In the early 20th century, the discovery of the the calming effects of chlorpromazine birthed a new class of medicines to be known at that time as tranquillisers or ataractics (from the Greek ἀτάρακτος, meaning undisturbed). They were later know as the neuroleptics (from νεῦρον, neuron, but initially sinew or tendon, and λῆψις, to take hold or seize), a name that remains in use today.

The universal target of the antipsychotics is the D2 dopamine receptor. Many of the drugs act on the other dopamine receptors, as well as the receptors for histamine and serotonin, the alpha adrenoreceptors, and muscarinic ACh receptors. It follows, then, that the side effect profiles of each agent would differ by the relative antagonism at each of these sites.

First generation (typical) antipsychotics

The first antipsychotics were the phenothiazines, followed in short order by the butyrophenones and then the thioxanthenes and the diphenylbutylpiperidines.

Chlorpromazine

A phenothiazine and the first antipsychotic agent. It is a chlorinated form of promazine, which is no longer in use.

Promethazine

Trade name Phenergan, this phenothiazine is used as a sedating antihistamine and as an antiemetic for morning sickness. Its actions at the dopamine receptor produce neuroleptic effects (including the risk of acute dystonia and tardive dyskinesia).

Prochlorperazine

Also a phenothiazine antipsychotic, though used mostly in the treatment of migraine and nausea (particularly vestibular nausea).

Periciazine

There is not much research comparing periciazine to the other antipsychotics, so it remains in use for psychotic disorders as well as for adjunctive treatment of severe anxiety. It is a phenothiazine derivative.

Haloperidol

Developed in the 1950s, Haldol was the first butyrophenone brought to market. It is used in palliative care as an antiemetic.

Haloperidol is often considered the antipsychotic with the smallest risk of reduction in seizure threshold. The evidence would suggest aripiprazole, risperidone, and haloperidol carry the lowest risk.

Droperidol

Also developed by Janssen Pharmaceutica, droperidol came into use in the early 1960s in Denmark. Its primary indication is the prevention and treatment of post-operative nausea and vomiting (PONV), though it remains an effective antipsychotic. It is also a butyrophenone.

There were reports in the late 90s of the risk of QT prolongation and Torsades de Pointes (TdP). In response Janssen Pharmaceutica halted production of droperidol; this also interrupted the supply of the reagents used in the production of droperidol and limited its availability in America. In December of 2001, the FDA implemented a black box warning. As it turns out, the deaths the precipitated this warning seemed to come largely from a collection of patients who died from TdP after receiving doses in excess of ten times the standard. Despite reviews demonstrating that the risks were not significant higher than with the 5-HT3 antagonists). As of 2023, droperidol still carries its boxed warning.

Zuclopenthixol

The cis isomer of clopenthixol, a thiozanthene. Both clopenthixol and zuclopenthixol were introduced by Lundbeck, the former in 1961 and the latter in 1978.

Pimozide

There are not many diphenylbutylpiperidines, and pimozide is probably to only one in routine use. Aside from treatment of schizophrenia, it is also indicated for Tourette syndrome.

Atypical antipsychotics

The idea of atypicality (and the corresponding typicality of the first generation antipsychotics) arose from the unwanted side effects of the early antipsychotics. The extrapyramidal effects and development of tardive dyskinesia, as well and weight gain and prolactin stimulation, often limit the usefulness of neuroleptic medicines. There is also an idea that they should be more efficacious in patients with disease resistant to treatment with typical agents.

Unfortunately, the weight gain on atypical agents is usually worse and the rest of the criteria are violated by one or many drugs. The separation into typical and atypical antipsychotics has limited clinical utility and is probably an academic waste of time. For precisely this reason, the author has retained this useless classification; these notes should be nothing if not academic. It is also convenient that most of the “atypical” agents derive for different parent compounds than the “typical” agents.

Amisulpride

A benzamide antipsychotic the produces selective antagonism of the D2 and D3 receptors. It is one of the few drugs with activity against both positive and negative symptoms in schizophrenia. Lower doses antagonise the presynaptic autoreceptors and improve the negative symptom burdern. Higher doses of amisulpride produce a more classical inhibition of dopaminergic neurotransmission and treat the positive symptoms of schizophrenia and other psychoses.

Benzisoxazole dervatives:

These medicines end in -done. The author has only encountered the two described below, but their handy naming scheme solves that.

Risperidone

Aside from primary psychotic disorders, risperidone is also used as the first line agent in the treatment of aggression and psychosis in Alzheimer dementia.

Paliperidone

Paliperidone is the primary active metabolite of risperidone. Its mechanism of action is poorly understood but likely to be quite similar to its parent drug. In New Zealand, it is only available as a depot injection in the form of a palmitate ester; other formulations are no longer available.

Tricyclics:

Quetiapine

While probably used more as a sleeping tablet (read tranquilliser) than as an antipsychotic, it also the only one in this list with proved efficacy as monotherapy for major depressive disorder and bipolar disorder. One might call it a true neuroleptic… It is a dibenzothiazepine.

Clozapine

A dibenzodiazepine known for its penchant to cause agranulocytosis. It lacks common use for this reason, though some psychiatrists believe it is rather under prescribed. All patients on clozapine in New Zealand must be registered with a monitoring program; the manufactures run these systems.

Clozapine has the highest proconvulsant activity.

Olanzapine

A common antipsychotic, olanzipine is also used for the treatment of nausea and vomiting in oncology and palliative care as well as for appetite stimulation. It is a thienobenzodiazepine.

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