atypical antipsychotic atypical antipsychotic the atypical antipsychotics (aap), also known as second generation antipsychotics (sgas) and serotonin–dopamine antagonists (sdas), 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. atypical antipsychoticdrug classskeletal formula of clozapine, the first atypical antipsychotic (1972)synonymssecond generation antipsychotic, serotonin–dopamine antagonistin wikidata 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. 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." medical uses atypical antipsychotics are typically used to treat schizophrenia or bipolar disorder. they are also frequently used to treat agitation associated with dementia, anxiety disorder, autism spectrum disorder, and obsessive-compulsive disorder (an off-label use). in dementia, they should only be considered after other treatments have failed and if the patient is a risk to themselves and/or others. schizophrenia the first-line psychiatric treatment for schizophrenia is antipsychotic medication, 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. overall there is no good evidence that atypical antipsychotics have any therapeutic benefit for treating the negative symptoms of schizophrenia. there is very little evidence on which to base a risk and benefit assessment of using antipsychotics for long-term treatment. the choice of which antipsychotic to use for a specific patient is based on benefits, risks, and costs. it is debatable whether, as a class, typical or atypical antipsychotics are better. both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages. 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%. 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. in turn, risperidone, olanzapine, and aripiprazole have been recommended for the treatment of first-episode psychosis. 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. 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. 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). 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. compliance has not been shown to be different between the two types. 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. 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. each drug has its own mechanism, as rdr. if 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. 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. 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. major depressive disorder in non-psychotic major depressive disorder (mdd), some sgas have demonstrated significant efficacy as adjunctive agents; and, such agents include: aripiprazole brexpiprazole olanzapine quetiapine ziprasidone whereas only quetiapine has demonstrated efficacy as a monotherapy in non-psychotic mdd. olanzapine/fluoxetine is an efficacious treatment in both psychotic and non-psychotic mdd. aripiprazole, brexpiprazole, olanzapine, and quetiapine have been approved as adjunct treatment for mdd by the fda in the united states. quetiapine, lurasidone, and lumateperone 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. 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. in the subsequent 5 years, the use of atypical antipsychotics to treat dementia decreased by nearly 50%. comparison table of efficacy relative efficacy of sgas generic drug nameschizophreniamaniabipolar maintenancebipolar depressionadjunct in major depressive disorder amisulpride+++ ? ? ? ? (+++ as a dysthymia monotherapy, however) aripiprazole++++++/+-+++ asenapine+++++++ ? (some evidence has suggested efficacy in treating depressive symptoms in mixed/manic episodes) ? blonanserin++ ? ? ? ? cariprazine+++ ? ? ? ? clozapine++++++++++++ ? iloperidone+ ? ? ? ? lurasidone+ ? ?+++ ? melperone+++/++ ? ? ? ? olanzapine+++++++++++/++ (+++ when combined with fluoxetine)++ paliperidone++ ? ? ? ? perospirone+ ? ?? ? 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. among the other side effects that have been suggested is that atypical antipsychotics increase the risk of cardiovascular disease. kabinoff et al. 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. 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. 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. 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). atypical