antipsychotic

Antipsychotics are most frequently used for the following conditions:

• Schizophrenia
• Schizoaffective disorder most commonly in conjunction with either an antidepressant (in the case of the depressive subtype) or a mood stabilizer (in the case of the bipolar subtype). Antipsychotics possess mood stabilizing properties and thus they may be used as standalone medication to treat mood dysregulation.
• Bipolar disorder (acute mania and mixed episodes) may be treated with either typical or atypical antipsychotics, although atypical antipsychotics are usually preferred because they tend to have more favourable adverse effect profiles and, according to a recent meta-analysis, they tend to have a lower liability for causing conversion from mania to depression.{{cite journal | vauthors = Goikolea JM, Colom F, Torres I, Capapey J, Valentí M, Undurraga J, Grande I, Sanchez-Moreno J, Vieta E | title = Lower rate of depressive switch following antimanic treatment with second-generation antipsychotics versus haloperidol | journal = Journal of Affective Disorders | volume = 144 | issue = 3 | pages = 191–8 | date = January 2013 | pmid = 23089129 | doi = 10.1016/j.jad.2012.07.038 }}
• Psychotic depression. In this indication it is a common practice for the psychiatrist to prescribe a combination of an atypical antipsychotic and an antidepressant as this practice is best supported by the evidence.
• Treatment-resistant depression as an adjunct to standard antidepressant therapy.

Given the limited options available to treat the behavioral problems associated with dementia, other pharmacological and non-pharmacological interventions are usually attempted before using antipsychotics. A risk-to-benefit analysis is performed to weigh the risk of the adverse effects of antipsychotics versus: the potential benefit, the adverse effects of alternative interventions, and the risk of failing to intervene when a patient's behavior becomes unsafe.{{cite web|title=American Psychiatric Association Five Things Physicians and Patients Should Question|url=http://www.choosingwisely.org/doctor-patient-lists/american-psychiatric-association/|work=Choosing Wisely|access-date=23 September 2013|url-status = live|archive-url=https://web.archive.org/web/20131203174206/http://www.choosingwisely.org/doctor-patient-lists/american-psychiatric-association/|archive-date=3 December 2013}} The same can be said for insomnia, in which they are not recommended as first-line therapy. There are evidence-based indications for using antipsychotics in children (e.g., tic disorder, bipolar disorder, psychosis), but the use of antipsychotics outside of those contexts (e.g., to treat behavioral problems) warrants significant caution.

Antipsychotics are used to treat tics associated with Tourette syndrome.{{cite journal | vauthors = Budman CL | title = The role of atypical antipsychotics for treatment of Tourette's syndrome: an overview | journal = Drugs | volume = 74 | issue = 11 | pages = 1177–1193 | date = July 2014 | pmid = 25034359 | doi = 10.1007/s40265-014-0254-0 | s2cid = 24378317 }} Aripiprazole, an atypical antipsychotic, is used as add-on medication to ameliorate sexual dysfunction as a symptom of selective serotonin reuptake inhibitor (SSRI) antidepressants in women.{{cite journal | vauthors = Basson R, Gilks T | title = Women's sexual dysfunction associated with psychiatric disorders and their treatment | journal = Women's Health | volume = 14 | pages = 1745506518762664 | date = 2018-01-01 | pmid = 29649948 | pmc = 5900810 | doi = 10.1177/1745506518762664 }}{{Rp|10}} Quetiapine is used to treat generalized anxiety disorder.{{cite journal | vauthors = Kreys TJ, Phan SV | title = A literature review of quetiapine for generalized anxiety disorder | journal = Pharmacotherapy | volume = 35 | issue = 2 | pages = 175–188 | date = February 2015 | pmid = 25689246 | doi = 10.1002/phar.1529 | s2cid = 24744675 }}

{{Main|Schizophrenia#Medication}}

Antipsychotic drug treatment is a key component of schizophrenia treatment recommendations by the National Institute of Health and Care Excellence (NICE),{{cite web|url=http://guidance.nice.org.uk/CG178|title=Psychosis and schizophrenia in adults (CG178)|date=12 February 2014 |url-status = live|archive-url=https://web.archive.org/web/20140304005556/http://guidance.nice.org.uk/CG178|archive-date=4 March 2014}} the American Psychiatric Association,{{cite web|url=https://psychiatryonline.org/guidelines|title=American Psychiatric Association Practice Guidelines|website=Psychiatry Online}} and the British Society for Psychopharmacology.{{cite journal | vauthors = Barnes TR | s2cid = 40089561 | title = Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology | journal = Journal of Psychopharmacology | volume = 25 | issue = 5 | pages = 567–620 | date = May 2011 | pmid = 21292923 | doi = 10.1177/0269881110391123 }} The main aim of treatment with antipsychotics is to reduce the positive symptoms of psychosis, that include delusions and hallucinations. There is mixed evidence to support a significant impact of antipsychotic use on primary negative symptoms (such as apathy, lack of emotional affect, and lack of interest in social interactions) or on cognitive symptoms (memory impairments, reduced ability to plan and execute tasks).{{cite journal | vauthors = Miyamoto S, Miyake N, Jarskog LF, Fleischhacker WW, Lieberman JA | title = Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents | journal = Molecular Psychiatry | volume = 17 | issue = 12 | pages = 1206–27 | date = December 2012 | pmid = 22584864 | doi = 10.1038/mp.2012.47 | doi-access = free }}{{cite journal | vauthors = Hartling L, Abou-Setta AM, Dursun S, Mousavi SS, Pasichnyk D, Newton AS | title = Antipsychotics in adults with schizophrenia: comparative effectiveness of first-generation versus second-generation medications: a systematic review and meta-analysis | journal = Annals of Internal Medicine | volume = 157 | issue = 7 | pages = 498–511 | date = October 2012 | pmid = 22893011 | doi = 10.7326/0003-4819-157-7-201210020-00525 | doi-access = free }} In general, the efficacy of antipsychotic treatment in reducing positive symptoms appears to increase with the severity of baseline symptoms.{{cite journal | vauthors = Furukawa TA, Levine SZ, Tanaka S, Goldberg Y, Samara M, Davis JM, Cipriani A, Leucht S | title = Initial severity of schizophrenia and efficacy of antipsychotics: participant-level meta-analysis of 6 placebo-controlled studies | journal = JAMA Psychiatry | volume = 72 | issue = 1 | pages = 14–21 | date = January 2015 | pmid = 25372935 | doi = 10.1001/jamapsychiatry.2014.2127 | doi-access = free }} All antipsychotic medications work relatively the same way: by antagonizing D2 dopamine receptors. However, there are some differences when it comes to typical and atypical antipsychotics. For example, atypical antipsychotic medications have been seen to lower the neurocognitive impairment associated with schizophrenia more than conventional antipsychotics, although the reasoning and mechanics of this are still unclear to researchers.{{cite journal | vauthors = Keefe RS, Silva SG, Perkins DO, Lieberman JA | title = The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis | journal = Schizophrenia Bulletin | volume = 25 | issue = 2 | pages = 201–22 | date = 1 January 1999 | pmid = 10416727 | doi = 10.1093/oxfordjournals.schbul.a033374 | doi-access = free }}

Applications of antipsychotic drugs in the treatment of schizophrenia include prophylaxis for those showing symptoms that suggest that they are at high risk of developing psychosis; treatment of first-episode psychosis; maintenance therapy (a form of prophylaxis, maintenance therapy aims to maintain therapeutic benefit and prevent symptom relapse); and treatment of recurrent episodes of acute psychosis. A recent 2024 study found that using high doses of antipsychotics for schizophrenia was linked to a higher risk of mortality.{{Cite journal |last1=Brodeur |first1=Sébastien |last2=Chiu |first2=Yohann M. |last3=Courteau |first3=Josiane |last4=Dorais |first4=Marc |last5=Oliver |first5=Dominic |last6=Stip |first6=Emmanuel |last7=Fleury |first7=Marie-Josée |last8=Roy |first8=Marc-André |last9=Vanasse |first9=Alain |last10=Lesage |first10=Alain |last11=Leclerc |first11=Jacinthe |date=2024-11-22 |title=Medication Exposure and Mortality in Patients With Schizophrenia |journal=JAMA Network Open |language=en |volume=7 |issue=11 |pages=e2447137 |doi=10.1001/jamanetworkopen.2024.47137 |issn=2574-3805 |pmc=11584925 |pmid=39576638}} Researchers analyzed data from 32,240 individuals aged 17 to 64 diagnosed with schizophrenia between 2002 and 2012 to arrive at this conclusion.{{Cite web |date=2024-11-26 |title=Can Antipsychotics Increase Mortality Risk? A New Study Shows It Might |url=https://www.hcplive.com/view/can-antipsychotics-increase-mortality-risk-a-new-study-shows-it-might |access-date=2024-11-29 |website=HCP Live |language=en}}

Test batteries such as the PACE (Personal Assessment and Crisis Evaluation Clinic) and COPS (Criteria of Prodromal Syndromes), which measure low-level psychotic symptoms and cognitive disturbances, are used to evaluate people with early, low-level symptoms of psychosis. Test results are combined with family history information to identify patients in the "high-risk" group; they are considered to have a 20–40% risk of progression to frank psychosis within two years. These patients are often treated with low doses of antipsychotic drugs with the goal of reducing their symptoms and preventing progression to frank psychosis. While generally useful for reducing symptoms, clinical trials to date show little evidence that early use of antipsychotics improves long-term outcomes in those with prodromal symptoms, either alone or in combination with cognitive-behavioral therapy.{{cite web |url=http://www.nice.org.uk/guidance/cg178/resources/cg178-psychosis-and-schizophrenia-in-adults-full-guideline3 |title=NICE Treatment Guidance 2014 |access-date=7 August 2014 |url-status = live|archive-url=https://web.archive.org/web/20140813081133/http://www.nice.org.uk/guidance/cg178/resources/cg178-psychosis-and-schizophrenia-in-adults-full-guideline3 |archive-date=13 August 2014 }}

First-episode psychosis (FEP) is the first time that psychotic symptoms are presented. NICE recommends that all people presenting with first-episode psychosis be treated with both an antipsychotic drug and cognitive behavioral therapy (CBT). NICE further recommends that those expressing a preference for CBT alone be informed that combination treatment is more effective. A diagnosis of schizophrenia is not made at this time as it takes longer to be determined by both DSM-5 and ICD-11, and only around 60% of those presenting with a first episode of psychosis will later be diagnosed with schizophrenia.{{cite journal | vauthors = McGorry PD, Hartmann JA, Spooner R, Nelson B | title = Beyond the "at risk mental state" concept: transitioning to transdiagnostic psychiatry | journal = World Psychiatry | volume = 17 | issue = 2 | pages = 133–142 | date = June 2018 | pmid = 29856558 | pmc = 5980504 | doi = 10.1002/wps.20514 }}

The conversion rate for a first episode of drug induced psychosis to bipolar disorder or schizophrenia is lower, with 30% of people converting to either bipolar disorder or schizophrenia.{{cite journal | vauthors = Starzer MS, Nordentoft M, Hjorthøj C | title = Rates and Predictors of Conversion to Schizophrenia or Bipolar Disorder Following Substance-Induced Psychosis | journal = The American Journal of Psychiatry | volume = 175 | issue = 4 | pages = 343–350 | date = April 2018 | pmid = 29179576 | doi = 10.1176/appi.ajp.2017.17020223 | publisher = American Psychiatric Association Publishing | doi-access = free }} NICE makes no distinction between substance-induced psychosis and any other form of psychosis. The rate of conversion differs for different classes of drugs.

Pharmacological options for the specific treatment of FEP have been discussed in recent reviews.{{cite journal | vauthors = Robinson DG, Gallego JA, John M, Petrides G, Hassoun Y, Zhang JP, Lopez L, Braga RJ, Sevy SM, Addington J, Kellner CH, Tohen M, Naraine M, Bennett N, Greenberg J, Lencz T, Correll CU, Kane JM, Malhotra AK | display-authors = 6 | title = A Randomized Comparison of Aripiprazole and Risperidone for the Acute Treatment of First-Episode Schizophrenia and Related Disorders: 3-Month Outcomes | journal = Schizophrenia Bulletin | volume = 41 | issue = 6 | pages = 1227–1236 | date = November 2015 | pmid = 26338693 | pmc = 4601722 | doi = 10.1093/schbul/sbv125 }}{{cite journal | vauthors = Gómez-Revuelta M, Pelayo-Terán JM, Juncal-Ruiz M, Vázquez-Bourgon J, Suárez-Pinilla P, Romero-Jiménez R, Setién Suero E, Ayesa-Arriola R, Crespo-Facorro B | display-authors = 6 | title = Antipsychotic Treatment Effectiveness in First Episode of Psychosis: PAFIP 3-Year Follow-Up Randomized Clinical Trials Comparing Haloperidol, Olanzapine, Risperidone, Aripiprazole, Quetiapine, and Ziprasidone | journal = The International Journal of Neuropsychopharmacology | volume = 23 | issue = 4 | pages = 217–229 | date = April 2020 | pmid = 31974576 | pmc = 7177160 | doi = 10.1093/ijnp/pyaa004 }} The goals of treatment for FEP include reducing symptoms and potentially improving long-term treatment outcomes. Randomized clinical trials have provided evidence for the efficacy of antipsychotic drugs in achieving the former goal, with first-generation and second generation antipsychotics showing about equal efficacy. The evidence that early treatment has a favorable effect on long-term outcomes is equivocal.

Placebo-controlled trials of both first- and second-generation antipsychotic drugs consistently demonstrate the superiority of active drugs over placebos in suppressing psychotic symptoms. A large meta-analysis of 38 trials of antipsychotic drugs in schizophrenia with acute psychotic episodes showed an effect size of about 0.5.{{cite journal | vauthors = Leucht S, Arbter D, Engel RR, Kissling W, Davis JM | title = How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials | journal = Molecular Psychiatry | volume = 14 | issue = 4 | pages = 429–47 | date = April 2009 | pmid = 18180760 | doi = 10.1038/sj.mp.4002136 | doi-access = free }} There is little or no difference in efficacy among approved antipsychotic drugs, including both first- and second-generation agents.{{cite journal | vauthors = Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM | s2cid = 32085212 | title = Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis | journal = Lancet | volume = 382 | issue = 9896 | pages = 951–62 | date = September 2013 | pmid = 23810019 | doi = 10.1016/S0140-6736(13)60733-3 }} The efficacy of such drugs is suboptimal. Few patients achieve complete resolution of symptoms. Response rates, calculated using various cutoff values for symptom reduction, are low, and their interpretation is complicated by high placebo response rates and selective publication of clinical trial results.{{cite journal | vauthors = Beitinger R, Lin J, Kissling W, Leucht S | s2cid = 207408308 | title = Comparative remission rates of schizophrenic patients using various remission criteria | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 32 | issue = 7 | pages = 1643–51 | date = October 2008 | pmid = 18616969 | doi = 10.1016/j.pnpbp.2008.06.008 }}

The majority of patients treated with an antipsychotic drug will experience a response within four weeks. The goals of continuing treatment are to maintain suppression of symptoms, prevent relapse, improve quality of life, and support engagement in psychosocial therapy.

Maintenance therapy with antipsychotic drugs is clearly superior to placebo in preventing relapse but is associated with weight gain, movement disorders, and high dropout rates.{{cite journal | vauthors = Ceraso A, Lin JJ, Schneider-Thoma J, Siafis S, Tardy M, Komossa K, Heres S, Kissling W, Davis JM, Leucht S | display-authors = 6 | title = Maintenance treatment with antipsychotic drugs for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 2020 | issue = 8 | pages = CD008016 | date = August 2020 | pmid = 32840872 | doi = 10.1002/14651858.CD008016.pub3 | pmc = 9702459 | s2cid = 221306099 }} A 3-year trial following persons receiving maintenance therapy after an acute psychotic episode found that 33% obtained long-lasting symptom reduction, 13% achieved remission, and only 27% experienced satisfactory quality of life. The effect of relapse prevention on long term outcomes is uncertain, as historical studies show little difference in long term outcomes before and after the introduction of antipsychotic drugs.

While maintenance therapy clearly reduces the rate of relapses requiring hospitalization, a large observational study in Finland found that, in people that eventually discontinued antipsychotics, the risk of being hospitalized again for a mental health problem or dying increased the longer they were dispensed (and presumably took) antipsychotics prior to stopping therapy. If people did not stop taking antipsychotics, they remained at low risk for relapse and hospitalization compared to those that did.{{cite journal | vauthors = Tiihonen J, Tanskanen A, Taipale H | title = 20-Year Nationwide Follow-Up Study on Discontinuation of Antipsychotic Treatment in First-Episode Schizophrenia | journal = The American Journal of Psychiatry | volume = 175 | issue = 8 | pages = 765–773 | date = August 2018 | pmid = 29621900 | doi = 10.1176/appi.ajp.2018.17091001 | publisher = American Psychiatric Association Publishing | doi-access = free }} The authors speculated that the difference may be because the people that discontinued treatment after a longer time had more severe mental illness than those that discontinued antipsychotic therapy sooner.

A significant challenge in the use of antipsychotic drugs for the prevention of relapse is the poor rate of adherence. In spite of the relatively high rates of adverse effects associated with these drugs, some evidence, including higher dropout rates in placebo arms compared to treatment arms in randomized clinical trials, suggests that most patients who discontinue treatment do so because of suboptimal efficacy.{{cite journal | vauthors = Kinon BJ, Ascher-Svanum H, Adams DH, Chen L | s2cid = 203910 | title = The temporal relationship between symptom change and treatment discontinuation in a pooled analysis of 4 schizophrenia trials | journal = Journal of Clinical Psychopharmacology | volume = 28 | issue = 5 | pages = 544–9 | date = October 2008 | pmid = 18794651 | doi = 10.1097/JCP.0b013e318185e74a }} If someone experiences psychotic symptoms due to nonadherence, they may be compelled to receive treatment through a process called involuntary commitment, in which they can be forced to accept treatment (including antipsychotics). A person can also be committed to treatment outside of a hospital, called outpatient commitment.

Antipsychotics in long-acting injectable (LAI), or "depot", form have been suggested as a method of decreasing medication nonadherence (sometimes also called non-compliance).{{cite journal | vauthors = Park SC, Choi MY, Choi J, Park E, Tchoe HJ, Suh JK, Kim YH, Won SH, Chung YC, Bae KY, Lee SK, Park CM, Lee SH | display-authors = 6 | title = Comparative Efficacy and Safety of Long-acting Injectable and Oral Second-generation Antipsychotics for the Treatment of Schizophrenia: A Systematic Review and Meta-analysis | journal = Clinical Psychopharmacology and Neuroscience | volume = 16 | issue = 4 | pages = 361–375 | date = November 2018 | pmid = 30466208 | pmc = 6245299 | doi = 10.9758/cpn.2018.16.4.361 }} NICE advises LAIs be offered to patients when preventing covert, intentional nonadherence is a clinical priority.{{cite web|url=https://www.nice.org.uk/guidance/cg178/evidence/full-guideline-490503565|title=PSYCHOSIS and Schizophreniain adults: THE NICE GUIDELINE ON TREATMENT AND MANAGEMENT|page=10.11.1.27}} LAIs are used to ensure adherence in outpatient commitment.{{cite journal | vauthors = Lambert TJ, Singh BS, Patel MX | title = Community treatment orders and antipsychotic long-acting injections | journal = The British Journal of Psychiatry. Supplement | volume = 52 | issue = S52 | pages = S57-62 | date = November 2009 | pmid = 19880919 | doi = 10.1192/bjp.195.52.s57 | publisher = Royal College of Psychiatrists | doi-access = free }} A meta-analysis found that LAIs resulted in lower rates of rehospitalization with a hazard ratio of 0.83; however, these results were not statistically significant (the 95% confidence interval was 0.62 to 1.11).

{{Main|Bipolar disorder}}

Antipsychotics are routinely used, often in conjunction with mood stabilizers such as lithium/valproate, as a first-line treatment for manic and mixed episodes associated with bipolar disorder.{{cite book | vauthors = Taylor D, Paton C, Kapur S, Taylor D | title = The Maudsley prescribing guidelines in psychiatry | year=2012 | publisher = Wiley-Blackwell | location = Chichester, West Sussex, UK | isbn = 978-0-470-97948-8 | edition = 11th }}{{cite book | vauthors = Young LL, Kradjan WA, Guglielmo BJ, Corelli RL, Williams BR, Koda-Kimble MA | title = Applied therapeutics: the clinical use of drugs | year = 2009 | publisher = Wolters Kluwer Health/Lippincott Williams & Wilkins | location = Philadelphia | isbn = 978-0-7817-6555-8 | pages = 3040 | edition = 9th }} The reason for this combination is the therapeutic delay of the aforementioned mood stabilizers (for valproate therapeutic effects are usually seen around five days after treatment is commenced whereas lithium usually takes at least a week before the full therapeutic effects are seen) and the comparatively rapid antimanic effects of antipsychotic drugs.{{cite journal | vauthors = Correll CU, Sheridan EM, DelBello MP | title = Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute, randomized, placebo-controlled trials | journal = Bipolar Disorders | volume = 12 | issue = 2 | pages = 116–41 | date = March 2010 | pmid = 20402706 | doi = 10.1111/j.1399-5618.2010.00798.x }} The antipsychotics have a documented efficacy when used alone in acute mania/mixed episodes.

At least five atypical antipsychotics (lumateperone,{{cite web |title=DailyMed - CAPLYTA- lumateperone capsule |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=db730b06-6351-47fd-8183-e61e61bbead5 |access-date=2022-12-10 |website=dailymed.nlm.nih.gov}} cariprazine,{{cite journal | vauthors = Earley W, Burgess MV, Rekeda L, Dickinson R, Szatmári B, Németh G, McIntyre RS, Sachs GS, Yatham LN | display-authors = 6 | title = Cariprazine Treatment of Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Phase 3 Study | journal = The American Journal of Psychiatry | volume = 176 | issue = 6 | pages = 439–448 | date = June 2019 | pmid = 30845817 | doi = 10.1176/appi.ajp.2018.18070824 | s2cid = 73471270 | doi-access = free }} lurasidone,{{cite web | url = http://www.medscape.com/viewarticle/807204 | title = Lurasidone Approved for Bipolar Depression | vauthors = Lowes R | website = Medscape | access-date = 2 October 2013 |url-status = live| archive-url = https://web.archive.org/web/20131002013831/http://www.medscape.com/viewarticle/807204 | archive-date = 2 October 2013 | df = dmy-all | date = 1 July 2013}} olanzapine,{{cite journal | vauthors = Tohen M, Katagiri H, Fujikoshi S, Kanba S | title = Efficacy of olanzapine monotherapy in acute bipolar depression: a pooled analysis of controlled studies | journal = Journal of Affective Disorders | volume = 149 | issue = 1–3 | pages = 196–201 | date = July 2013 | pmid = 23485111 | doi = 10.1016/j.jad.2013.01.022 }} and quetiapine{{cite journal | vauthors = Thase ME | title = Quetiapine monotherapy for bipolar depression | journal = Neuropsychiatric Disease and Treatment | volume = 4 | issue = 1 | pages = 11–21 | date = February 2008 | pmid = 18728771 | pmc = 2515925 | doi = 10.2147/ndt.s1162 | doi-access = free }}) have also been found to possess efficacy in the treatment of bipolar depression as a monotherapy, whereas only olanzapine{{cite journal | vauthors = Tohen M, Greil W, Calabrese JR, Sachs GS, Yatham LN, Oerlinghausen BM, Koukopoulos A, Cassano GB, Grunze H, Licht RW, Dell'Osso L, Evans AR, Risser R, Baker RW, Crane H, Dossenbach MR, Bowden CL | display-authors = 6 | title = Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial | journal = The American Journal of Psychiatry | volume = 162 | issue = 7 | pages = 1281–1290 | date = July 2005 | pmid = 15994710 | doi = 10.1176/appi.ajp.162.7.1281 | s2cid = 20932562 }} and quetiapine{{cite journal | vauthors = Duffy A, Milin R, Grof P | title = Maintenance treatment of adolescent bipolar disorder: open study of the effectiveness and tolerability of quetiapine | journal = BMC Psychiatry | volume = 9 | pages = 4 | date = February 2009 | pmid = 19200370 | pmc = 2644292 | doi = 10.1186/1471-244X-9-4 | doi-access = free }}{{cite journal | vauthors = Weisler RH, Nolen WA, Neijber A, Hellqvist A, Paulsson B | title = Continuation of quetiapine versus switching to placebo or lithium for maintenance treatment of bipolar I disorder (Trial 144: a randomized controlled study) | journal = The Journal of Clinical Psychiatry | volume = 72 | issue = 11 | pages = 1452–1464 | date = November 2011 | pmid = 22054050 | doi = 10.4088/JCP.11m06878 }} have been proven to be effective broad-spectrum (i.e., against all three types of relapse—manic, mixed and depressive) prophylactic (or maintenance) treatments in patients with bipolar disorder. A recent Cochrane review also found that olanzapine had a less favourable risk/benefit ratio than lithium as a maintenance treatment for bipolar disorder.{{cite journal | vauthors = Cipriani A, Rendell JM, Geddes J | title = Olanzapine in long-term treatment for bipolar disorder | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD004367 | date = January 2009 | pmid = 19160237 | doi = 10.1002/14651858.CD004367.pub2 | veditors = Cipriani A | s2cid = 205173641 }}

The American Psychiatric Association and the UK National Institute for Health and Care Excellence recommend antipsychotics for managing acute psychotic episodes in schizophrenia or bipolar disorder, and as a longer-term maintenance treatment for reducing the likelihood of further episodes.{{cite journal | vauthors = Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, Kreyenbuhl J | title = Practice guideline for the treatment of patients with schizophrenia, second edition | journal = The American Journal of Psychiatry | volume = 161 | issue = 2 Suppl | pages = 1–56 | date = February 2004 | pmid = 15000267 }}{{cite journal | author = National Collaborating Centre | title=Schizophrenia | website=NCBI Bookshelf | year=2009 | pmid=20704054 | url=https://www.ncbi.nlm.nih.gov/books/NBK11681/ | access-date=2021-03-09}} They state that response to any given antipsychotic can be variable so that trials may be necessary, and that lower doses are to be preferred where possible. A number of studies have looked at levels of "compliance" or "adherence" with antipsychotic regimes and found that discontinuation (stopping taking them) by patients is associated with higher rates of relapse, including hospitalization.

Psychosis and agitation develop in as many as 80 percent of people living in nursing homes. Despite a lack of FDA approval and black-box warnings, atypical antipsychotics are very often prescribed to people with dementia. An assessment for an underlying cause of behavior is needed before prescribing antipsychotic medication for symptoms of dementia.{{Citation |author1 = AMDA – The Society for Post-Acute and Long-Term Care Medicine |author1-link = AMDA – The Society for Post-Acute and Long-Term Care Medicine |date = February 2014 |title = Ten Things Physicians and Patients Should Question |publisher = AMDA – The Society for Post-Acute and Long-Term Care Medicine |work = Choosing Wisely: an initiative of the ABIM Foundation |url = http://www.choosingwisely.org/doctor-patient-lists/amda/ |access-date = 20 April 2015 |url-status = live |archive-url = https://web.archive.org/web/20140913011101/http://www.choosingwisely.org/doctor-patient-lists/amda/ |archive-date = 13 September 2014 |df = dmy-all }}. Antipsychotics in old age dementia showed a modest benefit compared to placebo in managing aggression or psychosis, but this is combined with a fairly large increase in serious adverse events. Thus, antipsychotics should not be used routinely to treat dementia with aggression or psychosis, but may be an option in a few cases where there is severe distress or risk of physical harm to others.{{cite journal | vauthors = Ballard C, Waite J | title = The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD003476 | date = January 2006 | pmid = 16437455 | doi = 10.1002/14651858.CD003476.pub2 | veditors = Ballard CG | pmc = 11365591 }} Psychosocial interventions may reduce the need for antipsychotics.{{cite journal | vauthors = Lühnen J, Richter T, Calo S, Meyer G, Köpke S, Möhler R | title = Psychosocial interventions for reducing antipsychotic medication in care home residents | journal = The Cochrane Database of Systematic Reviews | volume = 2023 | issue = 8 | pages = CD008634 | date = August 2023 | pmid = 37650479 | pmc = 10471006 | doi = 10.1002/14651858.CD008634.pub3 }} In 2005, the FDA issued an advisory warning of an increased risk of death when atypical antipsychotics are used in dementia.{{cite journal | vauthors = Ventimiglia J, Kalali AH, Vahia IV, Jeste DV | title = An analysis of the intended use of atypical antipsychotics in dementia | journal = Psychiatry | volume = 7 | issue = 11 | pages = 14–17 | date = November 2010 | pmid = 21191528 | pmc = 3010964 }} In the subsequent 5 years, the use of atypical antipsychotics to treat dementia decreased by nearly 50%.

A number of atypical antipsychotics have some benefits when used in addition to other treatments in major depressive disorder.{{cite journal | vauthors = Komossa K, Depping AM, Gaudchau A, Kissling W, Leucht S | title = Second-generation antipsychotics for major depressive disorder and dysthymia | journal = The Cochrane Database of Systematic Reviews | issue = 12 | pages = CD008121 | date = December 2010 | volume = 2012 | pmid = 21154393 | doi = 10.1002/14651858.CD008121.pub2 | pmc = 11994262 }}{{cite journal | vauthors = Spielmans GI, Berman MI, Linardatos E, Rosenlicht NZ, Perry A, Tsai AC | title = Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes | journal = PLOS Medicine | volume = 10 | issue = 3 | pages = e1001403 | year = 2013 | pmid = 23554581 | pmc = 3595214 | doi = 10.1371/journal.pmed.1001403 | doi-access = free }} Aripiprazole, quetiapine extended-release, and olanzapine (when used in conjunction with fluoxetine) have received the Food and Drug Administration (FDA) labelling for this indication.Truven Health Analytics, Inc. DrugPoint System (Internet) [cited 2013 Oct 2]. Greenwood Village, CO: Thomsen Healthcare; 2013. There is, however, a greater risk of side effects with their use compared to using traditional antidepressants. The greater risk of serious side effects with antipsychotics is why, e.g., quetiapine was denied approval as monotherapy for major depressive disorder or generalized anxiety disorder, and instead was only approved as an adjunctive treatment in combination with traditional antidepressants.{{cite web |title=FDA Psychopharmacologic Drugs Advisory Committee Hearing |url=https://www.aacap.org/App_Themes/AACAP/docs/Advocacy/regulatory_issues/2009/FDA_Psychopharm_Hearing_Summary_Final.pdf |archive-url=https://ghostarchive.org/archive/20221009/https://www.aacap.org/App_Themes/AACAP/docs/Advocacy/regulatory_issues/2009/FDA_Psychopharm_Hearing_Summary_Final.pdf |archive-date=2022-10-09 |url-status=live |website=American Academy of Child & Adolescent Psychiatry |access-date=31 May 2020}}

A recent study on the use of antipsychotics in unipolar depression concluded that the use of those drugs in addition to antidepressants alone leads to a worse disease outcome. This effect is especially pronounced in younger patients with psychotic unipolar depression. Considering the wide use of such combination therapies, further studies on the side effects of antipychotics as an add-on therapy are warranted.{{cite journal |last1=Al-Wandi |first1=Ahmed |last2=Landén |first2=Mikael |last3=Nordenskjöld |first3=Axel |date=2023-11-06 |title=Antipsychotics in the maintenance phase for psychotic depression |journal=Acta Psychiatrica Scandinavica |volume=149 |issue=1 |pages=6–17 |language=en |doi=10.1111/acps.13628 |issn=0001-690X|doi-access=free |pmid=37932158 }}

Global antipsychotic utilization has seen a steady growth since the introduction of atypical (second-generation) antipsychotics and this is ascribed to off-label use for many other unapproved disorders.{{Cite journal |last1=Hálfdánarson |first1=Óskar |last2=Zoëga |first2=Helga |last3=Aagaard |first3=Lise |last4=Bernardo |first4=Miquel |last5=Brandt |first5=Lena |last6=Fusté |first6=Anna Coma |last7=Furu |first7=Kari |last8=Garuoliené |first8=Kristina |last9=Hoffmann |first9=Falk |last10=Huybrechts |first10=Krista F. |last11=Kalverdijk |first11=Luuk J. |last12=Kawakami |first12=Koji |last13=Kieler |first13=Helle |last14=Kinoshita |first14=Takuya |last15=Litchfield |first15=Melisa |date=October 2017 |title=International trends in antipsychotic use: A study in 16 countries, 2005-2014 |url=https://pubmed.ncbi.nlm.nih.gov/28755801/ |journal=European Neuropsychopharmacology |volume=27 |issue=10 |pages=1064–1076 |doi=10.1016/j.euroneuro.2017.07.001 |issn=1873-7862 |pmid=28755801|hdl=1959.4/unsworks_79133 |hdl-access=free }}{{Cite journal |last1=Radha Krishnan |first1=Ramya Padmavathy |last2=Harrison |first2=Christopher |last3=Buckley |first3=Nicholas |last4=Raubenheimer |first4=Jacques Eugene |date=April 2024 |title=On- and off-label utilisation of antipsychotics in Australia (2000–2021): Retrospective analysis of two medication datasets |journal=Australian & New Zealand Journal of Psychiatry |language=en |volume=58 |issue=4 |pages=320–333 |doi=10.1177/00048674231210209 |issn=0004-8674|doi-access=free |pmid=37941354 |pmc=10960313 }}{{Cite journal |last1=McKean |first1=Andrew |last2=Monasterio |first2=Erik |date=2012-05-01 |title=Off-label use of atypical antipsychotics: cause for concern? |url=https://pubmed.ncbi.nlm.nih.gov/22448598/ |journal=CNS Drugs |volume=26 |issue=5 |pages=383–390 |doi=10.2165/11632030-000000000-00000 |issn=1179-1934 |pmid=22448598}} Besides the above uses antipsychotics may be used for obsessive–compulsive disorder, post-traumatic stress disorder, personality disorders, Tourette syndrome, autism and agitation in those with dementia. Evidence however does not support the use of atypical antipsychotics in eating disorders or personality disorder.{{cite book |vauthors=Maglione M, Maher AR, Hu J, Wang Z, Shanman R, Shekelle PG, Roth B, Hilton L, Suttorp MJ | year = 2011 | title = Off-Label Use of Atypical Antipsychotics: An Update |series=Comparative Effectiveness Reviews, No. 43 | location = Rockville | publisher = Agency for Healthcare Research and Quality | pmid = 22973576 }} The atypical antipsychotic risperidone may be useful for obsessive–compulsive disorder.{{cite journal | vauthors = Maher AR, Theodore G | title = Summary of the comparative effectiveness review on off-label use of atypical antipsychotics | journal = Journal of Managed Care Pharmacy | volume = 18 | issue = 5 Suppl B | pages = S1-20 | date = June 2012 | pmid = 22784311 | doi = 10.18553/jmcp.2012.18.s5-b.1 | pmc = 10438344 | doi-access = free }} The use of low doses of antipsychotics for insomnia, while common, is not recommended as there is little evidence of benefit as well as concern regarding adverse effects.{{cite journal | vauthors = Coe HV, Hong IS | title = Safety of low doses of quetiapine when used for insomnia | journal = The Annals of Pharmacotherapy | volume = 46 | issue = 5 | pages = 718–722 | date = May 2012 | pmid = 22510671 | doi = 10.1345/aph.1Q697 | s2cid = 9888209 }} Some of the more serious adverse effects may also occur at the low doses used, such as dyslipidemia and neutropenia,{{cite journal | vauthors = Pillinger T, McCutcheon RA, Vano L, Mizuno Y, Arumuham A, Hindley G, Beck K, Natesan S, Efthimiou O, Cipriani A, Howes OD | display-authors = 6 | title = Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis | journal = The Lancet. Psychiatry | volume = 7 | issue = 1 | pages = 64–77 | date = January 2020 | pmid = 31860457 | pmc = 7029416 | doi = 10.1016/s2215-0366(19)30416-x }}{{cite journal | vauthors = Yoshida K, Takeuchi H | title = Dose-dependent effects of antipsychotics on efficacy and adverse effects in schizophrenia | journal = Behavioural Brain Research | volume = 402 | pages = 113098 | date = March 2021 | pmid = 33417992 | doi = 10.1016/j.bbr.2020.113098 | s2cid = 230507941 | doi-access = free }} and a recent network meta-analysis of 154 double-blind, randomized controlled trials of drug therapies vs. placebo for insomnia in adults found that quetiapine did not demonstrated any short-term benefits in sleep quality.{{cite journal | vauthors = De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, Kurtulmus A, Tomlinson A, Mitrova Z, Foti F, Del Giovane C, Quested DJ, Cowen PJ, Barbui C, Amato L, Efthimiou O, Cipriani A | display-authors = 6 | title = Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis | language = English | journal = Lancet | volume = 400 | issue = 10347 | pages = 170–184 | date = July 2022 | pmid = 35843245 | doi = 10.1016/S0140-6736(22)00878-9 | s2cid = 250536370 | doi-access = free | hdl = 11380/1288245 | hdl-access = free }} Low dose antipsychotics may also be used in treatment of impulse-behavioural and cognitive-perceptual symptoms of borderline personality disorder.{{cite book | publisher = American Psychiatric Association Publications | author = Work Group on Borderline Personality Disorder|title=Practice Guideline for the Treatment of Patients With Borderline Personality Disorder|url=https://books.google.com/books?id=xvQ2QKok3-oC|access-date=5 June 2013|year=2001 |page=4|isbn=978-0-89042-319-6}} Despite the lack of evidence supporting the benefit of antipsychotics in people with personality disorders, 1 in 4 who do not have a serious mental illness are prescribed them in UK primary care. Many people receive these medication for over a year, contrary to NICE guidelines.{{cite journal |date=2022-11-10 |title=Antipsychotics are commonly prescribed to people with personality disorders, contrary to guidelines |url=https://evidence.nihr.ac.uk/alert/antipsychotics-commonly-prescribed-people-personality-disorders-contrary-guidelines/ |journal=NIHR Evidence |language=en |doi=10.3310/nihrevidence_54520|s2cid=253467990 |url-access=subscription }}{{cite journal | vauthors = Hardoon S, Hayes J, Viding E, McCrory E, Walters K, Osborn D | title = Prescribing of antipsychotics among people with recorded personality disorder in primary care: a retrospective nationwide cohort study using The Health Improvement Network primary care database | journal = BMJ Open | volume = 12 | issue = 3 | pages = e053943 | date = March 2022 | pmid = 35264346 | pmc = 8968526 | doi = 10.1136/bmjopen-2021-053943 }}

In children they may be used in those with disruptive behavior disorders, mood disorders and pervasive developmental disorders or intellectual disability.{{cite journal | vauthors = Zuddas A, Zanni R, Usala T | s2cid = 1254352 | title = Second generation antipsychotics (SGAs) for non-psychotic disorders in children and adolescents: a review of the randomized controlled studies | journal = European Neuropsychopharmacology | volume = 21 | issue = 8 | pages = 600–20 | date = August 2011 | pmid = 21550212 | doi = 10.1016/j.euroneuro.2011.04.001 }} Antipsychotics are only weakly recommended for Tourette syndrome, because although they are effective, side effects are common.{{cite journal | vauthors = Pringsheim T, Doja A, Gorman D, McKinlay D, Day L, Billinghurst L, Carroll A, Dion Y, Luscombe S, Steeves T, Sandor P | title = Canadian guidelines for the evidence-based treatment of tic disorders: pharmacotherapy | journal = Canadian Journal of Psychiatry | volume = 57 | issue = 3 | pages = 133–43 | date = March 2012 | pmid = 22397999 | doi = 10.1177/070674371205700302 | doi-access = free }} The situation is similar for those on the autism spectrum.{{cite journal | vauthors = McPheeters ML, Warren Z, Sathe N, Bruzek JL, Krishnaswami S, Jerome RN, Veenstra-Vanderweele J | s2cid = 2903864 | title = A systematic review of medical treatments for children with autism spectrum disorders | journal = Pediatrics | volume = 127 | issue = 5 | pages = e1312–21 | date = May 2011 | pmid = 21464191 | doi = 10.1542/peds.2011-0427 }}

Much of the evidence for the off-label use of antipsychotics (for example, for dementia, OCD, PTSD, personality disorders, Tourette's) was of insufficient scientific quality to support such use, especially as there was strong evidence of increased risks of stroke, tremors, significant weight gain, sedation, and gastrointestinal problems.{{cite press release |title=Evidence Lacking to Support Many Off-label Uses of Atypical Antipsychotics |publisher=Agency for Healthcare Research and Quality |date=17 January 2007 |url=http://archive.ahrq.gov/news/press/pr2007/antipsypr.htm |access-date=29 July 2013 |url-status = live|archive-url=https://web.archive.org/web/20130225052120/http://archive.ahrq.gov/news/press/pr2007/antipsypr.htm |archive-date=25 February 2013 }} A UK review of unlicensed usage in children and adolescents reported a similar mixture of findings and concerns.{{cite journal | doi=10.1192/apt.bp.108.005652 | title=Prescribing antipsychotics for children and adolescents | year=2010 | vauthors = James AC | journal = Advances in Psychiatric Treatment | volume = 16 | issue = 1 | pages = 63–75 | doi-access = free }} A survey of children with pervasive developmental disorder found that 16.5% were taking an antipsychotic drug, most commonly for irritability, aggression, and agitation. Both risperidone and aripiprazole have been approved by the US FDA for the treatment of irritability in autistic children and adolescents.Truven Health Analytics, Inc. DRUGDEX System (Internet) [cited 2013 Oct 10]. Greenwood Village, CO: Thomsen Healthcare; 2013. A review in the UK found that the use of antipsychotics in England doubled between 2000 and 2019. Children were prescribed antipsychotics for conditions for which there is no approval, such as autism.{{cite journal |date=2023-04-18 |title=Antipsychotics are increasingly prescribed to children and teenagers |url=https://evidence.nihr.ac.uk/alert/antipsychotics-are-increasingly-prescribed-to-children-and-teenagers/ |journal=NIHR Evidence |language=en |doi=10.3310/nihrevidence_57289|s2cid=258224542 |url-access=subscription }}{{cite journal | vauthors = Radojčić MR, Pierce M, Hope H, Senior M, Taxiarchi VP, Trefan L, Swift E, Abel KM | display-authors = 6 | title = Trends in antipsychotic prescribing to children and adolescents in England: cohort study using 2000-19 primary care data | journal = The Lancet. Psychiatry | volume = 10 | issue = 2 | pages = 119–128 | date = February 2023 | pmid = 36638816 | doi = 10.1016/s2215-0366(22)00404-7 | s2cid = 255703855 | doi-access = free }}

Aggressive challenging behavior in adults with intellectual disability is often treated with antipsychotic drugs despite lack of an evidence base. A recent randomized controlled trial, however, found no benefit over placebo and recommended that the use of antipsychotics in this way should no longer be regarded as an acceptable routine treatment.{{cite journal | vauthors = Romeo R, Knapp M, Tyrer P, Crawford M, Oliver-Africano P | s2cid = 34448894 | title = The treatment of challenging behaviour in intellectual disabilities: cost-effectiveness analysis | journal = Journal of Intellectual Disability Research | volume = 53 | issue = 7 | pages = 633–43 | date = July 2009 | pmid = 19460067 | doi = 10.1111/j.1365-2788.2009.01180.x }}

Antipsychotics may be an option, together with stimulants, in people with ADHD and aggressive behavior when other treatments have not worked.{{cite journal | vauthors = Linton D, Barr AM, Honer WG, Procyshyn RM | title = Antipsychotic and psychostimulant drug combination therapy in attention deficit/hyperactivity and disruptive behavior disorders: a systematic review of efficacy and tolerability | journal = Current Psychiatry Reports | volume = 15 | issue = 5 | pages = 355 | date = May 2013 | pmid = 23539465 | doi = 10.1007/s11920-013-0355-6 | s2cid = 45484062 }} They have not been found to be useful for the prevention of delirium among those admitted to hospital.{{cite journal | vauthors = Oh ES, Needham DM, Nikooie R, Wilson LM, Zhang A, Robinson KA, Neufeld KJ | title = Antipsychotics for Preventing Delirium in Hospitalized Adults: A Systematic Review | journal = Annals of Internal Medicine | volume = 171 | issue = 7 | pages = 474–484 | date = October 2019 | pmid = 31476766 | doi = 10.7326/M19-1859 | doi-access = free }}

Aside from reduced extrapyramidal symptoms, and with the clear exception of clozapine, it is unclear whether the atypical (second-generation) antipsychotics offer advantages over older, first generation antipsychotics.{{cite journal | vauthors = Kane JM, Correll CU | title = Pharmacologic treatment of schizophrenia | journal = Dialogues in Clinical Neuroscience | volume = 12 | issue = 3 | pages = 345–57 | year = 2010 | doi = 10.31887/DCNS.2010.12.3/jkane | pmid = 20954430 | pmc = 3085113 }} Amisulpride, olanzapine, risperidone and clozapine may be more effective but are associated with greater side effects.{{cite journal | vauthors = Barry SJ, Gaughan TM, Hunter R | title = Schizophrenia | journal = BMJ Clinical Evidence | volume = 2012 | date = June 2012 | pmid = 23870705 | pmc = 3385413 }} Typical antipsychotics have equal drop-out and symptom relapse rates to atypicals when used at low to moderate dosages.{{cite journal | vauthors = Schultz SH, North SW, Shields CG | title = Schizophrenia: a review | journal = American Family Physician | volume = 75 | issue = 12 | pages = 1821–9 | date = June 2007 | pmid = 17619525 | url = https://www.aafp.org/afp/2007/0615/p1821.html | citeseerx=10.1.1.602.7571 }}

Clozapine is an effective treatment for those who respond poorly to other drugs ("treatment-resistant" or "refractory" schizophrenia),{{cite journal | vauthors = Taylor DM, Duncan-McConnell D | s2cid = 27270415 | title = Refractory schizophrenia and atypical antipsychotics | journal = Journal of Psychopharmacology | volume = 14 | issue = 4 | pages = 409–18 | year = 2000 | pmid = 11198061 | doi = 10.1177/026988110001400411 }} but it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people.{{cite journal | vauthors = Essali A, Al-Haj Haasan N, Li C, Rathbone J | title = Clozapine versus typical neuroleptic medication for schizophrenia | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD000059 | date = January 2009 | volume = 2009 | pmid = 19160174 | doi = 10.1002/14651858.CD000059.pub2 | pmc = 7065592 }}

Due to bias in the research the accuracy of comparisons of atypical antipsychotics is a concern.{{cite journal | vauthors = Heres S, Davis J, Maino K, Jetzinger E, Kissling W, Leucht S | s2cid = 3849348 | title = Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics | journal = The American Journal of Psychiatry | volume = 163 | issue = 2 | pages = 185–94 | date = February 2006 | pmid = 16449469 | doi = 10.1176/appi.ajp.163.2.185 }}

In 2005, a US government body, the National Institute of Mental Health published the results of a major independent study (the CATIE project).{{cite journal | vauthors = Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK | s2cid = 22499842 | title = Effectiveness of antipsychotic drugs in patients with chronic schizophrenia | journal = The New England Journal of Medicine | volume = 353 | issue = 12 | pages = 1209–23 | date = September 2005 | pmid = 16172203 | doi = 10.1056/NEJMoa051688 | url = https://cdr.lib.unc.edu/downloads/g732dk11n | doi-access = free }} No other atypical studied (risperidone, quetiapine, and ziprasidone) did better than the first-generation antipsychotic perphenazine on the measures used, nor did they produce fewer adverse effects than the typical antipsychotic perphenazine, although more patients discontinued perphenazine owing to extrapyramidal effects compared to the atypical agents (8% vs. 2% to 4%).{{cite journal | vauthors = Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM | s2cid = 1071537 | title = Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis | journal = Lancet | volume = 373 | issue = 9657 | pages = 31–41 | date = January 2009 | pmid = 19058842 | doi = 10.1016/S0140-6736(08)61764-X }} This is significant because any patient with tardive dyskinesia was specifically excluded from randomization to perphenazine; i.e., in the CATIE study the patient cohort randomized to receive perphenazne was at lower risk of having extrapyramidal symptoms.{{cite journal |last1=Swartz |first1=Marvin S. |last2=Stroup |first2=T. Scott |last3=McEvoy |first3=Joseph P. |last4=Davis |first4=Sonia M. |last5=Rosenheck |first5=Robert A. |last6=Keefe |first6=Richard S. E. |last7=Hsiao |first7=John K. |last8=Lieberman |first8=Jeffrey A. |date=May 2008 |title=Special Section on Implications of CATIE: What CATIE Found: Results From the Schizophrenia Trial |journal=Psychiatric Services |language=en |volume=59 |issue=5 |pages=500–506 |doi=10.1176/ps.2008.59.5.500 |pmid=18451005 |pmc=5033643 |issn=1075-2730}}

Atypical antipsychotics do not appear to lead to improved rates of medication adherence compared to typical antipsychotics.{{cite journal | vauthors = Voruganti LP, Baker LK, Awad AG | s2cid = 34935 | title = New generation antipsychotic drugs and compliance behaviour | journal = Current Opinion in Psychiatry | volume = 21 | issue = 2 | pages = 133–9 | date = March 2008 | pmid = 18332660 | doi = 10.1097/YCO.0b013e3282f52851 }}

Many researchers question the first-line prescribing of atypicals over typicals, and some even question the distinction between the two classes.{{cite journal | vauthors = Paczynski RP, Alexander GC, Chinchilli VM, Kruszewski SP | title = Quality of evidence in drug compendia supporting off-label use of typical and atypical antipsychotic medications | journal = The International Journal of Risk & Safety in Medicine | volume = 24 | issue = 3 | pages = 137–146 | date = January 2012 | pmid = 22936056 | doi = 10.3233/JRS-2012-0567 }}{{cite journal | vauthors = Owens DC |title=How CATIE brought us back to Kansas: a critical re-evaluation of the concept of atypical antipsychotics and their place in the treatment of schizophrenia|journal=Advances in Psychiatric Treatment |volume=14 |issue=1 |pages=17–28 |year=2008 |doi=10.1192/apt.bp.107.003970|doi-access=free }}{{cite journal | vauthors = Fischer-Barnicol D, Lanquillon S, Haen E, Zofel P, Koch HJ, Dose M, Klein HE | title = Typical and atypical antipsychotics--the misleading dichotomy. Results from the Working Group 'Drugs in Psychiatry' (AGATE) | journal = Neuropsychobiology | volume = 57 | issue = 1–2 | pages = 80–87 | year = 2008 | pmid = 18515977 | doi = 10.1159/000135641 | s2cid = 2669203 }} In contrast, other researchers point to the significantly higher risk of tardive dyskinesia and other extrapyramidal symptoms with the typicals and for this reason alone recommend first-line treatment with the atypicals, notwithstanding a greater propensity for metabolic adverse effects in the latter.{{cite journal | vauthors = Casey DE | title = Tardive dyskinesia and atypical antipsychotic drugs | journal = Schizophrenia Research | volume = 35 | issue = Suppl 1 | pages = S61–S66 | date = March 1999 | pmid = 10190226 | doi = 10.1016/S0920-9964(98)00160-1 | s2cid = 31807817 }} The UK government organization NICE recently revised its recommendation favoring atypicals, to advise that the choice should be an individual one based on the particular profiles of the individual drug and on the patient's preferences.

The re-evaluation of the evidence has not necessarily slowed the bias toward prescribing the atypicals.{{cite journal | vauthors = Makhinson M | title = Biases in medication prescribing: the case of second-generation antipsychotics | journal = Journal of Psychiatric Practice | volume = 16 | issue = 1 | pages = 15–21 | date = January 2010 | pmid = 20098227 | doi = 10.1097/01.pra.0000367774.11260.e4 | s2cid = 46530288 }}

Antipsychotics, such as risperidone, quetiapine, and olanzapine, have been used as hallucinogen antidotes or "trip killers" to block the effects of serotonergic psychedelics like psilocybin and lysergic acid diethylamide (LSD).{{cite journal | vauthors = Halman A, Kong G, Sarris J, Perkins D | title = Drug-drug interactions involving classic psychedelics: A systematic review | journal = J Psychopharmacol | volume = 38 | issue = 1 | pages = 3–18 | date = January 2024 | pmid = 37982394 | pmc = 10851641 | doi = 10.1177/02698811231211219 | url = }}{{cite journal | vauthors = Yates G, Melon E | title = Trip-killers: a concerning practice associated with psychedelic drug use | journal = Emerg Med J | volume = 41 | issue = 2 | pages = 112–113 | date = January 2024 | pmid = 38123961 | doi = 10.1136/emermed-2023-213377 | url = https://s3.amazonaws.com/crawl.prod.proquest.com/fpcache/71f445805bfb61341cbc438c8ae23bd3.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjEBMaCXVzLWVhc3QtMSJIMEYCIQDETX7YpaG5THA%2FNbKR0d92wr6h%2Bgg9preNcKjAsEqo%2BQIhAIlPGGWOeUc23LqhBzRYbxvSXB9aqSe2vVonl4nacAhhKp0CCLz%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEQABoMNTE4MzQ2ODQ4MzQxIgy9ji58Qtbi%2BavuKeYq8QEDL1U5KZDQ0bXFyVapeqJgE%2FX6x8DcJfFU8DAXYZPSQEwrIdfPbZWcYsH340deru%2FUHnNaGGpuHFoVzui%2FMbqBz7MANcowj%2FL1%2BQZzQ5hXh5KM3BW8E6NRzrQyuPRmBy7kQUkx8%2BjTN%2BXSMgF%2FCAs6Dn9fScgBGz3ddkwRZXDkjasqMP65RCPKhagK68cyMbf3oX%2BKS8a4Kltc2rk3CnWEhOKrZU4mIxq07DikLAXQbl8YRZJIkeOhN5TgBaLWJqyn1td2VWCMymAaFsqtPWHwXnEfsolRlfDooe6QXfE2YwX5PxBVJU7GPXRgrAqPjwtJMOCHgsEGOpwBYif%2BaDMBdz3IEghuvCvorAS0mkHzdcOz%2Fi7AzuN9nch%2FIm8llhMsN41aAWHuSG25pnhhftauFsg7rbGsrW2nl2kq2upi9zP7y%2Fnqk93jcP0kr0jM8zU12bYoSTsToQJsshH4N%2BTQUMwlzRQfeVv8MXdq%2BgSTTzJrWNwT1yNzye3rSHjvOumbNl6sgBISw7QqRzhB6hZTuf8AcI%2B7&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20250511T111826Z&X-Amz-SignedHeaders=host&X-Amz-Credential=ASIAXRL7BHBKRAKCQVVB%2F20250511%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Expires=3600&X-Amz-Signature=20bb1b90e4c8dbaa4115c954387617ebe2f55269bdd517692f1380193ed3f769 | archive-url = https://web.archive.org/web/20250511111827/https://s3.amazonaws.com/crawl.prod.proquest.com/fpcache/71f445805bfb61341cbc438c8ae23bd3.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjEBMaCXVzLWVhc3QtMSJIMEYCIQDETX7YpaG5THA%2FNbKR0d92wr6h%2Bgg9preNcKjAsEqo%2BQIhAIlPGGWOeUc23LqhBzRYbxvSXB9aqSe2vVonl4nacAhhKp0CCLz%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEQABoMNTE4MzQ2ODQ4MzQxIgy9ji58Qtbi%2BavuKeYq8QEDL1U5KZDQ0bXFyVapeqJgE%2FX6x8DcJfFU8DAXYZPSQEwrIdfPbZWcYsH340deru%2FUHnNaGGpuHFoVzui%2FMbqBz7MANcowj%2FL1%2BQZzQ5hXh5KM3BW8E6NRzrQyuPRmBy7kQUkx8%2BjTN%2BXSMgF%2FCAs6Dn9fScgBGz3ddkwRZXDkjasqMP65RCPKhagK68cyMbf3oX%2BKS8a4Kltc2rk3CnWEhOKrZU4mIxq07DikLAXQbl8YRZJIkeOhN5TgBaLWJqyn1td2VWCMymAaFsqtPWHwXnEfsolRlfDooe6QXfE2YwX5PxBVJU7GPXRgrAqPjwtJMOCHgsEGOpwBYif%2BaDMBdz3IEghuvCvorAS0mkHzdcOz%2Fi7AzuN9nch%2FIm8llhMsN41aAWHuSG25pnhhftauFsg7rbGsrW2nl2kq2upi9zP7y%2Fnqk93jcP0kr0jM8zU12bYoSTsToQJsshH4N%2BTQUMwlzRQfeVv8MXdq%2BgSTTzJrWNwT1yNzye3rSHjvOumbNl6sgBISw7QqRzhB6hZTuf8AcI%2B7&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20250511T111826Z&X-Amz-SignedHeaders=host&X-Amz-Credential=ASIAXRL7BHBKRAKCQVVB%2F20250511%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Expires=3600&X-Amz-Signature=20bb1b90e4c8dbaa4115c954387617ebe2f55269bdd517692f1380193ed3f769 | url-status = dead | archive-date = 2025-05-11 }}{{cite journal | vauthors = Suran M | title = Study Finds Hundreds of Reddit Posts on "Trip-Killers" for Psychedelic Drugs | journal = JAMA | volume = 331 | issue = 8 | pages = 632–634 | date = February 2024 | pmid = 38294772 | doi = 10.1001/jama.2023.28257 | url = }}{{cite journal | vauthors = Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Bäbler A, Vogel H, Hell D | title = Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action | journal = NeuroReport | volume = 9 | issue = 17 | pages = 3897–3902 | date = December 1998 | pmid = 9875725 | doi = 10.1097/00001756-199812010-00024 | url = }}

{{for|more detailed comparison of atypical antipsychotics|Atypical antipsychotic#Adverse effects}}

Generally, more than one antipsychotic drug should not be used at a time because of increased adverse effects.{{Citation|title=Five Things Physicians and Patients Should Question|date=September 2013|url=http://www.choosingwisely.org/doctor-patient-lists/american-psychiatric-association/|author1=American Psychiatric Association|author1-link=American Psychiatric Association|work=Choosing Wisely: an initiative of the ABIM Foundation|publisher=American Psychiatric Association|access-date=30 December 2013|url-status = live|archive-url=https://web.archive.org/web/20131203174206/http://www.choosingwisely.org/doctor-patient-lists/american-psychiatric-association/|archive-date=3 December 2013}}, which cites

• {{cite book|year=2006|title=Practice Guideline for the Treatment of Patients With Schizophrenia | edition = Second |volume=1|doi=10.1176/appi.books.9780890423363.45859|isbn=978-0-89042-336-3 | publisher = American Psychiatric Association|doi-broken-date=4 December 2024 }}
• {{Citation|title=Specifications Manual for Joint Commission National Quality Core Measures|date=30 June 2013|url=http://www.jointcommission.org/specifications_manual_joint_commission_national_quality_core_measures.aspx|author=Joint Commission|author-link=Joint Commission|chapter=HBIPS-4, Patients discharged on multiple antipsychotic medications|chapter-url=http://manual.jointcommission.org/releases/TJC2013A/MIF0119.html|access-date=27 October 2013|url-status = live|archive-url=https://web.archive.org/web/20131110024015/http://www.jointcommission.org/specifications_manual_joint_commission_national_quality_core_measures.aspx|archive-date=10 November 2013}}
• {{cite journal | vauthors = Stahl SM, Grady MM | title = A critical review of atypical antipsychotic utilization: comparing monotherapy with polypharmacy and augmentation | journal = Current Medicinal Chemistry | volume = 11 | issue = 3 | pages = 313–27 | date = February 2004 | pmid = 14965234 | doi = 10.2174/0929867043456070 }}

Use of antipsychotics is associated with reductions in brain tissue volumes,{{cite journal |vauthors=Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V |date=February 2011 |title=Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia |journal=Archives of General Psychiatry |volume=68 |issue=2 |pages=128–137 |doi=10.1001/archgenpsychiatry.2010.199 |pmc=3476840 |pmid=21300943}}{{cite journal |vauthors=Moncrieff J, Leo J |date=September 2010 |title=A systematic review of the effects of antipsychotic drugs on brain volume |journal=Psychological Medicine |volume=40 |issue=9 |pages=1409–1422 |doi=10.1017/S0033291709992297 |pmid=20085668 |s2cid=23522488}} including white matter reduction,{{cite journal |display-authors=6 |vauthors=Chopra S, Fornito A, Francey SM, O'Donoghue B, Cropley V, Nelson B, Graham J, Baldwin L, Tahtalian S, Yuen HP, Allott K, Alvarez-Jimenez M, Harrigan S, Sabaroedin K, Pantelis C, Wood SJ, McGorry P |date=July 2021 |title=Differentiating the effect of antipsychotic medication and illness on brain volume reductions in first-episode psychosis: A Longitudinal, Randomised, Triple-blind, Placebo-controlled MRI Study |journal=Neuropsychopharmacology |volume=46 |issue=8 |pages=1494–1501 |doi=10.1038/s41386-021-00980-0 |pmc=8209146 |pmid=33637835}} an effect which is dose-dependent and time-dependent. However, a recent controlled trial suggests that second generation antipsychoticsplease see Chopra et al 2021: Strengths and limitations "only examined risperidone and paliperidone" combined with intensive psychosocial therapyplease see Chopra et al 2021: Method Study design may potentially prevent pallidal brain volume loss in first episode psychosis.please see Chopra et al 2021: Introduction, 3rd paragraph, Lieberman JA, et al. 2005 & Shao Y et al 2015, and Chopra et al: Are antipsychotics neuroprotective? 1st paragraph last sentence

Some atypicals are associated with considerable weight gain, diabetes and the risk of metabolic syndrome.{{cite journal |vauthors=Barry SJ, Gaughan TM, Hunter R |date=June 2012 |title=Schizophrenia |journal=BMJ Clin Evid |volume=2012 |issue= |pages= |pmc=3385413 |pmid=23870705}} Unwanted side effects cause people to stop treatment, resulting in relapses.{{cite journal |vauthors=Nakata Y, Kanahara N, Iyo M |date=December 2017 |title=Dopamine supersensitivity psychosis in schizophrenia: Concepts and implications in clinical practice |journal=Journal of Psychopharmacology |volume=31 |issue=12 |pages=1511–1518 |doi=10.1177/0269881117728428 |pmid=28925317 |s2cid=1957881}} Risperidone (atypical) has a similar rate of extrapyramidal symptoms to haloperidol (typical). A rare but potentially lethal condition of neuroleptic malignant syndrome (NMS) has been associated with the use of antipsychotics. Through its early recognition, and timely intervention rates have declined. However, an awareness of the syndrome is advised to enable intervention.{{cite journal |vauthors=Ware MR, Feller DB, Hall KL |date=4 January 2018 |title=Neuroleptic Malignant Syndrome: Diagnosis and Management |journal=The Primary Care Companion for CNS Disorders |volume=20 |issue=1 |doi=10.4088/PCC.17r02185 |pmid=29325237}} Another less rare condition of tardive dyskinesia can occur due to long-term use of antipsychotics, developing after months or years of use. It is more often reported with use of typical antipsychotics.{{cite journal |vauthors=Carbon M, Kane JM, Leucht S, Correll CU |date=October 2018 |title=Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis |journal=World Psychiatry |volume=17 |issue=3 |pages=330–340 |doi=10.1002/wps.20579 |pmc=6127753 |pmid=30192088}} Very rarely antipsychotics may cause tardive psychosis.{{cite book |url=https://books.google.com/books?id=Sy7OBgAAQBAJ&pg=PA791 |title=Textbook of Clinical Neuropsychiatry and Behavioral Neuroscience, Third Edition |vauthors=Moore DP, Puri BK |date=2012 |publisher=CRC Press |isbn=978-1-4441-6494-7 |page=791 |language=en |archive-url=https://web.archive.org/web/20171125213437/https://books.google.com/books?id=Sy7OBgAAQBAJ&pg=PA791 |archive-date=25 November 2017 |url-status=live}}

Clozapine is associated with side effects that include weight gain, tiredness, and hypersalivation. More serious adverse effects include seizures, NMS, neutropenia, and agranulocytosis (lowered white blood cell count) and its use needs careful monitoring.{{cite journal |display-authors=etal |vauthors=De Berardis D, Rapini G, Olivieri L |date=May 2018 |title=Safety of antipsychotics for the treatment of schizophrenia: a focus on the adverse effects of clozapine |journal=Therapeutic Advances in Drug Safety |volume=9 |issue=5 |pages=237–256 |doi=10.1177/2042098618756261 |pmc=5956953 |pmid=29796248}}{{cite journal |vauthors=Legge SE, Walters JT |date=March 2019 |title=Genetics of clozapine-associated neutropenia: recent advances, challenges and future perspective |journal=Pharmacogenomics |volume=20 |issue=4 |pages=279–290 |doi=10.2217/pgs-2018-0188 |pmc=6563116 |pmid=30767710}}

Clozapine is also associated with thromboembolism (including pulmonary embolism), myocarditis, and cardiomyopathy.{{cite journal |vauthors=Kritharides L, Chow V, Lambert TJ |date=6 February 2017 |title=Cardiovascular disease in patients with schizophrenia |journal=The Medical Journal of Australia |volume=206 |issue=2 |pages=91–95 |doi=10.5694/mja16.00650 |pmid=28152356 |s2cid=5388097}}{{cite journal |vauthors=Sarvaiya N, Lapitskaya Y, Dima L, Manu P |date=August 2018 |title=Clozapine-Associated Pulmonary Embolism: A High-Mortality, Dose-Independent and Early-Onset Adverse Effect |journal=American Journal of Therapeutics |volume=25 |issue=4 |pages=e434–e438 |doi=10.1097/MJT.0000000000000806 |pmid=29985823 |s2cid=51608744}} A systematic review of clozapine-associated pulmonary embolism indicates that this adverse effect can often be fatal, and that it has an early onset, and is dose-dependent. The findings advised the consideration of using a prevention therapy for venous thromboembolism after starting treatment with clozapine, and continuing this for six months. Constipation is three times more likely to occur with the use of clozapine, and severe cases can lead to ileus and bowel ischemia resulting in many fatalities. Very rare clozapine adverse effects include periorbital edema due to several possible mechanisms (e.g., inhibition of platelet-derived growth factor receptors leading to increased vascular permeability, antagonism of renal dopamine receptors with electrolyte and fluid imbalance and immune-mediated hypersensitivity reactions).{{cite journal | vauthors = Teodoro T, Nogueira V, Aldeias J, Teles Martins M, Salgado J | title = Clozapine Associated Periorbital Edema in First Episode Psychosis: A Case Report of a Rare Adverse Effect in Treatment-Resistant Schizophrenia | journal = Journal of Clinical Psychopharmacology | date = September 2022 | volume = 42 | issue = 6 | pages = 594–596 | pmid = 36066404 | doi = 10.1097/JCP.0000000000001600| s2cid = 252088054 }}

However, the risk of serious adverse effects from clozapine is low, and there are the beneficial effects to be gained of a reduced risk of suicide, and aggression.{{cite journal |vauthors=Sriretnakumar V, Huang E, Müller DJ |date=2015 |title=Pharmacogenetics of clozapine treatment response and side-effects in schizophrenia: an update |journal=Expert Opinion on Drug Metabolism & Toxicology |volume=11 |issue=11 |pages=1709–31 |doi=10.1517/17425255.2015.1075003 |pmid=26364648 |s2cid=207492339}} Typical antipsychotics and atypical risperidone can have a side effect of sexual dysfunction.{{cite journal |vauthors=Picchioni MM, Murray RM |date=July 2007 |title=Schizophrenia |journal=BMJ |volume=335 |issue=7610 |pages=91–5 |doi=10.1136/bmj.39227.616447.BE |pmc=1914490 |pmid=17626963}} Clozapine, olanzapine, and quetiapine are associated with beneficial effects on sexual functioning helped by various psychotherapies.{{cite journal |display-authors=etal |vauthors=Adam RL, Sidi H, Midin M |date=2018 |title=The Role of Atypical Antipsychotics in Sexuality: Road to Recovery in Schizophrenia |journal=Current Drug Targets |volume=19 |issue=12 |pages=1402–1411 |doi=10.2174/1389450118666170502130126 |pmid=28464773 |s2cid=41487184}}

Common (≥ 1% and up to 50% incidence for most antipsychotic drugs) adverse effects of antipsychotics include:{{cite journal | vauthors = Muench J, Hamer AM | title = Adverse effects of antipsychotic medications | journal = American Family Physician | volume = 81 | issue = 5 | pages = 617–22 | date = March 2010 | pmid = 20187598 }}

• Dysphoria and apathy (due to dopamine receptor blockade)
• Sedation (particularly common with asenapine, clozapine, olanzapine, quetiapine, chlorpromazine and zotepine)
• Headaches
• Dizziness
• Diarrhea
• Anxiety
• Extrapyramidal side effects (particularly common with first-generation antipsychotics), which include:
• Akathisia, an often distressing sense of inner restlessness.
• Dystonia, an abnormal muscle contraction
• Pseudoparkinsonism, symptoms that are similar to what people with Parkinson's disease experience, including tremulousness and drooling
• Hyperprolactinaemia (rare for those treated with clozapine, quetiapine and aripiprazole), which can cause:
• Galactorrhoea, the unusual secretion of breast milk.
• Gynaecomastia, abnormal growth of breast tissue
• Sexual dysfunction (in both sexes)
• Osteoporosis
• Orthostatic hypotension
• Weight gain (particularly prominent with clozapine, olanzapine, quetiapine and zotepine, can be counteracted by starting the drug with metformin{{cite journal | vauthors = Praharaj SK, Jana AK, Goyal N, Sinha VK | title = Metformin for olanzapine-induced weight gain: a systematic review and meta-analysis | journal = British Journal of Clinical Pharmacology | volume = 71 | issue = 3 | pages = 377–82 | date = March 2011 | pmid = 21284696 | pmc = 3045546 | doi = 10.1111/j.1365-2125.2010.03783.x }}{{cite journal |last1=Yu |first1=O |last2=Lu |first2=M |last3=Lai |first3=TKY |last4=Hahn |first4=M |last5=Agarwal |first5=SM |last6=O'Donoghue |first6=B |last7=Ebdrup |first7=BH |last8=Siskind |first8=D |title=Metformin co-commencement at time of antipsychotic initiation for attenuation of weight gain: a systematic review and meta-analysis. |journal=Therapeutic Advances in Psychopharmacology |date=2024 |volume=14 |pages=20451253241255476 |doi=10.1177/20451253241255476 |pmid=38827016|doi-access=free|pmc=11141220 }})
• Anticholinergic side-effects (common for olanzapine, clozapine; less likely on risperidone{{cite journal | vauthors = Lieberman JA | title = Managing anticholinergic side effects | journal = Primary Care Companion to the Journal of Clinical Psychiatry | volume = 6 | issue = Suppl 2 | pages = 20–3 | year = 2004 | pmid = 16001097 | pmc = 487008 }}) such as:
• Blurred vision
• Constipation
• Dry mouth (although hypersalivation may also occur)
• Reduced perspiration
• Tardive dyskinesia appears to be more frequent with high-potency first-generation antipsychotics, such as haloperidol, and tends to appear after chronic and not acute treatment. It is characterized by slow (hence the tardive) repetitive, involuntary and purposeless movements, most often of the face, lips, legs, or torso, which tend to resist treatment and are frequently irreversible. The rate of appearance of TD is about 5% per year of use of antipsychotic drug (whatever the drug used)
• Breast cancer: a systematic review and meta-analysis of observational studies with over 2 million individuals estimated an association between antipsychotic use and breast cancer by over 30%.{{cite web|url=https://neurosciencenews.com/antipsychotic-breast-cancer-21367/|title=Antipsychotic Use Associated With Elevated Risk of Breast Cancer|date=September 6, 2022|author=University of Hong Kong}}

Rare/Uncommon (<1% incidence for most antipsychotic drugs) adverse effects of antipsychotics include:

• Blood dyscrasias (e.g., agranulocytosis, leukopenia, and neutropaenia), which is more common in patients on clozapine.
• Metabolic syndrome and other metabolic problems such as type II diabetes mellitus — particularly common with clozapine, olanzapine and zotepine. In American studies African Americans appeared to be at a heightened risk for developing type II diabetes mellitus.{{cite journal | vauthors = Koller EA, Doraiswamy PM | title = Olanzapine-associated diabetes mellitus | journal = Pharmacotherapy | volume = 22 | issue = 7 | pages = 841–52 | date = July 2002 | pmid = 12126218 | doi = 10.1592/phco.22.11.841.33629 | s2cid = 27314943 | url = https://zenodo.org/record/1236343 }} Evidence suggests that females are more sensitive to the metabolic side effects of first-generation antipsychotic drugs than males.{{cite journal | vauthors = Weston-Green K, Huang XF, Deng C | s2cid = 30384727 | title = Sensitivity of the female rat to olanzapine-induced weight gain—far from the clinic? | journal = Schizophrenia Research | volume = 116 | issue = 2–3 | pages = 299–300 | date = February 2010 | pmid = 19840894 | doi = 10.1016/j.schres.2009.09.034 | url = https://ro.uow.edu.au/cgi/viewcontent.cgi?article=2408&context=smhpapers }} Metabolic adverse effects appear to be mediated by antagonizing the histamine H₁ and serotonin 5-HT_2C receptors and perhaps by interacting with other neurochemical pathways in the central nervous system.{{cite journal | vauthors = Weston-Green K, Huang XF, Deng C | title = Alterations to melanocortinergic, GABAergic and cannabinoid neurotransmission associated with olanzapine-induced weight gain | journal = PLOS ONE | volume = 7 | issue = 3 | pages = e33548 | year = 2012 | pmid = 22438946 | pmc = 3306411 | doi = 10.1371/journal.pone.0033548 | veditors = Chang AY | bibcode = 2012PLoSO...733548W | doi-access = free }}
• Neuroleptic malignant syndrome, a potentially fatal condition characterized by:
• Autonomic instability, which can manifest with tachycardia, nausea, vomiting, diaphoresis, etc.
• Hyperthermia — elevated body temperature.
• Mental status change (confusion, hallucinations, coma, etc.)
• Muscle rigidity
• Laboratory abnormalities (e.g., elevated creatine kinase, reduced iron plasma levels, electrolyte abnormalities, etc.)
• Pancreatitis{{cite journal | vauthors = Koller EA, Cross JT, Doraiswamy PM, Malozowski SN | title = Pancreatitis associated with atypical antipsychotics: from the Food and Drug Administration's MedWatch surveillance system and published reports | journal = Pharmacotherapy | volume = 23 | issue = 9 | pages = 1123–30 | date = September 2003 | pmid = 14524644 | doi = 10.1592/phco.23.10.1123.32759 | s2cid = 39945446 | url = https://zenodo.org/record/1236345 }}
• QT interval prolongation — more prominent in those treated with amisulpride, pimozide, sertindole, thioridazine and ziprasidone.
• Torsades de pointes
• Seizures, particularly in people treated with chlorpromazine and clozapine.
• Thromboembolism
• Myocardial infarction
• Stroke
• Pisa syndrome

{{see also|List of long term side effects of antipsychotics}}

Antipsychotic use has been linked to a 21x higher incidence of dementia in the United States by age 65.{{Cite journal |last1=Stroup |first1=T. Scott |last2=Olfson |first2=Mark |last3=Huang |first3=Cecilia |last4=Wall |first4=Melanie M. |last5=Goldberg |first5=Terry |last6=Devanand |first6=Davangere P. |last7=Gerhard |first7=Tobias |date=June 2021 |title=Age-Specific Prevalence and Incidence of Dementia Diagnoses Among Older US Adults With Schizophrenia |journal=JAMA Psychiatry |volume=78 |issue=6 |pages=632–641 |doi=10.1001/jamapsychiatry.2021.0042 |issn=2168-622X |pmc=7948106 |pmid=33688938}} Both atypical and typical antipsychotics have a higher hazard ratio for dementia risk.{{Cite journal |last1=Ma |first1=Li-Yun |last2=Ou |first2=Ya-Nan |last3=Gao |first3=Pei-Yang |last4=Fu |first4=Yan |last5=Zhang |first5=Dan-Dan |last6=Yang |first6=Liu |last7=Feng |first7=Jian-Feng |last8=Cheng |first8=Wei |last9=Tan |first9=Lan |last10=Yu |first10=Jin-Tai |date=2024-03-15 |title=Associations between antipsychotics exposure and dementia risk: A prospective cohort study of 415,100 participants |url=https://www.sciencedirect.com/science/article/abs/pii/S0165032724000387 |journal=Journal of Affective Disorders |volume=349 |pages=201–209 |doi=10.1016/j.jad.2024.01.029 |pmid=38199419 |issn=0165-0327|url-access=subscription }} In 2024 testable hypotheses were proposed for the mechanism{{Cite journal |last1=Jonas |first1=Katherine |last2=Abi-Dargham |first2=Anissa |last3=Kotov |first3=Roman |date=2021-12-01 |title=Two hypotheses on the high incidence of dementia in psychotic disorders |journal=JAMA Psychiatry |language=en |volume=78 |issue=12 |pages=1305–1306 |doi=10.1001/jamapsychiatry.2021.2584 |pmid=34524413 |pmc=10805107 }} responsible for cortical thinning till dementia.

Some studies have found decreased life expectancy associated with the use of antipsychotics, and argued that more studies are needed.{{cite journal | vauthors = Weinmann S, Read J, Aderhold V | s2cid = 8143217 | title = Influence of antipsychotics on mortality in schizophrenia: systematic review | journal = Schizophrenia Research | volume = 113 | issue = 1 | pages = 1–11 | date = August 2009 | pmid = 19524406 | doi = 10.1016/j.schres.2009.05.018 }}{{cite journal | vauthors = Joukamaa M, Heliövaara M, Knekt P, Aromaa A, Raitasalo R, Lehtinen V | title = Schizophrenia, neuroleptic medication and mortality | journal = The British Journal of Psychiatry | volume = 188 | issue = 2 | pages = 122–7 | date = February 2006 | pmid = 16449697 | doi = 10.1192/bjp.188.2.122 | doi-access = free }} Antipsychotics may also increase the risk of early death in individuals with dementia.{{cite journal | title = American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults | journal = Journal of the American Geriatrics Society | volume = 60 | issue = 4 | pages = 616–31 | date = April 2012 | pmid = 22376048 | pmc = 3571677 | doi = 10.1111/j.1532-5415.2012.03923.x | author1 = American Geriatrics Society 2012 Beers Criteria Update Expert Panel }} Antipsychotics typically worsen symptoms in people with depersonalisation disorder.{{cite journal |vauthors=Medford N, Sierra M, Baker D, David A |year=2005 |title=Understanding and treating depersonalisation disorder |journal=Advances in Psychiatric Treatment |volume=11 |issue=2 |pages=92–100 |doi=10.1192/apt.11.2.92 |url=http://apt.rcpsych.org/cgi/content/full/11/2/92#SEC5 |url-status = live|archive-url=https://web.archive.org/web/20110716095835/http://apt.rcpsych.org/cgi/content/full/11/2/92#SEC5 |archive-date=16 July 2011 |doi-access=free }} Antipsychotic polypharmacy (prescribing two or more antipsychotics at the same time for an individual) is a common practice but not evidence-based or recommended, and there are initiatives to curtail it.{{cite journal | vauthors = Patrick V, Levin E, Schleifer S | s2cid = 43114395 | title = Antipsychotic polypharmacy: is there evidence for its use? | journal = Journal of Psychiatric Practice | volume = 11 | issue = 4 | pages = 248–57 | date = July 2005 | pmid = 16041235 | doi = 10.1097/00131746-200507000-00005 }} Similarly, the use of excessively high doses (often the result of polypharmacy) continues despite clinical guidelines and evidence indicating that it is usually no more effective but is usually more harmful.{{cite journal | vauthors = Ito H, Koyama A, Higuchi T | title = Polypharmacy and excessive dosing: psychiatrists' perceptions of antipsychotic drug prescription | journal = The British Journal of Psychiatry | volume = 187 | issue = 3 | pages = 243–7 | date = September 2005 | pmid = 16135861 | doi = 10.1192/bjp.187.3.243 | doi-access = free }} A meta-analysis of observational studies with over two million individuals has suggested a moderate association of antipsychotic use with breast cancer.{{cite journal | vauthors = Leung JC, Ng DW, Chu RY, Chan EW, Huang L, Lum DH, Chan EW, Smith DJ, Wong IC, Lai FT | display-authors = 6 | title = Association of antipsychotic use with breast cancer: a systematic review and meta-analysis of observational studies with over 2 million individuals | journal = Epidemiology and Psychiatric Sciences | volume = 31 | pages = e61 | date = September 2022 | pmid = 36059215 | pmc = 9483823 | doi = 10.1017/S2045796022000476 }}

Loss of grey matter and other brain structural changes over time are observed amongst people diagnosed with schizophrenia. Meta-analyses of the effects of antipsychotic treatment on grey matter volume and the brain's structure have reached conflicting conclusions. A 2020 study concluded that atypical antipsychotics are linked to cortical thinning and cognitive decline{{Cite journal |last1=Feng |first1=Ruiqi |last2=Womer |first2=Fay Y. |last3=Edmiston |first3=E. Kale |last4=Chen |first4=Yifan |last5=Wang |first5=Yinshan |last6=Chang |first6=Miao |last7=Yin |first7=Zhiyang |last8=Wei |first8=Yange |last9=Duan |first9=Jia |last10=Ren |first10=Sihua |last11=Li |first11=Chao |last12=Liu |first12=Zhuang |last13=Jiang |first13=Xiaowei |last14=Wei |first14=Shengnan |last15=Li |first15=Songbai |date=2020-12-10 |title=Antipsychotic Effects on Cortical Morphology in Schizophrenia and Bipolar Disorders |journal=Frontiers in Neuroscience |volume=14 |pages=579139 |doi=10.3389/fnins.2020.579139 |doi-access=free |issn=1662-4548 |pmc=7758211 |pmid=33362453}} in the mid (20 months) to long-term. A 2012 meta-analysis concluded that grey matter loss is greater in patients treated with first generation antipsychotics relative to those treated with atypicals, and hypothesized a protective effect of atypicals as one possible explanation.{{cite journal | vauthors = Vita A, De Peri L, Deste G, Sacchetti E | title = Progressive loss of cortical gray matter in schizophrenia: a meta-analysis and meta-regression of longitudinal MRI studies | journal = Translational Psychiatry | volume = 2 | issue = 11 | pages = e190 | date = November 2012 | pmid = 23168990 | pmc = 3565772 | doi = 10.1038/tp.2012.116 }} A second 2012 meta-analysis suggested that treatment with antipsychotics was associated with increased grey matter loss.{{cite journal | vauthors = Radua J, Borgwardt S, Crescini A, Mataix-Cols D, Meyer-Lindenberg A, McGuire PK, Fusar-Poli P | title = Multimodal meta-analysis of structural and functional brain changes in first episode psychosis and the effects of antipsychotic medication | journal = Neuroscience and Biobehavioral Reviews | volume = 36 | issue = 10 | pages = 2325–33 | date = November 2012 | pmid = 22910680 | doi = 10.1016/j.neubiorev.2012.07.012 | doi-access = free }} Animal studies found that monkeys exposed to both first- and second-generation antipsychotics experience significant reduction in brain volume, resulting in an 8-11% reduction in brain volume with preserved neuron count and decreased glial cell count over a 17–27 month period.{{cite journal | vauthors = Dorph-Petersen KA, Pierri JN, Perel JM, Sun Z, Sampson AR, Lewis DA | title = The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys | journal = Neuropsychopharmacology | volume = 30 | issue = 9 | pages = 1649–1661 | date = September 2005 | pmid = 15756305 | doi = 10.1038/sj.npp.1300710 | s2cid = 205679212 | doi-access = free }}{{Cite journal |last1=Konopaske |first1=Glenn T. |last2=Dorph-Petersen |first2=Karl-Anton |last3=Pierri |first3=Joseph N. |last4=Wu |first4=Qiang |last5=Sampson |first5=Allan R. |last6=Lewis |first6=David A. |date=June 2007 |title=Effect of Chronic Exposure to Antipsychotic Medication on Cell Numbers in the Parietal Cortex of Macaque Monkeys |url=https://www.nature.com/articles/1301233 |journal=Neuropsychopharmacology |language=en |volume=32 |issue=6 |pages=1216–1223 |doi=10.1038/sj.npp.1301233 |issn=1740-634X |pmid=17063154}}

The National Association of State Mental Health Program Directors said that antipsychotics are not interchangeable, and it recommends including trying at least one weight-neutral treatment for those patients with potential metabolic issues.{{cite journal | vauthors = Parks J, Radke A, Parker G, Foti ME, Eilers R, Diamond M, Svendsen D, Tandon R | display-authors = 6 | title = Principles of antipsychotic prescribing for policy makers, circa 2008. Translating knowledge to promote individualized treatment | journal = Schizophrenia Bulletin | volume = 35 | issue = 5 | pages = 931–936 | date = September 2009 | pmid = 18385207 | pmc = 2728806 | doi = 10.1093/schbul/sbn019 }}

Subtle, long-lasting forms of akathisia are often overlooked or confused with post-psychotic depression, in particular when they lack the extrapyramidal aspect that psychiatrists have been taught to expect when looking for signs of akathisia.{{cite journal | vauthors = Hirose S | title = The causes of underdiagnosing akathisia | journal = Schizophrenia Bulletin | volume = 29 | issue = 3 | pages = 547–58 | year = 2003 | pmid = 14609248 | doi = 10.1093/oxfordjournals.schbul.a007027 | citeseerx = 10.1.1.618.3326 | df = dmy-all }}

Adverse effect on cognitive function{{cite journal | vauthors = Rehse M, Bartolovic M, Baum K, Richter D, Weisbrod M, Roesch-Ely D | title = Influence of Antipsychotic and Anticholinergic Loads on Cognitive Functions in Patients with Schizophrenia | journal = Schizophrenia Research and Treatment | volume = 2016 | pages = 8213165 | date = 2016 | pmid = 27144021 | pmc = 4842070 | doi = 10.1155/2016/8213165 | doi-access = free }}{{cite journal | vauthors = Tampi RR, Tampi DJ, Balachandran S, Srinivasan S | title = Antipsychotic use in dementia: a systematic review of benefits and risks from meta-analyses | journal = Therapeutic Advances in Chronic Disease | volume = 7 | issue = 5 | pages = 229–245 | date = September 2016 | pmid = 27583123 | pmc = 4994396 | doi = 10.1177/2040622316658463 }}{{cite journal | vauthors = MacKenzie NE, Kowalchuk C, Agarwal SM, Costa-Dookhan KA, Caravaggio F, Gerretsen P, Chintoh A, Remington GJ, Taylor VH, Müeller DJ, Graff-Guerrero A, Hahn MK | display-authors = 6 | title = Antipsychotics, Metabolic Adverse Effects, and Cognitive Function in Schizophrenia | journal = Frontiers in Psychiatry | volume = 9 | pages = 622 | date = 2018-12-05 | pmid = 30568606 | pmc = 6290646 | doi = 10.3389/fpsyt.2018.00622 | doi-access = free }} and increased risk of death in people with dementia along with worsening of symptoms has been described in the literature.{{cite journal | vauthors = Mueller C, John C, Perera G, Aarsland D, Ballard C, Stewart R | title = Antipsychotic use in dementia: the relationship between neuropsychiatric symptom profiles and adverse outcomes | journal = European Journal of Epidemiology | volume = 36 | issue = 1 | pages = 89–101 | date = January 2021 | pmid = 32415541 | pmc = 7847435 | doi = 10.1007/s10654-020-00643-2 }}{{cite journal | vauthors = Steinberg M, Lyketsos CG | title = Atypical antipsychotic use in patients with dementia: managing safety concerns | journal = The American Journal of Psychiatry | volume = 169 | issue = 9 | pages = 900–906 | date = September 2012 | pmid = 22952071 | pmc = 3516138 | doi = 10.1176/appi.ajp.2012.12030342 }}

Antipsychotics, due to acting as dopamine D₂ receptor antagonists and thereby stimulating pituitary lactotrophs, may have a risk of prolactinoma with long-term use.{{cite journal | vauthors = Durrani US, Vasireddy S, Arshad MZ, Paracha A, Paracha MA, Waheed F, Abid A, Siddiqui Z, Thomure M | title = The Effect of Antipsychotics on Prolactinoma Growth: A Radiological and Serological Analysis | journal = Cureus | volume = 15 | issue = 11 | pages = e49342 | date = November 2023 | pmid = 38143631 | pmc = 10748855 | doi = 10.7759/cureus.49342 | doi-access = free | url = }}{{cite journal | vauthors = Edinoff AN, Silverblatt NS, Vervaeke HE, Horton CC, Girma E, Kaye AD, Kaye A, Kaye JS, Garcia AJ, Neuchat EE, Eubanks TN, Varrassi G, Viswanath O, Urits I | title = Hyperprolactinemia, Clinical Considerations, and Infertility in Women on Antipsychotic Medications | journal = Psychopharmacol Bull | volume = 51 | issue = 2 | pages = 131–148 | date = March 2021 | pmid = 34092827 | pmc = 8146565 | doi = | url = }} This is also responsible for their induction of hyperprolactinemia (high prolactin levels).

{{See also|Drug withdrawal#Prescription medicine}}

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.{{cite book |editor1-first=BMJ | editor = Joint Formulary Committee | title = British National Formulary | edition = 57 | date = March 2009 |publisher=Royal Pharmaceutical Society of Great Britain |location=United Kingdom |isbn=978-0-85369-845-6 |page=192 |chapter=4.2.1 |quote=Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.}} Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.{{cite book | vauthors = Haddad P, Haddad PM, Dursun S, Deakin B |title=Adverse Syndromes and Psychiatric Drugs: A Clinical Guide |date=2004 |publisher=OUP Oxford |isbn=978-0-19-852748-0 |pages=207–216 |url=https://books.google.com/books?id=CWR7DwAAQBAJ&pg=PA207 |language=en}} Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Withdrawal symptoms can be severe and long lasting, or permanent.{{Cite journal |last=Read |first=John |date=2022-06-01 |title=The experiences of 585 people when they tried to withdraw from antipsychotic drugs |url=https://www.sciencedirect.com/science/article/pii/S2352853222000165 |journal=Addictive Behaviors Reports |volume=15 |pages=100421 |doi=10.1016/j.abrep.2022.100421 |issn=2352-8532}}

A randomised controlled trial compared maintenance therapy with gradual dose reduction or discontinuation among people with long-term psychosis. At 2 years, people in the reduction group were twice as likely to relapse (25%) as those in the maintenance group (13%). Moreover, those in the reduction group had no improvement in social functioning (a measure combining people's ability to look after themselves, work, study and take part in family and social activities), side effects, quality of life, symptoms, or bodyweight.{{Cite journal |last1=Moncrieff |first1=Joanna |last2=Crellin |first2=Nadia |last3=Stansfeld |first3=Jacki |last4=Cooper |first4=Ruth |last5=Marston |first5=Louise |last6=Freemantle |first6=Nick |last7=Lewis |first7=Glyn |last8=Hunter |first8=Rachael |last9=Johnson |first9=Sonia |last10=Barnes |first10=Thomas |last11=Morant |first11=Nicola |last12=Pinfold |first12=Vanessa |last13=Smith |first13=Ruth |last14=Kent |first14=Lyn |last15=Darton |first15=Katherine |date=1 November 2023 |title=Antipsychotic dose reduction and discontinuation versus maintenance treatment in people with schizophrenia and other recurrent psychotic disorders in England (the RADAR trial): an open, parallel-group, randomised controlled trial |url=https://doi.org/10.1016/s2215-0366(23)00258-4 |journal=The Lancet Psychiatry |volume=10 |issue=11 |pages=848–859 |doi=10.1016/s2215-0366(23)00258-4 |pmid=37778356 |issn=2215-0366}}{{Cite journal |date=23 January 2025 |title=What is the impact of a gradual reduction of antipsychotics? |url=https://evidence.nihr.ac.uk/alert/what-is-the-impact-of-a-gradual-reduction-of-antipsychotics/ |journal=NIHR Evidence}}

There is evidence that withdrawal syndrome of antipsychotics can result in psychosis.{{cite journal | vauthors = Moncrieff J | s2cid = 6267180 | title = Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse | journal = Acta Psychiatrica Scandinavica | volume = 114 | issue = 1 | pages = 3–13 | date = July 2006 | pmid = 16774655 | doi = 10.1111/j.1600-0447.2006.00787.x }} This has occurred in patients who had previously no history of psychosis, but were taking antipsychotics for another reason. Tardive dyskinesia can also occur when the medication is stopped.

Unexpected psychotic episodes have been observed in patients withdrawing from clozapine. This is referred to as supersensitivity psychosis, not to be equated with tardive dyskinesia.{{cite journal | vauthors = Nakata Y, Kanahara N, Iyo M | title = Dopamine supersensitivity psychosis in schizophrenia: Concepts and implications in clinical practice | journal = Journal of Psychopharmacology | volume = 31 | issue = 12 | pages = 1511–1518 | date = December 2017 | pmid = 28925317 | doi = 10.1177/0269881117728428 | s2cid = 1957881 }}

Tardive dyskinesia may abate during withdrawal from the antipsychotic agent, or it may persist.{{cite journal | vauthors = Glazer WM | title = Expected incidence of tardive dyskinesia associated with atypical antipsychotics | journal = The Journal of Clinical Psychiatry | volume = 61 | issue = Suppl 4 | pages = 21–6 | year = 2000 | pmid = 10739327 }}

Withdrawal effects may also occur when switching a person from one antipsychotic to another, (it is presumed due to variations of potency and receptor activity). Such withdrawal effects can include cholinergic rebound, an activation syndrome, and motor syndromes including dyskinesias. These adverse effects are more likely during rapid changes between antipsychotic agents, so making a gradual change between antipsychotics minimises these withdrawal effects.{{cite journal | vauthors = Lambert TJ | title = Switching antipsychotic therapy: what to expect and clinical strategies for improving therapeutic outcomes | journal = The Journal of Clinical Psychiatry | volume = 68 | issue = Suppl 6 | pages = 10–3 | year = 2007 | pmid = 17650054 }} The British National Formulary recommends a gradual dose reduction when discontinuing antipsychotic treatment to avoid acute withdrawal symptoms or rapid relapse.{{cite book | author = BMJ Group | title=British National Formulary |edition=57|date=March 2009 |publisher=Royal Pharmaceutical Society of Great Britain |location=United Kingdom |page=192 |chapter=4.2.1|quote=Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.}} The process of cross-titration involves gradually increasing the dose of the new medication while gradually decreasing the dose of the old medication.

City and Hackney Clinical Commissioning Group found more than 1,000 patients in their area in July 2019 who had not had regular medication reviews or health checks because they were not registered as having serious mental illness. On average they had been taking these drugs for six years. If this is typical of practice in England more than 100,000 patients are probably in the same position.{{cite news |title=Up to 100,000 on antipsychotics with no review |url=https://www.hsj.co.uk/mental-health/exclusive-up-to-100000-on-antipsychotics-with-no-review/7026726.article |access-date=22 March 2020 |publisher=Health Service Journal |date=27 January 2020}}

File:Chlorpromazine.svg

File:Haloperidol.svg

File:Quetiapine.svg

Clinically used antipsychotic medications are listed below by drug group. Trade names appear in parentheses. A 2013 review has stated that the division of antipsychotics into first and second generation is perhaps not accurate.

Notes:

† indicates drugs that are no longer (or were never) marketed in English-speaking countries.

‡ denotes drugs that are no longer (or were never to begin with) marketed in the United States. Some antipsychotics are not firmly placed in either first-generation or second-generation classes.

# denotes drugs that have been withdrawn worldwide.

{{Main|Typical antipsychotic}}

{{Main|Butyrophenones}}

• Benperidol^‡
• Bromperidol^†
• Droperidol^‡
• Haloperidol (Haldol)
• Moperone (discontinued)^†
• Pipamperone (discontinued)^†
• Timiperone ^†

• Fluspirilene ‡
• Penfluridol ‡
• Pimozide

{{Main|Phenothiazines}}

• Acepromazine ^† — although it is mostly used in veterinary medicine.
• Chlorpromazine (Thorazine)
• Cyamemazine ^†
• Dixyrazine ^†
• Fluphenazine
• Levomepromazine^‡
• Mesoridazine (discontinued)^†
• Perazine
• Pericyazine^‡
• Perphenazine
• Pipotiazine ^‡
• Prochlorperazine
• Promazine (discontinued)
• Promethazine
• Prothipendyl ^†
• Thioproperazine^‡ (only English-speaking country it is available in is Canada)
• Thioridazine (discontinued)
• Trifluoperazine
• Triflupromazine (discontinued)^†

{{Main|Thioxanthenes}}

• Chlorprothixene ^†
• Clopenthixol
• Flupentixol ^‡
• Thiothixene
• Zuclopenthixol ^‡

This category is for drugs that have been called both first and second-generation, depending on the literature being used.

• Sulpiride ^‡
• Sultopride ^†
• Veralipride ^†

• Carpipramine ^†
• Clocapramine ^†
• Clorotepine ^†
• Clotiapine ^‡
• Loxapine
• Mosapramine ^†

• Molindone ^#

{{Main|Atypical antipsychotic}}

• Amisulpride (Socian) ^‡ – Selective dopamine antagonist. Higher doses (greater than 400 mg) act upon post-synaptic dopamine receptors resulting in a reduction in the positive symptoms of schizophrenia, such as psychosis. Lower doses, however, act upon dopamine autoreceptors, resulting in increased dopamine transmission, improving the negative symptoms of schizophrenia. Lower doses of amisulpride have also been shown to have antidepressant and anxiolytic effects in non-schizophrenic patients, leading to its use in dysthymia and social phobias.
• Nemonapride ^† – Used in Japan.
• Remoxipride ^# – Has a risk of causing aplastic anaemia and, hence, has been withdrawn from the market worldwide. It has also been found to possess relatively low (virtually absent) potential to induce hyperprolactinaemia and extrapyramidal symptoms, likely attributable to its comparatively weak binding to (and, hence, rapid dissociation from) the D₂ receptor.{{cite journal | vauthors = Seeman P |title=Atypical Antipsychotics: Mechanism of Action |journal=Focus |date=January 2004 |volume=2 |issue=1 |pages=48–58 |doi=10.1176/foc.2.1.48 |url=https://focus.psychiatryonline.org/doi/full/10.1176/foc.2.1.48 |url-access=subscription }}
• Sultopride – An atypical antipsychotic of the benzamide chemical class used in Europe, Japan, and Hong Kong for the treatment of schizophrenia. It was launched by Sanofi-Aventis in 1976. Sultopride acts as a selective D2 and D3 receptor antagonist.

• Iloperidone (Fanapt) – Approved by the US FDA in 2009, it is fairly well tolerated, although hypotension, dizziness, and somnolence were very common side effects. Has not received regulatory approval in other countries, however.
• Paliperidone (Invega) – Primary, active metabolite of risperidone that was approved in 2006.
• Perospirone ^† – Has a higher incidence of extrapyramidal side effects than other atypical antipsychotics.{{cite journal | vauthors = Onrust SV, McClellan K | title = Perospirone | journal = CNS Drugs | volume = 15 | issue = 4 | pages = 329–37; discussion 338 | year = 2001 | pmid = 11463136 | doi = 10.2165/00023210-200115040-00006 | s2cid = 262520276 }}
• Risperidone (Risperdal) – Divided dosing is recommended until initial titration is completed, at which time the drug can be administered once daily. Used off-label to treat Tourette syndrome and anxiety disorder.
• Ziprasidone (Geodon) – Approved in 2004{{cite journal | vauthors = Nemeroff CB, Lieberman JA, Weiden PJ, Harvey PD, Newcomer JW, Schatzberg AF, Kilts CD, Daniel DG | title = From clinical research to clinical practice: a 4-year review of ziprasidone | journal = CNS Spectrums | volume = 10 | issue = 11 Suppl 17 | pages = 1–20 | date = November 2005 | pmid = 16381088 | doi = 10.1017/S1092852900019842 | s2cid = 26738197 }} to treat bipolar disorder. Side-effects include a prolonged QT interval in the heart, which can be dangerous for patients with heart disease or those taking other drugs that prolong the QT interval.
• Lurasidone (Latuda) – Approved by the US FDA for schizophrenia and bipolar depression, and for use as schizophrenia treatment in Canada.

• Melperone ^† – Only used in a few European countries. No English-speaking country has licensed it to date.
• Lumateperone (Caplyta)

• Asenapine (Saphris) – Of the dibenzo-oxepino pyrrole class of atypical antipsychotics. Used for the treatment of schizophrenia and acute mania associated with bipolar disorder.
• Clozapine (Clozaril) – Of the dibenzodiazepine class of atypical antipsychotics. Requires routine laboratory monitoring of complete blood counts every one to four weeks due to the risk of agranulocytosis. It has unparalleled efficacy in the treatment of treatment-resistant schizophrenia.
• Olanzapine (Zyprexa) – Of the theienobenzodiazepine class of atypical antipsychotics. Used to treat psychotic disorders including schizophrenia, acute manic episodes, and maintenance of bipolar disorder. Used as an adjunct to antidepressant therapy, either alone or in combination with fluoxetine as Symbyax.
• Quetiapine (Seroquel) – Of the dibenzothiazepine class of atypical antipsychotics. Used primarily to treat bipolar disorder and schizophrenia. Also used and licensed in a few countries (including Australia, the United Kingdom and the United States) as an adjunct to antidepressant therapy in patients with major depressive disorder. It's the only antipsychotic that's demonstrated efficacy as a monotherapy for the treatment of major depressive disorder and bipolar disorder (it treats mixed mood swings alone). It indirectly serves as a norepinephrine reuptake inhibitor by means of its active metabolite, norquetiapine.
• Zotepine – Of the dibenzothiepin class of atypical antipsychotic indicated for acute and chronic schizophrenia. It is still used in Japan and was once used in Germany but it was discontinued.^†

• Blonanserin – Approved by the PMDA in 2008. Used in Japan and South Korea.
• Pimavanserin – A selective 5-HT_2A receptor antagonist approved for the treatment of Parkinson's disease psychosis in 2016.
• Sertindole ^‡ – Developed by the Danish pharmaceutical company H. Lundbeck. Like the other atypical antipsychotics, it is believed to have antagonist activity at dopamine and serotonin receptors in the brain.

Third generation antipsychotics are recognized as demonstrating D₂ receptor partial agonism{{cite journal |last=Winans |first=Elizabeth |date=2003-12-01 |title=Aripiprazole |url=https://academic.oup.com/ajhp/article/60/23/2437/5143288 |journal=American Journal of Health-System Pharmacy |language=en |volume=60 |issue=23 |pages=2437–2445 |doi=10.1093/ajhp/60.23.2437 |pmid=14686220 |issn=1079-2082}} as opposed to the D₂ and 5HT-_2A receptor antagonism of second-generation (atypical) antipsychotics and D2 antagonism of first-generation (typical) antipsychotics.{{cite journal |vauthors=Mailman RB, Murthy V |date=2010 |title=Third generation antipsychotic drugs: partial agonism or receptor functional selectivity? |journal=Current Pharmaceutical Design |volume=16 |issue=5 |pages=488–501 |doi=10.2174/138161210790361461 |pmc=2958217 |pmid=19909227}}

• Lumateperone (Caplyta) – In December 2019, lumateperone, a presynaptic D₂ receptor partial agonist and postsynaptic D₂ receptor antagonist, received its first global approval in the US for the treatment of schizophrenia in adults.{{cite web |title=Caplyta (lumateperone) FDA Approval History |url=https://www.drugs.com/history/caplyta.html |access-date=2022-11-20 |website=Drugs.com |language=en}} In 2020 and 2021 FDA approved for depressive episodes associated with bipolar I or II disorder in adults, as monotherapy and as adjunctive therapy with lithium or valproate.

• Aripiprazole (Abilify) - Partial agonist at the D₂ receptor. Considered the prototypical third-generation antipsychotic.{{cite journal |vauthors=Swainston Harrison T, Perry CM |year=2004 |title=Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder |journal=Drugs |volume=64 |issue=15 |pages=1715–36 |doi=10.2165/00003495-200464150-00010 |pmid=15257633}}
• Aripiprazole lauroxil (Abilify Maintena) – Long-acting version of aripiprazole for injection.
• Brexpiprazole (Rexulti) – Partial agonist of the D₂ receptor. Successor of aripiprazole.
• Brilaroxazine – A D_2/3/4 and 5-HT_1A partial agonist and 5-HT_2A/2B/7 antagonist
• Cariprazine (Vraylar, Reagila) – A D₃-preferring D_2/3 partial agonist.

• Xanomeline/trospium chloride (Cobenfy) - A fixed-dose combination of xanomeline and trospium chloride. Xanomeline is a functionally selective muscarinic M₄ and M₁ receptor agonist. Trospium chloride is a peripherally-acting non-selective muscarinic antagonist.{{cite web | title=Cobenfy- xanomeline and trospium chloride capsule, coated pellets; Cobenfy- xanomeline and trospium chloride kit | website=DailyMed | date=30 September 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8f0e73bf-6025-44f6-ab64-0983322de0df | access-date=12 March 2025}} Xanomeline/trospium chloride was approved for medical use in the United States in September 2024.

Antipsychotic drugs such as haloperidol and chlorpromazine tend to block dopamine D₂ receptors in the dopaminergic pathways of the brain. This means that dopamine released in these pathways has less effect. Excess release of dopamine in the mesolimbic pathway has been linked to psychotic experiences. Decreased dopamine release in the prefrontal cortex, and excess dopamine release in other pathways, are associated with psychotic episodes in schizophrenia and bipolar disorder.{{cite journal | vauthors = Pickar D, Litman RE, Konicki PE, Wolkowitz OM, Breier A | title = Neurochemical and Neural Mechanisms of Positive and Negative Symptoms in Schizophrenia | journal = Modern Problems of Pharmacopsychiatry | volume = 24 | pages = 124–151 | year = 1990 | pmid = 1970851 | doi = 10.1159/000418015 | isbn = 978-3-8055-5050-5 | series = Modern Trends in Pharmacopsychiatry }}{{cite journal | vauthors = Liemburg EJ, Knegtering H, Klein HC, Kortekaas R, Aleman A | title = Antipsychotic medication and prefrontal cortex activation: a review of neuroimaging findings | journal = European Neuropsychopharmacology | volume = 22 | issue = 6 | pages = 387–400 | date = June 2012 | pmid = 22300864 | doi = 10.1016/j.euroneuro.2011.12.008 | s2cid = 24877454 }}

In addition to the antagonistic effects of dopamine, antipsychotics (in particular atypical antipsychotics) also antagonize 5-HT_2A receptors. Different alleles of the 5-HT_2A receptor have been associated with schizophrenia and other psychoses, including depression.{{cite journal | vauthors = McDonald C, Murphy KC | title = The new genetics of schizophrenia | journal = The Psychiatric Clinics of North America | volume = 26 | issue = 1 | pages = 41–63 | date = March 2003 | pmid = 12683259 | doi = 10.1016/S0193-953X(02)00030-8 }}{{cite journal | vauthors = Schmidt CJ, Sorensen SM, Kehne JH, Carr AA, Palfreyman MG | title = The role of 5-HT2A receptors in antipsychotic activity | journal = Life Sciences | volume = 56 | issue = 25 | pages = 2209–22 | year = 1995 | pmid = 7791509 | doi = 10.1016/0024-3205(95)00210-W }} Higher concentrations of 5-HT_2A receptors in cortical and subcortical areas, in particular in the right caudate nucleus have been historically recorded.

Typical antipsychotics are not particularly selective and also block dopamine receptors in the mesocortical pathway, tuberoinfundibular pathway, and the nigrostriatal pathway. Blocking D₂ receptors in these other pathways is thought to produce some unwanted side effects that the typical antipsychotics can produce (see above). They were commonly classified on a spectrum of low potency to high potency, where potency referred to the ability of the drug to bind to dopamine receptors, and not to the effectiveness of the drug. High-potency antipsychotics such as haloperidol, in general, have doses of a few milligrams and cause less sleepiness and calming effects than low-potency antipsychotics such as chlorpromazine and thioridazine, which have dosages of several hundred milligrams. The latter have a greater degree of anticholinergic and antihistaminergic activity, which can counteract dopamine-related side-effects.{{cite journal | vauthors = Tiwari P, Panik R, Bhattacharya A, Ahirwar D, Chandy A |date=December 2012 |title=Evidences of possible side effects of neuroleptic drugs: A systematic review |journal=Asian Pacific Journal of Reproduction |volume=1 |issue=4 |pages=330–336 |doi=10.1016/s2305-0500(13)60105-0 |issn=2305-0500|doi-access=free }}

Atypical antipsychotic drugs have a similar blocking effect on D₂ receptors; however, most also act on serotonin receptors, especially 5-HT_2A and 5-HT_2C receptors. Both clozapine and quetiapine appear to bind just long enough to elicit antipsychotic effects but not long enough to induce extrapyramidal side effects and prolactin hypersecretion.{{cite journal | vauthors = Stahl SM |title=Describing an Atypical Antipsychotic: Receptor Binding and Its Role in Pathophysiology |journal=Primary Care Companion to the Journal of Clinical Psychiatry |year=2003 |volume=5 |issue=Suppl. 3 |pages=9–13 |url=https://www.psychiatrist.com/wp-content/uploads/2021/02/24453_describing-atypical-antipsychotic-receptor-binding.pdf |archive-url=https://ghostarchive.org/archive/20221009/https://www.psychiatrist.com/wp-content/uploads/2021/02/24453_describing-atypical-antipsychotic-receptor-binding.pdf |archive-date=2022-10-09 |url-status=live }} 5-HT_2A antagonism increases dopaminergic activity in the nigrostriatal pathway, leading to a lowered extrapyramidal side effect liability among the atypical antipsychotics.{{cite book | vauthors = Meltzer HY | title = Current Antipsychotics | chapter = Serotonergic Mechanisms as Targets for Existing and Novel Antipsychotics | volume = 212 | issue = 212 | pages = 87–124 | year = 2012 | pmid = 23129329 | doi = 10.1007/978-3-642-25761-2_4 | isbn = 978-3-642-25760-5 | series = Handbook of Experimental Pharmacology }}

Xanomeline/trospium chloride was approved for medical use in the United States in September 2024. It was the first antipsychotic to not act on D₂ receptors. The mechanism of action instead relies on xanomeline's functional selectivity for the M1 and M4 muscarinic receptors, with trospium chloride, a peripherally selective antimuscarinic added to counteract xanomeline's unwanted peripheral muscarinic effects.{{cite press release | title=FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia | website=U.S. Food and Drug Administration (FDA) | date=26 September 2024 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia | access-date=27 September 2024 | archive-date=27 September 2024 | archive-url=https://web.archive.org/web/20240927004824/https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia | url-status=dead }} {{PD-notice}}{{cite press release | title=U.S. Food and Drug Administration Approves Bristol Myers Squibb's Cobenfy (xanomeline and trospium chloride), a First-In-Class Muscarinic Agonist for the Treatment of Schizophrenia in Adults | publisher=Bristol Myers Squibb | via=Business Wire | date=27 September 2024 | url=https://www.businesswire.com/news/home/20240925382351/en/U.S.-Food-and-Drug-Administration-Approves-Bristol-Myers-Squibb%E2%80%99s-COBENFY%E2%84%A2-xanomeline-and-trospium-chloride-a-First-In-Class-Muscarinic-Agonist-for-the-Treatment-of-Schizophrenia-in-Adults | access-date=27 September 2024}}

Through the ability of most antipsychotics to antagonize 5-HT_2A serotonin pathways enabling a sensitisation of postsynaptic serotonin receptors, MDMA exposure can be more intense because it has more excitatory receptors to activate. The same effect can be observed with the D₂ antagonizing with normal amphetamine (with this just being hypothetical as there is the fact that antipsychotics sensitize receptors,{{cite journal | vauthors = Li M | title = Antipsychotic-induced sensitization and tolerance: Behavioral characteristics, developmental impacts, and neurobiological mechanisms | journal = Journal of Psychopharmacology | volume = 30 | issue = 8 | pages = 749–770 | date = August 2016 | pmid = 27371498 | pmc = 4944179 | doi = 10.1177/0269881116654697 }} with exact these postsynaptic receptors (5-HT_2A, D₂) being flooded by the respective neurotransmitter (serotonin, dopamine) from amphetamine exposure).{{cite journal | vauthors = Nawaratne V, McLaughlin SP, Mayer FP, Gichi Z, Mastriano A, Carvelli L | title = Prolonged Amphetamine Exposures Increase the Endogenous Human Dopamine Receptors 2 at the Cellular Membrane in Cells Lacking the Dopamine Transporter | journal = Frontiers in Cellular Neuroscience | volume = 15 | pages = 681539 | year = 2021 | pmid = 34512264 | pmc = 8427050 | doi = 10.3389/fncel.2021.681539 | doi-access = free }}{{cite journal | vauthors = Orejarena MJ, Lanfumey L, Maldonado R, Robledo P | title = Involvement of 5-HT2A receptors in MDMA reinforcement and cue-induced reinstatement of MDMA-seeking behaviour | journal = The International Journal of Neuropsychopharmacology | volume = 14 | issue = 7 | pages = 927–940 | date = August 2011 | pmid = 20942998 | doi = 10.1017/S1461145710001215 | doi-access = free | hdl = 10230/25548 | hdl-access = free }}

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{{Pharmacokinetics of long-acting injectable antipsychotics}}

File:Timeline of the development of antipsychotic drugs, OWID.png

File:Thorazine advert.jpg) from the 1950s, reflecting the perceptions of psychosis, including the now-discredited perception of a tendency towards violence, from the time when antipsychotics were discoveredThe text reads: "When the patient lashes out against 'them' – THORAZINE (brand of chlorpromazine) quickly puts an end to his violent outburst. 'Thorazine' is especially effective when the psychotic episode is triggered by delusions or hallucinations. At the outset of treatment, Thorazine's combination of antipsychotic and sedative effects provides both emotional and physical calming. Assaultive or destructive behavior is rapidly controlled. As therapy continues, the initial sedative effect gradually disappears. But the antipsychotic effect continues, helping to dispel or modify delusions, hallucinations and confusion, while keeping the patient calm and approachable. SMITH KLINE AND FRENCH LABORATORIES leaders in psychopharmaceutical research."]]

The original antipsychotic drugs were happened upon largely by chance and then tested for their effectiveness. The first, chlorpromazine, was developed as a surgical anesthetic. It was first used on psychiatric patients because of its powerful calming effect; at the time it was regarded as a non-permanent "pharmacological lobotomy".{{cite journal | vauthors = Pieters T, Majerus B | title = The introduction of chlorpromazine in Belgium and the Netherlands (1951–1968); tango between old and new treatment features | journal = Studies in History and Philosophy of Biological and Biomedical Sciences | volume = 42 | issue = 4 | pages = 443–452 | date = December 2011 | pmid = 22035718 | doi = 10.1016/j.shpsc.2011.05.003 | url = http://orbilu.uni.lu/handle/10993/2251 | access-date = 26 February 2017 | archive-date = 9 July 2017 | archive-url = https://web.archive.org/web/20170709194021/http://orbilu.uni.lu/handle/10993/2251 | url-status = dead }} Lobotomy at the time was used to treat many behavioral disorders, including psychosis, although its effect was to markedly reduce behavior and mental functioning of all types. However, chlorpromazine proved to reduce the effects of psychosis in a more effective and specific manner than lobotomy, even though it was known to be capable of causing severe sedation. The underlying neurochemistry involved has since been studied in detail, and subsequent antipsychotic drugs have been developed by rational drug design.

The discovery of chlorpromazine's psychoactive effects in 1952 led to further research that resulted in the development of antidepressants, anxiolytics, and the majority of other drugs now used in the management of psychiatric conditions. In 1952, Henri Laborit described chlorpromazine only as inducing indifference towards what was happening around them in nonpsychotic, nonmanic patients, and Jean Delay and Pierre Deniker described it as controlling manic or psychotic agitation. The former claimed to have discovered a treatment for agitation in anyone, and the latter team claimed to have discovered a treatment for psychotic illness.{{cite book | vauthors = Healy D | date = 2005 | title = Psychiatric Drugs Explained. | edition = 4th | location = Britain | publisher = Elsevier Limited | pages = 8, 17 }}

Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs.{{cite journal | vauthors = King C, Voruganti LN | title = What's in a name? The evolution of the nomenclature of antipsychotic drugs | journal = Journal of Psychiatry & Neuroscience | volume = 27 | issue = 3 | pages = 168–175 | date = May 2002 | pmid = 12066446 | pmc = 161646 }} In the late 1950s the most widely used term was "neuroleptic", followed by "major tranquilizer" and then "ataraxic". The first recorded use of the term tranquilizer dates from the early nineteenth century.{{cite web| title = tranquillizer, n| work = Oxford English Dictionary| access-date = 9 August 2011| year = 1989| url =http://www.oed.com/view/Entry/204569}} In 1953 Frederik F. Yonkman, a chemist at the Swiss-based Cibapharmaceutical company, first used the term tranquilizer to differentiate reserpine from the older sedatives.{{cite book | vauthors = Healy D |chapter=The Intersection of Psychopharmacology and Psychiatry in the Second Half of the Twentieth Century |title=History of Psychiatry and Medical Psychology|year=2008|publisher=Springer US|location=Boston, MA|isbn=978-0-387-34707-3| veditors = Wallace ER, Gach J |page=421|doi=10.1007/978-0-387-34708-0_13}} The word neuroleptic was coined in 1955 by Delay and Deniker after their discovery (1952) of the antipsychotic effects of chlorpromazine. It is derived from the {{langx|el|"νεῦρον"}} (neuron, originally meaning "sinew" but today referring to the nerves) and "λαμβάνω" (lambanō, meaning "take hold of"). Thus, the word means taking hold of one's nerves. It was often taken to refer also to common side effects such as reduced activity in general, as well as lethargy and impaired motor control. Although these effects are unpleasant and in some cases harmful, they were at one time, along with akathisia, considered a reliable sign that the drug was working. The term "ataraxy" was coined by the neurologist Howard Fabing and the classicist Alister Cameron to describe the observed effect of psychic indifference and detachment in patients treated with chlorpromazine.{{cite book| publisher = Cambridge University Press| isbn = 978-0-521-63353-6| vauthors = Owens DG | title = A guide to the extrapyramidal side-effects of antipsychotic drugs| date = 13 April 1999| url = https://books.google.com/books?id=RwRSahg71GkC&pg=PA12| page = 12|url-status = live| archive-url = https://web.archive.org/web/20160318004651/https://books.google.com/books?id=RwRSahg71GkC&pg=PA12| archive-date = 18 March 2016| df = dmy-all}} This term derived from the Greek adjective "ἀτάρακτος" (ataraktos), which means "not disturbed, not excited, without confusion, steady, calm". In the use of the terms "tranquilizer" and "ataractic", medical practitioners distinguished between the "major tranquilizers" or "major ataractics", which referred to drugs used to treat psychoses, and the "minor tranquilizers" or "minor ataractics", which referred to drugs used to treat neuroses. While popular during the 1950s, these terms are infrequently used today. They are being abandoned in favor of "antipsychotic", which refers to the drug's desired effects. Today, "minor tranquilizer" can refer to anxiolytic and/or hypnotic drugs such as the benzodiazepines and nonbenzodiazepines, which are useful as generally short-term management for insomnia together with cognitive behavioral therapy for insomnia.{{cite journal | vauthors = Wilson S, Anderson K, Baldwin D, Dijk DJ, Espie A, Espie C, Gringras P, Krystal A, Nutt D, Selsick H, Sharpley A | display-authors = 6 | title = British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders: An update | journal = Journal of Psychopharmacology | volume = 33 | issue = 8 | pages = 923–947 | date = August 2019 | pmid = 31271339 | doi = 10.1177/0269881119855343 | s2cid = 195797603 | url = https://eprints.soton.ac.uk/433092/1/BAP_sleep_consensus_update_DSB_19032019.docx }}{{cite book | publisher = Saunders| isbn = 978-0-7216-5257-3 | vauthors = Tasman A | title = Psychiatry Volume 2| page = 956| year = 1997}} They are potentially addictive sedatives.

Antipsychotics are broadly divided into two groups, the typical or first-generation antipsychotics and the atypical or second-generation antipsychotics. The difference between first- and second-generation antipsychotics is a subject of debate. The second-generation antipsychotics are generally distinguishable by the presence of 5HT2A receptor antagonism and a corresponding lower propensity for extrapyramidal side effects compared to first-generation antipsychotics.

The term major tranquilizer was used for older antipsychotic drugs. The term neuroleptic is often used as a synonym for antipsychotic, even though – strictly speaking – the two terms are not interchangeable. Antipsychotic drugs are a subgroup of neuroleptic drugs, because the latter have a wider range of effects.{{cite book|chapter-url=https://books.google.com/books?id=ea_QVG2BFy8C&pg=PA675|title=Lexicon of Psychiatry, Neurology, and the Neurosciences| vauthors = Ayd FJ |date=2000|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-2468-5|page=675|language=en|chapter=neuroleptic}}R. Elliott Ingersoll, Carl F. Rak (2015): Psychopharmacology for Mental Health Professionals: An Integrative Approach, Cengage Learning, Boston, pp. 150-186 and 342-349, {{ISBN|9781305537231}}.

Antipsychotics are a type of psychoactive or psychotropic medication.{{cite book| vauthors = Patel SC, Jakopac KA |title=Manual of Psychiatric Nursing Skills|date=2011|publisher=Jones & Bartlett Publishers|isbn=978-1-4496-1356-3|page=317|url=https://books.google.com/books?id=fN9932sGu1kC|language=en}}{{cite book|title=Drug Policy and the Public Good|date=2010|publisher=OUP Oxford|isbn=978-0-19-955712-7|page=329|url=https://books.google.com/books?id=Byur1yIJBaUC&pg=PA329|language=en}}

Antipsychotics were once among the biggest selling and most profitable of all drugs, generating $22 billion in global sales in 2008.[https://web.archive.org/web/20120218005726/http://www.healthcarefinancenews.com/press-release/pipeline-antipsychotic-drugs-drive-next-market-evolution Pipelineantipsychotic drugs to drive next market evolution (2009)]. Healthcarefinancenews.com (7 August 2009). By 2003 in the US, an estimated 3.21 million patients received antipsychotics, worth an estimated $2.82 billion. Over 2/3 of prescriptions were for the newer, more expensive atypicals, each costing on average $164 per year, compared to $40 for the older types.{{cite journal | vauthors = Aparasu RR, Bhatara V | title = Antipsychotic use and expenditure in the United States | journal = Psychiatric Services | volume = 57 | issue = 12 | pages = 1693 | date = December 2006 | pmid = 17158480 | doi = 10.1176/appi.ps.57.12.1693 }} By 2008, sales in the US reached $14.6 billion, the biggest selling drugs in the US by therapeutic class.[http://www.imshealth.com/portal/site/imshealth/menuitem.a46c6d4df3db4b3d88f611019418c22a/?vgnextoid=85f4a56216a10210VgnVCM100000ed152ca2RCRD&cpsextcurrchannel=1 2008 U.S. Sales and Prescription Information: Top Therapeutic Classes by U.S. Sales (PDF)] {{webarchive|url=https://web.archive.org/web/20100416162222/http://www.imshealth.com/portal/site/imshealth/menuitem.a46c6d4df3db4b3d88f611019418c22a/?vgnextoid=85f4a56216a10210VgnVCM100000ed152ca2RCRD&cpsextcurrchannel=1 |date=16 April 2010 }}. Imshealth.com.

In the five years since July 2017 the number of antipsychotic medicines dispensed in the community in the United Kingdom has increased by 11.2%. There have also been substantial price rises. Risperidone 6 mg tablets, the largest, increased from £3.09 in July 2017 to £41.16 in June 2022. The NHS is spending an additional £33 million annually on antipsychotics. Haloperidol 500 microgram tablets constituted £14.3 million of this.{{cite news |title=Data show 'spiralling' antipsychotic price increases of up to 1,200% in past five years |url=https://pharmaceutical-journal.com/article/news/data-show-spiralling-antipsychotic-price-increases-of-up-to-1200-in-past-five-years |access-date=29 September 2022 |publisher=Pharmaceutical Journal |date=24 August 2022}}

Antipsychotics in the nursing home population are often overprescribed, often for the purposes of making it easier to handle dementia patients. Federal efforts to reduce the use of antipsychotics in US nursing homes has led to a nationwide decrease in their usage in 2012.{{cite journal | vauthors = Gustafsson M, Karlsson S, Lövheim H | title = Inappropriate long-term use of antipsychotic drugs is common among people with dementia living in specialized care units | journal = BMC Pharmacology & Toxicology | volume = 14 | issue = 1 | pages = 10 | date = February 2013 | pmid = 23391323 | pmc = 3575309 | doi = 10.1186/2050-6511-14-10 | doi-access = free }}Risky Antipsychotic Drugs Still Overprescribed In Nursing Homes, https://www.npr.org/sections/health-shots/2018/02/05/583435517/risky-antipsychotic-drugs-still-overprescribed-in-nursing-homesAtypical antipsychotics: overrated and overprescribed, Glen Spielsman, https://pharmaceutical-journal.com/article/opinion/atypical-antipsychotics-overrated-and-overprescribed

Antipsychotics are sometimes administered as part of compulsory psychiatric treatment via inpatient (hospital) commitment or outpatient commitment.

They may be administered orally or, in some cases, through long-acting (depot) injections administered in the dorsgluteal, ventrogluteal or deltoid muscle. Short-acting parenteral formulations also exist, which are generally reserved for emergencies or when oral administration is otherwise impossible. The oral formulations include immediate release, extended release, and orally disintegrating products (which are not sublingual, and can help ensure that medications are swallowed instead of "cheeked"). Sublingual products (e.g., asenapine) also exist, which must be held under the tongue for absorption. The first transdermal formulation of an antipsychotic (transdermal asenapine, marketed as Secuado), was FDA-approved in 2019.{{cite journal | vauthors = Carrithers B, El-Mallakh RS | title = Transdermal Asenapine in Schizophrenia: A Systematic Review | journal = Patient Preference and Adherence | volume = 14 | pages = 1541–1551 | date = 18 March 2020 | pmid = 32943849 | pmc = 7468370 | doi = 10.2147/PPA.S235104 | doi-access = free }}

{{Main|Antipsychotics abuse}}

Certain second-generation antipsychotics are misused or abused for their sedative, tranquilizing, and (paradoxically) "hallucinogenic" effects.{{cite journal | vauthors = Bogart G |title=Abuse of second-generation antipsychotics: What prescribers need to know |journal=Current Psychiatry |date=2011 |volume=10 |issue=5 |pages=77–79 |url=https://www.mdedge.com/psychiatry/article/64323/addiction-medicine/abuse-second-generation-antipsychotics-what-prescribers}} The most commonly implicated second-generation antipsychotic is quetiapine. In case reports, quetiapine has been abused in doses taken by mouth (which is how the drug is available from the manufacturer), but also crushed and insufflated or mixed with water for injection into a vein. Olanzapine, another sedating second-generation antipsychotic, has also been misused for similar reasons. There is no standard treatment for antipsychotic abuse, though switching to a second-generation antipsychotic with less abuse potential (e.g., aripiprazole) has been used.

Joanna Moncrieff has argued that antipsychotic drug treatment is often undertaken as a means of control rather than to treat specific symptoms experienced by the patient.{{cite news | vauthors = James A |title=Myth of the antipsychotic |url=https://www.theguardian.com/commentisfree/2008/mar/02/mythoftheantipsychotic |work=The Guardian |date=2 March 2008 }}

Use of this class of drugs has a history of criticism in residential care. As the drugs used can make patients calmer and more compliant, critics claim that the drugs can be overused. Outside doctors can feel under pressure from care home staff.{{cite web |title=GPs under 'pressure' to issue neuroleptics, claims professor |url=https://www.chemistanddruggist.co.uk/cpd-article/gps-under-pressure-issue-neuroleptics-claims-professor |website=Chemist+Druggist |access-date=1 May 2020 |archive-date=20 October 2020 |archive-url=https://web.archive.org/web/20201020094759/https://www.chemistanddruggist.co.uk/cpd-article/gps-under-pressure-issue-neuroleptics-claims-professor |url-status=dead }}{{unreliable source?|date=May 2020}} In an official review commissioned by UK government ministers it was reported that the needless use of antipsychotic medication in dementia care was widespread and was linked to 1800 deaths per year.{{cite news | vauthors = Triggle N |title=Dementia drug use 'killing many' |url=http://news.bbc.co.uk/2/hi/health/8356423.stm |date=12 November 2009 }}{{cite news |title=UK study warns against anti-psychotics for dementia |url=https://www.reuters.com/article/dementia-drugs/uk-study-warns-against-anti-psychotics-for-dementia-idUSLC44347420091112 |work=Reuters |date=12 November 2009 }} In the US, the government has initiated legal action against the pharmaceutical company Johnson & Johnson for allegedly paying kickbacks to Omnicare to promote its antipsychotic risperidone (Risperdal) in nursing homes.{{cite news | vauthors = Hilzenrath DS |title=Justice suit accuses Johnson & Johnson of paying kickbacks |url=https://www.washingtonpost.com/wp-dyn/content/article/2010/01/15/AR2010011503903.html |newspaper=The Washington Post |date=16 January 2010 }}

There has also been controversy about the role of pharmaceutical companies in marketing and promoting antipsychotics, including allegations of downplaying or covering up adverse effects, expanding the number of conditions or illegally promoting off-label usage; influencing drug trials (or their publication) to try to show that the expensive and profitable newer atypicals were superior to the older cheaper typicals that were out of patent. Following charges of illegal marketing, settlements by two large pharmaceutical companies in the US set records for the largest criminal fines ever imposed on corporations.{{cite news | vauthors = Wilson D |title=Side Effects May Include Lawsuits |url=https://www.nytimes.com/2010/10/03/business/03psych.html |archive-url=https://web.archive.org/web/20101005023740/http://www.nytimes.com/2010/10/03/business/03psych.html |archive-date=2010-10-05 |url-access=limited |work=The New York Times |date=2 October 2010 }} One case involved Eli Lilly and Company's antipsychotic Zyprexa, and the other involved Bextra. In the Bextra case, the government also charged Pfizer with illegally marketing another antipsychotic, Geodon. In addition, AstraZeneca faces numerous personal-injury lawsuits from former users of Seroquel (quetiapine), amidst federal{{clarify|date=January 2022}} investigations of its marketing practices.{{cite news | vauthors = Wilson D |title=Drug Maker's E-Mail Released in Seroquel Lawsuit |url=https://www.nytimes.com/2009/02/28/business/28drug.html |work=The New York Times |date=27 February 2009 }} By expanding the conditions for which they were indicated, Astrazeneca's Seroquel and Eli Lilly's Zyprexa had become the biggest selling antipsychotics in 2008 with global sales of $5.5 billion and $5.4 billion respectively.

Harvard University medical professor Joseph Biederman conducted research on bipolar disorder in children that led to an increase in such diagnoses. A 2008 Senate{{which|date=January 2022}} investigation found that Biederman also received $1.6 million in speaking and consulting fees between 2000 and 2007, some of them undisclosed to Harvard, from companies including makers of antipsychotic drugs prescribed for children with bipolar disorder. Johnson & Johnson gave more than $700,000 to a research center that was headed by Biederman from 2002 to 2005, where research was conducted, in part, on Risperdal, the company's antipsychotic drug. Biederman has responded saying that the money did not influence him and that he did not promote a specific diagnosis or treatment.

Pharmaceutical companies have also been accused of attempting to set the mental health agenda through activities such as funding consumer advocacy groups.{{cite journal | vauthors = Gosden R, Beder S | title = Pharmaceutical industry agenda setting in mental health policies | journal = Ethical Human Sciences and Services | volume = 3 | issue = 3 | pages = 147–159 | date = 1 January 2001 | pmid = 15278977 | doi = 10.1891/1523-150X.3.3.147 | doi-broken-date = 1 November 2024 }}

It is recommended that persons with dementia who exhibit behavioral and psychological symptoms should not be given antipsychotics before trying other treatments.{{Citation |author1 = American Psychiatric Association |author1-link = American Psychiatric Association |date = September 2013 |title = Five Things Physicians and Patients Should Question |publisher = American Psychiatric Association |work = Choosing Wisely: an initiative of the ABIM Foundation |url = http://www.choosingwisely.org/doctor-patient-lists/american-psychiatric-association/ |access-date = 30 December 2013 |url-status = live|archive-url = https://web.archive.org/web/20131203174206/http://www.choosingwisely.org/doctor-patient-lists/american-psychiatric-association/ |archive-date = 3 December 2013 |df = dmy-all }}, which cites

• {{cite book|volume=1|year=2006|doi=10.1176/appi.books.9780890423967.152139|title = APA Practice Guidelines for the Treatment of Psychiatric Disorders: Comprehensive Guidelines and Guideline Watches|isbn = 978-0-89042-336-3 | author = American Psychiatric Association |chapter=Practice Guideline for the Treatment of Patients with Alzheimer's Disease and Other Dementias |publisher=American Psychiatric Association |location=Arlington, VA | edition = Second |doi-broken-date=4 December 2024 }}
• {{cite journal | vauthors = Aparasu RR, Bhatara V | title = Antipsychotic use and expenditure in the United States | journal = Psychiatric Services | volume = 57 | issue = 12 | pages = 1693 | date = December 2006 | pmid = 17158480 | doi = 10.1176/appi.ps.57.12.1693 }}
• {{cite journal | vauthors = Gitlin LN, Kales HC, Lyketsos CG | title = Nonpharmacologic management of behavioral symptoms in dementia | journal = JAMA | volume = 308 | issue = 19 | pages = 2020–9 | date = November 2012 | pmid = 23168825 | pmc = 3711645 | doi = 10.1001/jama.2012.36918 }}
• {{cite journal | vauthors = Maglione M, Maher AR, Hu J, Wang Z, Shanman R, Shekelle PG, Roth B, Hilton L, Suttorp MJ, Ewing BA, Motala A, Perry T | title = Off-Label Use of Atypical Antipsychotics: An Update | journal = AHRQ Comparative Effectiveness Reviews | date = Sep 2011 | pmid = 22132426 }}
• {{cite journal | vauthors = Richter T, Meyer G, Möhler R, Köpke S | s2cid = 42099598 | title = Psychosocial interventions for reducing antipsychotic medication in care home residents | journal = The Cochrane Database of Systematic Reviews | volume = 12 | pages = CD008634 | date = December 2012 | issue = 12 | pmid = 23235663 | doi = 10.1002/14651858.cd008634.pub2 | pmc=6492452}}{{Update inline|reason=Updated version https://www.ncbi.nlm.nih.gov/pubmed/37650479|date = September 2023}} When taking antipsychotics this population has increased risk of cerebrovascular effects, parkinsonism or extrapyramidal symptoms, sedation, confusion and other cognitive adverse effects, weight gain, and increased mortality. Physicians and caretakers of persons with dementia should try to address symptoms including agitation, aggression, apathy, anxiety, depression, irritability, and psychosis with alternative treatments whenever antipsychotic use can be replaced or reduced. Elderly persons often have their dementia treated first with antipsychotics and this is not the best management strategy.{{Citation |author1 = American Geriatrics Society |author1-link = American Geriatrics Society |title = Ten Things Physicians and Patients Should Question |publisher = American Geriatrics Society |work = Choosing Wisely: an initiative of the ABIM Foundation |url = http://www.choosingwisely.org/doctor-patient-lists/american-geriatrics-society/ |access-date = 1 August 2013 |url-status = live|archive-url = https://web.archive.org/web/20130901100140/http://www.choosingwisely.org/doctor-patient-lists/american-geriatrics-society/ |archive-date = 1 September 2013 |df = dmy-all }}, which cites
• {{cite journal | title = American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults | journal = Journal of the American Geriatrics Society | volume = 60 | issue = 4 | pages = 616–31 | date = April 2012 | pmid = 22376048 | pmc = 3571677 | doi = 10.1111/j.1532-5415.2012.03923.x | author1 = American Geriatrics Society 2012 Beers Criteria Update Expert Panel }}
• {{Citation |author=NICE |date=8 May 2013 |title=Dementia: Supporting people with dementia and their carers in health and social care Clinical guidelines, CG42 |publisher=NICE |url=http://www.nice.org.uk/CG042 |access-date=23 October 2013 |url-status = live|archive-url=https://web.archive.org/web/20130627220803/http://www.nice.org.uk/CG042 |archive-date=27 June 2013 |author-link=National Institute for Health and Care Excellence }}
• {{cite journal | vauthors = Maher AR, Maglione M, Bagley S, Suttorp M, Hu JH, Ewing B, Wang Z, Timmer M, Sultzer D, Shekelle PG | title = Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis | journal = JAMA | volume = 306 | issue = 12 | pages = 1359–69 | date = September 2011 | pmid = 21954480 | doi = 10.1001/jama.2011.1360 | doi-access = free }}
• {{cite journal | vauthors = Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, Lebowitz BD, Lyketsos CG, Ryan JM, Stroup TS, Sultzer DL, Weintraub D, Lieberman JA | s2cid = 5861676 | title = Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease | journal = The New England Journal of Medicine | volume = 355 | issue = 15 | pages = 1525–38 | date = October 2006 | pmid = 17035647 | doi = 10.1056/nejmoa061240 | url = https://cdr.lib.unc.edu/downloads/h989rc48f | doi-access = free }}

• List of investigational antipsychotics
• Antipsychotic switching
• Conditioned avoidance response test

{{Reflist|group=Note}}

{{Reflist|30em}}

{{refbegin}}

• {{cite journal | vauthors = Fallon P, Dursun S, Deakin B | title = Drug-induced supersensitivity psychosis revisited: characteristics of relapse in treatment-compliant patients | journal = Therapeutic Advances in Psychopharmacology | volume = 2 | issue = 1 | pages = 13–22 | date = February 2012 | pmid = 23983951 | pmc = 3736929 | doi = 10.1177/2045125311431105 }}

{{refend}}

{{Commons category|Antipsychotic drugs}}

• [https://web.archive.org/web/20140613015650/http://www.who.int/mental_health/mhgap/evidence/psychosis/q1/en/ Recommendations for the use of antipsychotics for treating psychosis], World Health Organization 2012
• {{usurped|1=[https://web.archive.org/web/20091216100740/http://www.australianprescriber.com/magazine/27/6/146/9 Are atypical antipsychotics advantageous? – the case for]}}, Australian Prescriber 2005 (note: pharmaceutical company conflict of interest statement at the end)
• {{usurped|1=[https://web.archive.org/web/20100527054436/http://www.australianprescriber.com/magazine/27/6/149/51/ Are atypical antipsychotics advantageous? – the case against]}}, Australian Prescriber 2005
• [http://psychopharmacologyinstitute.com/antipsychotics/first-generation-antipsychotics/ First Generation Antipsychotics: An Introduction], Psychopharmacology Institute, 2012
• [https://web.archive.org/web/20060218075500/http://www.fda.gov/bbs/topics/ANSWERS/2005/ANS01350.html FDA Public Health Advisory] – Public Health Advisory for Antipsychotic Drugs used for Treatment of Behavioral Disorders in Elderly Patients, fda.gov
• [http://www.rcpsych.ac.uk/mentalhealthinfo/treatments/antipsychoticmedication.aspx Antipsychotic Medication] – information from mental health charity The Royal College of Psychiatrists
• {{in lang|pt}} [https://web.archive.org/web/20061012215858/http://www.medicina.ufrj.br/cursos/FROTA%20LIVRO%20I%20%26%20II.pdf FROTA LH. Fifty Years of Antipsychotic Drugs in Psychiatry. "Cinqüenta Anos de Medicamentos Antipsicóticos em Psiquiatria."] 1st ed; Ebook: CD-Rom/On-Line Portuguese, {{ISBN|85-903827-1-0}}, File .pdf (Adobe Acrobat) 6Mb, Informática, Rio de Janeiro, August 2003, 486pp., medicina.ufrj.br

{{Antipsychotics}}

{{Major Drug Groups}}

{{Dopamine receptor modulators}}

{{Mood disorders}}

{{Chemical classes of psychoactive drugs}}

{{Authority control}}

Category:Psychiatry controversies

Category:Drug classes defined by psychological effects

Category:Dopamine antagonists