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{{Short description|Class of pharmaceutical drugs}}{{cs1 config|name-list-style=vanc}}{{Use mdy dates|date=January 2012}}

factoids

The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs),JOURNAL, Miyake, N, Miyamoto, S, Jarskog, LF, New serotonin/dopamine antagonists for the treatment of schizophrenia: are we making real progress?, Clinical Schizophrenia & Related Psychoses, October 2012, 6, 3, 122–33, 10.3371/CSRP.6.3.4, 23006237, BOOK, Sadock, Benjamin J., Sadock, Virginia A., Ruiz, Pedro, 2014, Kaplan & Sadock’s Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 11th, Philadelphia, Wolters Kluwer, 318, 978-1-60913-971-1, 881019573, are a group of antipsychotic drugs (antipsychotic drugs in general are also known as tranquilizers and neuroleptics, although the latter is usually reserved for the typical antipsychotics) largely introduced after the 1970s and used to treat psychiatric conditions. Some atypical antipsychotics have received regulatory approval (e.g. by the FDA of the US, the TGA of Australia, the MHRA of the UK) for schizophrenia, bipolar disorder, irritability in autism, and as an adjunct in major depressive disorder.Both generations of medication tend to block receptors in the brain’s dopamine pathways. Atypicals are less likely than haloperidol—the most widely used typical antipsychotic—to cause extrapyramidal motor control disabilities in patients such as unsteady Parkinson’s disease–type movements, body rigidity, and involuntary tremors. However, only a few of the atypicals have been demonstrated to be superior to lesser-used, low-potency first-generation antipsychotics in this regard.JOURNAL, 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, 6, Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis, Lancet, 382, 9896, 951–62, September 2013, 23810019, 10.1016/S0140-6736(13)60733-3, 32085212, JOURNAL, A roadmap to key pharmacologic principles in using antipsychotics, Primary Care Companion to the Journal of Clinical Psychiatry, 9, 6, 444–54, 2007, 18185824, 2139919, 10.4088/PCC.v09n0607, As experience with these agents has grown, several studies have questioned the utility of broadly characterizing antipsychotic drugs as “atypical/second generation” as opposed to “first generation”, noting that each agent has its own efficacy and side-effect profile. It has been argued that a more nuanced view in which the needs of individual patients are matched to the properties of individual drugs is more appropriate. Although atypical antipsychotics are thought to be safer than typical antipsychotics, they still have severe side effects, including tardive dyskinesia (a serious movement disorder), neuroleptic malignant syndrome, and increased risk of stroke, sudden cardiac death, blood clots, and diabetes. Significant weight gain may occur. Critics have argued that “the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction.“JOURNAL, Tyrer P, Kendall T, The spurious advance of antipsychotic drug therapy, Lancet, 373, 9657, 4–5, January 2009, 19058841, 10.1016/S0140-6736(08)61765-1, 19951248,

Medical uses

Atypical antipsychotics are typically used to treat schizophrenia or bipolar disorder.WEB, Respiridone,www.drugs.com/monograph/risperidone.html, The American Society of Health-System Pharmacists, 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).JOURNAL, Maher AR, Maglione M, Bagley S, Suttorp M, Hu JH, Ewing B, Wang Z, Timmer M, Sultzer D, Shekelle PG, 6, Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis, JAMA, 306, 12, 1359–69, September 2011, 21954480, 10.1001/jama.2011.1360, free, BOOK, Persecutory delusions: assessment, theory, and treatment, Garety PA, Freeman DB, Bentall RP, Oxford University Press, 2008, 978-0-19-920631-5, Oxford [Oxfordshire], 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.JOURNAL, American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults, Journal of the American Geriatrics Society, 60, 4, 616–31, April 2012, 22376048, 3571677, 10.1111/j.1532-5415.2012.03923.x, American Geriatrics Society 2012 Beers Criteria Update Expert Panel,

Schizophrenia

The first-line psychiatric treatment for schizophrenia is antipsychotic medication,WEB,www.nice.org.uk/nicemedia/pdf/CG82FullGuideline.pdf, Schizophrenia: Full national clinical guideline on core interventions in primary and secondary care, 2009-11-25, National Collaborating Centre for Mental Health, 2009-03-25, 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.JOURNAL, Aleman A, Lincoln TM, Bruggeman R, Melle I, Arends J, Arango C, Knegtering H, Treatment of negative symptoms: Where do we stand, and where do we go?, Schizophrenia Research, 186, 55–62, August 2017, 27293137, 10.1016/j.schres.2016.05.015, 4907333,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.JOURNAL, Fusar-Poli P, Papanastasiou E, Stahl D, Rocchetti M, Carpenter W, Shergill S, McGuire P, Treatments of Negative Symptoms in Schizophrenia: Meta-Analysis of 168 Randomized Placebo-Controlled Trials, Schizophrenia Bulletin, 41, 4, 892–9, July 2015, 25528757, 4466178, 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.JOURNAL, Murray RM, Quattrone D, Natesan S, van Os J, Nordentoft M, Howes O, Di Forti M, Taylor D, 6, Should psychiatrists be more cautious about the long-term prophylactic use of antipsychotics?, The British Journal of Psychiatry, 209, 5, 361–365, November 2016, 27802977, 10.1192/bjp.bp.116.182683,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, Submitted manuscript, free, The choice of which antipsychotic to use for a specific patient is based on benefits, risks, and costs.JOURNAL, van Os J, Kapur S, Schizophrenia, Lancet, 374, 9690, 635–45, August 2009, 19700006, 10.1016/S0140-6736(09)60995-8, 208792724, It is debatable whether, as a class, typical or atypical antipsychotics are better.JOURNAL, Kane JM, Correll CU, Pharmacologic treatment of schizophrenia, Dialogues in Clinical Neuroscience, 12, 3, 345–57, 2010, 10.31887/DCNS.2010.12.3/jkane, 20954430, 3085113, Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages.JOURNAL, Schultz SH, North SW, Shields CG, Schizophrenia: a review, American Family Physician, 75, 12, 1821–9, June 2007, 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%.JOURNAL, Smith T, Weston C, Lieberman J, Schizophrenia (maintenance treatment), American Family Physician, 82, 4, 338–9, August 2010, 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.JOURNAL, Siskind D, McCartney L, Goldschlager R, Kisely S, Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis, The British Journal of Psychiatry, 209, 5, 385–392, November 2016, 27388573, 10.1192/bjp.bp.115.177261, free, In turn, risperidone, olanzapine, and aripiprazole have been recommended for the treatment of first-episode psychosis.JOURNAL, Robinson, Delbert G., Gallego, Juan A., John, Majnu, Petrides, Georgios, Hassoun, Youssef, Zhang, Jian-Ping, Lopez, Leonardo, Braga, Raphael J., Sevy, Serge M., Addington, Jean, Kellner, Charles H., 2015, A Randomized Comparison of Aripiprazole and Risperidone for the Acute Treatment of First-Episode Schizophrenia and Related Disorders: 3-Month Outcomes, Schizophrenia Bulletin, 41, 6, 1227–1236, 10.1093/schbul/sbv125, 1745-1701, 4601722, 26338693, JOURNAL, Gómez-Revuelta, Marcos, Pelayo-Terán, José María, Juncal-Ruiz, María, Vázquez-Bourgon, Javier, Suárez-Pinilla, Paula, Romero-Jiménez, Rodrigo, Setién Suero, Esther, Ayesa-Arriola, Rosa, Benedicto Crespo-Facorro, Crespo-Facorro, Benedicto, 2020-04-23, Antipsychotic Treatment Effectiveness in First Episode of Psychosis: PAFIP 3-Year Follow-Up Randomized Clinical Trials Comparing Haloperidol, Olanzapine, Risperidone, Aripiprazole, Quetiapine, and Ziprasidone, The International Journal of Neuropsychopharmacology, 23, 4, 217–229, 10.1093/ijnp/pyaa004, 1469-5111, 7177160, 31974576,

Efficacy in the treatment of schizophrenia

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.JOURNAL, Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM, Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis, Lancet, 373, 9657, 31–41, January 2009, 19058842, 10.1016/S0140-6736(08)61764-X, 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.JOURNAL, Alexander GC, Gallagher SA, Mascola A, Moloney RM, Stafford RS, Increasing off-label use of antipsychotic medications in the United States, 1995-2008, Pharmacoepidemiology and Drug Safety, 20, 2, 177–84, February 2011, 21254289, 3069498, 10.1002/pds.2082, JOURNAL, Geddes J, Freemantle N, Harrison P, Bebbington P, Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis, BMJ, 321, 7273, 1371–6, December 2000, 11099280, 27538, 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).JOURNAL, Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK, 6, Effectiveness of antipsychotic drugs in patients with chronic schizophrenia, The New England Journal of Medicine, 353, 12, 1209–23, September 2005, 16172203, 10.1056/NEJMoa051688, Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators,cdr.lib.unc.edu/downloads/g732dk11n, 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.JOURNAL, Stroup TS, Lieberman JA, McEvoy JP, Swartz MS, Davis SM, Rosenheck RA, Perkins DO, Keefe RS, Davis CE, Severe J, Hsiao JK, 6, Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic, The American Journal of Psychiatry, 163, 4, 611–22, April 2006, 16585435, 10.1176/appi.ajp.163.4.611, Compliance has not been shown to be different between the two types.JOURNAL, Voruganti LP, Baker LK, Awad AG, New generation antipsychotic drugs and compliance behaviour, Current Opinion in Psychiatry, 21, 2, 133–9, March 2008, 18332660, 10.1097/YCO.0b013e3282f52851, 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.JOURNAL, Paczynski RP, Alexander GC, Chinchilli VM, Kruszewski SP, Quality of evidence in drug compendia supporting off-label use of typical and atypical antipsychotic medications, The International Journal of Risk & Safety in Medicine, 24, 3, 137–46, January 2012, 22936056, 10.3233/JRS-2012-0567, JOURNAL, 10.1192/apt.bp.107.003970, 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, 2008, Owens DC, Advances in Psychiatric Treatment, 14, 17–28, free, JOURNAL, Fischer-Barnicol D, Lanquillon S, Haen E, Zofel P, Koch HJ, Dose M, Klein HE, Typical and atypical antipsychotics--the misleading dichotomy. Results from the Working Group ‘Drugs in Psychiatry’ (AGATE), Neuropsychobiology, 57, 1–2, 80–7, 2008, 18515977, 10.1159/000135641, Working Group ‘Drugs in Psychiatry’, 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.BOOK, Anatomy of an Epidemic, 978-0307452412, Robert, Whitaker, 2010, Crown, 303,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.WEB, Receptor occupancy and drug response: Understanding the relationship,www.mdedge.com/psychiatry/article/173556/schizophrenia-other-psychotic-disorders/receptor-occupancy-and-drug, 2022-10-14, www.mdedge.com, en,

Bipolar disorder

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.BOOK, Taylor D, Paton C, Kapur S, The Maudsley Prescribing Guidelines, 12th, Informa Healthcare, 2012, 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.WEB, Soreff S, McInnes LA, Ahmed I, Talavera F, Bipolar Affective Disorder Treatment & Management,emedicine.medscape.com/article/286342-treatment, Medscape Reference, WebMD, 10 October 2013, 5 August 2013, WEB, Post RM, Keck P, Bipolar Disorder in adults: Maintenance treatment,www.uptodate.com/contents/bipolar-disorder-in-adults-maintenance-treatment, UpToDate, Wolters Kluwer Health, 10 October 2013, 30 July 2013,

Major depressive disorder

In non-psychotic major depressive disorder (MDD), some SGAs have demonstrated significant efficacy as adjunctive agents; and, such agents include:JOURNAL, Komossa K, Depping AM, Gaudchau A, Kissling W, Leucht S, Second-generation antipsychotics for major depressive disorder and dysthymia, The Cochrane Database of Systematic Reviews, 12, CD008121, December 2010, 21154393, 10.1002/14651858.CD008121.pub2, JOURNAL, Spielmans GI, Berman MI, Linardatos E, Rosenlicht NZ, Perry A, Tsai AC, Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes, PLOS Medicine, 10, 3, e1001403, 2013, 23554581, 3595214, 10.1371/journal.pmed.1001403, free, JOURNAL, Nelson JC, Papakostas GI, Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials, The American Journal of Psychiatry, 166, 9, 980–91, September 2009, 19687129, 10.1176/appi.ajp.2009.09030312, free, WEB,www.fda.gov/Drugs/InformationOnDrugs/ucm456977.htm, Drug Approvals and Databases - Drug Trials Snapshots: REXULTI for the treatment of major depressive disorder, Research, Center for Drug Evaluation and, www.fda.gov, en, 2018-10-18,

• Aripiprazole
• Brexpiprazole
• Cariprazine
• Olanzapine
• Quetiapine
• ZiprasidoneJOURNAL, Papakostas GI, Fava M, Baer L, Swee MB, Jaeger A, Bobo WV, Shelton RC, Ziprasidone Augmentation of Escitalopram for Major Depressive Disorder: Efficacy Results From a Randomized, Double-Blind, Placebo-Controlled Study, The American Journal of Psychiatry, 172, 12, 1251–8, December 2015, 26085041, 4843798, 10.1176/appi.ajp.2015.14101251,

whereas only quetiapine has demonstrated efficacy as a monotherapy in non-psychotic MDD.JOURNAL, Maneeton N, Maneeton B, Srisurapanont M, Martin SD, Quetiapine monotherapy in acute phase for major depressive disorder: a meta-analysis of randomized, placebo-controlled trials, BMC Psychiatry, 12, 160, September 2012, 23017200, 3549283, 10.1186/1471-244X-12-160, free, Olanzapine/fluoxetine is an efficacious treatment in both psychotic and non-psychotic MDD.JOURNAL, Rothschild AJ, Williamson DJ, Tohen MF, Schatzberg A, Andersen SW, Van Campen LE, Sanger TM, Tollefson GD, 6, A double-blind, randomized study of olanzapine and olanzapine/fluoxetine combination for major depression with psychotic features, Journal of Clinical Psychopharmacology, 24, 4, 365–73, August 2004, 15232326, 10.1097/01.jcp.0000130557.08996.7a, 36295165, Aripiprazole, brexpiprazole, cariprazine, olanzapine, and quetiapine have been approved as adjunct treatment for MDD by the FDA in the United States.JOURNAL, Roberts RJ, Lohano KK, El-Mallakh RS, Antipsychotics as antidepressants, Asia-Pacific Psychiatry, 8, 3, 179–88, September 2016, 25963405, 10.1111/appy.12186, 24264818, WEB,www.otsuka-us.com/discover/fda-approves-otsukalundbecks-rexulti-as-adjunctive-treatment-for-adults-with-mdd-and-schizophrenia, 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 lumateperoneWEB, DailyMed - CAPLYTA- lumateperone capsule,dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=db730b06-6351-47fd-8183-e61e61bbead5, 2023-01-11, dailymed.nlm.nih.gov, have been approved, as monotherapies, for bipolar depression, but as of present, lurasidone has not been approved for MDD.

Autism

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.

Dementia and Alzheimer’s disease

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.JOURNAL, Ventimiglia J, Kalali AH, Vahia IV, Jeste DV, An analysis of the intended use of atypical antipsychotics in dementia, Psychiatry, 7, 11, 14–7, November 2010, 21191528, 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.

Comparison table of efficacy{| class“wikitable collapsible collapsed” style@width:100%;”

! colspan=6 | {{resize|115%|Relative efficacy of SGAs}}! Generic Drug NameJOURNAL, Cipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton S, Purgato M, Spineli LM, Goodwin GM, Geddes JR, 6, Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis, Lancet, 378, 9799, 1306–15, October 2011, 21851976, 10.1016/S0140-6736(11)60873-8, 25512763, JOURNAL, Bishara D, Taylor D, Asenapine monotherapy in the acute treatment of both schizophrenia and bipolar I disorder, Neuropsychiatric Disease and Treatment, 5, 483–90, 2009, 19851515, 2762364, 10.2147/ndt.s5742, free, !! Schizophrenia !! Mania !! Bipolar Maintenance !! Bipolar Depression !! Adjunct in Major Depressive Disorder

Amisulpride >				| ? (+++ as a dysthymia monotherapy, however)

Aripiprazole >					JOURNAL = ACTA PSYCHIATRICA SCANDINAVICA	ISSUE = 6	DATE = DECEMBER 2014	DOI = 10.1111/ACPS.12343	| +++

Asenapine >					JOURNAL = BMC PSYCHIATRY	PAGES = 101	PMID = 21689438	DOI = 10.1186/1471-244X-11-101	| ?

Blonanserin >				| ?

Cariprazine >				| ?

Clozapine >				| ?

Iloperidone >				| ?

Lurasidone >				| ?

Melperone >				| ?

Olanzapine >				| ++

Paliperidone >				| ?

PerospironeKISHI T, IWATA N	JOURNAL = CNS DRUGS	ISSUE = 9	DATE = SEPTEMBER 2013	DOI = 10.1007/S40263-013-0085-7					| ?

Quetiapine >				| ++

Risperidone >				| +

Sertindole >				| ?

Ziprasidone >				| ?

Zotepine >				| ?

Legend: - Inefficacious + Less effective than most treatments, but still with some efficacy. ++ Standard, in terms of efficacy, treatment. No convincing evidence to say it is superior to other standard treatments. +++ Very efficacious agent. The efficacy of this treatment in the indication in question has been proven to be significantly greater than many other treatments.

Adverse effects

The side effects reportedly associated with the various atypical antipsychotics vary and are medication-specific. Generally speaking, atypical antipsychotics are widely believed to have a lower likelihood for the development of tardive dyskinesia than the typical antipsychotics. 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.WEB, Stroup TS, Marder S, Stein MB, Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment,www.uptodate.com/contents/pharmacotherapy-for-schizophrenia-acute-and-maintenance-phase-treatment, UpToDate, Wolters Kluwer, 10 October 2013, 23 October 2013, Among the other side effects that have been suggested is that atypical antipsychotics increase the risk of cardiovascular disease.JOURNAL, Kabinoff GS, Toalson PA, Healey KM, McGuire HC, Hay DP, Metabolic Issues With Atypical Antipsychotics in Primary Care: Dispelling the Myths, Primary Care Companion to the Journal of Clinical Psychiatry, 5, 1, 6–14, February 2003, 15156241, 353028, 10.4088/PCC.v05n0103, Kabinoff and colleagues (2003) found 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.Sexual side effects have also been reported when taking atypical antipsychotics.JOURNAL, Uçok A, Gaebel W, Side effects of atypical antipsychotics: a brief overview, World Psychiatry, 7, 1, 58–62, February 2008, 18458771, 2327229, 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.JOURNAL, Dorsey ER, Rabbani A, Gallagher SA, Conti RM, Alexander GC, Impact of FDA black box advisory on antipsychotic medication use, Archives of Internal Medicine, 170, 1, 96–103, January 2010, 20065205, 4598075, 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.JOURNAL, Gerhard T, Huybrechts K, Olfson M, Schneeweiss S, Bobo WV, Doraiswamy PM, Devanand DP, Lucas JA, Huang C, Malka ES, Levin R, Crystal S, 6, Comparative mortality risks of antipsychotic medications in community-dwelling older adults, The British Journal of Psychiatry, 205, 1, 44–51, July 2014, 23929443, 10.1192/bjp.bp.112.122499, 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).JOURNAL, Steinberg M, Lyketsos CG, Atypical antipsychotic use in patients with dementia: managing safety concerns, The American Journal of Psychiatry, 169, 9, 900–6, September 2012, 22952071, 3516138, 10.1176/appi.ajp.2012.12030342,

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.JOURNAL, Obsessive-compulsive symptoms with olanzapine, The International Journal of Neuropsychopharmacology, 1 September 2004, 1461-1457, 15231024, 375–377, 7, 3, 10.1017/S1461145704004456, Basil, Alevizos, Charalambos, Papageorgiou, George N., Christodoulou, free, JOURNAL, Olanzapine induced de-novo obsessive compulsive disorder in a patient with schizophrenia, Indian Journal of Pharmacology, 1 January 2012, 0253-7613, 3480803, 23112432, 649–650, 44, 5, 10.4103/0253-7613.100406, Gajanan, Kulkarni, Janardhanan C., Narayanaswamy, Suresh Bada, Math, free, JOURNAL, Olanzapine and obsessive-compulsive symptoms, European Neuropsychopharmacology, 1 September 2000, 0924-977X, 10974610, 385–387, 10, 5, L., Lykouras, I. M., Zervas, R., Gournellis, M., Malliori, A., Rabavilas, 10.1016/s0924-977x(00)00096-1, 276209, JOURNAL, Clozapine-Induced Obsessive-Compulsive Symptoms in Schizophrenia: A Critical Review, Current Neuropharmacology, 1 March 2012, 1570-159X, 3286851, 22942882, 88–95, 10, 1, 10.2174/157015912799362724, Frederike, Schirmbeck, Mathias, Zink,

Tardive dyskinesia

All of the atypical antipsychotics warn about the possibility of tardive dyskinesia in their package inserts and in the PDR. It is not possible to truly know the risks of tardive dyskinesia when taking atypicals, because tardive dyskinesia can take many decades to develop and the atypical antipsychotics are not old enough to have been tested over a long enough period of time to determine all of the long-term risks. 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.JOURNAL, Seeman P, Atypical antipsychotics: mechanism of action, Canadian Journal of Psychiatry, 47, 1, 27–38, February 2002, 11873706, 10.1177/070674370204700106, free, The typical antipsychotics remain attached to the D2 receptors and accumulate in the brain tissue which may lead to TD.Both typical and atypical antipsychotics can cause tardive dyskinesia.JOURNAL, Correll CU, Schenk EM, Tardive dyskinesia and new antipsychotics, Current Opinion in Psychiatry, 21, 2, 151–6, March 2008, 18332662, 10.1097/YCO.0b013e3282f53132, 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.

Metabolism

Recently, metabolic concerns have been of grave 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.JOURNAL, Consensus development conference on antipsychotic drugs and obesity and diabetes, Diabetes Care, 27, 2, 596–601, February 2004, 14747245, 10.2337/diacare.27.2.596, North American Association for the Study of Obesity, free, 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-HT2C 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.BOOK, Brunton L, Chabner B, Knollman B, Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th, McGraw Hill Professional, 2010, 417–455, Recent evidence suggests a role of the α1 adrenoceptor and 5-HT2A receptor in the metabolic effects of atypical antipsychotics. The 5-HT2A receptor, however, is also believed to play a crucial role in the therapeutic advantages of atypical antipsychotics over their predecessors, the typical antipsychotics.JOURNAL, Guenette MD, Giacca A, Hahn M, Teo C, Lam L, Chintoh A, Arenovich T, Remington G, 6, Atypical antipsychotics and effects of adrenergic and serotonergic receptor binding on insulin secretion in-vivo: an animal model, Schizophrenia Research, 146, 1–3, 162–9, May 2013, 23499243, 10.1016/j.schres.2013.02.023, 43719333, The two atypical antipsychotics with trials showing that had a low incidence of weight gain in large meta-analysis were lurasidone and aripiprazole.JOURNAL, Ng-Mak, Daisy, Tongbram, Vanita, Ndirangu, Kerigo, Rajagopalan, Krithika, Loebel, Antony, 2018-08-01, Efficacy and metabolic effects of lurasidone versus brexpiprazole in schizophrenia: a network meta-analysis, Journal of Comparative Effectiveness Research, 7, 8, 737–748, 10.2217/cer-2018-0016, 29697278, 13769615, 2042-6305, 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.JOURNAL, Pillinger, Toby, McCutcheon, Robert A., Vano, Luke, Mizuno, Yuya, Arumuham, Atheeshaan, Hindley, Guy, Beck, Katherine, Natesan, Sridhar, Efthimiou, Orestis, Cipriani, Andrea, Howes, Oliver D., 2020-01-01, 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, The Lancet Psychiatry, English, 7, 1, 64–77, 10.1016/S2215-0366(19)30416-X, 2215-0366, 31860457, 7029416, 209434994, free, Aripiprazole, asenapine, ziprazidone and lurasidone have low propensity to cause weight gain.Dayabandara M, Hanwella R, Ratnatunga S, Seneviratne S, Suraweera C, de Silva VA. Antipsychotic-associated weight gain: management strategies and impact on treatment adherence. Neuropsychiatr Dis Treat. 2017 Aug 22;13:2231-2241. doi: 10.2147/NDT.S113099. PMID: 28883731; PMCID: PMC5574691. Lumateperone was found to cause minimal weight gain in a long-term 12 month follow-up study.Satlin A, Durgam S, Vanover KE, Davis RE, Huo J, Mates S, Correll C. M205. LONG-TERM SAFETY OF LUMATEPERONE (ITI-007): METABOLIC EFFECTS IN A 1-YEAR STUDY. Schizophr Bull. 2020 May;46(Suppl 1):S214. doi: 10.1093/schbul/sbaa030.517. Epub 2020 May 18. PMCID: PMC7234755.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 it is a causal relationship the Kabinoff et al. suggest 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.JOURNAL, Wang, Yewei, Wang, Dandan, Cheng, Jie, Fang, Xinyu, Chen, Yan, Yu, Lingfang, Ren, Juanjuan, Tian, Yuan, Zhang, Chen, Efficacy and tolerability of pharmacological interventions on metabolic disturbance induced by atypical antipsychotics in adults: A systematic review and network meta-analysis, Journal of Psychopharmacology, September 2021, 35, 9, 1111–1119, 10.1177/02698811211035391, 34311625, 236451973, Despite increasing some risk factors, SGAs are not associated with excess cardiovascular mortality when used to treat serious psychiatric disorders.JOURNAL, Goldstein, Benjamin I., Baune, Bernhard T., Bond, David J., Chen, Pao-Huan, Eyler, Lisa, Fagiolini, Andrea, Gomes, Fabiano, Hajek, Tomas, Hatch, Jessica, McElroy, Susan L., McIntyre, Roger S., Prieto, Miguel, Sylvia, Louisa G., Tsai, Shang-Ying, Kcomt, Andrew, Fiedorowicz, Jess G., Call to action regarding the vascular-bipolar link: A report from the Vascular Task Force of the International Society for Bipolar Disorders, Bipolar Disorders, August 2020, 22, 5, 440–460, 10.1111/bdi.12921, free, 32356562, 7522687, 11343/251495, free,

Comparison table of adverse effects{| class“wikitable collapsible collapsed” style@width:100%;”

! colspan=15 | {{resize|115%|Comparison of side effects for atypical antipsychotics}}! Generic Name !! Weight gain !! Metabolic Effects !! EPS !! High prolactin !! Sedation !! Hypotension / Orthostasis !! QTc prolongation !! Anti-ACh effects !! Other adverse effects! Amisulpride

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| Seizures, suicidal ideation

! Aripiprazole

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anxiety, rhabdomyolysis, pancreatitis (30%}} >

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Pancreatitis>Acute haemorrhagic pancreatitis, immune hypersensitivity reaction, seizures (0.9%), status epilepticus, suicidal ideation (0.1–1%)

! Paliperidone

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| Agranulocytosis, leukopenia, priapism, dysphagia, hyperprolactinaemia, sexual dysfunction

! Perospirone

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Creatine phosphokinase>CPK elevation neuroleptic malignant syndrome

! Quetiapine

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| Agranulocytosis, leukopenia, neutropenia (0.3%), anaphylaxis, seizures (0.05–0.5%), priapism, tardive dyskinesia (0.1–5%), suicidal ideation, pancreatitis, syncope (0.3–1%)

! RemoxiprideJOURNAL, Holm AC, Edsman I, Lundberg T, Odlind B, Tolerability of remoxipride in the long term treatment of schizophrenia. An overview, Drug Safety, 8, 6, 445–56, June 1993, 8329149, 10.2165/00002018-199308060-00005, 43855244,

blue						blue			|There is a risk of aplastic anaemia risk which is what led to its removal from the market.

! Risperidone

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hyperprolactinaemia, sexual dysfunction,PARK YW, KIM Y, LEE JH

JOURNAL = THE WORLD JOURNAL OF MEN’S HEALTH

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DATE = DECEMBER 2012

PMC = 3623530, 10.5534/wjmh.2012.30.3.153, thrombotic thrombocytopenic purpura, cerebrovascular incident (