Classification of Anti-psychotics drugs


Antipsychotic drugs were discovered in the 1950s and currently over 20 compounds are licensed. They vary in clinical effects and especially in unwanted effects. Antipsychotics are classified in a number of ways and this brief guide touches on selected aspects of classification.

‘Typical’ and ‘atypical’ antipsychotics

Discovery of antipsychotic properties of chlorpromazine and its launch in 1953 stimulated synthesis of similar compounds, and introduced drugs such as haloperidol, flupentixol, prochlorperazine, sulpiride and trifluoperazine. These antipsychotics showed worthwhile clinical efficacy in psychosis, such as alleviation of ‘positive’ symptoms of schizophrenia. However, they were associated with unpleasant reactions, including extrapyramidal side effects; this reduced adherence to treatment.

The antipsychotic clozapine (first launched in 1972 but then withdrawn over concerns about agranulocytosis) was reintroduced in 1990 for restricted indications because it was found effective for schizophrenia refractory to other antipsychotics; also, extrapyramidal effects seemed less troublesome with clozapine. This led to clozapine being categorised an ‘atypical’ antipsychotic. Consequently, antipsychotics already in use became known as ‘conventional’, ‘typical’, ‘classical’ or ‘first-generation’ antipsychotics.

Originally, antipsychotic ‘atypicality’ was characterised by reduced tendency to cause catalepsy in laboratory animals—this was considered predictive of reduced likelihood of extrapyramidal effects. Following reintroduction of clozapine, antipsychotic development focused on mimicking and improving on its therapeutic effects. The resulting ‘atypical’ or ‘second-generation’ antipsychotics include amisulpride, aripiprazole, asenapine, olanzapine, paliperidone, quetiapine, and risperidone.

It was suggested that these second-generation drugs shared the antipsychotic efficacy of first-generation drugs but had lower potential for extrapyramidal effects and were generally better tolerated. Some considered them more effective against ‘negative’ symptoms of schizophrenia, but this has not been convincingly proven as a class effect. These effects were put down to second-generation antipsychotics having different receptor effects (such as preferential mesolimbic binding and 5HT2A antagonism).

However, designating antipsychotics as first-generation and second-generation may be of limited value: it probably exaggerates differences between groups and overstates similarities between members of each group. The implication that second-generation antipsychotics caused fewer adverse effects is not easily sustained. While second-generation antipsychotics were thought to cause less extrapyramidal effects, they are more commonly associated with adverse metabolic effects.

The March 2009 NICE guideline on schizophrenia no longer distinguishes between first-generation and second-generation antipsychotics (with the exception of clozapine); it recommends choosing an antipsychotic on the basis of all its effects and on the views of the patient and carers. Nevertheless, the ‘first-generation’ versus ‘second-generation’ classification persists in clinical practice and this module uses the division to aid understanding.

Chemical classification

Antipsychotics can also be divided according to their chemical structure (graphical formulas of selected antipsychotics are shown below). The early antipsychotics, especially the phenothiazines (eg chlorpromazine and trifluoperazine) and the thioxanthenes (eg flupentixol and zuclopenthixol), are structurally related to antihistamines such as promethazine.

Many second-generation antipsychotics such as dibenzodiazepines (clozapine), thiobenzodiazepines (olanzapine) and dibenzothiazepines (quetiapine) are chemically related to tricyclic antidepressants.

The substituted benzamides include sulpiride (generally considered ‘first-generation’) and amisulpride (considered ‘second-generation’).

The usefulness of chemical classification to the clinician is probably limited, but similarities in adverse effects among members of groups such as phenothiazines and thioxanthenes are worth understanding.

Therapeutic effect profile

The precise mechanism of action varies between antipsychotics, but the relevance of this variation to clinical effects has not been fully established.

For many antipsychotics, especially the older ones, there is an inverse relationship between affinity for the dopamine D2 receptor (particularly in the mesolimbic nuclei) and the dose for antipsychotic effect. Thus, ‘high-potency’ antipsychotics, such as haloperidol and fluphenazine, produce antipsychotic effect at a lower dose, but with greater propensity for extrapyramidal effects. ‘Low-potency’ antipsychotics such as chlorpromazine require higher doses for antipsychotic effect, which can increase risk of dose-related adverse effects (mediated through other receptors) such as sedation, but they have lower propensity for extrapyramidal effects.

Observation that clozapine is a relatively poor antagonist at the D2 receptor led to exploration of other mechanisms for antipsychotic effect, including activity at non-dopaminergic receptors (such as serotonergic 5HT2A antagonism) and at other classes of dopamine receptors. Aripiprazole, a relatively new antipsychotic, is thought to be a partial agonist at D2 receptors.

Adverse effect profile

Antipsychotics can also be subdivided by their propensity for adverse effects. While dopaminergic D2 antagonism in the mesolimbic area of the brain is though to underlie antipsychotic effect, preferential binding to D2 receptors in the nigrostriatal pathway can lead to extrapyramidal effects.

Preferential binding to D2 receptors in the tuberoinfundibular pathway of the anterior pituitary can lead to hyperprolactinaemia. It is thought that butyrophenones, phenothiazines, and thioxanthenes are particularly likely to cause hyperprolactinaemia, as are amisulpride, paliperidone and risperidone.

Antipsychotics with significant antagonism at the muscarinic M1 receptor can produce antimuscarinic (anticholinergic) effects which include blurred vision, constipation, urinary retention, sedation, memory impairment and sinus tachycardia.

Antipsychotics which antagonise the histamine H1 receptor are more likely to produce sedation and weight gain. Examples of antipsychotics which block both M1 and H1 receptors include phenothiazines, thioxanthenes, clozapine, olanzapine and quetiapine.

Antipsychotics which antagonise alpha1 adrenergic receptors are more likely to produce dizziness, postural hypotension, bradycardia and sedation. Examples include phenothiazines, thioxanthenes, clozapine, paliperidone, olanzapine, quetiapine and risperidone.

The risk of hypothermia seems highest with antipsychotics that strongly antagonise the serotonin 5HT2 receptor.

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