Antipsychotic

Template:Short description Template:Cs1 config Template:Use dmy dates Template:Infobox drug class Antipsychotics, previously known as neuroleptics<ref name=Fin2009>Template:Cite book</ref> and major tranquilizers,<ref>Template:Cite journal</ref> are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of other psychotic disorders.<ref name="Comparing 1-year effectiveness and">Template:Cite journal</ref><ref>Template:Cite journal</ref> They are also the mainstay, together with mood stabilizers, in the treatment of bipolar disorder.<ref name="Grande">Template:Cite journal</ref> Moreover, they are also used as adjuncts in the treatment of treatment-resistant major depressive disorder.

The use of antipsychotics may result in many unwanted side effects such as involuntary movement disorders, gynecomastia, impotence, weight gain and metabolic syndrome. Long-term use can produce adverse effects such as tardive dyskinesia, tardive dystonia, tardive akathisia, and brain tissue volume reduction.

The long term use of antipsychotics often changes the brain both structurally and chemically in a way that can be difficult or impossible to reverse. This can lead to long term or permanent dependence on the drug.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

First-generation antipsychotics (e.g., chlorpromazine, haloperidol, etc.), known as typical antipsychotics, were first introduced in the 1950s, and others were developed until the early 1970s.<ref name="Shen">Template:Cite journal</ref> Second-generation antipsychotics, known as atypical antipsychotics, arrived with the introduction of clozapine in the early 1970s followed by others (e.g., risperidone, olanzapine, etc.).<ref name="Aringhieri">Template:Cite journal</ref> Both generations of medication block receptors in the brain for dopamine, but atypicals block serotonin receptors as well. Third-generation antipsychotics were introduced in the 2000s and offer partial agonism, rather than blockade, of dopamine receptors.<ref name=":0" /> Neuroleptic, originating from Template:Langx (neuron) and {{#invoke:Lang|lang}} (take hold of)—thus meaning "which takes the nerve"—refers to both common neurological effects and side effects.<ref name="king" /> Template:TOC limit

Medical uses

Antipsychotics are most frequently used for the following conditions:

• Schizophrenia<ref name="Comparing 1-year effectiveness and"/>
• Schizoaffective disorder most commonly in conjunction with either an antidepressant (in the case of the depressive subtype) or a mood stabilizer (in the case of the bipolar subtype). Antipsychotics possess mood stabilizing properties and thus they may be used as standalone medication to treat mood dysregulation.
• Bipolar disorder (acute mania and mixed episodes) may be treated with either typical or atypical antipsychotics, although atypical antipsychotics are usually preferred because they tend to have more favourable adverse effect profiles<ref name=Lancet2009/> and, according to a recent meta-analysis, they tend to have a lower liability for causing conversion from mania to depression.<ref name="Haldep">Template:Cite journal</ref>
• Psychotic depression. In this indication it is a common practice for the psychiatrist to prescribe a combination of an atypical antipsychotic and an antidepressant as this practice is best supported by the evidence.<ref name = Maudsley/>
• Treatment-resistant depression as an adjunct to standard antidepressant therapy.<ref name = Maudsley />

Given the limited options available to treat the behavioral problems associated with dementia, other pharmacological and non-pharmacological interventions are usually attempted before using antipsychotics. A risk-to-benefit analysis is performed to weigh the risk of the adverse effects of antipsychotics versus: the potential benefit, the adverse effects of alternative interventions, and the risk of failing to intervene when a patient's behavior becomes unsafe.<ref name=Choose2013>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The same can be said for insomnia, in which they are not recommended as first-line therapy.<ref name=Choose2013/> There are evidence-based indications for using antipsychotics in children (e.g., tic disorder, bipolar disorder, psychosis), but the use of antipsychotics outside of those contexts (e.g., to treat behavioral problems) warrants significant caution.<ref name=Choose2013/>

Antipsychotics are used to treat tics associated with Tourette syndrome.<ref>Template:Cite journal</ref> Aripiprazole, an atypical antipsychotic, is used as add-on medication to ameliorate sexual dysfunction as a symptom of selective serotonin reuptake inhibitor (SSRI) antidepressants in women.<ref>Template:Cite journal</ref>Template:Rp Quetiapine is used to treat generalized anxiety disorder.<ref>Template:Cite journal</ref>

Schizophrenia

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Antipsychotic drug treatment is a key component of schizophrenia treatment recommendations by the National Institute of Health and Care Excellence (NICE),<ref name="NICE">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> the American Psychiatric Association,<ref name = "APA">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and the British Society for Psychopharmacology.<ref name = "BAP">Template:Cite journal</ref> The main aim of treatment with antipsychotics is to reduce the positive symptoms of psychosis, that include delusions and hallucinations.<ref name="Comparing 1-year effectiveness and"/> There is mixed evidence to support a significant impact of antipsychotic use on primary negative symptoms (such as apathy, lack of emotional affect, and lack of interest in social interactions) or on cognitive symptoms (memory impairments, reduced ability to plan and execute tasks).<ref>Template:Cite journal</ref><ref name="ReferenceA">Template:Cite journal</ref> In general, the efficacy of antipsychotic treatment in reducing positive symptoms appears to increase with the severity of baseline symptoms.<ref>Template:Cite journal</ref> All antipsychotic medications work relatively the same way: by antagonizing D2 dopamine receptors. However, there are some differences when it comes to typical and atypical antipsychotics. For example, atypical antipsychotic medications have been seen to lower the neurocognitive impairment associated with schizophrenia more than conventional antipsychotics, although the reasoning and mechanics of this are still unclear to researchers.<ref>Template:Cite journal</ref>

Applications of antipsychotic drugs in the treatment of schizophrenia include prophylaxis for those showing symptoms that suggest that they are at high risk of developing psychosis; treatment of first-episode psychosis; maintenance therapy (a form of prophylaxis, maintenance therapy aims to maintain therapeutic benefit and prevent symptom relapse); and treatment of recurrent episodes of acute psychosis.<ref name="Comparing 1-year effectiveness and"/><ref name = BAP /> A recent 2024 study found that using high doses of antipsychotics for schizophrenia was linked to a higher risk of mortality.<ref>Template:Cite journal</ref> Researchers analyzed data from 32,240 individuals aged 17 to 64 diagnosed with schizophrenia between 2002 and 2012 to arrive at this conclusion.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Prevention of psychosis and symptom improvement

Test batteries such as the PACE (Personal Assessment and Crisis Evaluation Clinic) and COPS (Criteria of Prodromal Syndromes), which measure low-level psychotic symptoms and cognitive disturbances, are used to evaluate people with early, low-level symptoms of psychosis. Test results are combined with family history information to identify patients in the "high-risk" group; they are considered to have a 20–40% risk of progression to frank psychosis within two years.<ref name = BAP/> These patients are often treated with low doses of antipsychotic drugs with the goal of reducing their symptoms and preventing progression to frank psychosis. While generally useful for reducing symptoms, clinical trials to date show little evidence that early use of antipsychotics improves long-term outcomes in those with prodromal symptoms, either alone or in combination with cognitive-behavioral therapy.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

First-episode psychosis

First-episode psychosis (FEP) is the first time that psychotic symptoms are presented. NICE recommends that all people presenting with first-episode psychosis be treated with both an antipsychotic drug and cognitive behavioral therapy (CBT). NICE further recommends that those expressing a preference for CBT alone be informed that combination treatment is more effective.<ref name = NICE /> A diagnosis of schizophrenia is not made at this time as it takes longer to be determined by both DSM-5 and ICD-11, and only around 60% of those presenting with a first episode of psychosis will later be diagnosed with schizophrenia.<ref name="McGorry">Template:Cite journal</ref>

The conversion rate for a first episode of drug induced psychosis to bipolar disorder or schizophrenia is lower, with 30% of people converting to either bipolar disorder or schizophrenia.<ref name="drug">Template:Cite journal</ref> NICE makes no distinction between substance-induced psychosis and any other form of psychosis. The rate of conversion differs for different classes of drugs.<ref name="drug"/>

Pharmacological options for the specific treatment of FEP have been discussed in recent reviews.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> The goals of treatment for FEP include reducing symptoms and potentially improving long-term treatment outcomes. Randomized clinical trials have provided evidence for the efficacy of antipsychotic drugs in achieving the former goal, with first-generation and second generation antipsychotics showing about equal efficacy. The evidence that early treatment has a favorable effect on long-term outcomes is equivocal.<ref name = NICE /><ref name = BAP />

Recurrent psychotic episodes

Placebo-controlled trials of both first- and second-generation antipsychotic drugs consistently demonstrate the superiority of active drugs over placebos in suppressing psychotic symptoms.<ref name = BAP /> A large meta-analysis of 38 trials of antipsychotic drugs in schizophrenia with acute psychotic episodes showed an effect size of about 0.5.<ref>Template:Cite journal</ref> There is little or no difference in efficacy among approved antipsychotic drugs, including both first- and second-generation agents.<ref name = NICE /><ref name = "Leucht_2013">Template:Cite journal</ref> The efficacy of such drugs is suboptimal. Few patients achieve complete resolution of symptoms. Response rates, calculated using various cutoff values for symptom reduction, are low, and their interpretation is complicated by high placebo response rates and selective publication of clinical trial results.<ref>Template:Cite journal</ref>

Maintenance therapy

The majority of patients treated with an antipsychotic drug will experience a response within four weeks. The goals of continuing treatment are to maintain suppression of symptoms, prevent relapse, improve quality of life, and support engagement in psychosocial therapy.<ref name="Comparing 1-year effectiveness and"/><ref name = BAP />

Maintenance therapy with antipsychotic drugs is clearly superior to placebo in preventing relapse but is associated with weight gain, movement disorders, and high dropout rates.<ref name="Ceraso_2020">Template:Cite journal</ref> A 3-year trial following persons receiving maintenance therapy after an acute psychotic episode found that 33% obtained long-lasting symptom reduction, 13% achieved remission, and only 27% experienced satisfactory quality of life. The effect of relapse prevention on long term outcomes is uncertain, as historical studies show little difference in long term outcomes before and after the introduction of antipsychotic drugs.<ref name = BAP />

While maintenance therapy clearly reduces the rate of relapses requiring hospitalization, a large observational study in Finland found that, in people that eventually discontinued antipsychotics, the risk of being hospitalized again for a mental health problem or dying increased the longer they were dispensed (and presumably took) antipsychotics prior to stopping therapy. If people did not stop taking antipsychotics, they remained at low risk for relapse and hospitalization compared to those that did.<ref name="Tiihonen Tanskanen Taipale 2018 pp. 765–773">Template:Cite journal</ref> The authors speculated that the difference may be because the people that discontinued treatment after a longer time had more severe mental illness than those that discontinued antipsychotic therapy sooner.<ref name="Tiihonen Tanskanen Taipale 2018 pp. 765–773" />

A significant challenge in the use of antipsychotic drugs for the prevention of relapse is the poor rate of adherence.<ref name="Comparing 1-year effectiveness and"/> In spite of the relatively high rates of adverse effects associated with these drugs, some evidence, including higher dropout rates in placebo arms compared to treatment arms in randomized clinical trials, suggests that most patients who discontinue treatment do so because of suboptimal efficacy.<ref name="Ceraso_2020" /><ref>Template:Cite journal</ref> If someone experiences psychotic symptoms due to nonadherence, they may be compelled to receive treatment through a process called involuntary commitment, in which they can be forced to accept treatment (including antipsychotics). A person can also be committed to treatment outside of a hospital, called outpatient commitment.

Antipsychotics in long-acting injectable (LAI), or "depot", form have been suggested as a method of decreasing medication nonadherence (sometimes also called non-compliance).<ref name="Comparing 1-year effectiveness and"/><ref name="lai">Template:Cite journal</ref> NICE advises LAIs be offered to patients when preventing covert, intentional nonadherence is a clinical priority.<ref name="nice-full-guidelines">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> LAIs are used to ensure adherence in outpatient commitment.<ref name="Comparing 1-year effectiveness and"/><ref name="cto">Template:Cite journal</ref> A meta-analysis found that LAIs resulted in lower rates of rehospitalization with a hazard ratio of 0.83; however, these results were not statistically significant (the 95% confidence interval was 0.62 to 1.11).<ref name="lai"/>

Bipolar disorder

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Antipsychotics are routinely used, often in conjunction with mood stabilizers such as lithium/valproate, as a first-line treatment for manic and mixed episodes associated with bipolar disorder.<ref name= "Maudsley">Template:Cite book</ref><ref name= Young >Template:Cite book</ref> The reason for this combination is the therapeutic delay of the aforementioned mood stabilizers (for valproate therapeutic effects are usually seen around five days after treatment is commenced whereas lithium usually takes at least a week<ref name = "Young" /> before the full therapeutic effects are seen) and the comparatively rapid antimanic effects of antipsychotic drugs.<ref name="pmid20402706">Template:Cite journal</ref> The antipsychotics have a documented efficacy when used alone in acute mania/mixed episodes.<ref name=Lancet2009/>

At least five atypical antipsychotics (lumateperone,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> cariprazine,<ref>Template:Cite journal</ref> lurasidone,<ref name="Lur">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> olanzapine,<ref name="OLD">Template:Cite journal</ref> and quetiapine<ref name = "QuetD">Template:Cite journal</ref>) have also been found to possess efficacy in the treatment of bipolar depression as a monotherapy, whereas only olanzapine<ref name="OlanM">Template:Cite journal</ref> and quetiapine<ref name="QuetM1">Template:Cite journal</ref><ref name="QuetM2">Template:Cite journal</ref> have been proven to be effective broad-spectrum (i.e., against all three types of relapse—manic, mixed and depressive) prophylactic (or maintenance) treatments in patients with bipolar disorder. A recent Cochrane review also found that olanzapine had a less favourable risk/benefit ratio than lithium as a maintenance treatment for bipolar disorder.<ref>Template:Cite journal</ref>

The American Psychiatric Association and the UK National Institute for Health and Care Excellence recommend antipsychotics for managing acute psychotic episodes in schizophrenia or bipolar disorder, and as a longer-term maintenance treatment for reducing the likelihood of further episodes.<ref name="pmid15000267">Template:Cite journal</ref><ref name="Centre">Template:Cite journal</ref> They state that response to any given antipsychotic can be variable so that trials may be necessary, and that lower doses are to be preferred where possible. A number of studies have looked at levels of "compliance" or "adherence" with antipsychotic regimes and found that discontinuation (stopping taking them) by patients is associated with higher rates of relapse, including hospitalization.

Dementia

Psychosis and agitation develop in as many as 80 percent of people living in nursing homes.<ref name="pmid21191528" /> Despite a lack of FDA approval and black-box warnings, atypical antipsychotics are very often prescribed to people with dementia.<ref name="pmid21191528" /> An assessment for an underlying cause of behavior is needed before prescribing antipsychotic medication for symptoms of dementia.<ref>Template:Citation.</ref> Antipsychotics in old age dementia showed a modest benefit compared to placebo in managing aggression or psychosis, but this is combined with a fairly large increase in serious adverse events. Thus, antipsychotics should not be used routinely to treat dementia with aggression or psychosis, but may be an option in a few cases where there is severe distress or risk of physical harm to others.<ref>Template:Cite journal</ref> Psychosocial interventions may reduce the need for antipsychotics.<ref>Template:Cite journal</ref> In 2005, the FDA issued an advisory warning of an increased risk of death when atypical antipsychotics are used in dementia.<ref name="pmid21191528">Template:Cite journal</ref> In the subsequent 5 years, the use of atypical antipsychotics to treat dementia decreased by nearly 50%.<ref name="pmid21191528" />

Major depressive disorder

A number of atypical antipsychotics have some benefits when used in addition to other treatments in major depressive disorder.<ref name = "Cochrane Dep">Template:Cite journal</ref><ref name="Plos">Template:Cite journal</ref> Aripiprazole, quetiapine extended-release, and olanzapine (when used in conjunction with fluoxetine) have received the Food and Drug Administration (FDA) labelling for this indication.<ref name = "DrugPoint">Truven Health Analytics, Inc. DrugPoint System (Internet) [cited 2013 Oct 2]. Greenwood Village, CO: Thomsen Healthcare; 2013.</ref> There is, however, a greater risk of side effects with their use compared to using traditional antidepressants.<ref name = "Cochrane Dep"/> The greater risk of serious side effects with antipsychotics is why, e.g., quetiapine was denied approval as monotherapy for major depressive disorder or generalized anxiety disorder, and instead was only approved as an adjunctive treatment in combination with traditional antidepressants.<ref name="AACAP FDA Psychopharm QTP Recap">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

A recent study on the use of antipsychotics in unipolar depression concluded that the use of those drugs in addition to antidepressants alone leads to a worse disease outcome. This effect is especially pronounced in younger patients with psychotic unipolar depression. Considering the wide use of such combination therapies, further studies on the side effects of antipychotics as an add-on therapy are warranted.<ref>Template:Cite journal</ref>

Other

Global antipsychotic utilization has seen a steady growth since the introduction of atypical (second-generation) antipsychotics and this is ascribed to off-label use for many other unapproved disorders.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Besides the above uses antipsychotics may be used for obsessive–compulsive disorder, post-traumatic stress disorder, personality disorders, Tourette syndrome, autism and agitation in those with dementia.<ref name=Rand2012/> Evidence however does not support the use of atypical antipsychotics in eating disorders or personality disorder.<ref name="Off-Label Use">Template:Cite book</ref> The atypical antipsychotic risperidone may be useful for obsessive–compulsive disorder.<ref name=Rand2012>Template:Cite journal</ref> The use of low doses of antipsychotics for insomnia, while common, is not recommended as there is little evidence of benefit as well as concern regarding adverse effects.<ref name="Off-Label Use"/><ref>Template:Cite journal</ref> Some of the more serious adverse effects may also occur at the low doses used, such as dyslipidemia and neutropenia,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and a recent network meta-analysis of 154 double-blind, randomized controlled trials of drug therapies vs. placebo for insomnia in adults found that quetiapine did not demonstrated any short-term benefits in sleep quality.<ref>Template:Cite journal</ref> Low dose antipsychotics may also be used in treatment of impulse-behavioural and cognitive-perceptual symptoms of borderline personality disorder.<ref>Template:Cite book</ref> Despite the lack of evidence supporting the benefit of antipsychotics in people with personality disorders, 1 in 4 who do not have a serious mental illness are prescribed them in UK primary care. Many people receive these medication for over a year, contrary to NICE guidelines.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

In children they may be used in those with disruptive behavior disorders, mood disorders and pervasive developmental disorders or intellectual disability.<ref>Template:Cite journal</ref> Antipsychotics are only weakly recommended for Tourette syndrome, because although they are effective, side effects are common.<ref>Template:Cite journal</ref> The situation is similar for those on the autism spectrum.<ref>Template:Cite journal</ref> Much of the evidence for the off-label use of antipsychotics (for example, for dementia, OCD, PTSD, personality disorders, Tourette's) was of insufficient scientific quality to support such use, especially as there was strong evidence of increased risks of stroke, tremors, significant weight gain, sedation, and gastrointestinal problems.<ref>Template:Cite press release</ref> A UK review of unlicensed usage in children and adolescents reported a similar mixture of findings and concerns.<ref>Template:Cite journal</ref> A survey of children with pervasive developmental disorder found that 16.5% were taking an antipsychotic drug, most commonly for irritability, aggression, and agitation. Both risperidone and aripiprazole have been approved by the US FDA for the treatment of irritability in autistic children and adolescents.<ref name = DD>Truven Health Analytics, Inc. DRUGDEX System (Internet) [cited 2013 Oct 10]. Greenwood Village, CO: Thomsen Healthcare; 2013.</ref> A review in the UK found that the use of antipsychotics in England doubled between 2000 and 2019. Children were prescribed antipsychotics for conditions for which there is no approval, such as autism.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Aggressive challenging behavior in adults with intellectual disability is often treated with antipsychotic drugs despite lack of an evidence base. A recent randomized controlled trial, however, found no benefit over placebo and recommended that the use of antipsychotics in this way should no longer be regarded as an acceptable routine treatment.<ref>Template:Cite journal</ref>

Antipsychotics may be an option, together with stimulants, in people with ADHD and aggressive behavior when other treatments have not worked.<ref>Template:Cite journal</ref> They have not been found to be useful for the prevention of delirium among those admitted to hospital.<ref>Template:Cite journal</ref>

Typicals vs atypicals

Aside from reduced extrapyramidal symptoms, and with the clear exception of clozapine, it is unclear whether the atypical (second-generation) antipsychotics offer advantages over older, first generation antipsychotics.<ref name="Comparing 1-year effectiveness and"/><ref name="ReferenceA"/><ref>Template:Cite journal</ref> Amisulpride, olanzapine, risperidone and clozapine may be more effective but are associated with greater side effects.<ref name="barry 2012">Template:Cite journal</ref> Typical antipsychotics have equal drop-out and symptom relapse rates to atypicals when used at low to moderate dosages.<ref name=AFP07>Template:Cite journal</ref>

Clozapine is an effective treatment for those who respond poorly to other drugs ("treatment-resistant" or "refractory" schizophrenia),<ref>Template:Cite journal</ref> but it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people.<ref>Template:Cite journal</ref>

Due to bias in the research the accuracy of comparisons of atypical antipsychotics is a concern.<ref>Template:Cite journal</ref>

In 2005, a US government body, the National Institute of Mental Health published the results of a major independent study (the CATIE project).<ref>Template:Cite journal</ref> No other atypical studied (risperidone, quetiapine, and ziprasidone) did better than the first-generation antipsychotic perphenazine on the measures used, nor did they produce fewer adverse effects than the typical antipsychotic perphenazine, although more patients discontinued perphenazine owing to extrapyramidal effects compared to the atypical agents (8% vs. 2% to 4%).<ref name=Lancet2009>Template:Cite journal</ref> This is significant because any patient with tardive dyskinesia was specifically excluded from randomization to perphenazine; i.e., in the CATIE study the patient cohort randomized to receive perphenazne was at lower risk of having extrapyramidal symptoms.<ref>Template:Cite journal</ref>

Atypical antipsychotics do not appear to lead to improved rates of medication adherence compared to typical antipsychotics.<ref>Template:Cite journal</ref>

Many researchers question the first-line prescribing of atypicals over typicals, and some even question the distinction between the two classes.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> In contrast, other researchers point to the significantly higher risk of tardive dyskinesia and other extrapyramidal symptoms with the typicals and for this reason alone recommend first-line treatment with the atypicals, notwithstanding a greater propensity for metabolic adverse effects in the latter.<ref name="pmid10190226">Template:Cite journal</ref> The UK government organization NICE recently revised its recommendation favoring atypicals, to advise that the choice should be an individual one based on the particular profiles of the individual drug and on the patient's preferences.

The re-evaluation of the evidence has not necessarily slowed the bias toward prescribing the atypicals.<ref name="pmid20098227">Template:Cite journal</ref>

Other uses

Antipsychotics, such as risperidone, quetiapine, and olanzapine, have been used as hallucinogen antidotes or "trip killers" to block the effects of serotonergic psychedelics like psilocybin and lysergic acid diethylamide (LSD).<ref name="HalmanKongSarris2024">Template:Cite journal</ref><ref name="YatesMelon2024">Template:Cite journal</ref><ref name="Suran2024">Template:Cite journal</ref><ref name="VollenweiderVollenweider-ScherpenhuyzenBäbler1998">Template:Cite journal</ref>

Adverse effects

Generally, more than one antipsychotic drug should not be used at a time because of increased adverse effects.<ref name="APAfive polypharmacy">Template:Citation, which cites

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Use of antipsychotics is associated with reductions in brain tissue volumes,<ref name="Ho">Template:Cite journal</ref><ref name="Moncrieff">Template:Cite journal</ref> including white matter reduction,<ref name="Chopra">Template:Cite journal</ref> an effect which is dose-dependent and time-dependent.<ref name="Ho" /><ref name="Moncrieff" /> However, a recent controlled trial suggests that second generation antipsychotics<ref>please see Chopra et al 2021: Strengths and limitations "only examined risperidone and paliperidone"</ref> combined with intensive psychosocial therapy<ref>please see Chopra et al 2021: Method Study design</ref> may potentially prevent pallidal brain volume loss in first episode psychosis.<ref>please see Chopra et al 2021: Introduction, 3rd paragraph, Lieberman JA, et al. 2005 & Shao Y et al 2015, and Chopra et al: Are antipsychotics neuroprotective? 1st paragraph last sentence</ref><ref name="Chopra" />

Some atypicals are associated with considerable weight gain, diabetes and the risk of metabolic syndrome.<ref name="Barry2012">Template:Cite journal</ref> Unwanted side effects cause people to stop treatment, resulting in relapses.<ref name="Nakata2">Template:Cite journal</ref> Risperidone (atypical) has a similar rate of extrapyramidal symptoms to haloperidol (typical).<ref name="Barry2012" /> A rare but potentially lethal condition of neuroleptic malignant syndrome (NMS) has been associated with the use of antipsychotics. Through its early recognition, and timely intervention rates have declined. However, an awareness of the syndrome is advised to enable intervention.<ref name="Ware">Template:Cite journal</ref> Another less rare condition of tardive dyskinesia can occur due to long-term use of antipsychotics, developing after months or years of use. It is more often reported with use of typical antipsychotics.<ref name="Carbon">Template:Cite journal</ref> Very rarely antipsychotics may cause tardive psychosis.<ref>Template:Cite book</ref>

Clozapine is associated with side effects that include weight gain, tiredness, and hypersalivation. More serious adverse effects include seizures, NMS, neutropenia, and agranulocytosis (lowered white blood cell count) and its use needs careful monitoring.<ref name="De Berardis">Template:Cite journal</ref><ref name="Legge">Template:Cite journal</ref>

Clozapine is also associated with thromboembolism (including pulmonary embolism), myocarditis, and cardiomyopathy.<ref name="Kritharides">Template:Cite journal</ref><ref name="Sarvaiya">Template:Cite journal</ref> A systematic review of clozapine-associated pulmonary embolism indicates that this adverse effect can often be fatal, and that it has an early onset, and is dose-dependent. The findings advised the consideration of using a prevention therapy for venous thromboembolism after starting treatment with clozapine, and continuing this for six months.<ref name="Sarvaiya" /> Constipation is three times more likely to occur with the use of clozapine, and severe cases can lead to ileus and bowel ischemia resulting in many fatalities.<ref name="De Berardis" /> Very rare clozapine adverse effects include periorbital edema due to several possible mechanisms (e.g., inhibition of platelet-derived growth factor receptors leading to increased vascular permeability, antagonism of renal dopamine receptors with electrolyte and fluid imbalance and immune-mediated hypersensitivity reactions).<ref>Template:Cite journal</ref>

However, the risk of serious adverse effects from clozapine is low, and there are the beneficial effects to be gained of a reduced risk of suicide, and aggression.<ref name="Sriretnakumar">Template:Cite journal</ref> Typical antipsychotics and atypical risperidone can have a side effect of sexual dysfunction.<ref name="BMJ07">Template:Cite journal</ref> Clozapine, olanzapine, and quetiapine are associated with beneficial effects on sexual functioning helped by various psychotherapies.<ref name="Adam">Template:Cite journal</ref>

By rate

Common (≥ 1% and up to 50% incidence for most antipsychotic drugs) adverse effects of antipsychotics include:<ref>Template:Cite journal</ref>

• Dysphoria and apathy (due to dopamine receptor blockade)
• Sedation (particularly common with asenapine, clozapine, olanzapine, quetiapine, chlorpromazine and zotepine<ref name = "Leucht_2013" />)
• Headaches
• Dizziness
• Diarrhea
• Anxiety
• Extrapyramidal side effects (particularly common with first-generation antipsychotics), which include:
  • Akathisia, an often distressing sense of inner restlessness.
  • Dystonia, an abnormal muscle contraction
  • Pseudoparkinsonism, symptoms that are similar to what people with Parkinson's disease experience, including tremulousness and drooling
• Hyperprolactinaemia (rare for those treated with clozapine, quetiapine and aripiprazole<ref name = "Maudsley" /><ref name = "Leucht_2013" />), which can cause:
  • Galactorrhoea, the unusual secretion of breast milk.
  • Gynaecomastia, abnormal growth of breast tissue
  • Sexual dysfunction (in both sexes)
  • Osteoporosis
• Orthostatic hypotension
• Weight gain (particularly prominent with clozapine, olanzapine, quetiapine and zotepine,<ref name = "Leucht_2013" /> can be counteracted by starting the drug with metformin<ref name=PraharajJana2011>Template:Cite journal</ref><ref>Template:Cite journal</ref>)
• Anticholinergic side-effects (common for olanzapine, clozapine; less likely on risperidone<ref name="Lieberman, 2004">Template:Cite journal</ref>) such as:
  • Blurred vision
  • Constipation
  • Dry mouth (although hypersalivation may also occur)
  • Reduced perspiration
• Tardive dyskinesia appears to be more frequent with high-potency first-generation antipsychotics, such as haloperidol, and tends to appear after chronic and not acute treatment. It is characterized by slow (hence the tardive) repetitive, involuntary and purposeless movements, most often of the face, lips, legs, or torso, which tend to resist treatment and are frequently irreversible. The rate of appearance of TD is about 5% per year of use of antipsychotic drug (whatever the drug used)
• Breast cancer: a systematic review and meta-analysis of observational studies with over 2 million individuals estimated an association between antipsychotic use and breast cancer by over 30%.<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

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

• Blood dyscrasias (e.g., agranulocytosis, leukopenia, and neutropaenia), which is more common in patients on clozapine.
• Metabolic syndrome and other metabolic problems such as type II diabetes mellitus — particularly common with clozapine, olanzapine and zotepine. In American studies African Americans appeared to be at a heightened risk for developing type II diabetes mellitus.<ref>Template:Cite journal</ref> Evidence suggests that females are more sensitive to the metabolic side effects of first-generation antipsychotic drugs than males.<ref>Template:Cite journal</ref> Metabolic adverse effects appear to be mediated by antagonizing the histamine H₁ and serotonin 5-HT_2C receptors<ref name = "GG" /> and perhaps by interacting with other neurochemical pathways in the central nervous system.<ref>Template:Cite journal</ref>
• Neuroleptic malignant syndrome, a potentially fatal condition characterized by:
  • Autonomic instability, which can manifest with tachycardia, nausea, vomiting, diaphoresis, etc.
  • Hyperthermia — elevated body temperature.
  • Mental status change (confusion, hallucinations, coma, etc.)
  • Muscle rigidity
  • Laboratory abnormalities (e.g., elevated creatine kinase, reduced iron plasma levels, electrolyte abnormalities, etc.)
• Pancreatitis<ref name="pmid14524644">Template:Cite journal</ref>
• QT interval prolongation — more prominent in those treated with amisulpride, pimozide, sertindole, thioridazine and ziprasidone.<ref name = "Maudsley" /><ref name = "Leucht_2013" />
• Torsades de pointes
• Seizures, particularly in people treated with chlorpromazine and clozapine.
• Thromboembolism
• Myocardial infarction
• Stroke
• Pisa syndrome

Long-term effects

Template:See also Antipsychotic use has been linked to a 21x higher incidence of dementia in the United States by age 65.<ref>Template:Cite journal</ref> Both atypical and typical antipsychotics have a higher hazard ratio for dementia risk.<ref>Template:Cite journal</ref> In 2024 testable hypotheses were proposed for the mechanism<ref>Template:Cite journal</ref> responsible for cortical thinning till dementia.

Some studies have found decreased life expectancy associated with the use of antipsychotics, and argued that more studies are needed.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Antipsychotics may also increase the risk of early death in individuals with dementia.<ref>Template:Cite journal</ref> Antipsychotics typically worsen symptoms in people with depersonalisation disorder.<ref name=utdp>Template:Cite journal</ref> Antipsychotic polypharmacy (prescribing two or more antipsychotics at the same time for an individual) is a common practice but not evidence-based or recommended, and there are initiatives to curtail it.<ref name="APAfive polypharmacy"/><ref>Template:Cite journal</ref> Similarly, the use of excessively high doses (often the result of polypharmacy) continues despite clinical guidelines and evidence indicating that it is usually no more effective but is usually more harmful.<ref name="APAfive polypharmacy"/><ref>Template:Cite journal</ref> A meta-analysis of observational studies with over two million individuals has suggested a moderate association of antipsychotic use with breast cancer.<ref>Template:Cite journal</ref>

Loss of grey matter and other brain structural changes over time are observed amongst people diagnosed with schizophrenia. Meta-analyses of the effects of antipsychotic treatment on grey matter volume and the brain's structure have reached conflicting conclusions. A 2020 study concluded that atypical antipsychotics are linked to cortical thinning and cognitive decline<ref>Template:Cite journal</ref> in the mid (20 months) to long-term. A 2012 meta-analysis concluded that grey matter loss is greater in patients treated with first generation antipsychotics relative to those treated with atypicals, and hypothesized a protective effect of atypicals as one possible explanation.<ref>Template:Cite journal</ref> A second 2012 meta-analysis suggested that treatment with antipsychotics was associated with increased grey matter loss.<ref>Template:Cite journal</ref> Animal studies found that monkeys exposed to both first- and second-generation antipsychotics experience significant reduction in brain volume, resulting in an 8-11% reduction in brain volume with preserved neuron count and decreased glial cell count over a 17–27 month period.<ref name="Nature 2005">Template:Cite journal</ref><ref>Template:Cite journal</ref>

The National Association of State Mental Health Program Directors said that antipsychotics are not interchangeable, and it recommends including trying at least one weight-neutral treatment for those patients with potential metabolic issues.<ref>Template:Cite journal</ref>

Subtle, long-lasting forms of akathisia are often overlooked or confused with post-psychotic depression, in particular when they lack the extrapyramidal aspect that psychiatrists have been taught to expect when looking for signs of akathisia.<ref name="pmid14609248">Template:Cite journal</ref>

Adverse effect on cognitive function<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and increased risk of death in people with dementia along with worsening of symptoms has been described in the literature.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Antipsychotics, due to acting as dopamine D₂ receptor antagonists and thereby stimulating pituitary lactotrophs, may have a risk of prolactinoma with long-term use.<ref name="DurraniVasireddyArshad2023">Template:Cite journal</ref><ref name="EdinoffSilverblattVervaeke2021">Template:Cite journal</ref> This is also responsible for their induction of hyperprolactinemia (high prolactin levels).<ref name="DurraniVasireddyArshad2023" /><ref name="EdinoffSilverblattVervaeke2021" />

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.<ref name="Group 2009 192">Template:Cite book</ref> Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.<ref name=Had2004>Template:Cite book</ref> Other symptoms may include restlessness, increased sweating, and trouble sleeping.<ref name=Had2004/> Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.<ref name=Had2004/> Withdrawal symptoms can be severe and long lasting, or permanent.<ref>Template:Cite journal</ref>

A randomised controlled trial compared maintenance therapy with gradual dose reduction or discontinuation among people with long-term psychosis. At 2 years, people in the reduction group were twice as likely to relapse (25%) as those in the maintenance group (13%). Moreover, those in the reduction group had no improvement in social functioning (a measure combining people's ability to look after themselves, work, study and take part in family and social activities), side effects, quality of life, symptoms, or bodyweight.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

There is evidence that withdrawal syndrome of antipsychotics can result in psychosis.<ref name="ReferenceB">Template:Cite journal</ref> This has occurred in patients who had previously no history of psychosis, but were taking antipsychotics for another reason.<ref name="ReferenceB" /> Tardive dyskinesia can also occur when the medication is stopped.<ref name=Had2004/>

Unexpected psychotic episodes have been observed in patients withdrawing from clozapine. This is referred to as supersensitivity psychosis, not to be equated with tardive dyskinesia.<ref name="ReferenceB"/><ref name="Nakata">Template:Cite journal</ref>

Tardive dyskinesia may abate during withdrawal from the antipsychotic agent, or it may persist.<ref name="Glazer-2000">Template:Cite journal</ref>

Withdrawal effects may also occur when switching a person from one antipsychotic to another, (it is presumed due to variations of potency and receptor activity). Such withdrawal effects can include cholinergic rebound, an activation syndrome, and motor syndromes including dyskinesias. These adverse effects are more likely during rapid changes between antipsychotic agents, so making a gradual change between antipsychotics minimises these withdrawal effects.<ref name="Lambert-2007">Template:Cite journal</ref> The British National Formulary recommends a gradual dose reduction when discontinuing antipsychotic treatment to avoid acute withdrawal symptoms or rapid relapse.<ref>Template:Cite book</ref> The process of cross-titration involves gradually increasing the dose of the new medication while gradually decreasing the dose of the old medication.

City and Hackney Clinical Commissioning Group found more than 1,000 patients in their area in July 2019 who had not had regular medication reviews or health checks because they were not registered as having serious mental illness. On average they had been taking these drugs for six years. If this is typical of practice in England more than 100,000 patients are probably in the same position.<ref>Template:Cite news</ref>

List of agents

File:Chlorpromazine.svg

Chlorpromazine

File:Haloperidol.svg

Haloperidol

File:Quetiapine.svg

Quetiapine

Clinically used antipsychotic medications are listed below by drug group. Trade names appear in parentheses. A 2013 review has stated that the division of antipsychotics into first and second generation is perhaps not accurate.<ref name = "Leucht_2013" />

Notes:

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

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

# denotes drugs that have been withdrawn worldwide.

First-generation (typical)

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

Butyrophenones

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

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

Diphenylbutylpiperidines

• Fluspirilene ‡
• Penfluridol ‡
• Pimozide

Phenothiazines

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

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

Thioxanthenes

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

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

Disputed/unknown

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

Benzamides

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

Tricyclics

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

Others

• Molindone ^#

Second-generation (atypical)

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

Benzamides

• Amisulpride (Socian) ^‡ – Selective dopamine antagonist. Higher doses (greater than 400 mg) act upon post-synaptic dopamine receptors resulting in a reduction in the positive symptoms of schizophrenia, such as psychosis. Lower doses, however, act upon dopamine autoreceptors, resulting in increased dopamine transmission, improving the negative symptoms of schizophrenia. Lower doses of amisulpride have also been shown to have antidepressant and anxiolytic effects in non-schizophrenic patients, leading to its use in dysthymia and social phobias.
• Nemonapride ^† – Used in Japan.
• Remoxipride ^# – Has a risk of causing aplastic anaemia and, hence, has been withdrawn from the market worldwide. It has also been found to possess relatively low (virtually absent) potential to induce hyperprolactinaemia and extrapyramidal symptoms, likely attributable to its comparatively weak binding to (and, hence, rapid dissociation from) the D₂ receptor.<ref name=atyp>Template:Cite journal</ref>
• Sultopride – An atypical antipsychotic of the benzamide chemical class used in Europe, Japan, and Hong Kong for the treatment of schizophrenia. It was launched by Sanofi-Aventis in 1976. Sultopride acts as a selective D2 and D3 receptor antagonist.

Benzisoxazoles/benzisothiazoles

• Iloperidone (Fanapt) – Approved by the US FDA in 2009, it is fairly well tolerated, although hypotension, dizziness, and somnolence were very common side effects. Has not received regulatory approval in other countries, however.
• Paliperidone (Invega) – Primary, active metabolite of risperidone that was approved in 2006.
• Perospirone ^† – Has a higher incidence of extrapyramidal side effects than other atypical antipsychotics.<ref name = "CNS Drugs">Template:Cite journal</ref>
• Risperidone (Risperdal) – Divided dosing is recommended until initial titration is completed, at which time the drug can be administered once daily. Used off-label to treat Tourette syndrome and anxiety disorder.
• Ziprasidone (Geodon) – Approved in 2004<ref>Template:Cite journal</ref> to treat bipolar disorder. Side-effects include a prolonged QT interval in the heart, which can be dangerous for patients with heart disease or those taking other drugs that prolong the QT interval.
• Lurasidone (Latuda) – Approved by the US FDA for schizophrenia and bipolar depression, and for use as schizophrenia treatment in Canada.

Butyrophenones

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

Tricyclics

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

Others

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

Third-generation

Third generation antipsychotics are recognized as demonstrating D₂ receptor partial agonism<ref>Template:Cite journal</ref> as opposed to the D₂ and 5HT-_2A receptor antagonism of second-generation (atypical) antipsychotics and D2 antagonism of first-generation (typical) antipsychotics.<ref name=":0">Template:Cite journal</ref>

Butyrophenone(s)

• Lumateperone (Caplyta) – In December 2019, lumateperone, a presynaptic D₂ receptor partial agonist and postsynaptic D₂ receptor antagonist, received its first global approval in the US for the treatment of schizophrenia in adults.<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref> In 2020 and 2021 FDA approved for depressive episodes associated with bipolar I or II disorder in adults, as monotherapy and as adjunctive therapy with lithium or valproate.

Phenylpiperazines/quinolinones/benzoxazinones

• Aripiprazole (Abilify) - Partial agonist at the D₂ receptor. Considered the prototypical third-generation antipsychotic.<ref>Template:Cite journal</ref>
• Aripiprazole lauroxil (Abilify Maintena) – Long-acting version of aripiprazole for injection.
• Brexpiprazole (Rexulti) – Partial agonist of the D₂ receptor. Successor of aripiprazole.
• Brilaroxazine – A D_2/3/4 and 5-HT_1A partial agonist and 5-HT_2A/2B/7 antagonist
• Cariprazine (Vraylar, Reagila) – A D₃-preferring D_2/3 partial agonist.

Muscarinic agonists

• Xanomeline/trospium chloride (Cobenfy) - A fixed-dose combination of xanomeline and trospium chloride. Xanomeline is a functionally selective muscarinic M₄ and M₁ receptor agonist. Trospium chloride is a peripherally-acting non-selective muscarinic antagonist.<ref name="Cobenfy FDA label">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref> Xanomeline/trospium chloride was approved for medical use in the United States in September 2024.

Mechanism of action

Antipsychotic drugs such as haloperidol and chlorpromazine tend to block dopamine D₂ receptors in the dopaminergic pathways of the brain. This means that dopamine released in these pathways has less effect. Excess release of dopamine in the mesolimbic pathway has been linked to psychotic experiences. Decreased dopamine release in the prefrontal cortex, and excess dopamine release in other pathways, are associated with psychotic episodes in schizophrenia and bipolar disorder.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

In addition to the antagonistic effects of dopamine, antipsychotics (in particular atypical antipsychotics) also antagonize 5-HT_2A receptors. Different alleles of the 5-HT_2A receptor have been associated with schizophrenia and other psychoses, including depression.<ref name="McDonald 41–63">Template:Cite journal</ref><ref>Template:Cite journal</ref> Higher concentrations of 5-HT_2A receptors in cortical and subcortical areas, in particular in the right caudate nucleus have been historically recorded.<ref name="McDonald 41–63"/>

Typical antipsychotics are not particularly selective and also block dopamine receptors in the mesocortical pathway, tuberoinfundibular pathway, and the nigrostriatal pathway. Blocking D₂ receptors in these other pathways is thought to produce some unwanted side effects that the typical antipsychotics can produce (see above). They were commonly classified on a spectrum of low potency to high potency, where potency referred to the ability of the drug to bind to dopamine receptors, and not to the effectiveness of the drug. High-potency antipsychotics such as haloperidol, in general, have doses of a few milligrams and cause less sleepiness and calming effects than low-potency antipsychotics such as chlorpromazine and thioridazine, which have dosages of several hundred milligrams. The latter have a greater degree of anticholinergic and antihistaminergic activity, which can counteract dopamine-related side-effects.<ref>Template:Cite journal</ref>

Atypical antipsychotic drugs have a similar blocking effect on D₂ receptors; however, most also act on serotonin receptors, especially 5-HT_2A and 5-HT_2C receptors. Both clozapine and quetiapine appear to bind just long enough to elicit antipsychotic effects but not long enough to induce extrapyramidal side effects and prolactin hypersecretion.<ref name=Atypicality>Template:Cite journal</ref> 5-HT_2A antagonism increases dopaminergic activity in the nigrostriatal pathway, leading to a lowered extrapyramidal side effect liability among the atypical antipsychotics.<ref name = Atypicality /><ref>Template:Cite book</ref>

Xanomeline/trospium chloride was approved for medical use in the United States in September 2024. It was the first antipsychotic to not act on D₂ receptors. The mechanism of action instead relies on xanomeline's functional selectivity for the M1 and M4 muscarinic receptors, with trospium chloride, a peripherally selective antimuscarinic added to counteract xanomeline's unwanted peripheral muscarinic effects.<ref name="Cobenfy FDA label" /><ref name="FDA PR 20240926">Template:Cite press release Template:PD-notice</ref><ref>Template:Cite press release</ref>

Through the ability of most antipsychotics to antagonize 5-HT_2A serotonin pathways enabling a sensitisation of postsynaptic serotonin receptors, MDMA exposure can be more intense because it has more excitatory receptors to activate. The same effect can be observed with the D₂ antagonizing with normal amphetamine (with this just being hypothetical as there is the fact that antipsychotics sensitize receptors,<ref>Template:Cite journal</ref> with exact these postsynaptic receptors (5-HT_2A, D₂) being flooded by the respective neurotransmitter (serotonin, dopamine) from amphetamine exposure).<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Comparison of medications

Overview

Generic name Class Type Brand name(s) Launch Developer/Originator(s) Refs Amisulpride Benzamide Disputed Solian 1986 Sanofi-Synthélabo <ref name="Sanchez2012" /><ref name="IUPACFischer2006">Template:Cite book</ref><ref name="Lidow2000">Template:Cite book</ref> Aripiprazole Phenylpiperazine/Quinolinone Atypical Abilify 2002 Otsuka/Bristol-Myers Squibb <ref name="Sanchez2012" /><ref name="pmid16082416">Template:Cite journal</ref> Aripiprazole lauroxil Phenylpiperazine/Quinolinone Atypical Aristada 2015 Alkermes citation CitationClass=web }}</ref> Asenapine Tricyclic/Dibenzoxapinopyrrole Atypical Saphris/Sycrest 2009 Organon/Merck citation CitationClass=web }}</ref> Benperidol Butyrophenone Typical Anquil 1966 Janssen <ref name="Sanchez2012">Template:Cite book</ref> Blonanserin Pyridinylpiperazine Atypical Lonasen 2008 Sumitomo Dainippon/Mitsubishi Tanabe citation CitationClass=web }}</ref> Brexpiprazole Phenylpiperazine/Quinolinone Atypical Rexulti 2015 Otsuka/Lundbeck citation CitationClass=web }}</ref> Bromperidol Butyrophenone Typical Impromem 1981 Janssen <ref name="Sanchez2012" /><ref name="pmid16082416" /> Cariprazine Phenylpiperazine Atypical Vraylar/Reagila 2015 Gedeon Richter/Actavis citation CitationClass=web }}</ref> Carpipramine Tricyclic/Dibenzazepine Disputed Defecton/Prazinil 1977 Pierre Fabre <ref name="Sanchez2012" /> Chlorpromazine Tricyclic/Phenothiazine Typical Thorazine 1952 Rhône-Poulenc/GlaxoSmithKline <ref name="Sanchez2012" /><ref name="pmid16082416" /> Chlorprothixene Tricyclic/Thioxanthene Disputed Truxal 1959 Roche <ref name="Sanchez2012" /><ref name="pmid16082416" /><ref name="Csernansky2012">Template:Cite book</ref> Clocapramine Tricyclic/Dibenzazepine Disputed Clofekton/Padrasen 1974 Yoshitomi <ref name="Publishing2013">Template:Cite book</ref> Clopenthixol Tricyclic/Thioxanthene Typical Sordinol/Ciatyl 1961 Lundbeck <ref name="Publishing2013-Clopenthixol">Template:Cite book</ref> Clorotepine Tricyclic/Dibenzothiepin Disputed Clotepin 1971 Spofa <ref name="Protiva2010">Template:Cite journal</ref><ref name="pmid5576292">Template:Cite journal</ref> Clotiapine Tricyclic/Dibenzothiazepine Disputed Etumine 1966 Sandoz/Wander <ref name="GaleResearch1991" /><ref name="pmid16126373">Template:Cite journal</ref> Clozapine Tricyclic/Dibenzodiazepine Atypical Clozaril 1972 Sandoz-Novartis <ref name="Sanchez2012" /><ref name="pmid16082416" /> Cyamemazine Tricyclic/Phenothiazine Disputed Tercian 1972 Aventis <ref name="Sanchez2012" /><ref name="pmid15492772">Template:Cite journal</ref> Droperidol Butyrophenone Typical Dridol/Droleptan/Inapsine 1963 Janssen-Cilag <ref name="Sanchez2012" /><ref name="LamberthDinges2012">Template:Cite book</ref> Flupentixol Tricyclic/Thioxanthene Typical Fluanxol 1965 Lundbeck <ref name="Sanchez2012" /><ref name="Pedersen1996">Template:Cite journal</ref> Fluphenazine Tricyclic/Phenothiazine Typical Prolixin 1959 Bristol-Myers Squibb <ref name="Sanchez2012" /><ref name="pmid16082416" /> Fluspirilene Diphenylbutylpiperidine Typical Imap 1970 Janssen <ref name="Sanchez2012" /> Haloperidol Butyrophenone Typical Haldol 1959 Janssen <ref name="Sanchez2012" /><ref name="pmid16082416" /> Iloperidone Benzisoxazole Atypical Fanapt 2010 Novartis citation CitationClass=web }}</ref> Levomepromazine Tricyclic/Phenothiazine Disputed Nozinan/Levoprome 1957 Rhône-Poulenc <ref name="Sanchez2012" /><ref name="Csernansky2012" /><ref name="Shorter2009">Template:Cite book</ref> Levosulpiride Benzamide Disputed Levopraid 1987 Abbott <ref name="Sanchez2012" /> Loxapine Tricyclic/Dibenzoxazepine Disputed Loxitane/Loxapac 1975 Wyeth <ref name="Sanchez2012" /><ref name="pmid16082416" /><ref name="pmid10340686">Template:Cite journal</ref> Lurasidone Benzisothiazole Atypical Latuda 2010 Sumitomo Dainippon/Sunovion citation CitationClass=web }}</ref> Melperone Butyrophenone Disputed Buronil 1967 Lundbeck <ref name="pmid16082416" /> Mesoridazine Tricyclic/Phenothiazine Typical Serentil 1967 Novartis-Boehringer <ref name="pmid16082416" /> Molindone Dihydroindolone Disputed Moban 1975 Abbott <ref name="pmid16082416" /> Mosapramine Tricyclic/Dibenzazepine Disputed Cremin 1991 Mitsubishi Pharma <ref name="Sanchez2012" /> Nemonapride Benzamide Disputed Emilace/Emirace 1991 Yamanouchi citation CitationClass=web }}</ref> Olanzapine Tricyclic/Thienobenzodiazepine Atypical Zyprexa 1996 Lilly <ref name="Sanchez2012" /><ref name="pmid16082416" /> Paliperidone Benzisoxazole Atypical Invega 2007 Janssen-Cilag/Johnson & Johnson citation CitationClass=web }}</ref> Paliperidone palmitate Benzisoxazole Atypical Invega Sustenna/Xeplion 2009 Janssen-Cilag/Johnson & Johnson citation CitationClass=web }}</ref> Penfluridol Diphenylbutylpiperidine Typical Semap 1973 Janssen <ref name="Vardanyan2017" /><ref name="pmid4604881">Template:Cite journal</ref> Perazine Tricyclic/Phenothiazine Typical Taxilan 1958 Promonta <ref name="pmid24425538">Template:Cite journal</ref> Periciazine Tricyclic/Phenothiazine Typical Neuleptil/Neulactil 1964 Rhône-Poulenc <ref name="Sanchez2012" /><ref name="pmid24825770">Template:Cite journal</ref> Perospirone Benzisothiazole Atypical Lullan 2001 Sumitomo Dainippon/Mitsubishi Tanabe citation CitationClass=web }}</ref> Perphenazine Tricyclic/Phenothiazine Typical Trilafon 1957 Schering-Plough <ref name="Sanchez2012" /><ref name="pmid16082416" /> Pimavanserin Dibenzylpiperidinylurea Atypical Nuplazid 2016 ACADIA Pharmaceuticals citation CitationClass=web }}</ref> Pimozide Diphenylbutylpiperidine Typical Orap 1969 Janssen <ref name="Sanchez2012" /><ref name="pmid16082416" /> Pipamperone Butyrophenone Disputed Dipiperon 1961 Janssen <ref name="GaleResearch1991">Template:Cite book</ref><ref name="Vardanyan2017">Template:Cite book</ref> Pipotiazine Tricyclic/Phenothiazine Typical Piportil 1973 Rhône-Poulenc/Aventis <ref name="Sanchez2012" /><ref name="Publishing2013-Pipotiazine">Template:Cite book</ref> Prochlorperazine Tricyclic/Phenothiazine Typical Compazine 1956 Rhône-Poulenc/GlaxoSmithKline <ref name="Sanchez2012" /><ref name="pmid16082416" /><ref name="Shorter2009" /> Promazine Tricyclic/Phenothiazine Typical Sparine 1956 Wyeth <ref name="Sanchez2012" /> Quetiapine Tricyclic/Dibenzothiazepine Atypical Seroquel 1997 AstraZeneca <ref name="Sanchez2012" /><ref name="pmid16082416" /> Remoxipride Benzamide Disputed Roxiam 1990 AstraZeneca <ref name="Sanchez2012" /><ref name="Lidow2000" /><ref name="pmid16082416" /> Risperidone Benzisoxazole Atypical Risperdal 1993 Janssen <ref name="Sanchez2012" /><ref name="pmid16082416" /> Sertindole Imidazolidinone Atypical Serdolect 1996 Lundbeck <ref name="Sanchez2012" /><ref name="pmid16082416" /> Spiperone Butyrophenone Typical Spiropitan 1969 Eisai <ref name="Publishing2007-Spiperone">Template:Cite book</ref> Sulpiride Benzamide Disputed Dogmatil 1968 Delagrange/Fujisawa <ref name="Sanchez2012" /><ref name="Lidow2000" /><ref name="pmid16082416" /> Sultopride Benzamide Disputed Barnetil 1976 Delagrange/Sanofi-Synthélabo <ref name="Sanchez2012" /><ref name="Publishing2013-Sultopride">Template:Cite book</ref> Thioridazine Tricyclic/Phenothiazine Typical Melleril 1958 Novartis <ref name="Sanchez2012" /><ref name="pmid16082416" /> Tiapride Benzamide Disputed Tiapridal 1975 Sanofi-Synthélabo <ref name="Sanchez2012" /> Tiotixene Tricyclic/Thioxanthene Typical Navane 1967 Pfizer <ref name="Sanchez2012" /><ref name="pmid16082416" /><ref name="Publishing2013-Tiotixene">Template:Cite book</ref> Trifluoperazine Tricyclic/Phenothiazine Typical Stelazine 1958 GlaxoSmithKline <ref name="Sanchez2012" /><ref name="pmid16082416" /> Triflupromazine Tricyclic/Phenothiazine Typical Vesprin 1957 Bristol-Myers Squibb <ref name="Sanchez2012" /> Veralipride Benzamide Disputed Agreal 1980 Sanofi-Synthélabo <ref name="Sanchez2012" /> Ziprasidone Benzisothiazole Atypical Geodon 2000 Pfizer <ref name="Sanchez2012" /><ref name="pmid16082416" /> Zotepine Tricyclic/Dibenzothiepin Atypical Zoleptil 1982 Fujisawa <ref name="Sanchez2012" /><ref name="pmid16082416" /> Zuclopenthixol Tricyclic/Thioxanthene Typical Clopixol/Cisordinol 1978 Lundbeck <ref name="Sanchez2012" /><ref name="Publishing2013-Clopenthixol" /><ref name="Pedersen1996" />

Tolerability (as propensity for adverse effects)
Generic name <ref name=Lancet2009/><ref name = "Maudsley"/><ref name = "Leucht_2013" /><ref name = "AMH">Template:Cite book</ref><ref name = "BNF">Template:Cite book</ref>	Discontinuation rate<ref name = "Leucht_2013" /> (OR with 95% CI)	Anticholinergic effects	Sedation	EPSE	Weight Gain	Metabolic AEs	QTc prolongation (ORs & 95% CIs)	PE	Hypotension	Notes (e.g., notable AEs*)
Amisulpride	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Torsades de Pointes common on overdose.<ref>Template:Cite journal</ref> Has a comparatively low penetrability of the blood–brain barrier.
Amoxapine	Template:Dunno	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Amoxapine is also an antidepressant. Very toxic in overdose due to the potential for renal failure and seizures.
Aripiprazole	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Only clinically utilised antipsychotic that does not act by antagonising the D2 receptor and rather partially agonises this receptor.
Asenapine	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Oral hypoesthesia. Has a complex pharmacologic profile.
Blonanserin<ref name="Deeks, ED; Keating, GM 65–84">Template:Cite journal</ref><ref name="Tenjin, T; Miyamoto, S; Ninomiya, Y; Kitajima, R; Ogino, S; Miyake, N; Yamaguchi, N 2013 587–594">Template:Cite journal</ref>	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Only used in a few East Asian countries.
Chlorpromazine	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	First marketed antipsychotic, sort of the prototypical low-potency first-generation (typical) antipsychotic.
Clozapine	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Notable AEs: Agranulocytosis, neutropaenia, leukopaenia and myocarditis. Dose-dependent seizure risk.<ref>{{#invoke:citation/CS1|citation	CitationClass=web }}</ref> Overall the most effective antipsychotic, on average. Usually reserved for treatment-resistant cases or highly suicidal patients.
Droperidol	Template:Dunno	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Dunno	Template:Shade	Template:Dunno	Mostly used for postoperative nausea and vomiting.
Flupenthixol	Template:Dunno	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Also used in lower doses for depression.
Fluphenazine	Template:Shade<ref>Template:Cite journal</ref>	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	High-potency first-generation (typical) antipsychotic.
Haloperidol	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Prototypical high-potency first-generation (typical) antipsychotic.
Iloperidone	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	?
Levomepromazine	Template:Dunno	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Dunno	Template:Shade	Template:Shade	Also used as an analgesic, agitation, anxiety and emesis.
Loxapine	Template:Shade<ref>Template:Cite journal</ref>	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Dunno	Template:Shade	Template:Shade	?
Lurasidone	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	May be particularly helpful in ameloriating the cognitive symptoms of schizophrenia, likely due to its 5-HT7 receptor.<ref>Template:Cite journal</ref>
Melperone	Template:Dunno	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Several smaller low-quality clinical studies have reported its efficacy in the treatment of treatment-resistant schizophrenia. Only approved for use in a few European countries. It is known that off-licence prescribing of melperone is occurring in the United Kingdom.<ref>Template:Cite journal</ref> Is a butyrophenone, low-potency atypical antipsychotic that has been tried as a treatment for Parkinson's disease psychosis, although with negative results.
Molindone<ref name = MD>Template:Cite book</ref>	Template:Dunno	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Dunno	Template:Shade	Template:Shade	Withdrawn from the market. Seems to promote weight loss (which is rather unusual for an antipsychotic seeing how they tend to promote weight gain).<ref name = MD/>
Olanzapine	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	?
Paliperidone	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Active metabolite of risperidone.
Perazine	Template:Shade<ref>Template:Cite journal</ref>	Template:Dunno	Template:Dunno	Template:Dunno	Template:Dunno	Template:Dunno	Template:Dunno	Template:Dunno	Template:Dunno	Limited data available on adverse effects.
Periciazine	Template:Dunno	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Dunno	Template:Shade	Template:Shade	Also used to treat severe anxiety. Not licensed for use in the US.
Perospirone<ref>Template:Cite journal</ref>	Template:Dunno	Template:Shade	Template:Shade	Template:Shade<ref name = Mart>Template:Cite book</ref>	Template:Shade	Template:Dunno	Template:Shade	Template:Shade	Template:Shade	Usually grouped with the atypical antipsychotics despite its relatively high propensity for causing extrapyramidal side effects.<ref name = Mart/>
Perphenazine	Template:Shade<ref>Template:Cite journal</ref>	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Has additional antiemetic effects.
Pimozide	Template:Shade<ref>Template:Cite journal</ref>	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	High potency first-generation (typical) antipsychotic.
Pipotiazine	Template:Dunno	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Dunno	Template:Shade	Template:Shade	Only available in the UK.
Prochlorperazine	Template:Dunno	Template:Dunno	Template:Dunno	Template:Shade	Template:Dunno	Template:Dunno	Template:Shade	Template:Shade	Template:Dunno	Primarily used in medicine as an antiemetic.
Quetiapine	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Binds to the D2 receptor in a hit and run fashion. That is it rapidly dissociates from said receptor and hence produces antipsychotic effects but does not bind to the receptor long enough to produce extrapyramidal side effects and hyperprolactinaemia.
Remoxipride	Template:Dunno	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Removed from the market amidst concerns about an alarmingly high rate of aplastic anaemia.
Risperidone	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	?
Sertindole	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Not licensed for use in the US.
Sulpiride	Template:Shade<ref>Template:Cite journal</ref>	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Not licensed for use in the US.
Thioridazine	Template:Shade<ref>Template:Cite journal</ref>	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Dose-dependent risk for degenerative retinopathies.<ref>Template:Cite journal</ref> Found utility in reducing the resistance of multidrug and even extensively resistant strains of tuberculosis to antibiotics.
Tiotixene	Template:Dunno	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	?
Trifluoperazine	Template:Shade<ref>Template:Cite journal</ref>	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Dunno	Template:Shade	Template:Shade	?
Ziprasidone	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	?
Zotepine	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	citation	CitationClass=web }}</ref> Not licensed for use in the US.
Zuclopenthixol	Template:Dunno	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Shade	Template:Dunno	Template:Shade	Template:Shade	Not licensed for use in the US.
Note: "Notable" is to mean side-effects that are particularly unique to the antipsychotic drug in question. For example, clozapine is notorious for its ability to cause agranulocytosis. If data on the propensity of a particular drug to cause a particular AE is unavailable an estimation is substituted based on the pharmacologic profile of the drug. Template:Col-begin Template:Col-break Acronyms used: AE – Adverse effect OR – Odds ratio CI – Confidence Interval EPSE – Extrapyramidal Side Effect QTc – Corrected QT interval PE – Prolactin elevation Template:Col-break Legend: - very low propensity for this AE + low propensity/severity for this AE ++ moderate propensity/severity for this AE +++ high propensity/severity for this AE

Binding affinity

Ki [nM] toward cloned human receptors (unless otherwise specified)<ref group = Note>Bolded drug names indicate drugs that are metabolites of clinically-marketed antipsychotics.</ref> Drug name<ref name = "GG">Template:Cite book</ref><ref>{{#invoke:citation/CS1|citation CitationClass=web }}</ref>!! SERT !! 5-HT1A !! 5-HT2A !! 5-HT2C !! 5-HT6 !! 5-HT7 !! α1A !! α2A !! α2C !! NET !! D1 !! D2 !! D3 !! D4 !! 5-HT2A/D2 !!H1 !! M1 !! M3 Amisulpride >10,000 >10,000 8,304 >10,000 4,154 73.5 >10,000 1,114 1,540 >10,000 >10,000 2.2 2.4 2,370 3774.5 >10,000 >10,000 >10,000 Aripiprazole 1,081 5.6 8.7 22.4 642.4 9.97 25.85 74.1 37.63 2091.5 1,173.5 1.64 5.35 514 5.3 27.93 6,778 4,678 Asenapine<ref name="pmid18308814">Template:Cite journal</ref> ND 2.5 0.06 0.03 0.25 0.13 1.2 1.2 1.2 ND 1.4 1.3 0.42 1.1 0.0462 1.0 8,128 8,128 Blonanserin<ref name="Ishiyama_2007">Template:Cite journal</ref> ND 804 0.812 26.4 41.9 183 26.7 (RB) 530 (RC) ND ND 1,070 0.142 0.494 150 5.72 765 100 ND Brexpiprazole ND 0.12 0.47 ND 58 3.7 3.8 15 0.59 ND 160 0.3 1.1 6.3 1.567 19 ND >10,000 N-DEBN<ref name="Deeks, ED; Keating, GM 65–84"/> ND ND 1.28 4.50 5.03 206 (RC) ND ND ND ND 1,020 1.38 0.23 ND 0.93 ND ND ND Chlorpromazine 1,296 2,115.5 4.5 15.6 17.0 28.4 0.28 184 46 2,443 76.3 1.40 4.65 5.33 3.21 3.09 32.3 57.0 Clozapine 1,624 123.7 5.35 9.44 13.5 17.95 1.62 37 6.0 3,168 266.3 157 269.1 26.4 0.0341 1.13 6.17 19.25 Norclozapine 316.6 13.9 10.9 11.9 (RC) 11.6 60.1 104.8 137.6 117.7 493.9 14.3 94.5 153 63.94 0.115 3.4 67.6 95.7 cis-Flupenthixol ND 8,028 87.5 (HFC) 102.2 (RC) ND ND ND ND ND ND 3.5 0.35 1.75 66.3 250 0.86 ND ND Fluphenazine 5,950 1,039.9 37.93 982.5 34.67 8.00 6.45 314.1 28.9 3,076 17.33 0.30 1.75 40.0 126.4 14.15 1,095 1,441 Haloperidol 3,256 2,066.83 56.81 4,801 5,133 377.6 12.0 801.5 403 2,112 121.8 0.7 3.96 2.71 81.2 1698 >10,000 >10,000 Iloperidone ND 93.21 1.94 147 63.09 112 0.3 160 16.2 1479 129.32 10.86 10.55 13.75 0.179 12 4,898 >10,000 Loxapine >10,000 2,456 6.63 13.25 31.0 87.6 31.0 150.9 80.0 5,698 54 28.1 19.33 7.80 0.236 4.90 119.45 211.33 Amoxapine 58 ND 0.5 2.0 (RC) 50 40.21 50 ND ND 16 ND 20.8 21.0 21.0 0.0240 25 1,000 1,000 Lurasidone<ref name="Ishiyama_2007"/><ref name="pmid20404009">Template:Cite journal</ref> ND 6.8 2.0 415 ND 0.5 48 1.6 10.8 ND 262 1.7 ND ND 1.18 >10,000 >10,000 >10,000 Melperone ND 2,200 (HB) 230 2,100 (HB) 1,254 (RC) 578 (HB) 180 (HB) 150 (HB) ND ND ND 194 8.95 555 1.186 580 >10,000 >10,000 Molindone ND 3,797 3773 >10,000 1,008 3,053 2,612 1,097 172.6 ND ND 6.0 72.5 2,950 628.83 2,130 ND >10,000 Olanzapine 3,676 2282 3.73 10.2 8.07 105.2 112 314 28.9 >10,000 70.33 34.23 47.0 14.33 0.109 2.19 2.5 56.33 Paliperidone 3,717 616.6 0.71 48 2,414 2.7 2.5 17.35 7.35 >10,000 41.04 0.7 0.5 54.3 1.104 18.8 >10,000 >10,000 Perphenazine ND 421 5.6 132 17 23 10 810.5 85.2 ND ND 0.14 0.13 17 40 8 1,500 1,848 Pimozide ND 650 48.35 2,112 71 0.5 197.7 1,593 376.5 ND >10,000 1.45 0.25 1.8 33.34 692.2 800 (HB) 1,955 Prochlorperazine ND 5,900 (HC) 15 (HC) 122 148 (RC) 196 (RC) 23.8 (HB) 1,694.91 (HB) ND ND ND 0.65 2.90 5.40 23.1 18.86 (HB) 555.55 (HB) ND Quetiapine >10,000 394.2 912 1,843 948.75 307.6 22 3,630 28.85 >10,000 994.5 379 340 2,019 2.41 6.90 489 1631.5 Norquetiapine<ref name="pmid24062697">Template:Cite journal</ref> ND 45 48 107 ND 76 144 237 ND 12 99.8 (RC) 196 ND ND 0.245 3.5 38.3 (RC) ND Risperidone >10,000 422.88 0.17 12 2057.17 6.6 5 16.5 1.3 >10,000 243.53 3.57 2.0 4.66 0.0476 20.05 >10,000 >10,000 Sertindole ND 280 0.39 0.9 5.4 28 1.8 640 450 ND ND 2.35 2.30 4.92 0.166 130 >5,000 2,692 Sulpiride ND >10,000 >10,000 (RC) >10,000 (RC) 5,000 (RC) 4,000 (RC) >10,000 (RB) 4,893 (RB) ND ND >10,000 9.80 8.05 54 >1,000 >10,000 (RB) >10,000 (RB) >10,000 (RB) Thioridazine 1,259 144.35 27.67 53 57.05 99 3.15 134.15 74.9 842 94.5 2.20 1.50 6.00 12.58 16.5 12.8 29 Tiotixene 3,878 410.2 50 1355.5 245.47 15.25 11.5 79.95 51.95 >10,000 51 0.12 0.40 203 416.7 8 >10,000 >10,000 Trifluoperazine ND 950 74 378 144 290.8 24 653.7 391.5 ND ND 1.12 ND 38.1 66.07 63 ND 1,001 Ziprasidone 112 54.67 0.73 13 60.95 6.31 18 160 68 44 30 4.35 7.85 52.9 0.1678 62.67 >10,000 >10,000 Zotepine 151 470.5 2.7 3.2 6 12 7 208 106 530 71 25 6.4 18 0.108 3.21 18 73 Acronyms used: Template:Col-begin Template:Col-break HFC – Human frontal cortex receptor RB – Rat brain receptor RC – Cloned rat receptor ND – No data HB – Human brain receptor HC – Human cortex receptor N-DEBN – N-desethylblonanserin

Pharmacokinetics

citation CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation CitationClass=web }}</ref><ref name=DM>{{#invoke:citation/CS1|citation CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation CitationClass=web }}</ref>!! Bioavailability !! t1/2 parent drug (active metabolite) !! Protein binding !! tmax !!Cmax !! Vd !! Excretion !! Routes !! Metabolism enzymes<ref name = GG/> !! Active metabolites Amisulpride 48% 12 h 16% 3–4 h Template:Nowrap 5.8 L/kg Faeces (20%), urine (50%, when given IV) Oral Template:Dunno None Aripiprazole 87% (Oral), 100% (IM) 75 h (94 h) 99% 3–5 h Template:Dunno 4.9 L/kg Faeces (55%), urine (25%) Oral, IM (including depot) CYP2D6, CYP3A4 Dehydroaripiprazole Asenapine 35% (sublingual) 24 h 95% 0.5–1.5 h 4 ng/mL 20–25 L/kg Urine (50%), faeces (40%) Sublingual CYP1A2, UGT1A4, CYP2D6 None Blonanserin<ref name="Deeks, ED; Keating, GM 65–84"/><ref name="Tenjin, T; Miyamoto, S; Ninomiya, Y; Kitajima, R; Ogino, S; Miyake, N; Yamaguchi, N 2013 587–594"/><ref>Template:Cite journal</ref> 55% 10.7–16.2 h (single dosing), 67.9 h (repeated dosing) ≥ 99.7% 1.5–2 h 0.14–0.76 ng/mL (0.57 ng/mL for repeated dosing) 8560–9500 L Urine (59%), faeces (30%) Oral CYP3A4 N-desethylblonanserin Chlorpromazine 20% 30 h 92–97% Template:Dunno Template:Dunno 20 L/kg Urine Oral, IM, IV CYP2D6 Several active metabolites Clozapine 50–60% 12 h 97% 1.5–2.5 h 102–771 ng/mL 4.67 L/kg Urine (50%), faeces (30%) Oral CYP1A2, CYP2D6, CYP3A4 Norclozapine Droperidol Template:Dunno 2 h (8–12 h) Extensive 60 min (IM) Template:Dunno 2 L/kg (adults), 0.58 L/kg (children) Urine (75%), faeces (22%) IM, IV Template:Dunno None Flupentixol 40–55% (Oral) 35 h Template:Dunno 7 days (depot) Template:Dunno 12–14 L/kg Urine Oral, IM (including depot) Template:Dunno None Fluphenazine 2.7% (Oral) 14–16 h, 14 days (depot) Template:Dunno 2 h (Oral), 8–10 h (depot) Template:Dunno Template:Dunno Urine, faeces Oral, IM (including depot) Template:Dunno None Haloperidol 60–70% (Oral) 10–20 h (short-acting IM), 3 weeks (depot) 92% 2–6 h (Oral), 10–20 min (short-acting IM), 6–7 days (depot) Template:Dunno 8–18 L/kg Urine (30%), faeces (15%) Oral, IM, IV CYP3A4 None Iloperidone 96% Template:Dunno 95% 2–4 h Template:Dunno 1340–2800 L Urine (45–58%), faeces (20–22%) Oral CYP3A4, CYP2D6 None notable. Levomepromazine Template:Dunno 30 h Template:Dunno 2–3 h Template:Dunno Template:Dunno Urine, faeces IM, IV Template:Dunno Methotrimeprazine sulfoxide Loxapine High 6–8 h (Inhaled), 4–12 h (Oral) 96.6% 2 min (inhaled), 2 h (oral), 5 h (IM) 257 ng/mL (inhaled), 6–13 ng/mL (Oral) Template:Dunno Urine (56–70%), faeces [Only oral data available] Oral, IM, Inhalation CYP1A2, CYP3A4, CYP2D6 Amoxapine (a tricyclic antidepressant), 7-OH loxapine, 8-OH loxapine Lurasidone 9–19% 18 h 99% 1–3 h Template:Dunno 6173 L Urine (9%), faeces (80%) Oral CYP3A4 2 active Melperone<ref>Template:Cite journal</ref> 54% (Oral via syrup), 65% (Oral via tablets), 87% (IM) 2.1–6.4 h (Oral), Template:Nowrap (IM) 50% 1.6–2.4 h (Oral, tablets), 1 h (Oral, syrup) Template:Nowrap (25 mg, orally), 2228–3416 ng/mL (50 mg, orally), Template:Nowrap (100 mg, orally) Template:Nowrap (10 mg), Template:Nowrap (20 mg) Urine (70% as metabolites, 5.5–10.4% as parent drug) Oral, IM Template:Dunno None Olanzapine 87% (Oral) 30 h 93% 6 h (Oral), 15–45 min (short-acting IM), 7 days (depot) 4–20.4 mg/mL<ref>Template:Cite journal</ref> 1000 L Urine (57%), faeces (30%) Oral, IM (including depot) CYP1A2 None Paliperidone 28% (Oral) 23 h (Oral), 25–49 days (IM) 74% 24 h (Oral), 13 days (IM) 8.85–11.7 ng/mL<ref>Template:Cite journal</ref> 390–487 L Urine (80%), faeces (11%) Oral, IM (depot) CYP3A4, CYP2D6 None Periciazine Template:Dunno 12 h Template:Dunno 2 h 150 ng/mL Template:Dunno Urine Oral Template:Dunno ? Perospirone<ref name="CNS Drugs" /> Template:Dunno 1.9–2.5 h 92% 1.5 h 5.7 ng/mL Template:Dunno Urine (0.4% as unchanged drug) Oral Template:Dunno None Perphenazine Template:Dunno 9–12 h (10–19 h) Template:Dunno 1–3 h; 2–4 h (metabolite) 0.984 ng/mL; 0.509 ng/mL Template:Dunno Urine, faeces Oral CYP2D6 7-OH perphenazine Pimozide 40–50% 55 h Template:Dunno 6–8 h 4–19 ng/mL (dose-dependent) Template:Dunno Urine Oral CYP3A4, CYP2D6 None Prochlorperazine 12.5% 6.8–9 h High Template:Dunno Template:Dunno 12.9–17.7 L/h Urine, bile Oral, IM, IV Template:Dunno N-desmethylprochlorperazine Quetiapine 100% 6 h (IR), 7 h (XR); active metabolite: 12 h 83% 1.5 h (IR), 6 h (XR) @ 250 mg q8hr 778 ng/mL (male), 879 ng/mL (female)<ref>Template:Cite journal</ref> 6–14 L/kg Urine (73%), faeces (20%) Oral CYP3A4 Norquetiapine (a norepinephrine reuptake inhibitor and 5-HT1A receptor partial agonist) Risperidone 70% 3–17 h (24 h) 90% (active metabolite: 77%) 3–17 h Template:Dunno 1–2 L/kg Urine (70%), faeces (14%) Oral, IM (including depot) CYP2D6 Paliperidone Sertindole Template:Dunno 3 days 99.5% 10 h Template:Dunno 20 L/kg Urine (4%), faeces (46–56%) Oral CYP2D6 None Sulpiride<ref>Template:Cite journal</ref> 27 ± 9% 8 h 40% 3-6 h Template:Dunno Template:Nowrap Urine, faeces Oral Template:Dunno None Thioridazine Template:Dunno 24 h 95% Template:Dunno Template:Dunno Template:Dunno Template:Dunno Oral CYP2D6 None Tiotixene Template:Dunno 24 h 90% Template:Dunno Template:Dunno Template:Dunno Template:Dunno Oral CYP1A2 None Trifluoperazine Template:Dunno 24 h Template:Dunno Template:Dunno Template:Dunno Template:Dunno Template:Dunno Oral Template:Dunno None Ziprasidone 60% (Oral), 100% (IM) 7 h (Oral), 2–5 h (IM) 99% 6–8 h (Oral), ≤ 60 min (IM) Template:Dunno 1.5 L/kg Faeces (66%), urine (20%) Oral, IM CYP3A4, CYP1A2 None Zotepine<ref>Template:Cite journal</ref><ref>Product Information: Nipolept(R), zotepine. Klinge Pharma GmbH, Munich, 1996.</ref> 7–13% 13.7–15.9 h (12 h) 97% 1-4 h 31–240 10 L/kg Urine (17%) Oral CYP1A2, CYP3A4 Norzotepine (a norepinephrine reuptake inhibitor) Zuclopenthixol 49% 20 h 98% 2–12 h (mean: 4 h) Template:Dunno 20 L/kg Faeces, urine (10%) Oral, IM (including depot) CYP2D6 None

History

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

Timeline of the development of antipsychotic drugs

File:Thorazine advert.jpg

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

The original antipsychotic drugs were happened upon largely by chance and then tested for their effectiveness. The first, chlorpromazine, was developed as a surgical anesthetic. It was first used on psychiatric patients because of its powerful calming effect; at the time it was regarded as a non-permanent "pharmacological lobotomy".<ref name=pieters>Template:Cite journal</ref> Lobotomy at the time was used to treat many behavioral disorders, including psychosis, although its effect was to markedly reduce behavior and mental functioning of all types. However, chlorpromazine proved to reduce the effects of psychosis in a more effective and specific manner than lobotomy, even though it was known to be capable of causing severe sedation. The underlying neurochemistry involved has since been studied in detail, and subsequent antipsychotic drugs have been developed by rational drug design.

The discovery of chlorpromazine's psychoactive effects in 1952 led to further research that resulted in the development of antidepressants, anxiolytics, and the majority of other drugs now used in the management of psychiatric conditions. In 1952, Henri Laborit described chlorpromazine only as inducing indifference towards what was happening around them in nonpsychotic, nonmanic patients, and Jean Delay and Pierre Deniker described it as controlling manic or psychotic agitation. The former claimed to have discovered a treatment for agitation in anyone, and the latter team claimed to have discovered a treatment for psychotic illness.<ref>Template:Cite book</ref>

Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs.<ref name="king">Template:Cite journal</ref> In the late 1950s the most widely used term was "neuroleptic", followed by "major tranquilizer" and then "ataraxic".<ref name="king"/> The first recorded use of the term tranquilizer dates from the early nineteenth century.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In 1953 Frederik F. Yonkman, a chemist at the Swiss-based Cibapharmaceutical company, first used the term tranquilizer to differentiate reserpine from the older sedatives.<ref>Template:Cite book</ref> The word neuroleptic was coined in 1955 by Delay and Deniker after their discovery (1952) of the antipsychotic effects of chlorpromazine.<ref name="king"/> It is derived from the Template:Langx (neuron, originally meaning "sinew" but today referring to the nerves) and "λαμβάνω" (lambanō, meaning "take hold of"). Thus, the word means taking hold of one's nerves. It was often taken to refer also to common side effects such as reduced activity in general, as well as lethargy and impaired motor control. Although these effects are unpleasant and in some cases harmful, they were at one time, along with akathisia, considered a reliable sign that the drug was working.<ref name=pieters /> The term "ataraxy" was coined by the neurologist Howard Fabing and the classicist Alister Cameron to describe the observed effect of psychic indifference and detachment in patients treated with chlorpromazine.<ref>Template:Cite book</ref> This term derived from the Greek adjective "ἀτάρακτος" (ataraktos), which means "not disturbed, not excited, without confusion, steady, calm".<ref name="king"/> In the use of the terms "tranquilizer" and "ataractic", medical practitioners distinguished between the "major tranquilizers" or "major ataractics", which referred to drugs used to treat psychoses, and the "minor tranquilizers" or "minor ataractics", which referred to drugs used to treat neuroses.<ref name="king"/> While popular during the 1950s, these terms are infrequently used today. They are being abandoned in favor of "antipsychotic", which refers to the drug's desired effects.<ref name="king"/> Today, "minor tranquilizer" can refer to anxiolytic and/or hypnotic drugs such as the benzodiazepines and nonbenzodiazepines, which are useful as generally short-term management for insomnia together with cognitive behavioral therapy for insomnia.<ref>Template:Cite journal</ref><ref>Template:Cite book</ref> They are potentially addictive sedatives.

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

Society and culture

Terminology

The term major tranquilizer was used for older antipsychotic drugs. The term neuroleptic is often used as a synonym for antipsychotic, even though – strictly speaking – the two terms are not interchangeable. Antipsychotic drugs are a subgroup of neuroleptic drugs, because the latter have a wider range of effects.<ref name=":1">Template:Cite book</ref><ref>R. Elliott Ingersoll, Carl F. Rak (2015): Psychopharmacology for Mental Health Professionals: An Integrative Approach, Cengage Learning, Boston, pp. 150-186 and 342-349, Template:ISBN.</ref>

Antipsychotics are a type of psychoactive or psychotropic medication.<ref>Template:Cite book</ref><ref>Template:Cite book</ref>

Sales

Antipsychotics were once among the biggest selling and most profitable of all drugs, generating $22 billion in global sales in 2008.<ref name="healthcarefinancenews.com">Pipelineantipsychotic drugs to drive next market evolution (2009). Healthcarefinancenews.com (7 August 2009).</ref> By 2003 in the US, an estimated 3.21 million patients received antipsychotics, worth an estimated $2.82 billion. Over 2/3 of prescriptions were for the newer, more expensive atypicals, each costing on average $164 per year, compared to $40 for the older types.<ref name="pmid17158480">Template:Cite journal</ref> By 2008, sales in the US reached $14.6 billion, the biggest selling drugs in the US by therapeutic class.<ref>2008 U.S. Sales and Prescription Information: Top Therapeutic Classes by U.S. Sales (PDF) Template:Webarchive. Imshealth.com.</ref>

In the five years since July 2017 the number of antipsychotic medicines dispensed in the community in the United Kingdom has increased by 11.2%. There have also been substantial price rises. Risperidone 6 mg tablets, the largest, increased from £3.09 in July 2017 to £41.16 in June 2022. The NHS is spending an additional £33 million annually on antipsychotics. Haloperidol 500 microgram tablets constituted £14.3 million of this.<ref>Template:Cite news</ref>

Overprescription

Antipsychotics in the nursing home population are often overprescribed, often for the purposes of making it easier to handle dementia patients. Federal efforts to reduce the use of antipsychotics in US nursing homes has led to a nationwide decrease in their usage in 2012.<ref>Template:Cite journal</ref><ref>Risky Antipsychotic Drugs Still Overprescribed In Nursing Homes, https://www.npr.org/sections/health-shots/2018/02/05/583435517/risky-antipsychotic-drugs-still-overprescribed-in-nursing-homes</ref><ref>Atypical antipsychotics: overrated and overprescribed, Glen Spielsman, https://pharmaceutical-journal.com/article/opinion/atypical-antipsychotics-overrated-and-overprescribed</ref>

Legal

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

Formulations

They may be administered orally or, in some cases, through long-acting (depot) injections administered in the dorsgluteal, ventrogluteal or deltoid muscle. Short-acting parenteral formulations also exist, which are generally reserved for emergencies or when oral administration is otherwise impossible. The oral formulations include immediate release, extended release, and orally disintegrating products (which are not sublingual, and can help ensure that medications are swallowed instead of "cheeked"). Sublingual products (e.g., asenapine) also exist, which must be held under the tongue for absorption. The first transdermal formulation of an antipsychotic (transdermal asenapine, marketed as Secuado), was FDA-approved in 2019.<ref name="Carrithers 2020">Template:Cite journal</ref>

Recreational use

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Certain second-generation antipsychotics are misused or abused for their sedative, tranquilizing, and (paradoxically) "hallucinogenic" effects.<ref name="Bogart 2011">Template:Cite journal</ref> The most commonly implicated second-generation antipsychotic is quetiapine.<ref name="Bogart 2011" /> In case reports, quetiapine has been abused in doses taken by mouth (which is how the drug is available from the manufacturer), but also crushed and insufflated or mixed with water for injection into a vein.<ref name="Bogart 2011" /> Olanzapine, another sedating second-generation antipsychotic, has also been misused for similar reasons.<ref name="Bogart 2011" /> There is no standard treatment for antipsychotic abuse, though switching to a second-generation antipsychotic with less abuse potential (e.g., aripiprazole) has been used.<ref name="Bogart 2011" />

Controversy

Joanna Moncrieff has argued that antipsychotic drug treatment is often undertaken as a means of control rather than to treat specific symptoms experienced by the patient.<ref name="guard 1">Template:Cite news</ref>

Use of this class of drugs has a history of criticism in residential care. As the drugs used can make patients calmer and more compliant, critics claim that the drugs can be overused. Outside doctors can feel under pressure from care home staff.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}Template:Unreliable source?</ref> In an official review commissioned by UK government ministers it was reported that the needless use of antipsychotic medication in dementia care was widespread and was linked to 1800 deaths per year.<ref>Template:Cite news</ref><ref>Template:Cite news</ref> In the US, the government has initiated legal action against the pharmaceutical company Johnson & Johnson for allegedly paying kickbacks to Omnicare to promote its antipsychotic risperidone (Risperdal) in nursing homes.<ref name=Hilzenrath>Template:Cite news</ref>

There has also been controversy about the role of pharmaceutical companies in marketing and promoting antipsychotics, including allegations of downplaying or covering up adverse effects, expanding the number of conditions or illegally promoting off-label usage; influencing drug trials (or their publication) to try to show that the expensive and profitable newer atypicals were superior to the older cheaper typicals that were out of patent. Following charges of illegal marketing, settlements by two large pharmaceutical companies in the US set records for the largest criminal fines ever imposed on corporations.<ref name=bied2010>Template:Cite news</ref> One case involved Eli Lilly and Company's antipsychotic Zyprexa, and the other involved Bextra. In the Bextra case, the government also charged Pfizer with illegally marketing another antipsychotic, Geodon.<ref name=bied2010/> In addition, AstraZeneca faces numerous personal-injury lawsuits from former users of Seroquel (quetiapine), amidst federalTemplate:Clarify investigations of its marketing practices.<ref>Template:Cite news</ref> By expanding the conditions for which they were indicated, Astrazeneca's Seroquel and Eli Lilly's Zyprexa had become the biggest selling antipsychotics in 2008 with global sales of $5.5 billion and $5.4 billion respectively.<ref name="healthcarefinancenews.com"/>

Harvard University medical professor Joseph Biederman conducted research on bipolar disorder in children that led to an increase in such diagnoses. A 2008 SenateTemplate:Which investigation found that Biederman also received $1.6 million in speaking and consulting fees between 2000 and 2007, some of them undisclosed to Harvard, from companies including makers of antipsychotic drugs prescribed for children with bipolar disorder. Johnson & Johnson gave more than $700,000 to a research center that was headed by Biederman from 2002 to 2005, where research was conducted, in part, on Risperdal, the company's antipsychotic drug. Biederman has responded saying that the money did not influence him and that he did not promote a specific diagnosis or treatment.<ref name=bied2010/>

Pharmaceutical companies have also been accused of attempting to set the mental health agenda through activities such as funding consumer advocacy groups.<ref name="pmid15278977">Template:Cite journal</ref>

Special populations

It is recommended that persons with dementia who exhibit behavioral and psychological symptoms should not be given antipsychotics before trying other treatments.<ref name="APAfive dementia">Template:Citation, which cites

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• Template:Cite journal</ref>Template:Update inline When taking antipsychotics this population has increased risk of cerebrovascular effects, parkinsonism or extrapyramidal symptoms, sedation, confusion and other cognitive adverse effects, weight gain, and increased mortality.<ref name="APAfive dementia"/> Physicians and caretakers of persons with dementia should try to address symptoms including agitation, aggression, apathy, anxiety, depression, irritability, and psychosis with alternative treatments whenever antipsychotic use can be replaced or reduced.<ref name="APAfive dementia"/> Elderly persons often have their dementia treated first with antipsychotics and this is not the best management strategy.<ref name="AGSfive">Template:Citation, which cites
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See also

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

Further reading

• Template:Cite journal

External links

• Recommendations for the use of antipsychotics for treating psychosis, World Health Organization 2012
• Template:Usurped, Australian Prescriber 2005 (note: pharmaceutical company conflict of interest statement at the end)
• Template:Usurped, Australian Prescriber 2005
• First Generation Antipsychotics: An Introduction, Psychopharmacology Institute, 2012
• FDA Public Health Advisory – Public Health Advisory for Antipsychotic Drugs used for Treatment of Behavioral Disorders in Elderly Patients, fda.gov
• Antipsychotic Medication – information from mental health charity The Royal College of Psychiatrists
• Template:In lang FROTA LH. Fifty Years of Antipsychotic Drugs in Psychiatry. "Cinqüenta Anos de Medicamentos Antipsicóticos em Psiquiatria." 1st ed; Ebook: CD-Rom/On-Line Portuguese, Template:ISBN, File .pdf (Adobe Acrobat) 6Mb, Informática, Rio de Janeiro, August 2003, 486pp., medicina.ufrj.br