkinsonism raises vulnerability to later effects, including tardive dyskinesia.

• Continued D2 blockade masks extrapyramidal effects, so they can emerge or worsen when an antipsychotic is reduced, stopped or switched.

Acute dystonia

• Acute dystonia is painful, sustained, involuntary muscle spasm caused by a high-potency D2 antagonist.

• Reactions are named by the part affected, such as oculogyric crisis, torticollis, trismus (jaw), tongue protrusion and opisthotonus.

• It is commonest in young men, particularly those who are antipsychotic-naive.

• Consciousness is preserved and pain can be severe; laryngeal dystonia is an airway emergency.

• First-line treatment is a parenteral antimuscarinic, such as procyclidine 5 to 10 mg intramuscularly or intravenously, or benzatropine, which restores the dopamine-acetylcholine balance within minutes.

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Akathisia

• Akathisia is a distressing, subjective inner urge to move, relieved by restless voluntary movement such as pacing, rocking or shifting weight.

• Aripiprazole often causes it.

• Restless legs syndrome differs: the sensations are in the legs and come at rest in the evening or at night.

• Restlessness also occurs with anxiety, mania and agitation, and mistaking akathisia for psychosis leads to harmful dose increases.

Manage it in this order:

1. Lower the antipsychotic dose.

2. If the dose cannot be lowered, add a drug that damps adrenergic drive, such as propranolol or clonidine, or switch; never add more D2 blockade.

• Antimuscarinics are not routine treatment for akathisia.

• Tetrabenazine, a vesicular monoamine transporter 2 (VMAT2) dopamine depleter, does not relieve akathisia and can cause it.

Drug-induced parkinsonism

• Drug-induced parkinsonism is rigidity, bradykinesia and tremor with reduced facial expression and a shuffling gait.

• Older age and female sex both raise the risk, so older women are most affected.

• Previous stroke raises the risk because it has already reduced dopaminergic reserve.

• Slowing can be mistaken for depression or negative symptoms, and persistent symptoms need neurological review for unmasked Parkinson's disease.

• Manage it by lowering the dose or switching to an antipsychotic with weaker D2 blockade.

• An antimuscarinic treats it, but review it promptly because of cognitive and autonomic harms.

Tardive syndromes

Tardive dyskinesia

• Tardive dyskinesia is irregular, repetitive orofacial movement, such as lip smacking, chewing and tongue protrusion, after years of antipsychotic treatment.

• Patients often do not notice it, so examine at baseline and periodically with a structured scale such as the Abnormal Involuntary Movement Scale.

• Movements increase with distraction, which is why a movement examination uses activation manoeuvres.

• Second-generation drugs of low D2 affinity carry a lower risk than first-generation drugs.

• Vulnerability factors are older age, female sex, intellectual disability, diabetes mellitus and previous motor side effects.

• Antimuscarinics do not prevent tardive dyskinesia and may worsen it.

Management:

• Use the lowest effective dose and avoid abrupt withdrawal, which can worsen movements and cause relapse.

• About half of cases remit within about a year of lowering or stopping the antipsychotic.

• Clozapine is an option when antipsychotic treatment is still needed.

• Tetrabenazine, a VMAT2 inhibitor, is the only drug with a UK licence for tardive dyskinesia; monitor for depression, sedation and parkinsonism.

Tardive dystonia

• Tardive dystonia emerges after months to years, whereas acute dystonia appears within hours to days.

• Botulinum toxin injected into the affected muscle treats focal, persistent tardive dystonia that has not responded to an anticholinergic, whereas tetrabenazine suits tardive dyskinesia and chorea.

Neuroleptic malignant syndrome

Cause and risk

• Neuroleptic malignant syndrome follows any marked fall in dopaminergic transmission, usually D2 blockade by haloperidol or second-generation drugs such as olanzapine.

• It can also follow abrupt withdrawal of dopaminergic treatment for Parkinson's disease and, rarely, serotonergic antidepressants.

• Incidence is roughly 0.07% to 0.2% of people given antipsychotics.

• Risk rises with high-potency, not low-potency, drugs, rapid titration, the parenteral route, dehydration, agitation, a previous episode and pre-existing Parkinson's disease.

• Demographic and familial factors do not raise the risk.

Features

It develops within days of starting or raising an antipsychotic. Act on a suggestive picture without waiting for every feature.

• The core features are fever, severe generalised lead-pipe rigidity, altered consciousness and autonomic instability.

• Autonomic instability shows as tachycardia, not bradycardia, labile blood pressure and heavy sweating from released sympathetic outflow.

• Creatine kinase (CK) is markedly raised because sustained rigidity causes rhabdomyolysis, which can lead to renal injury, hyperkalaemia and arrhythmias.

Management

1. Stop the causative antipsychotic and get urgent medical care.

2. Give fluids and cooling, correct electrolytes, and monitor renal function, CK and cardiorespiratory status serially.

3. Severe cases need critical care, where specialists may use dantrolene, bromocriptine or electroconvulsive therapy.

• Rechallenge waits at least two weeks after full recovery and uses a structurally unrelated drug with low D2 affinity, such as quetiapine, started low and titrated slowly with monitoring.

Serotonin syndrome

• Serotonin syndrome follows excess serotonergic exposure, especially combinations involving a monoamine oxidase inhibitor (MAOI).

• It comprises altered mental state, autonomic instability and neuromuscular hyperactivity.

• The hallmark is neuromuscular excitation: myoclonus, clonus and hyperreflexia, most marked in the lower limbs, which the Hunter criteria use.

• Causes include antidepressants, lithium, tramadol, pethidine, fentanyl, linezolid, methylene blue and ecstasy (MDMA).

• St John's wort is serotonergic itself and can precipitate the syndrome, particularly alongside another serotonergic drug.

• Stop the causative drugs, give benzodiazepines for agitation and muscle activity, and treat severe hyperthermia with cooling, paralysis and ventilation, since antipyretics do not work.

• Cyproheptadine blocks 5-HT2A receptors, whose stimulation drives the neurological features; specialists may use it, though evidence is limited.

• Allow five to six weeks after fluoxetine before an MAOI, and at least two weeks after an irreversible MAOI before many serotonergic drugs.

Telling neuroleptic malignant syndrome from serotonin syndrome

Both cause fever, autonomic change and confusion.