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[Pharmacology](https://durgical.com/en/pharmacology/) · Class

# Second-generation antipsychotics

The «atypical» antipsychotics: fewer movement side effects than the older drugs, but several cause weight gain, diabetes and high lipids.

Updated 2026-11-01

## What they are

Antipsychotics that combine D2 blockade (or partial agonism, as with aripiprazole) with strong 5-HT2A blockade. They treat schizophrenia and bipolar mania, and some have further uses (bipolar depression, irritability in autism, Tourette's disorder). Clozapine is the reference drug for treatment-resistant schizophrenia.

## Mechanism of action

Blocking 5-HT2A receptors increases dopamine release in the striatum and cortex, so they cause fewer extrapyramidal effects at doses that still block mesolimbic D2. Their H1, 5-HT2C, α1 and muscarinic actions differ from drug to drug and explain sedation, weight gain and hypotension.

Target: Dopamine D2 and serotonin 5-HT2A receptors

## Key points

- Metabolic risk is highest with clozapine and olanzapine, then quetiapine; lower with aripiprazole and ziprasidone. Weight, waist, glucose and lipids are checked before and during treatment; this is how they feed metabolic syndrome and obesity.
- Clozapine can cause severe neutropenia (agranulocytosis): the absolute neutrophil count is checked before starting and regularly during treatment.
- Risperidone raises prolactin the most; aripiprazole, a partial agonist, tends to lower it but often causes akathisia.
- Extrapyramidal effects, tardive dyskinesia and neuroleptic malignant syndrome are less frequent than with the older drugs but still occur.
- Like all antipsychotics, they carry a warning of higher mortality in older people with dementia-related psychosis.

## Drugs in this class

- [**Clozapine** The most effective antipsychotic for treatment-resistant schizophrenia; it can cause severe neutropenia, so blood… Dopamine D2 receptor](https://durgical.com/en/pharmacology/clozapine/)
- [**Olanzapine** An atypical antipsychotic for schizophrenia and bipolar mania; effective but with one of the highest risks of weight… Dopamine D2 receptor](https://durgical.com/en/pharmacology/olanzapine/)
- [**Quetiapine** A sedating atypical antipsychotic for schizophrenia and for both manic and depressive phases of bipolar disorder; few… Dopamine D2 receptor](https://durgical.com/en/pharmacology/quetiapine/)
- [**Risperidone** An atypical antipsychotic for schizophrenia, bipolar mania and irritability in autism; the atypical that raises… Dopamine D2 receptor](https://durgical.com/en/pharmacology/risperidone/)
- [**Aripiprazole** An atypical antipsychotic that is a partial agonist at D2: little prolactin rise and lower metabolic risk, but… Dopamine D2 receptor (partial agonist); serotonin 5-HT1A receptor shown](https://durgical.com/en/pharmacology/aripiprazole/)

## Others in the class

- Paliperidone
- Ziprasidone
- Lurasidone
- Asenapine
- Cariprazine
- Brexpiprazole

## Test yourself

Think of the answer, then tap the question to see it.

## Which receptor action is thought to explain the lower rate of extrapyramidal effects of atypical antipsychotics?

Strong 5-HT2A blockade, which increases striatal dopamine release and offsets part of the D2 blockade there.

## Which two atypical antipsychotics carry the highest risk of weight gain and diabetes?

Clozapine and olanzapine.

## Which atypical antipsychotic is most associated with high prolactin?

Risperidone (and its active metabolite).

## What blood test is essential during clozapine treatment, and why?

The absolute neutrophil count, because clozapine can cause severe neutropenia with life-threatening infections.

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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: [DailyMed - CLOZAPINE tablet](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=883b5d43-0339-7dc1-f775-93791fb9b978) (DailyMed (U.S. National Library of Medicine), 2026); [DailyMed - OLANZAPINE tablet](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2ae07ad4-4e58-4740-9f02-035ec061fefc) (DailyMed (U.S. National Library of Medicine), 2026); Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed., ch. 19 (McGraw Hill, 2023).

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