Atypical antipsychotic

Atypical antipsychotics are typically used to treat schizophrenia or bipolar disorder.{{cite web|title=Respiridone|url=https://www.drugs.com/monograph/risperidone.html|work=The American Society of Health-System Pharmacists|access-date=April 3, 2011}} They are also frequently used to treat agitation associated with dementia, anxiety disorder, autism spectrum disorder, persecutory delusion and obsessive-compulsive disorder (an off-label use).{{cite journal | vauthors = Maher AR, Maglione M, Bagley S, Suttorp M, Hu JH, Ewing B, Wang Z, Timmer M, Sultzer D, Shekelle PG | display-authors = 6 | 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 book |title=Persecutory delusions: assessment, theory, and treatment |vauthors=Garety PA, Freeman DB, Bentall RP |publisher=Oxford University Press |year=2008 |isbn=978-0-19-920631-5 |location=Oxford [Oxfordshire] |pages=313}} In dementia, they should only be considered after other treatments have failed and if the patient is a risk to themselves and/or others.{{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 }}

The first-line psychiatric treatment for schizophrenia is antipsychotic medication,{{cite web|url=http://www.nice.org.uk/nicemedia/pdf/CG82FullGuideline.pdf|title=Schizophrenia: Full national clinical guideline on core interventions in primary and secondary care |access-date=2009-11-25 |publisher=National Collaborating Centre for Mental Health|date=2009-03-25 |work=Gaskell and the British Psychological Society}} which can reduce the positive symptoms of schizophrenia in about 8–15 days. Antipsychotics only appear to improve secondary negative symptoms of schizophrenia in the short term and may worsen negative symptoms overall.{{cite journal | vauthors = Aleman A, Lincoln TM, Bruggeman R, Melle I, Arends J, Arango C, Knegtering H | title = Treatment of negative symptoms: Where do we stand, and where do we go? | journal = Schizophrenia Research | volume = 186 | pages = 55–62 | date = August 2017 | pmid = 27293137 | doi = 10.1016/j.schres.2016.05.015 | s2cid = 4907333 | url = https://pure.rug.nl/ws/files/48756184/1_s2.0_S0920996416302390_main.pdf }} Overall there is no good evidence that atypical antipsychotics have any therapeutic benefit for treating the negative symptoms of schizophrenia.{{cite journal | vauthors = Fusar-Poli P, Papanastasiou E, Stahl D, Rocchetti M, Carpenter W, Shergill S, McGuire P | title = Treatments of Negative Symptoms in Schizophrenia: Meta-Analysis of 168 Randomized Placebo-Controlled Trials | journal = Schizophrenia Bulletin | volume = 41 | issue = 4 | pages = 892–9 | date = July 2015 | pmid = 25528757 | pmc = 4466178 | doi = 10.1093/schbul/sbu170 }}

There is very little evidence on which to base a risk and benefit assessment of using antipsychotics for long-term treatment.{{cite journal | vauthors = Murray RM, Quattrone D, Natesan S, van Os J, Nordentoft M, Howes O, Di Forti M, Taylor D | display-authors = 6 | title = Should psychiatrists be more cautious about the long-term prophylactic use of antipsychotics? | journal = The British Journal of Psychiatry | volume = 209 | issue = 5 | pages = 361–365 | date = November 2016 | pmid = 27802977 | doi = 10.1192/bjp.bp.116.182683 | url = https://kclpure.kcl.ac.uk/portal/en/publications/should-psychiatrists-be-more-cautious-about-the-longterm-prophylactic-use-of-antipsychotics(52ba3d1b-990c-4031-b597-d67edc569318).html | type = Submitted manuscript | doi-access = free }}

The choice of which antipsychotic to use for a specific patient is based on benefits, risks, and costs.{{cite journal | vauthors = van Os J, Kapur S | title = Schizophrenia | journal = Lancet | volume = 374 | issue = 9690 | pages = 635–45 | date = August 2009 | pmid = 19700006 | doi = 10.1016/S0140-6736(09)60995-8 | s2cid = 208792724 }} It is debatable whether, as a class, typical or atypical antipsychotics are better.{{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 }} Both have equal drop-out and symptom relapse rates when typicals are 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 }} There is a good response in 40–50% of patients, a partial response in 30–40%, and treatment resistance (failure of symptoms to respond satisfactorily after six weeks to two of three different antipsychotics) in the remaining 20%.{{cite journal | vauthors = Smith T, Weston C, Lieberman J | title = Schizophrenia (maintenance treatment) | journal = American Family Physician | volume = 82 | issue = 4 | pages = 338–9 | date = August 2010 | pmid = 20704164 }} Clozapine is considered a first choice treatment for treatment resistant schizophrenia, especially in the short term; in the longer-terms the risks of adverse effects complicate the choice.{{cite journal | vauthors = Siskind D, McCartney L, Goldschlager R, Kisely S | title = Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis | journal = The British Journal of Psychiatry | volume = 209 | issue = 5 | pages = 385–392 | date = November 2016 | pmid = 27388573 | doi = 10.1192/bjp.bp.115.177261 | doi-access = free }} In turn, risperidone, olanzapine, and aripiprazole have been recommended for the treatment of first-episode psychosis.{{cite journal|last1=Robinson|first1=Delbert G.|last2=Gallego|first2=Juan A.|last3=John|first3=Majnu|last4=Petrides|first4=Georgios|last5=Hassoun|first5=Youssef|last6=Zhang|first6=Jian-Ping|last7=Lopez|first7=Leonardo|last8=Braga|first8=Raphael J.|last9=Sevy|first9=Serge M.|last10=Addington|first10=Jean|last11=Kellner|first11=Charles H.|date=2015|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|doi=10.1093/schbul/sbv125|issn=1745-1701|pmc=4601722|pmid=26338693}}{{cite journal|last1=Gómez-Revuelta|first1=Marcos|last2=Pelayo-Terán|first2=José María|last3=Juncal-Ruiz|first3=María|last4=Vázquez-Bourgon|first4=Javier|last5=Suárez-Pinilla|first5=Paula|last6=Romero-Jiménez|first6=Rodrigo|last7=Setién Suero|first7=Esther|last8=Ayesa-Arriola|first8=Rosa|author9-link=Benedicto Crespo-Facorro|last9=Crespo-Facorro|first9=Benedicto|date=2020-04-23|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|doi=10.1093/ijnp/pyaa004|issn=1469-5111|pmc=7177160|pmid=31974576}}

The utility of broadly grouping the antipsychotics into first generation and atypical categories has been challenged. It has been argued that a more nuanced view, matching the properties of individual drugs to the needs of specific patients is preferable.{{cite journal | vauthors = Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM | 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 | s2cid = 1071537 }} While the atypical (second-generation) antipsychotics were marketed as offering greater efficacy in reducing psychotic symptoms while reducing side effects (and extrapyramidal symptoms in particular) than typical medications, the results showing these effects often lacked robustness, and the assumption was increasingly challenged even as atypical prescriptions were soaring.{{cite journal | vauthors = Alexander GC, Gallagher SA, Mascola A, Moloney RM, Stafford RS | title = Increasing off-label use of antipsychotic medications in the United States, 1995-2008 | journal = Pharmacoepidemiology and Drug Safety | volume = 20 | issue = 2 | pages = 177–84 | date = February 2011 | pmid = 21254289 | pmc = 3069498 | doi = 10.1002/pds.2082 }}{{cite journal | vauthors = Geddes J, Freemantle N, Harrison P, Bebbington P | title = Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis | journal = BMJ | volume = 321 | issue = 7273 | pages = 1371–6 | date = December 2000 | pmid = 11099280 | pmc = 27538 | doi = 10.1136/bmj.321.7273.1371 }} In 2005 the US government body NIMH published the results of a major independent (not funded by the pharmaceutical companies) multi-site, double-blind 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 | display-authors = 6 | 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 | author13 = Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators | url = https://cdr.lib.unc.edu/downloads/g732dk11n | doi-access = free }} This study compared several atypical antipsychotics to an older, mid-potency typical antipsychotic, perphenazine, among 1,493 persons with schizophrenia. The study found that only olanzapine outperformed perphenazine in discontinuation rate (the rate at which people stopped taking it due to its effects). The authors noted an apparent superior efficacy of olanzapine to the other drugs in terms of reduction in psychopathology and rate of hospitalizations, but olanzapine was associated with relatively severe metabolic effects such as a major weight gain problem (averaging 9.4 lbs over 18 months) and increases in glucose, cholesterol, and triglycerides. No other atypical studied (risperidone, quetiapine, and ziprasidone) did better than the typical perphenazine on the measures used, nor did they produce fewer adverse effects than the typical antipsychotic perphenazine (a result supported by a meta-analysis by Leucht et al. published in The Lancet), although more patients discontinued perphenazine owing to extrapyramidal effects compared to the atypical agents (8% vs. 2% to 4%, P=0.002). A phase 2 part of this CATIE study roughly replicated these findings.{{cite journal | vauthors = Stroup TS, Lieberman JA, McEvoy JP, Swartz MS, Davis SM, Rosenheck RA, Perkins DO, Keefe RS, Davis CE, Severe J, Hsiao JK | display-authors = 6 | title = Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic | journal = The American Journal of Psychiatry | volume = 163 | issue = 4 | pages = 611–22 | date = April 2006 | pmid = 16585435 | doi = 10.1176/appi.ajp.163.4.611 }} Compliance has not been shown to be different between the two types.{{cite journal | vauthors = Voruganti LP, Baker LK, Awad AG | 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 | s2cid = 34935 }} Overall evaluations of the CATIE and other studies have led many researchers to question the first-line prescribing of atypicals over typicals, or even to 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 = 137–46 | date = January 2012 | pmid = 22936056 | doi = 10.3233/JRS-2012-0567 }}{{cite journal |doi=10.1192/apt.bp.107.003970 |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 |year=2008 | vauthors = Owens DC | journal = Advances in Psychiatric Treatment |volume=14 |pages=17–28|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 = 80–7 | year = 2008 | pmid = 18515977 | doi = 10.1159/000135641 | author8 = Working Group 'Drugs in Psychiatry' | s2cid = 2669203 }}

It has been suggested that there is no validity to the term "second-generation antipsychotic drugs" and that the drugs that currently occupy this category are not identical to each other in mechanism, efficacy, and side-effect profiles.{{cite book | title = Anatomy of an Epidemic | isbn = 978-0307452412 | first = Robert | last = Whitaker | year = 2010 | publisher = Crown | page = [https://archive.org/details/anatomyofepidemi00whit/page/303 303] | url = https://archive.org/details/anatomyofepidemi00whit/page/303 }}

Each drug has its own mechanism, as Dr. Rif S. El-Mallakh, explained regarding the binding site and occupancy with a focus on the dopamine D2 receptor:

In general, when an antagonist of a neurotransmitter receptor is used, it must occupy a minimum of 65% to 70% of the target receptor to be effective. This is clearly the case when the target is a postsynaptic receptor, such as the dopamine D2 receptor. Similarly, despite significant variability in antidepressant response, blockade of 65% to 80% of presynaptic transport proteins—such as the serotonin reuptake pumps when considering serotoninergic antidepressants, or the norepinephrine reuptake pumps when considering noradrenergic agents such as nortriptyline—is necessary for these medications to be effective.... Depending on the level of intrinsic activity of a partial agonist and clinical goal, the clinician may aim for a different level of receptor occupancy. For example, aripiprazole will act as a dopamine agonist at lower concentrations, but blocks the receptor at higher concentrations. Unlike antagonist antipsychotics, which require only 65% to 70% D2 receptor occupancy to be effective, aripiprazole receptor binding at effective antipsychotic doses is 90% to 95%. Since aripiprazole has an intrinsic activity of approximately 30% (i.e., when it binds, it stimulates the D2 receptor to about 30% of the effect of dopamine binding to the receptor), binding to 90% of the receptors, and displacing endogenous dopamine, allows aripiprazole to replace the background or tonic tone of dopamine, which has been measured at 19% in people with schizophrenia and 9% in controls. Clinically, this still appears as the minimal effective dose achieving maximal response without significant parkinsonism despite >90% receptor occupancy.{{cite web |title=Receptor occupancy and drug response: Understanding the relationship |url=https://www.mdedge.com/psychiatry/article/173556/schizophrenia-other-psychotic-disorders/receptor-occupancy-and-drug |access-date=2022-10-14 |website=www.mdedge.com |language=en}}

In bipolar disorder, SGAs are most commonly used to rapidly control acute mania and mixed episodes, often in conjunction with mood stabilizers (which tend to have a delayed onset of action in such cases) such as lithium and valproate. In milder cases of mania or mixed episodes, mood stabilizer monotherapy may be attempted first.{{cite book | vauthors = Taylor D, Paton C, Kapur S |title=The Maudsley Prescribing Guidelines |edition = 12th |publisher=Informa Healthcare |year=2012 |pages=12–152, 173–196, 222–235}} SGAs are also used to treat other aspects of the disorder (such as acute bipolar depression or as a prophylactic treatment) as adjuncts or as a monotherapy, depending on the drug. Both quetiapine and olanzapine have demonstrated significant efficacy in all three treatment phases of bipolar disorder. Lurasidone (trade name Latuda) has demonstrated some efficacy in the acute depressive phase of bipolar disorder.{{cite web | vauthors = Soreff S, McInnes LA, Ahmed I, Talavera F | title=Bipolar Affective Disorder Treatment & Management | url = http://emedicine.medscape.com/article/286342-treatment | work=Medscape Reference|publisher=WebMD|access-date=10 October 2013|date=5 August 2013}}{{cite web| vauthors = Post RM, Keck P | title = Bipolar Disorder in adults: Maintenance treatment|url=http://www.uptodate.com/contents/bipolar-disorder-in-adults-maintenance-treatment|work=UpToDate|publisher=Wolters Kluwer Health|access-date=10 October 2013|date=30 July 2013}}

In non-psychotic major depressive disorder (MDD), some SGAs have demonstrated significant efficacy as adjunctive agents; and, such agents include:{{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 | 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 }}{{cite journal | vauthors = Nelson JC, Papakostas GI | title = Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials | journal = The American Journal of Psychiatry | volume = 166 | issue = 9 | pages = 980–91 | date = September 2009 | pmid = 19687129 | doi = 10.1176/appi.ajp.2009.09030312 | doi-access = free }}{{cite web|url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-rexulti|title=Drug Approvals and Databases - Drug Trials Snapshots: REXULTI for the treatment of major depressive disorder|last=Research|first=Center for Drug Evaluation and|website=www.fda.gov|language=en|access-date=2018-10-18}}

• Aripiprazole
• Brexpiprazole
• Cariprazine
• Olanzapine
• Quetiapine
• Ziprasidone{{cite journal | vauthors = Papakostas GI, Fava M, Baer L, Swee MB, Jaeger A, Bobo WV, Shelton RC | title = Ziprasidone Augmentation of Escitalopram for Major Depressive Disorder: Efficacy Results From a Randomized, Double-Blind, Placebo-Controlled Study | journal = The American Journal of Psychiatry | volume = 172 | issue = 12 | pages = 1251–8 | date = December 2015 | pmid = 26085041 | pmc = 4843798 | doi = 10.1176/appi.ajp.2015.14101251 }}

whereas only quetiapine has demonstrated efficacy as a monotherapy in non-psychotic MDD.{{cite journal | vauthors = Maneeton N, Maneeton B, Srisurapanont M, Martin SD | title = Quetiapine monotherapy in acute phase for major depressive disorder: a meta-analysis of randomized, placebo-controlled trials | journal = BMC Psychiatry | volume = 12 | pages = 160 | date = September 2012 | pmid = 23017200 | pmc = 3549283 | doi = 10.1186/1471-244X-12-160 | doi-access = free }} Olanzapine/fluoxetine is an efficacious treatment in both psychotic and non-psychotic MDD.{{cite journal | vauthors = Rothschild AJ, Williamson DJ, Tohen MF, Schatzberg A, Andersen SW, Van Campen LE, Sanger TM, Tollefson GD | display-authors = 6 | title = A double-blind, randomized study of olanzapine and olanzapine/fluoxetine combination for major depression with psychotic features | journal = Journal of Clinical Psychopharmacology | volume = 24 | issue = 4 | pages = 365–73 | date = August 2004 | pmid = 15232326 | doi = 10.1097/01.jcp.0000130557.08996.7a | s2cid = 36295165 }}

Aripiprazole, brexpiprazole, cariprazine, olanzapine, and quetiapine have been approved as adjunct treatment for MDD by the FDA in the United States.{{cite journal | vauthors = Roberts RJ, Lohano KK, El-Mallakh RS | title = Antipsychotics as antidepressants | journal = Asia-Pacific Psychiatry | volume = 8 | issue = 3 | pages = 179–88 | date = September 2016 | pmid = 25963405 | doi = 10.1111/appy.12186 | s2cid = 24264818 }}{{cite web|url=https://www.otsuka-us.com/discover/fda-approves-otsukalundbecks-rexulti-as-adjunctive-treatment-for-adults-with-mdd-and-schizophrenia|title=U.S. FDA Approves Otsuka and Lundbeck's REXULTI (Brexpiprazole) as Adjunctive Treatment for Adults with Major Depressive Disorder and as a Treatment for Adults with Schizophrenia {{!}} Discover Otsuka|website=Otsuka in the U.S.|language=en-US|access-date=2018-10-18}} Cariprazine, Quetiapine, lurasidone, and 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=2023-01-11 |website=dailymed.nlm.nih.gov}} have been approved, as monotherapies, for bipolar depression, but as of present, lurasidone has not been approved for MDD.

Both risperidone and aripiprazole have received FDA approval for irritability in autism.Truven Health Analytics, Inc. DRUGDEX System (Internet) [cited 2013 Oct 10]. Greenwood Village, CO: Thomsen Healthcare; 2013.

Between May 2007 and April 2008, Dementia and Alzheimer's together accounted for 28% of atypical antipsychotic use in patients aged 65 or older. The U.S. Food and Drug Administration requires that all atypical antipsychotics carry a black box warning that the medication has been associated with an increased risk of mortality in elderly patients. 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 = 14–7 | date = November 2010 | pmid = 21191528 | pmc = 3010964 }} In the subsequent 5 years, the use of atypical antipsychotics to treat dementia decreased by nearly 50%. As of now, the only FDA-approved atypical antipsychotic for alzheimer-related dementia is brexpiprazole.

The side effects reportedly associated with the various atypical antipsychotics vary and are medication-specific.

Both typical and atypical antipsychotics can cause tardive dyskinesia.{{cite journal |vauthors=Correll CU, Schenk EM |date=March 2008 |title=Tardive dyskinesia and new antipsychotics |journal=Current Opinion in Psychiatry |volume=21 |issue=2 |pages=151–6 |doi=10.1097/YCO.0b013e3282f53132 |pmid=18332662 |s2cid=37288246}} According to one study, rates are lower with the atypicals at 3.9% per year as opposed to the typicals at 5.5% per year. However, tardive dyskinesia typically develops after long-term (possibly decades) use of antipsychotics. It is not clear if atypical antipsychotics, having been in use for a relatively short time, produce a lower incidence of tardive dyskinesia.{{cite web | vauthors = Stroup TS, Marder S, Stein MB |title=Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment|url=http://www.uptodate.com/contents/pharmacotherapy-for-schizophrenia-acute-and-maintenance-phase-treatment|work=UpToDate|publisher=Wolters Kluwer|access-date=10 October 2013|date=23 October 2013}}

One hypothesis as to why atypicals have a lower risk of tardive dyskinesia is because they are much less fat-soluble than the typical antipsychotics and because they are readily released from D2 receptor and brain tissue.{{cite journal |vauthors=Seeman P |date=February 2002 |title=Atypical antipsychotics: mechanism of action |journal=Canadian Journal of Psychiatry |volume=47 |issue=1 |pages=27–38 |doi=10.1177/070674370204700106 |pmid=11873706 |doi-access=free}} The typical antipsychotics remain attached to the D2 receptors and accumulate in the brain tissue which may lead to TD.

It has been suggested that atypical antipsychotics increase the risk of cardiovascular disease.{{cite journal | vauthors = Kabinoff GS, Toalson PA, Healey KM, McGuire HC, Hay DP | title = Metabolic Issues With Atypical Antipsychotics in Primary Care: Dispelling the Myths | journal = Primary Care Companion to the Journal of Clinical Psychiatry | volume = 5 | issue = 1 | pages = 6–14 | date = February 2003 | pmid = 15156241 | pmc = 353028 | doi = 10.4088/PCC.v05n0103 }}{{Cite journal |last=Díaz-Domínguez |first=Daniel Alejandro |last2=de la Rosa-Donlucas |first2=Francisco |last3=Romans-Demaria |first3=Laura |last4=Grajales-Almeida |first4=José Ramón |last5=Sauer-Vera |first5=Tizbé |last6=Sotelo-Monroy |first6=Gabriel Eugenio |date=2013-12-01 |title=Prevalence of Metabolic Syndrome and Associated Risk Factors in Hospitalized Patients with Schizophrenia in Mexico |url=https://www.tandfonline.com/doi/abs/10.2753/IMH0020-7411420405 |journal=International Journal of Mental Health |volume=42 |issue=4 |pages=95–104 |doi=10.2753/IMH0020-7411420405 |issn=0020-7411|url-access=subscription }} However, Kabinoff and colleagues (2003) suggest that the increase in cardiovascular disease is seen regardless of the treatment received, and that it is instead caused by many different factors such as lifestyle or diet.

Despite increasing some risk factors, SGAs are not associated with excess cardiovascular mortality when used to treat serious psychiatric disorders.{{cite journal |last1=Goldstein |first1=Benjamin I. |last2=Baune |first2=Bernhard T. |last3=Bond |first3=David J. |last4=Chen |first4=Pao-Huan |last5=Eyler |first5=Lisa |last6=Fagiolini |first6=Andrea |last7=Gomes |first7=Fabiano |last8=Hajek |first8=Tomas |last9=Hatch |first9=Jessica |last10=McElroy |first10=Susan L. |last11=McIntyre |first11=Roger S. |last12=Prieto |first12=Miguel |last13=Sylvia |first13=Louisa G. |last14=Tsai |first14=Shang-Ying |last15=Kcomt |first15=Andrew |date=August 2020 |title=Call to action regarding the vascular-bipolar link: A report from the Vascular Task Force of the International Society for Bipolar Disorders |journal=Bipolar Disorders |volume=22 |issue=5 |pages=440–460 |doi=10.1111/bdi.12921 |pmc=7522687 |pmid=32356562 |doi-access=free |hdl-access=free |last16=Fiedorowicz |first16=Jess G. |hdl=11343/251495}}

Sexual side effects have also been reported when taking atypical antipsychotics.{{cite journal | vauthors = Uçok A, Gaebel W | title = Side effects of atypical antipsychotics: a brief overview | journal = World Psychiatry | volume = 7 | issue = 1 | pages = 58–62 | date = February 2008 | pmid = 18458771 | pmc = 2327229 | doi = 10.1002/j.2051-5545.2008.tb00154.x }} In males antipsychotics reduce sexual interest, impair sexual performance with the main difficulties being failure to ejaculate. In females there may be abnormal menstrual cycles and infertility. In both males and females the breasts may become enlarged and a fluid will sometimes ooze from the nipples. Sexual adverse effects caused by some antipsychotics are a result of an increase of prolactin. Sulpiride and Amisulpiride, as well as Risperdone and paliperidone (to a lesser extent), cause a high increase of prolactin.

In April 2005, the US Food and Drug Administration (FDA) issued an advisory and subsequent black box warning regarding the risks of atypical antipsychotic use among elderly patients with dementia. The FDA advisory was associated with decreases in the use of atypical antipsychotics, especially among elderly patients with dementia.{{cite journal | vauthors = Dorsey ER, Rabbani A, Gallagher SA, Conti RM, Alexander GC | title = Impact of FDA black box advisory on antipsychotic medication use | journal = Archives of Internal Medicine | volume = 170 | issue = 1 | pages = 96–103 | date = January 2010 | pmid = 20065205 | pmc = 4598075 | doi = 10.1001/archinternmed.2009.456 }} Subsequent research reports confirmed the mortality risks associated with the use of both conventional and atypical antipsychotics to treat patients with dementia. Consequently, in 2008 the FDA issued although a black box warning for classical neuroleptics. Data on treatment efficacies are strongest for atypical antipsychotics. Adverse effects in patients with dementia include an increased risk of mortality and cerebrovascular events, as well as metabolic effects, extrapyramidal symptoms, falls, cognitive worsening, cardiac arrhythmia, and pneumonia.{{cite journal | vauthors = Gerhard T, Huybrechts K, Olfson M, Schneeweiss S, Bobo WV, Doraiswamy PM, Devanand DP, Lucas JA, Huang C, Malka ES, Levin R, Crystal S | display-authors = 6 | title = Comparative mortality risks of antipsychotic medications in community-dwelling older adults | journal = The British Journal of Psychiatry | volume = 205 | issue = 1 | pages = 44–51 | date = July 2014 | pmid = 23929443 | doi = 10.1192/bjp.bp.112.122499 | doi-access = free }} Conventional antipsychotics may pose an even greater safety risk. No clear efficacy evidence exists to support the use of alternative psychotropic classes (e.g. antidepressants, anticonvulsants) in patients with dementia.{{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 = 900–6 | date = September 2012 | pmid = 22952071 | pmc = 3516138 | doi = 10.1176/appi.ajp.2012.12030342 }}

{{main|Obsessive–compulsive disorder#Drug-induced OCD}}

Many different types of medication can induce in patients that have never had symptoms before. A new chapter about OCD in the DSM-5 (2013) now specifically includes drug-induced OCD.

There are reports that some atypical antipsychotics could cause drug-induced OCD in already schizophrenic patients.{{cite journal|title = Obsessive-compulsive symptoms with olanzapine|journal = The International Journal of Neuropsychopharmacology|date = 1 September 2004|issn = 1461-1457|pmid = 15231024|pages = 375–377|volume = 7|issue = 3|doi = 10.1017/S1461145704004456|first1 = Basil|last1 = Alevizos|first2 = Charalambos|last2 = Papageorgiou|first3 = George N.|last3 = Christodoulou|doi-access = free}}{{cite journal|title = Olanzapine induced de-novo obsessive compulsive disorder in a patient with schizophrenia|journal = Indian Journal of Pharmacology|date = 1 January 2012|issn = 0253-7613|pmc = 3480803|pmid = 23112432|pages = 649–650|volume = 44|issue = 5|doi = 10.4103/0253-7613.100406|first1 = Gajanan|last1 = Kulkarni|first2 = Janardhanan C.|last2 = Narayanaswamy|first3 = Suresh Bada|last3 = Math | doi-access=free }}{{cite journal|title = Olanzapine and obsessive-compulsive symptoms|journal = European Neuropsychopharmacology|date = 1 September 2000|issn = 0924-977X|pmid = 10974610|pages = 385–387|volume = 10|issue = 5|first1 = L.|last1 = Lykouras|first2 = I. M.|last2 = Zervas|first3 = R.|last3 = Gournellis|first4 = M.|last4 = Malliori|first5 = A.|last5 = Rabavilas|doi=10.1016/s0924-977x(00)00096-1|s2cid = 276209}}{{cite journal|title = Clozapine-Induced Obsessive-Compulsive Symptoms in Schizophrenia: A Critical Review|journal = Current Neuropharmacology|date = 1 March 2012|issn = 1570-159X|pmc = 3286851|pmid = 22942882|pages = 88–95|volume = 10|issue = 1|doi = 10.2174/157015912799362724|first1 = Frederike|last1 = Schirmbeck|first2 = Mathias|last2 = Zink}}

Recently, metabolic side effects have been of considerable concern to clinicians, patients and the FDA. In 2003, the Food and Drug Administration (FDA) required all manufacturers of atypical antipsychotics to change their labeling to include a warning about the risks of hyperglycemia and diabetes with atypical antipsychotics. It must also be pointed out that although all atypicals must carry the warning on their labeling, some evidence shows that atypicals are not equal in their effects on weight and insulin sensitivity.{{cite journal | title = Consensus development conference on antipsychotic drugs and obesity and diabetes | journal = Diabetes Care | volume = 27 | issue = 2 | pages = 596–601 | date = February 2004 | pmid = 14747245 | doi = 10.2337/diacare.27.2.596 | author4 = North American Association for the Study of Obesity | doi-access = free | author3 = American Association of Clinical Endocrinologists }} The general consensus is that clozapine and olanzapine are associated with the greatest effects on weight gain and decreased insulin sensitivity, followed by risperidone and quetiapine. Ziprasidone and aripiprazole are thought to have the smallest effects on weight and insulin resistance, but clinical experience with these newer agents is not as developed as that with the older agents. The mechanism of these adverse effects is not completely understood but it is believed to result from a complex interaction between a number of pharmacologic actions of these drugs. Their effects on weight are believed to mostly derive from their actions on the H₁ and 5-HT_2C receptors, while their effects on insulin sensitivity are believed to be the result of a combination of their effects on body weight (as increased body mass is known to be a risk factor for insulin resistance) and their antagonistic effects on the M₃ receptor. Some of the newer agents, however, such as risperidone and its metabolite paliperidone, ziprasidone, lurasidone, aripiprazole, asenapine and iloperidone, have clinically insignificant effects on the M₃ receptor and appear to carry a lower risk of insulin resistance. Whereas clozapine, olanzapine and quetiapine (indirectly via its active metabolite, norquetiapine) all antagonise the M₃ receptor at therapeutic-relevant concentrations.{{cite book | vauthors = Brunton L, Chabner B, Knollman B |title=Goodman and Gilman's The Pharmacological Basis of Therapeutics |edition=12th |publisher=McGraw Hill Professional |year=2010 | pages = 417–455}}

Recent evidence suggests a role of the α₁ adrenoceptor and 5-HT_2A receptor in the metabolic effects of atypical antipsychotics. The 5-HT_2A receptor, however, is also believed to play a crucial role in the therapeutic advantages of atypical antipsychotics over their predecessors, the typical antipsychotics.{{cite journal | vauthors = Guenette MD, Giacca A, Hahn M, Teo C, Lam L, Chintoh A, Arenovich T, Remington G | display-authors = 6 | title = Atypical antipsychotics and effects of adrenergic and serotonergic receptor binding on insulin secretion in-vivo: an animal model | journal = Schizophrenia Research | volume = 146 | issue = 1–3 | pages = 162–9 | date = May 2013 | pmid = 23499243 | doi = 10.1016/j.schres.2013.02.023 | s2cid = 43719333 }}

The two atypical antipsychotics with trials showing that had a low incidence of weight gain in large meta-analysis were lurasidone and aripiprazole.{{cite journal |last1=Ng-Mak |first1=Daisy |last2=Tongbram |first2=Vanita |last3=Ndirangu |first3=Kerigo |last4=Rajagopalan |first4=Krithika |last5=Loebel |first5=Antony |date=2018-08-01 |title=Efficacy and metabolic effects of lurasidone versus brexpiprazole in schizophrenia: a network meta-analysis |journal=Journal of Comparative Effectiveness Research |volume=7 |issue=8 |pages=737–748 |doi=10.2217/cer-2018-0016 |pmid=29697278 |s2cid=13769615 |issn=2042-6305|doi-access=free }} In a meta-analysis of 18 antipsychotics, olanzapine and clozapine exhibited the worst metabolic parameters and aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasidone the most benign parameters.{{cite journal |last1=Pillinger |first1=Toby |last2=McCutcheon |first2=Robert A. |last3=Vano |first3=Luke |last4=Mizuno |first4=Yuya |last5=Arumuham |first5=Atheeshaan |last6=Hindley |first6=Guy |last7=Beck |first7=Katherine |last8=Natesan |first8=Sridhar |last9=Efthimiou |first9=Orestis |last10=Cipriani |first10=Andrea |last11=Howes |first11=Oliver D. |date=2020-01-01 |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 |language=English |volume=7 |issue=1 |pages=64–77 |doi=10.1016/S2215-0366(19)30416-X |issn=2215-0366 |pmid=31860457|pmc=7029416 |s2cid=209434994 |doi-access=free }} Aripiprazole, asenapine, ziprasidone and lurasidone have low propensity to cause weight gain.{{cite journal |vauthors=Dayabandara M, Hanwella R, Ratnatunga S, Seneviratne S, Suraweera C, de Silva VA |title=Antipsychotic-associated weight gain: management strategies and impact on treatment adherence |journal=Neuropsychiatr Dis Treat |volume=13 |issue= |pages=2231–2241 |date=2017 |pmid=28883731 |pmc=5574691 |doi=10.2147/NDT.S113099 |doi-access=free}}

Lumateperone was found to cause minimal weight gain in a long-term 12 month follow-up study.{{cite journal |vauthors=Satlin A, Durgam S, Vanover KE, Davis RE, Huo J, Mates S, Correll C |title=M205. Long-Term Safety of Lumateperone (ITI-007): Metabolic Effects in a 1-Year Study |journal=Schizophr Bull |volume=46 |issue=Suppl 1 |pages=S214 |date=May 2020 |doi=10.1093/schbul/sbaa030.517 |pmc=7234755}}

A study by Sernyak and colleagues found that the prevalence of diabetes in atypical antipsychotic treatments was statistically significantly higher than that of conventional treatment. The authors of this study suggest that there is a causal relationship between atypical antipsychotics and diabetes, however Kabinoff et al. argue that the findings only suggest a temporal association. Kabinoff et al. suggest that there is insufficient data from large studies to demonstrate a consistent or significant difference in the risk of insulin resistance during treatment with various atypical antipsychotics. Prescribing topiramate, zonisamide, metformin, GLP-1 receptor agonists, or nizatidine alongside an antipsychotic significantly reduces weight gain.{{cite journal |last1=Wang |first1=Yewei |last2=Wang |first2=Dandan |last3=Cheng |first3=Jie |last4=Fang |first4=Xinyu |last5=Chen |first5=Yan |last6=Yu |first6=Lingfang |last7=Ren |first7=Juanjuan |last8=Tian |first8=Yuan |last9=Zhang |first9=Chen |title=Efficacy and tolerability of pharmacological interventions on metabolic disturbance induced by atypical antipsychotics in adults: A systematic review and network meta-analysis |journal=Journal of Psychopharmacology |date=September 2021 |volume=35 |issue=9 |pages=1111–9 |doi=10.1177/02698811211035391|pmid=34311625 |s2cid=236451973 }}

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 |last1=Haddad |first1=Peter |last2=Haddad |first2=Peter M. |last3=Dursun |first3=Serdar |last4=Deakin |first4=Bill |title=Adverse Syndromes and Psychiatric Drugs: A Clinical Guide |date=2004 |publisher=OUP Oxford |isbn=9780198527480 |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. Symptoms generally resolve after a short period of time.

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.{{cite journal | vauthors = Moncrieff J | 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 | s2cid = 6267180 }} It may also result in reoccurrence of the condition that is being treated.{{cite book |last1=Sacchetti |first1=Emilio |last2=Vita |first2=Antonio |last3=Siracusano |first3=Alberto |last4=Fleischhacker |first4=Wolfgang |title=Adherence to Antipsychotics in Schizophrenia |date=2013 |publisher=Springer Science & Business Media |isbn=9788847026797 |page=85 |url=https://books.google.com/books?id=odE-AgAAQBAJ&pg=PA85 |language=en}} Rarely tardive dyskinesia can occur when the medication is stopped.

The atypical antipsychotics integrate with the serotonin (5-HT), norepinephrine (α, β), and dopamine (DA) receptors in order to effectively treat schizophrenia.{{cite book |last=Stahl |first=Stephen M. |url=https://books.google.com/books?id=jwfrLrYc7d0C&q=5ht |title=Antipsychotics and Mood Stabilizers: Stahl's Essential Psychopharmacology, 3rd Edition |date=2008-03-27 |publisher=Cambridge University Press |isbn=978-0-521-88664-2 |language=en}}

D₂ Receptor: Hyperactive dopaminergic activity on D₂ receptors in the mesolimbic pathway is responsible for the positive symptoms of schizophrenia (hallucinations, delusions, paranoia). After taking an antipsychotic, antagonism of D₂ receptors occurs throughout the entire brain, leading to a number of deleterious side effects from D₂ receptor antagonism throughout the entire dopamine pathway system. It's not possible to affect D₂ receptors only in the mesolimbic pathway,{{refn|group=Stahl AP Explained 1 -|name=S1|p. 329-336.}} but 5-HT_2A receptor antagonism reverses these side effects to some extent.{{refn|group=Stahl AP Explained 1 -|name=S2|p. 346-352.}} Reducing D₂ dopaminergic activity in the mesolimbic pathway also results in an anhedonic effect, reducing pleasure and motivation. In the mesocortical pathway to the DLPFC and VMPFC, endogenous D₂ receptor dopamine activity is sometimes low in schizophrenia, resulting in cognitive, affective, and, broadly, the negative symptoms of schizophrenia. D₂ receptor antagonism further compounds these problems. In the nigrostriatal pathway, D₂ receptor antagonism results in extrapyramidal symptoms. If this antagonism occurs long enough, symptoms of EPS may become permanent, even if antipsychotic use is discontinued. In the tuberoinfundibular pathway, D₂ receptor antagonism results in elevated prolactin. If prolactin levels become high enough, hyperprolactinaemia may occur, resulting in sexual dysfunction, weight gain, more rapid demineralization of bones, and possibly galactorrhea and amenorrhea.{{refn|group=Stahl AP Explained 1 -|name=S1|}}

5-HT_2A Receptor: When serotonin is released on to postsynaptic 5-HT_2A receptors, the dopamine neuron is inhibited, thus acting as a brake on dopamine release.{{refn|group=Stahl AP Explained 1 -|name=S2|}} This brake is disrupted through action of a 5-HT_2A antagonist, which disinhibits the dopamine neuron, stimulating dopamine release. The result of this is that dopamine competes with antipsychotic D₂ antagonistic action at D₂ receptors, thereby reducing antagonistic binding there and eliminating or lowering D₂ antagonistic effects in several pathways of the dopamine system.{{refn|group=Stahl AP Explained 1 -|name=S2|}} In the nigrostriatal pathway, it reduces EPS. In the tuberoinfundibular pathway, it reduces or eliminates prolactin elevation.{{refn|group=Stahl AP Explained 1 -|name=S3|p. 355-360.}} Dopamine release in the mesolimbic pathway from 5-HT_2A antagonism does not appear to be as robust as in the other pathways of the dopamine system, thereby accounting for why atypical antipsychotics still retain part of their efficacy against the positive symptoms of schizophrenia through their D₂ antagonism.{{refn|group=Stahl AP Explained 1 -|name=S3|}} When 5-HT_2A antagonistic agent particles occupy 5-HT_2A receptors in the mesocortical pathway and in the prefrontal cortex, the negative symptoms of schizophrenia, affective symptoms, and cognitive deficits and abnormalities are treated and reduced.{{refn|group=Stahl AP Explained 1 -|name=S3|}} Furthermore, 5-HT_2A receptor antagonism blocks the serotonergic excitation of cortical pyramidal cells, reducing glutamate release, which in turn lowers hyperactive dopaminergic D₂ receptor activity in the mesolimbic pathway, reducing or eliminating the positive symptoms of schizophrenia.{{refn|group=Stahl AP Explained 1 -|name=S3|}}{{cite book|url=https://books.google.com/books?id=jwfrLrYc7d0C&q=5ht2a++release+dopamine&pg=PA105 |title=Antipsychotics and Mood Stabilizers: Stahl's Essential Psychopharmacology .. |author=Stephen M. Stahl |page=105 |date=2008-03-27 |publisher=Cambridge University Press |access-date=2016-09-30|isbn=9780521886642 }}{{cite journal | vauthors = Egerton A, Ahmad R, Hirani E, Grasby PM | title = Modulation of striatal dopamine release by 5-HT2A and 5-HT2C receptor antagonists: [11C]raclopride PET studies in the rat | journal = Psychopharmacology | volume = 200 | issue = 4 | pages = 487–96 | date = November 2008 | pmid = 18597077 | doi = 10.1007/s00213-008-1226-4 | s2cid = 11800154 }}

Brexpiprazole, approved by the US FDA in 2015, has a similar binding profile to aripiprazole as a partial D2 agonist with moderate histamine binding, but with brexipiprazole has a higher affinity for serotonin receptor 5-HT_2A.

Some effects of 5-HT_1A receptor activation include decreased aggressive behavior/ideation,{{cite journal | vauthors = de Boer SF, Koolhaas JM | title = 5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis | journal = European Journal of Pharmacology | volume = 526 | issue = 1–3 | pages = 125–39 | date = December 2005 | pmid = 16310183 | doi = 10.1016/j.ejphar.2005.09.065 }} increased sociability, and decreased anxiety and depression.{{primary source inline|date=February 2018}} Blockade of the 5-HT_2C receptor increases serotonin, releasing norepinephrine and dopamine within the brain. But neuronal reuptake of norepinephrine is limited sharply by some antipsychotics, e.g. ziprasidone. Increased norepinephrine can cause increased glucose(blood sugar) levels.{{cite web|url=https://www.cardiosmart.org/Healthwise/d003/23/d00323 |title=norepinephrine |website=Cardiosmart.org |date=2010-12-15 |access-date=2016-09-30}}{{cite book |url=https://books.google.com/books?id=dMKoFySox7kC&pg=PA401 |title=Diabetic Neuropathy: Clinical Management |page=401 |date= 2008-02-01|access-date=2016-09-30|isbn=9781597453110 | last1 = Veves |first1=Aristidis |last2=Malik |first2=Rayaz A |publisher=Springer }}{{cite web |url=https://www.boundless.com/biology/textbooks/boundless-biology-textbook/osmotic-regulation-and-the-excretory-system-41/hormonal-control-of-osmoregulatory-functions-232/epinephrine-and-norepinephrine-867-12114/ |title=Epinephrine and Norepinephrine |website=Boundless.com |access-date=2016-09-30 |archive-url=https://web.archive.org/web/20161013053954/https://www.boundless.com/biology/textbooks/boundless-biology-textbook/osmotic-regulation-and-the-excretory-system-41/hormonal-control-of-osmoregulatory-functions-232/epinephrine-and-norepinephrine-867-12114/ |archive-date=October 13, 2016 |url-status=dead |df=mdy-all }} Increased blood sugar levels by increased norepinephrine causes hunger in many humans, which is why weight gain occurs with some antipsychotics if the norepinephrine is not inhibited.{{cite web|url=http://www.rxwiki.com/cariprazine |title=Cariprazine - Side Effects, Uses, Dosage, Overdose, Pregnancy, Alcohol |website=RxWiki.com |date=September 17, 2015 |access-date=2016-09-30}}{{cite web |url=http://www.invega.com/side-effects-schizophrenia-treatment |title=INVEGA Side Effects - Schizophrenia Treatment – INVEGA (paliperidone) |website=Invega.com |date=2016-05-17 |access-date=2016-09-30 |archive-url=https://web.archive.org/web/20160817063943/http://www.invega.com/side-effects-schizophrenia-treatment |archive-date=August 17, 2016 |url-status=dead |df=mdy-all }}{{cite web|url=http://diabetesupdate.blogspot.se/2007/08/hunger-is-symptom.html |title=Diabetes Update: Hunger is a Symptom |website=Diabetesupdate.blogspot.se |date=2007-08-08 |access-date=2016-09-30}}{{cite web|url=http://healthvermont.gov/prevent/diabetes/high_low_sugar.aspx |title=High & Low Blood Sugar |website=Healthvermont.gov |access-date=2016-09-30}}{{cite web|url=https://rexulti.com/us/mdd/important-safety-information/ |title=REXULTI (brexpiprazole) {{pipe}} Important Safety Information |website=Rexulti.com |access-date=2016-09-30}} Inhibition of norepinephrine stabilizes mood in humans.{{cite book|url=https://books.google.com/books?id=jwfrLrYc7d0C&pg=PA172 |title=Antipsychotics and Mood Stabilizers: Stahl's Essential Psychopharmacology .. |author=Stephen M. Stahl |page=172 |date=2008-03-27 |publisher=Cambridge University Press |access-date=2016-09-30|isbn=9780521886642 }} 5-HT₆ receptor antagonists improve cognition, learning, and memory.{{cite journal | vauthors = King MV, Marsden CA, Fone KC | title = A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory | journal = Trends in Pharmacological Sciences | volume = 29 | issue = 9 | pages = 482–92 | date = September 2008 | pmid = 19086256 | doi = 10.1016/j.tips.2008.07.001 }} The 5-HT₇ receptor is very potent for the mitigation of bipolar conditions and also yields an antidepressant effect. The antipsychotics asenapine,{{cite journal | vauthors = Shahid M, Walker GB, Zorn SH, Wong EH | title = Asenapine: a novel psychopharmacologic agent with a unique human receptor signature | journal = Journal of Psychopharmacology | volume = 23 | issue = 1 | pages = 65–73 | date = January 2009 | pmid = 18308814 | doi = 10.1177/0269881107082944 | s2cid = 206489515 }} lurasidone,{{cite web|url=http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/200603Orig1s000PharmR.pdf |archive-url=https://web.archive.org/web/20161003115210/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/200603Orig1s000PharmR.pdf |url-status=dead |archive-date=October 3, 2016 |title=Pharmcology Reviews : 200603 |website=Accessdata.fda.gov |access-date=2016-09-30}}{{cite journal | vauthors = Ishibashi T, Horisawa T, Tokuda K, Ishiyama T, Ogasa M, Tagashira R, Matsumoto K, Nishikawa H, Ueda Y, Toma S, Oki H, Tanno N, Saji I, Ito A, Ohno Y, Nakamura M | display-authors = 6 | title = Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5-hydroxytryptamine 7 (5-HT7) and 5-HT1A receptor activity | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 334 | issue = 1 | pages = 171–81 | date = July 2010 | pmid = 20404009 | doi = 10.1124/jpet.110.167346 | s2cid = 12893717 }} risperidone,National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Aug 10]. ChapelHill (NC): University of North Carolina. 1998-2013. Available from: {{cite web |url=http://pdsp.med.unc.edu/pdsp.php |title=PDSP Database - UNC |access-date=2016-05-16 |url-status=dead |archive-url=https://web.archive.org/web/20131108013656/http://pdsp.med.unc.edu/pdsp.php |archive-date=2013-11-08 }} and aripiprazole{{cite book|url=https://books.google.com/books?id=s8CXrbimviMC&pg=PT209 |title=Pharmacology and Physiology for Anesthesia: Foundations and Clinical .. | first1 = Hugh C. | last1 = Hemmings | first2 = Talmage D. | last2 = Egan | page = 209 |access-date=2016-09-30|isbn=978-1437716795 |year=2013 |publisher=Elsevier Health Sciences }} are very potent at the 5-HT₇ receptor. Antagonistic affinity for the H₁ receptor also has an antidepressant effect. H₁ antagonism blocks serotonin and norepinephrine reuptake. Patients with increased histamine levels have been observed to have lower serotonin levels.{{cite book|url=https://books.google.com/books?id=59fsAwAAQBAJ&pg=PA61 |title=Varcarolis' Foundations of Psychiatric Mental Health Nursing: A Clinical .. |author=Margaret Jordan Halter |page=61 |date= 2014-03-12|publisher=Elsevier Health Sciences |access-date=2016-09-30|isbn=9781455728886 }} However, the H₁ receptor is linked to weight gain. To have partial agonism at the 5-HT_1A receptor can yield absence of weight gain in an antipsychotic. This is very relevant for ziprasidone,{{cite book| title = Psychiatry, 2 Volume Set | last1 = Tasman | first1 = Allan | last2 = Kay | first2 = Jerald | last3 = First | first3 = Michael B. | last4 = Lieberman | first4 = Jeffrey A. | last5 = Riba| first5 = Michelle | date = 2015-03-30 | publisher = John Wiley & Sons | isbn = 978-1-118-84547-9 | url = https://books.google.com/books?id=YEkoBgAAQBAJ&pg=PA2096 }}{{cite web|url=https://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1a.pdf |archive-url=https://web.archive.org/web/20030308070927/http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1a.pdf |url-status=dead |archive-date=March 8, 2003 |title=FDA : Psychopharmacological Drugs Advisory Committee : Briefing Document for ZELDOX CAPSULES (Ziprasidone HCl) |date=July 19, 2000 |website=Fda.gov |access-date=2016-09-30}} but it creates a risk for a prolonged QTc interval.{{cite journal | vauthors = Wouters W, Tulp MT, Bevan P | title = Flesinoxan lowers blood pressure and heart rate in cats via 5-HT1A receptors | journal = European Journal of Pharmacology | volume = 149 | issue = 3 | pages = 213–23 | date = May 1988 | pmid = 2842163 | doi = 10.1016/0014-2999(88)90651-6 }}{{cite journal | vauthors = Horiuchi J, McDowall LM, Dampney RA | title = Role of 5-HT(1A) receptors in the lower brainstem on the cardiovascular response to dorsomedial hypothalamus activation | journal = Autonomic Neuroscience | volume = 142 | issue = 1–2 | pages = 71–6 | date = November 2008 | pmid = 18667366 | doi = 10.1016/j.autneu.2008.06.004 | s2cid = 20878941 }} On the other hand, blockade of the 5-HT₃ receptor removes the risk for a prolonged QTc interval, but then creates a larger risk for weight gain. Relation to the 5-HT₃ receptor increases caloric uptake and glucose,{{cite journal | vauthors = Weber S, Volynets V, Kanuri G, Bergheim I, Bischoff SC | title = Treatment with the 5-HT3 antagonist tropisetron modulates glucose-induced obesity in mice | journal = International Journal of Obesity | volume = 33 | issue = 12 | pages = 1339–47 | date = December 2009 | pmid = 19823183 | doi = 10.1038/ijo.2009.191 | doi-access = free }} which is seen in clozapine and olanzapine.{{cite journal|author1-link=Gabriella Gobbi | vauthors = Gobbi G, Janiri L | title = Clozapine blocks dopamine, 5-HT2 and 5-HT3 responses in the medial prefrontal cortex: an in vivo microiontophoretic study | journal = European Neuropsychopharmacology | volume = 10 | issue = 1 | pages = 43–9 | date = December 1999 | pmid = 10647096 | doi = 10.1016/S0924-977X(99)00055-3 | s2cid = 24251712 }}{{cite journal | vauthors = Navari RM | title = Olanzapine for the prevention and treatment of chronic nausea and chemotherapy-induced nausea and vomiting | journal = European Journal of Pharmacology | volume = 722 | pages = 180–6 | date = January 2014 | pmid = 24157985 | doi = 10.1016/j.ejphar.2013.08.048 }} Other ways for dopamine to resolve is to have agonism at both the D₂ receptor and 5-HT_1A receptor, which normalizes the dopamine level in the brain. This occurs with cariprazine and aripiprazole.

Whether the anhedonic, loss of pleasure and motivation effect resulting from dopamine insufficiency or blockade at D₂ receptors in the mesolimbic pathway, which is mediated in some part by antipsychotics (and despite dopamine release in the mesocortical pathway from 5-HT_2A antagonism, which is seen in atypical antipsychotics), or the positive mood, mood stabilization, and cognitive improvement effect resulting from atypical antipsychotic serotonergic activity is greater for the overall quality of life effect of an atypical antipsychotic is a question that is variable between individual experience and the atypical antipsychotic(s) being used.{{cite book|last1=Stahl|first1=Steven | title = Antipsychotics Explained 1 | publisher = University Psychiatry |url=https://universitypsychiatry.com/clientuploads/stahl/Stahl_3rd_ch10_Part1.pdf |archive-url=https://web.archive.org/web/20171107024320/https://universitypsychiatry.com/clientuploads/stahl/Stahl_3rd_ch10_Part1.pdf |archive-date=2017-11-07 }}

Inhibition. Disinhibition: The opposite process of inhibition, the turning on of a biological function. Release: Causes the appropriate neurotransmitters to be discharged in vesicles into the synapse where they attempt to bind to and activate a receptor. Downregulation and Upregulation.{{citation needed|date=March 2023}}

Note: Unless otherwise specified, the drugs below serve as antagonists/inverse agonists at the receptors listed.

Legend:

Atypical antipsychotics are most commonly administered orally.{{cite book |last1=McKim |first1=William |chapter=Antipsychotics |pages=241–260 |title=Drugs and Behavior: An Introduction to Behavioral Pharmacology |edition=6th |date=2007 |publisher=Prentice Hall |isbn=978-0-13-219788-5 |oclc=1301978997 |url=https://archive.org/details/drugsbehaviorint0000mcki_z4z0 }} Antipsychotics can also be injected, but this method is not as common. They are lipid-soluble, are readily absorbed from the digestive tract, and can easily pass the blood–brain barrier and placental barriers. Once in the brain, the antipsychotics work at the synapse by binding to the receptor.Culpepper, 2007{{full citation needed|date=August 2013}} Antipsychotics are completely metabolized in the body and the metabolites are excreted in urine. These drugs have relatively long half-lives. Each drug has a different half-life, but the occupancy of the D2 receptor falls off within 24 hours with atypical antipsychotics, while lasting over 24 hours for the typical antipsychotics. This may explain why relapse into psychosis happens quicker with atypical antipsychotics than with typical antipsychotics, as the drug is excreted faster and is no longer working in the brain. Physical dependence with these drugs is very rare. However, if the drug is abruptly discontinued, psychotic symptoms, movement disorders, and sleep difficulty may be observed. It is possible that withdrawal is rarely seen because the AAP are stored in body fat tissues and slowly released.

{{Pharmacokinetics of long-acting injectable antipsychotics}}

The first major tranquilizer or antipsychotic medication, chlorpromazine (Thorazine), a typical antipsychotic, was discovered in 1951 and introduced into clinical practice shortly thereafter. Clozapine (Clozaril), an atypical antipsychotic, fell out of favor due to concerns over drug-induced agranulocytosis. Following research indicating its effectiveness in treatment-resistant schizophrenia and the development of an adverse event monitoring system, clozapine re-emerged as a viable antipsychotic. According to Barker (2003), the three most-accepted atypical drugs are clozapine, risperidone, and olanzapine. However, he goes on to explain that clozapine is usually the last resort when other drugs fail. Clozapine can cause agranulocytosis (a decreased number of white blood cells), requiring blood monitoring for the patient. Despite the effectiveness of clozapine for treatment-resistant schizophrenia, agents with a more favorable side-effect profile were sought for widespread use. During the 1990s, olanzapine, risperidone, and quetiapine were introduced, with ziprasidone and aripiprazole following in the early 2000s. The atypical antipsychotic paliperidone was approved by the FDA in late 2006.{{Cite web |date=2006-12-19 |title=Approval Letter: 21-999 |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021999s000_APPROV.pdf |url-status=live |archive-url=https://web.archive.org/web/20160101215543/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021999s000_APPROV.pdf |archive-date=2016-01-01 |access-date=2025-02-22 |website=accessdata.fda.go}} The atypical antipsychotic asenapine (Saphris) was approved by the FDA in 2009.{{Cite web |date=2009-08-01 |title=Saphris (asenapine) prescribing information |url=http://www.spfiles.com/pisaphrisv1.pdf |url-status=dead |archive-url=https://web.archive.org/web/20091122102620/http://www.spfiles.com/pisaphrisv1.pdf |archive-date=2009-11-22 |access-date=2025-02-05 |publisher=Schering Corporation}}

The atypical antipsychotics have found favor among clinicians and are now considered to be first-line treatments for schizophrenia and are gradually replacing the typical antipsychotics. In the past, most researchers have agreed that the defining characteristics of atypical antipsychotics are the decreased incidence of extrapyramidal side effects (EPS){{cite journal | vauthors = Farah A | title = Atypicality of atypical antipsychotics | journal = Primary Care Companion to the Journal of Clinical Psychiatry | volume = 7 | issue = 6 | pages = 268–74 | year = 2005 | pmid = 16498489 | pmc = 1324958 | doi = 10.4088/PCC.v07n0602 }} and an absence of sustained prolactin elevation.

The terminology can still be imprecise. The definition of "atypicality" was based upon the absence of extrapyramidal side effects, but there is now a clear understanding that atypical antipsychotics can still induce these effects (though to a lesser degree than typical antipsychotics).{{cite journal | vauthors = Weiden PJ | title = EPS profiles: the atypical antipsychotics are not all the same | journal = Journal of Psychiatric Practice | volume = 13 | issue = 1 | pages = 13–24 | date = January 2007 | pmid = 17242588 | doi = 10.1097/00131746-200701000-00003 | s2cid = 46319827 }} Recent literature focuses more upon specific pharmacological actions and less upon categorization of an agent as "typical" or "atypical". There is no clear dividing line between the typical and atypical antipsychotics therefore categorization based on the action is difficult.

More recent research is questioning the notion that second-generation antipsychotics are superior to first generation typical antipsychotics. Using a number of parameters to assess quality of life, Manchester University researchers found that typical antipsychotics were no worse than atypical antipsychotics. The research was funded by the National Health Service (NHS) of the UK.{{cite journal | vauthors = Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP, Murray RM, Markwick A, Lewis SW | display-authors = 6 | title = Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1) | journal = Archives of General Psychiatry | volume = 63 | issue = 10 | pages = 1079–87 | date = October 2006 | pmid = 17015810 | doi = 10.1001/archpsyc.63.10.1079 | doi-access = free }} Because each medication (whether first or second generation) has its own profile of desirable and adverse effects, a neuropsychopharmacologist may recommend one of the older ("typical" or first generation) or newer ("atypical" or second generation) antipsychotics alone or in combination with other medications, based on the symptom profile, response pattern, and adverse effects history of the individual patient.

Between May 2007 and April 2008, 5.5 million Americans filled at least one prescription for an atypical antipsychotic.{{cite journal | vauthors = Cascade E, Kalali AH, Cummings JL | title = Use of atypical antipsychotics in the elderly | journal = Psychiatry | volume = 5 | issue = 7 | pages = 28–31 | date = July 2008 | pmid = 19727265 | pmc = 2695730 }} In patients under the age of 65, 71% of patients were prescribed an atypical antipsychotic to treat Schizophrenia or Bipolar Disorder where this dropped to 38% in patients aged 65 or above.

Despite the name "antipsychotics", the drugs are commonly used for a variety of conditions that do not involve psychosis. Some healthcare professionals reported avoiding the name "atypical antipsychotic" when prescribing the drug to patients who had bipolar disorder.{{cite journal |last1=Mattingly |first1=Greg |last2=Matthews-Hayes |first2=Tina |last3=Patel |first3=Mehul D. |last4=Kramer |first4=Kenneth |last5=Stahl |first5=Stephen M. |title=Do We Need a New Nomenclature for Atypical Antipsychotics? A Survey of Health Care Professionals and Patients |journal=The Primary Care Companion for CNS Disorders |date=2023 |volume=25 |issue=1 |pages=45835 |doi=10.4088/PCC.22m03331 |url=https://www.psychiatrist.com/pcc/do-we-need-a-new-nomenclature-for-atypical-antipsychotics-a-survey-of-health-care-professionals-and-patients/ |language=English |issn=2155-7780|doi-access=free |pmid=36821764 }}

{{Reflist|group=Note}}

Stahl: AP Explained 1

{{reflist|group=Stahl AP Explained 1 -}}

• List of antidepressants

{{Reflist|30em}}

{{refbegin}}

• {{cite journal | vauthors = Elmorsy E, Smith PA | title = Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics | journal = Biochemical and Biophysical Research Communications | volume = 460 | issue = 3 | pages = 857–62 | date = May 2015 | pmid = 25824037 | doi = 10.1016/j.bbrc.2015.03.122 | url = http://eprints.nottingham.ac.uk/43322/8/Bioen%20BBSRC_final.pdf | access-date = December 14, 2019 | archive-date = July 22, 2018 | archive-url = https://web.archive.org/web/20180722092306/http://eprints.nottingham.ac.uk/43322/8/Bioen%20BBSRC_final.pdf | url-status = dead }}
• {{cite journal | vauthors = Simpson GM | title = Atypical antipsychotics and the burden of disease | journal = The American Journal of Managed Care | volume = 11 | issue = 8 Suppl | pages = S235-41 | date = September 2005 | pmid = 16180961 }}
• [https://www.usatoday.com/news/health/2006-05-01-atypical-drugs_x.htm New antipsychotic drugs carry risks for children (USA Today 2006)]
• {{cite press release |title=NIMH Study to Guide Treatment Choices for Schizophrenia |publisher=National Institute of Mental Health |date=September 19, 2005 |url=http://www.nih.gov/news/pr/sep2005/nimh-19.htm |access-date=August 18, 2013 |url-status=dead |archive-url=https://web.archive.org/web/20130902024224/http://www.nih.gov/news/pr/sep2005/nimh-19.htm |archive-date=September 2, 2013 |df=mdy }}

{{refend}}

• {{Commons category-inline}}

{{Antipsychotics}}

{{Dopamine receptor modulators}}

{{Serotonin receptor modulators}}

{{DEFAULTSORT:Atypical Antipsychotic}}

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Category:Hallucinogen antidotes

Category:Psychopharmacology

Category:Treatment of psychosis