3.3.2.1 Antipsychotics

The D2 receptor

• The D2 receptor is an inhibitory metabotropic receptor coupled to Gi/o proteins, and it lowers cyclic AMP and suppresses prolactin release.

• D2 receptors sit postsynaptically and also presynaptically as autoreceptors.

• Raising cyclic AMP belongs to the D1-like family, not to D2.

• Most antipsychotics are D2 antagonists, while aripiprazole, brexpiprazole and cariprazine are partial agonists.

• D2 antagonists differ in affinity, dissociation rate, brain penetration and other receptor targets.

• D2 action is not the only route, because muscarinic drugs also have demonstrated antipsychotic efficacy.

D2 occupancy

Raclopride is a selective D2 and D3 antagonist used as a reversible positron emission tomography (PET) radioligand to measure occupancy. Ranges vary by drug, region and method.

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• Partial agonists tolerate higher occupancy than antagonists.

• Active metabolites add to occupancy, for example 9-hydroxyrisperidone, and N-desmethylclozapine (norclozapine), the major active metabolite of clozapine.

• Depot injections reduce fluctuations from missed doses, and time to steady state is specific to each product.

• Fortnightly risperidone microsphere injection releases almost nothing for the first three weeks and reaches steady state after about four injections, around six to eight weeks.

Dopamine pathways

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• Efficacy against positive symptoms comes from mesolimbic D2 blockade, which is how first-generation drugs work.

• The aberrant salience hypothesis holds that inappropriate dopamine signals make neutral events seem important, and treatment reduces this significance.

• D2 engagement begins at once, but clinical improvement develops over days to weeks.

Extrapyramidal side effects

• Extrapyramidal side effects come from nigrostriatal D2 blockade, not from the other receptor actions of antipsychotics.

• High-potency first-generation drugs such as haloperidol and trifluoperazine carry the greatest burden.

• Fewer extrapyramidal side effects is the one dependable gain of switching to a second-generation drug.

• 5-HT2A antagonism, which most atypical drugs add and typical drugs lack, is proposed to lower the burden by increasing nigrostriatal and prefrontal dopamine release.

• This explanation is incomplete, because amisulpride has little 5-HT2A activity and risperidone still causes dose-related parkinsonism.

• Antimuscarinic drugs relieve drug-induced parkinsonism by shifting the striatal balance between dopamine and acetylcholine.

• Haloperidol has almost no antimuscarinic action, so acute dystonia is common, above all in young antipsychotic-naive men, and guidance pairs it with promethazine.

• Akathisia is told apart from parkinsonism, tardive dyskinesia and restless legs by its inner restlessness, and it is prominent with partial agonists.

• Tardive dyskinesia is attributed to postsynaptic nigrostriatal D2 receptors becoming more numerous and responsive after long-term blockade, so movements appear or worsen when the dose is cut.

• Aripiprazole long-acting injection is the preferred depot after extrapyramidal side effects, because partial agonism preserves some nigrostriatal dopaminergic tone.

• Dopamine blockade contributes to neuroleptic malignant syndrome.

Hyperprolactinaemia

• Tuberoinfundibular dopamine tonically inhibits prolactin release from anterior pituitary lactotrophs through D2 receptors, so blockade there raises prolactin.

• The pituitary lies outside the blood-brain barrier, so drugs that cross it poorly block pituitary D2 disproportionately and raise prolactin sharply while striatal occupancy stays modest.

• Raised prolactin suppresses the gonadal axis, so features are those of hypogonadism: amenorrhoea, low libido, galactorrhoea, gynaecomastia in men and bone loss, never increased sexual function.

• The amenorrhoea is secondary, because prolactin disturbs cycles already established.

• Hyperprolactinaemia is often asymptomatic, so the decision to act weighs symptoms, long-term risk and the benefit of the current drug, not the number alone.

• Sexual dysfunction tracks prolactin, so it is greatest with haloperidol, risperidone and amisulpride and least with aripiprazole.

• Aripiprazole lowers antipsychotic-induced hyperprolactinaemia by restoring dopaminergic tone at lactotrophs, either added at low dose to the causative drug or substituted for it.

Receptor profiles of individual drugs

A partial agonist activates a receptor less than a full agonist, so it reduces signalling when dopamine is abundant and adds signalling when dopamine is scarce.

• Cariprazine is told from aripiprazole and brexpiprazole by its D3 preference; theirs is D2-preferring.

• The benzamides are told from most antipsychotics by lacking a multi-receptor profile.

• Aripiprazole carries a warning of impulse-control disorders such as new gambling, because partial agonism keeps some ventral striatal dopamine signalling, as pramipexole does in Parkinson's disease.

• Switching abruptly from a full antagonist to a partial agonist may worsen symptoms.

• 5-HT1A partial agonism may contribute to effects on mood and anxiety.

Other receptor actions

• Low-potency drugs such as chlorpromazine bind strongly outside the dopamine system, and combined H1, muscarinic and alpha-1 blockade gives marked sedation.

• Quetiapine 25 mg occupies H1 but barely D2, so it causes morning hangover without antipsychotic effect.

Postural hypotension and priapism

• Alpha-1 blockade blunts vasoconstriction on standing, and the baroreflex answers with a faster heart rate.

• Clozapine and quetiapine block alpha-1 strongly and carry the highest orthostatic risk, while selective D2 agents and partial agonists block least.

• Amisulpride has negligible alpha-1 affinity, so it is a suitable switch when another antipsychotic causes orthostatic hypotension.

• Priapism follows alpha-1 blockade, which impairs sympathetic detumescence in the corpora cavernosa, and chlorpromazine, risperidone and trazodone are most associated.

Weight and metabolic effects

• Weight gain is more common with second-generation drugs, through greater H1 and 5-HT2C antagonism, and is often fastest early in treatment.

• Appetite, sedation, insulin effects and sleep changes all add to metabolic harm.

• Metabolic risk is low with ziprasidone, lurasidone, aripiprazole and amisulpride, and high with clozapine and olanzapine.

• Aripiprazole has the lowest weight-gain liability among commonly used antipsychotics.

QTc prolongation

• Blocking the cardiac hERG potassium channel (the rapid delayed rectifier) lengthens the corrected QT interval (QTc), risking torsades de pointes and sudden cardiac death.

• Thioridazine, sertindole and pimozide lengthen QTc far more than other antipsychotics, and sertindole has the greatest effect of the three.

• Thioridazine carries the highest risk of sudden cardiac death, through marked dose-related QTc prolongation, which led to its restriction and withdrawal.

• Pimozide needs an electrocardiogram (ECG) before and during treatment and avoidance of CYP3A4 inhibitors such as clarithromycin.

• Haloperidol and chlorpromazine have only moderate QTc effects.

• Haloperidol is the psychotropic most associated with torsades de pointes, more so than a selective serotonin reuptake inhibitor (SSRI).

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Clozapine adverse effects

• Hypersalivation is the commonest effect, with weight gain, sedation, constipation and tachycardia also frequent, while agranulocytosis affects under 1%.

• Neutropenia and agranulocytosis are idiosyncratic and unrelated to dose, whereas seizures and H1, alpha-1 and salivary effects rise with dose and plasma level.

Antimuscarinic effects

• Clozapine is strongly antimuscarinic, so it slows gut transit, causing constipation, ileus and bowel ischaemia.

• It also lifts vagal restraint on the heart, so resting tachycardia is common and usually benign, while myocarditis, cardiomyopathy, serositis and thromboembolism are uncommon.

• In a 2016 systematic review meta-regression, only an inpatient setting predicted constipation, not patient, dose or duration variables.

• Once obstruction is excluded, stimulant laxatives (senna with docusate) are first-line; bulk-forming agents are avoided and osmotic agents added later.

Hypersalivation

• Clozapine hypersalivation is thought to arise from muscarinic M4 agonism, with alpha-2 antagonism and slowed swallowing contributing; anticholinergic and D2 actions do not explain it.

• Off-label treatments reduce salivary flow (antimuscarinics, an alpha-2 agonist, amisulpride), and a muscarinic stimulant would worsen drooling.

Seizures

• Clozapine lowers the seizure threshold in a dose- and plasma-level-dependent way, with a projected cumulative risk of 10% by 3.8 years.

• Seizures are managed by lowering the dose and adding anticonvulsant cover, so treatment can continue.

Myocarditis

• Suspected myocarditis presents with fever and resting tachycardia, usually within two months of starting, and is tested with troponin and C-reactive protein (CRP).

• Clozapine stops if troponin exceeds twice the upper limit of normal or CRP exceeds 100 mg/L.

• Peripheral eosinophilia points to a hypersensitivity mechanism, whereas troponin, CRP and ECG show injury, inflammation or strain without revealing the cause.

Neutropenia and restarting

More than 80% of agranulocytosis cases occur within the first 18 weeks.

• After more than 48 hours without clozapine, tolerance to its hypotensive, sedative and seizure-provoking effects is lost, so it is re-titrated from 12.5 mg once or twice daily.