[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Pharmacology](https://durgical.com/en/pharmacology/) › Psychosis and mania: neurotransmitters and treatment # Psychosis and mania: neurotransmitters and treatment Why psychosis is linked to dopamine, serotonin and glutamate, and how antipsychotics and mood stabilisers are used in schizophrenia and bipolar disorder. Updated Nov 12, 2026 Psychosis means losing contact with reality, with hallucinations, delusions or disorganised thinking. It occurs in schizophrenia, bipolar disorder, severe depression, dementia and drug intoxication. Most antipsychotics block dopamine D2 receptors, but serotonin and glutamate also shape symptoms and side effects. ## Key points - Positive symptoms of schizophrenia are linked to excess dopamine activity in the associative striatum, not only the classic mesolimbic pathway. - Drugs that block NMDA glutamate receptors (phencyclidine, ketamine) or stimulate 5-HT2A receptors can mimic psychosis. - Antipsychotic effect appears above roughly sixty percent D2 occupancy; above about eighty percent, movement side effects become likely. - Second-generation drugs combine weaker D2 blockade with stronger 5-HT2A blockade; clozapine is reserved for treatment-resistant schizophrenia. - Lithium, some antiseizure drugs and most second-generation antipsychotics are used in mania and bipolar disorder. ## Symptoms of schizophrenia - Positive: hallucinations, delusions, disorganised speech and behaviour. - Negative: apathy, lack of motivation, reduced expression and social drive. - Cognitive: poor attention, working memory and planning; these drive much of the disability and respond poorly to antipsychotics. ## Dopamine The dopamine hypothesis began with two facts: drugs that release dopamine, such as amphetamines, can cause psychosis, and all classic antipsychotics block D2 receptors. Imaging now places the excess dopamine activity mainly in the associative striatum. Reduced dopamine D1 signalling in the prefrontal cortex may contribute to cognitive deficits. Blocking D2 receptors in the nigrostriatal pathway explains the movement side effects, including acute dystonia early in treatment and tardive dyskinesia after long-term use. ## Serotonin and glutamate Two drug effects implicate other transmitters: serotonin 5-HT2A agonists (hallucinogens) and NMDA glutamate receptor antagonists such as phencyclidine and ketamine can both produce psychotic symptoms. Blocking 5-HT2A receptors increases dopamine release in the prefrontal cortex and basal ganglia, which lowers the risk of movement side effects. Pimavanserin and lumateperone show that 5-HT2A blockade itself has antipsychotic activity. Genetic studies point to genes for synapse formation, neuronal migration and glutamate and dopamine transmission. Newer drugs act on muscarinic receptors instead of blocking dopamine directly. ## Treatment of schizophrenia Antipsychotics may calm agitation within hours, but hallucinations and delusions take days to weeks to improve. Drug choice depends mainly on side effects, because no clinical feature predicts response to a particular agent. First-generation drugs cause more movement problems; many second-generation drugs cause weight gain and raise glucose and lipids, which need monitoring. Clozapine is the drug for treatment-resistant schizophrenia and for persistent suicidality; it needs regular blood tests because of a rare but serious blood side effect. Psychological therapies such as CBT, family therapy and coordinated specialty care work alongside medicines. Nonadherence is common and often relates to side effects, cognitive problems, substance use and limited insight. ## Mania and bipolar disorder Most second-generation antipsychotics are approved for acute mania; first-generation drugs work but carry more movement side effects. Lithium is approved for mania and bipolar disorder and may lower suicide risk with long-term use; it needs monitoring of blood levels and kidney and thyroid function. Some antiseizure drugs act as mood stabilisers, particularly for mixed symptoms or rapid cycling. Under the stricter EU rule, valproate is banned for bipolar disorder in pregnancy and is not started in girls or women who could become pregnant unless alternatives are unsuitable and a pregnancy prevention programme is in place. ## Older adults with dementia Antipsychotics are used only for short-term management of psychosis or severe behavioural symptoms in dementia, because they increase the risk of stroke and death in this group (a boxed warning in the US). ## Test yourself Think of the answer, then tap the question to see it. ## Which drug effects support a role for glutamate in psychosis? NMDA glutamate receptor antagonists such as phencyclidine and ketamine can produce psychotic symptoms. ## Why do second-generation antipsychotics cause fewer movement side effects? They block D2 receptors more weakly and 5-HT2A receptors strongly, which raises dopamine release in the basal ganglia. ## What is the main indication for clozapine, and what monitoring does it need? Treatment-resistant schizophrenia (and persistent suicidality); regular blood tests because of a rare but serious blood side effect. ## Why are antipsychotics used cautiously in older adults with dementia? They increase the risk of stroke and death in this group. [Add to my cards (4)](https://durgical.app/estudiar/?add=/en/pharmacology/topics/psychosis-and-mania-neurotransmitters-and-treatment/) [More Pharmacology questions →](https://durgical.com/en/practice/?f=pharmacology) ## Example drugs - [Haloperidol](https://durgical.com/en/pharmacology/haloperidol/) - [Risperidone](https://durgical.com/en/pharmacology/risperidone/) - [Olanzapine](https://durgical.com/en/pharmacology/olanzapine/) - [Aripiprazole](https://durgical.com/en/pharmacology/aripiprazole/) - [Clozapine](https://durgical.com/en/pharmacology/clozapine/) - [Pimavanserin](https://durgical.com/en/pharmacology/pimavanserin/) - [Lumateperone](https://durgical.com/en/pharmacology/lumateperone/) - [Xanomeline and trospium](https://durgical.com/en/pharmacology/xanomeline-and-trospium/) - [Lithium carbonate](https://durgical.com/en/pharmacology/lithium-carbonate/) - [Valproic acid](https://durgical.com/en/pharmacology/valproic-acid/) ## Connections ## Related classes 4 - [First-generation antipsychotics](https://durgical.com/en/pharmacology/classes/first-generation-antipsychotics/) - [Second-generation antipsychotics](https://durgical.com/en/pharmacology/classes/second-generation-antipsychotics/) - [Muscarinic antipsychotics](https://durgical.com/en/pharmacology/classes/muscarinic-antipsychotics/) - [Mood stabilizers](https://durgical.com/en/pharmacology/classes/mood-stabilizers/) [← All of pharmacology](https://durgical.com/en/pharmacology/) Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given. Sources: [Valproate and related substances - referral | European Medicines Agency (EMA)](https://www.ema.europa.eu/en/medicines/human/referrals/valproate-related-substances-0) (European Medicines Agency, 2026); [Treatment - Schizophrenia - NHS](https://www.nhs.uk/mental-health/conditions/schizophrenia/treatment/) (NHS (UK), 2026); [Mental Health Medications - National Institute of Mental Health (NIMH)](https://www.nimh.nih.gov/health/topics/mental-health-medications) (National Institute of Mental Health, 2026). ## **Spotted a mistake?** We are always improving for the community. Tell us what is wrong and our team will review it. Report a mistake Representative model, for educational purposes only. --- Source: https://durgical.com/en/pharmacology/topics/psychosis-and-mania-neurotransmitters-and-treatment/ License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). 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