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Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of psychotropic medication primarily used to manage psychosis (including , , paranoia or disordered thought), principally in schizophrenia but also in a range of other psychotic disorders. They are also the mainstay, together with , in the treatment of bipolar disorder. 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, 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.
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. 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.). 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. Neuroleptic, originating from ( neuron) and λαμβάνω]] ( take hold of)—thus meaning "which takes the nerve"—refers to both common neurological effects and side effects.
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. The same can be said for insomnia, in which they are not recommended as first-line therapy. There are evidence-based indications for using antipsychotics in children (e.g., tic disorder, bipolar disorder, psychosis), but the use of antipsychotics outside of those contexts (e.g., to treat behavioral problems) warrants significant caution.
Antipsychotics are used to treat tics associated with Tourette syndrome. 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. Quetiapine is used to treat generalized anxiety disorder.
Applications of antipsychotic drugs in the treatment of schizophrenia include prophylaxis for those showing symptoms that suggest that they are at high risk of developing psychosis; treatment of first-episode psychosis; maintenance therapy (a form of prophylaxis, maintenance therapy aims to maintain therapeutic benefit and prevent symptom relapse); and treatment of recurrent episodes of acute psychosis. A recent 2024 study found that using high doses of antipsychotics for schizophrenia was linked to a higher risk of mortality. Researchers analyzed data from 32,240 individuals aged 17 to 64 diagnosed with schizophrenia between 2002 and 2012 to arrive at this conclusion.
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. NICE makes no distinction between substance-induced psychosis and any other form of psychosis. The rate of conversion differs for different classes of drugs.
Pharmacological options for the specific treatment of FEP have been discussed in recent reviews. 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.
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. A 3-year trial following persons receiving maintenance therapy after an acute psychotic episode found that 33% obtained long-lasting symptom reduction, 13% achieved remission, and only 27% experienced satisfactory quality of life. The effect of relapse prevention on long term outcomes is uncertain, as historical studies show little difference in long term outcomes before and after the introduction of antipsychotic drugs.
While maintenance therapy clearly reduces the rate of relapses requiring hospitalization, a large observational study in Finland found that, in people that eventually discontinued antipsychotics, the risk of being hospitalized again for a mental health problem or dying increased the longer they were dispensed (and presumably took) antipsychotics prior to stopping therapy. If people did not stop taking antipsychotics, they remained at low risk for relapse and hospitalization compared to those that did. The authors speculated that the difference may be because the people that discontinued treatment after a longer time had more severe mental illness than those that discontinued antipsychotic therapy sooner.
A significant challenge in the use of antipsychotic drugs for the prevention of relapse is the poor rate of adherence. In spite of the relatively high rates of adverse effects associated with these drugs, some evidence, including higher dropout rates in placebo arms compared to treatment arms in randomized clinical trials, suggests that most patients who discontinue treatment do so because of suboptimal efficacy. 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 Depot injection (LAI), or "depot", form have been suggested as a method of decreasing medication nonadherence (sometimes also called non-compliance). NICE advises LAIs be offered to patients when preventing covert, intentional nonadherence is a clinical priority. LAIs are used to ensure adherence in outpatient commitment. 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).
At least five atypical antipsychotics (lumateperone, cariprazine, lurasidone, olanzapine, and quetiapine) have also been found to possess efficacy in the treatment of bipolar depression as a monotherapy, whereas only olanzapine and quetiapine 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.
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. 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.
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.
In children they may be used in those with disruptive behavior disorders, and pervasive developmental disorders or intellectual disability. Antipsychotics are only weakly recommended for Tourette syndrome, because although they are effective, side effects are common. The situation is similar for those on the autism spectrum.
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. A UK review of unlicensed usage in children and adolescents reported a similar mixture of findings and concerns. A survey of children with pervasive developmental disorder found that 16.5% were taking an antipsychotic drug, most commonly for irritability, aggression, and agitation. Both risperidone and aripiprazole have been approved by the US FDA for the treatment of irritability in autistic children and adolescents.Truven Health Analytics, Inc. DRUGDEX System (Internet) cited. Greenwood Village, CO: Thomsen Healthcare; 2013. A review in the UK found that the use of antipsychotics in England doubled between 2000 and 2019. Children were prescribed antipsychotics for conditions for which there is no approval, such as autism.
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.
Antipsychotics may be an option, together with stimulants, in people with ADHD and aggressive behavior when other treatments have not worked. They have not been found to be useful for the prevention of delirium among those admitted to hospital.
Clozapine is an effective treatment for those who respond poorly to other drugs ("treatment-resistant" or "refractory" schizophrenia), but it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people.
Due to bias in the research the accuracy of comparisons of atypical antipsychotics is a concern.
In 2005, a US government body, the National Institute of Mental Health published the results of a major independent study (the CATIE project). 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%). 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.
Atypical antipsychotics do not appear to lead to improved rates of medication adherence compared to typical antipsychotics.
Many researchers question the first-line prescribing of atypicals over typicals, and some even question the distinction between the two classes. 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. 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.
Use of antipsychotics is associated with reductions in brain tissue volumes, including white matter reduction, an effect which is dose-dependent and time-dependent. However, a recent controlled trial suggests that second generation antipsychoticsplease see Chopra et al 2021: Strengths and limitations "only examined risperidone and paliperidone" combined with intensive psychosocial therapyplease see Chopra et al 2021: Method Study design may potentially prevent pallidal brain volume loss in first episode psychosis.please see Chopra et al 2021: Introduction, 3rd paragraph, Lieberman JA, et al. 2005 & Shao Y et al 2015, and Chopra et al: Are antipsychotics neuroprotective? 1st paragraph last sentence
Some atypicals are associated with considerable weight gain, diabetes and the risk of metabolic syndrome. Unwanted side effects cause people to stop treatment, resulting in relapses. Risperidone (atypical) has a similar rate of extrapyramidal symptoms to haloperidol (typical). A rare but potentially lethal condition of neuroleptic malignant syndrome (NMS) has been associated with the use of antipsychotics. Through its early recognition, and timely intervention rates have declined. However, an awareness of the syndrome is advised to enable intervention. 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. Very rarely antipsychotics may cause tardive psychosis.
Clozapine is associated with side effects that include weight gain, tiredness, and hypersalivation. More serious adverse effects include , NMS, neutropenia, and agranulocytosis (lowered white blood cell count) and its use needs careful monitoring.
Clozapine is also associated with thromboembolism (including pulmonary embolism), myocarditis, and cardiomyopathy. A systematic review of clozapine-associated pulmonary embolism indicates that this adverse effect can often be fatal, and that it has an early onset, and is dose-dependent. The findings advised the consideration of using a prevention therapy for venous thromboembolism after starting treatment with clozapine, and continuing this for six months. Constipation is three times more likely to occur with the use of clozapine, and severe cases can lead to Ileum and bowel ischemia resulting in many fatalities. Very rare clozapine adverse effects include periorbital edema due to several possible mechanisms (e.g., inhibition of platelet-derived growth factor receptors leading to increased vascular permeability, antagonism of renal dopamine receptors with electrolyte and fluid imbalance and immune-mediated hypersensitivity reactions).
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. Typical antipsychotics and atypical risperidone can have a side effect of sexual dysfunction. Clozapine, olanzapine, and quetiapine are associated with beneficial effects on sexual functioning helped by various psychotherapies.
Rare/Uncommon (<1% incidence for most antipsychotic drugs) adverse effects of antipsychotics include:
Some studies have found decreased life expectancy associated with the use of antipsychotics, and argued that more studies are needed. Antipsychotics may also increase the risk of early death in individuals with dementia. Antipsychotics typically worsen symptoms in people with depersonalisation disorder. 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. 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. A meta-analysis of observational studies with over two million individuals has suggested a moderate association of antipsychotic use with breast cancer.
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 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. A second 2012 meta-analysis suggested that treatment with antipsychotics was associated with increased grey matter loss. 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.
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.
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.
Adverse effect on cognitive function and increased risk of death in people with dementia along with worsening of symptoms has been described in the literature.
Antipsychotics, due to acting as dopamine D2 receptor antagonists and thereby stimulating pituitary gland , may have a risk of prolactinoma with long-term use. This is also responsible for their induction of hyperprolactinemia (high prolactin levels).
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.
There is evidence that withdrawal syndrome of antipsychotics can result in psychosis. This has occurred in patients who had previously no history of psychosis, but were taking antipsychotics for another reason. Tardive dyskinesia can also occur when the medication is stopped.
Unexpected psychotic episodes have been observed in patients withdrawing from clozapine. This is referred to as supersensitivity psychosis, not to be equated with tardive dyskinesia.
Tardive dyskinesia may abate during withdrawal from the antipsychotic agent, or it may persist.
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 . These adverse effects are more likely during rapid changes between antipsychotic agents, so making a gradual change between antipsychotics minimises these withdrawal effects. The British National Formulary recommends a gradual dose reduction when discontinuing antipsychotic treatment to avoid acute withdrawal symptoms or rapid relapse. The process of cross-titration involves gradually increasing the dose of the new medication while gradually decreasing the dose of the old medication.
City and Hackney Clinical Commissioning Group found more than 1,000 patients in their area in July 2019 who had not had regular medication reviews or health checks because they were not registered as having serious mental illness. On average they had been taking these drugs for six years. If this is typical of practice in England more than 100,000 patients are probably in the same position.
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.
In addition to the antagonistic effects of dopamine, antipsychotics (in particular atypical antipsychotics) also antagonize 5-HT2A receptors. Different of the 5-HT2A receptor have been associated with schizophrenia and other psychoses, including depression. Higher concentrations of 5-HT2A receptors in cortical and subcortical areas, in particular in the right caudate nucleus have been historically recorded.
Typical antipsychotics are not particularly selective and also block dopamine receptors in the mesocortical pathway, tuberoinfundibular pathway, and the nigrostriatal pathway. Blocking D2 receptors in these other pathways is thought to produce some unwanted side effects that the typical antipsychotics can produce (see above). They were commonly classified on a spectrum of low potency to high potency, where potency referred to the ability of the drug to bind to dopamine receptors, and not to the effectiveness of the drug. High-potency antipsychotics such as haloperidol, in general, have doses of a few milligrams and cause less sleepiness and calming effects than low-potency antipsychotics such as chlorpromazine and thioridazine, which have dosages of several hundred milligrams. The latter have a greater degree of anticholinergic and antihistaminergic activity, which can counteract dopamine-related side-effects.
Atypical antipsychotic drugs have a similar blocking effect on D2 receptors; however, most also act on serotonin receptors, especially 5-HT2A and 5-HT2C 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. 5-HT2A antagonism increases dopaminergic activity in the nigrostriatal pathway, leading to a lowered extrapyramidal side effect liability among the atypical antipsychotics.
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.
Through the ability of most antipsychotics to antagonize 5-HT2A 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, with exact these postsynaptic receptors (5-HT2A, D2) being flooded by the respective neurotransmitter (serotonin, dopamine) from amphetamine exposure).
Acronyms used:
Legend:
The discovery of chlorpromazine's psychoactive effects in 1952 led to further research that resulted in the development of , , 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.
Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs. In the late 1950s the most widely used term was "neuroleptic", followed by "major tranquilizer" and then "ataraxic". The first recorded use of the term tranquilizer dates from the early nineteenth century. In 1953 Frederik F. Yonkman, a chemist at the Swiss-based Cibapharmaceutical company, first used the term tranquilizer to differentiate reserpine from the older .
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.
Antipsychotics are a type of psychoactive or psychotropic medication.
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.
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. 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. 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.
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. One case involved Eli Lilly and Company's antipsychotic Zyprexa, and the other involved Bextra. In the Bextra case, the government also charged Pfizer with illegally marketing another antipsychotic, Geodon. In addition, AstraZeneca faces numerous personal-injury lawsuits from former users of Seroquel (quetiapine), amidst federal investigations of its marketing practices. By expanding the conditions for which they were indicated, Astrazeneca's Seroquel and Eli Lilly's Zyprexa had become the biggest selling antipsychotics in 2008 with global sales of $5.5 billion and $5.4 billion respectively.
Harvard University medical professor Joseph Biederman conducted research on bipolar disorder in children that led to an increase in such diagnoses. A 2008 Senate investigation found that Biederman also received $1.6 million in speaking and consulting fees between 2000 and 2007, some of them undisclosed to Harvard, from companies including makers of antipsychotic drugs prescribed for children with bipolar disorder. Johnson & Johnson gave more than $700,000 to a research center that was headed by Biederman from 2002 to 2005, where research was conducted, in part, on Risperdal, the company's antipsychotic drug. Biederman has responded saying that the money did not influence him and that he did not promote a specific diagnosis or treatment.
Pharmaceutical companies have also been accused of attempting to set the mental health agenda through activities such as funding consumer advocacy groups.
Schizophrenia
Antipsychotic drug treatment is a key component of schizophrenia treatment recommendations by the National Institute of Health and Care Excellence (NICE), the American Psychiatric Association, and the British Society for Psychopharmacology. The main aim of treatment with antipsychotics is to reduce the positive symptoms of psychosis, that include delusions and hallucinations. There is mixed evidence to support a significant impact of antipsychotic use on primary negative symptoms (such as apathy, lack of emotional affect, and lack of interest in social interactions) or on cognitive symptoms (memory impairments, reduced ability to plan and execute tasks). In general, the efficacy of antipsychotic treatment in reducing positive symptoms appears to increase with the severity of baseline symptoms. 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.
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. 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.
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. 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.
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. A large meta-analysis of 38 trials of antipsychotic drugs in schizophrenia with acute psychotic episodes showed an effect size of about 0.5. There is little or no difference in efficacy among approved antipsychotic drugs, including both first- and second-generation agents. 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.
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.
Bipolar disorder
Antipsychotics are routinely used, often in conjunction with such as lithium/valproate, as a first-line treatment for manic and mixed episodes associated with bipolar disorder. (2025). 9780470979488, Wiley-Blackwell. ISBN 9780470979488 (2025). 9780781765558, Wolters Kluwer Health/Lippincott Williams & Wilkins. ISBN 9780781765558 The reason for this combination is the therapeutic delay of the aforementioned mood stabilizers (for valproate therapeutic effects are usually seen around five days after treatment is commenced whereas lithium usually takes at least a week before the full therapeutic effects are seen) and the comparatively rapid antimanic effects of antipsychotic drugs. The antipsychotics have a documented efficacy when used alone in acute mania/mixed episodes.
Dementia
Psychosis and agitation develop in as many as 80 percent of people living in nursing homes. Despite a lack of FDA approval and Boxed warning, atypical antipsychotics are very often prescribed to people with dementia. An assessment for an underlying cause of behavior is needed before prescribing antipsychotic medication for symptoms of dementia.. 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. Psychosocial interventions may reduce the need for antipsychotics. In 2005, the FDA issued an advisory warning of an increased risk of death when atypical antipsychotics are used in dementia. In the subsequent 5 years, the use of atypical antipsychotics to treat dementia decreased by nearly 50%.
Major depressive disorder
A number of atypical antipsychotics have some benefits when used in addition to other treatments in major depressive disorder. Aripiprazole, quetiapine extended-release, and olanzapine (when used in conjunction with fluoxetine) have received the Food and Drug Administration (FDA) labelling for this indication.Truven Health Analytics, Inc. DrugPoint System (Internet) cited. Greenwood Village, CO: Thomsen Healthcare; 2013. There is, however, a greater risk of side effects with their use compared to using traditional antidepressants. The greater risk of serious side effects with antipsychotics is why, e.g., quetiapine was denied approval as monotherapy for major depressive disorder or generalized anxiety disorder, and instead was only approved as an adjunctive treatment in combination with traditional antidepressants.
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. Besides the above uses antipsychotics may be used for obsessive–compulsive disorder, post-traumatic stress disorder, personality disorders, Tourette syndrome, autism and agitation in those with dementia. Evidence however does not support the use of atypical antipsychotics in or personality disorder. The atypical antipsychotic risperidone may be useful for obsessive–compulsive disorder. 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. Some of the more serious adverse effects may also occur at the low doses used, such as dyslipidemia and neutropenia, 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. Low dose antipsychotics may also be used in treatment of impulse-behavioural and cognitive-perceptual symptoms of borderline personality disorder.Work Group on Borderline Personality Disorder (2025). 9780890423196, American Psychiatric Association Publications. . ISBN 9780890423196 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.
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. Amisulpride, olanzapine, risperidone and clozapine may be more effective but are associated with greater side effects. Typical antipsychotics have equal drop-out and symptom relapse rates to atypicals when used at low to moderate dosages.
Other uses
Antipsychotics, such as risperidone, quetiapine, and olanzapine, have been used as trip killer to block the effects of serotonergic psychedelics like psilocybin and lysergic acid diethylamide (LSD).
Adverse effects
Generally, more than one antipsychotic drug should not be used at a time because of increased adverse effects., which cites
(2025). 9780890423363, American Psychiatric Association. ISBN 9780890423363
By rate
Common (≥ 1% and up to 50% incidence for most antipsychotic drugs) adverse effects of antipsychotics include:
Long-term effects
Antipsychotic use has been linked to a 21x higher incidence of dementia in the United States by age 65. Both atypical and typical antipsychotics have a higher hazard ratio for dementia risk. In 2024 testable hypotheses were proposed for the mechanism responsible for cortical thinning till dementia.
Discontinuation
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. (2009). 9780853698456, Royal Pharmaceutical Society of Great Britain. ISBN 9780853698456 Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, Hyperhidrosis, and Insomnia. Less commonly there may be a Vertigo, numbness, or muscle pains. Withdrawal symptoms can be severe and long lasting, or permanent.
List of agents
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.
First-generation (typical)
Butyrophenones
Diphenylbutylpiperidines
Phenothiazines
Thioxanthenes
Disputed/unknown
This category is for drugs that have been called both first and second-generation, depending on the literature being used.
Benzamides
Tricyclics
Others
Second-generation (atypical)
Benzamides
Benzisoxazoles/benzisothiazoles
Butyrophenones
Tricyclics
Others
Third-generation
Third generation antipsychotics are recognized as demonstrating D2 receptor Agonist as opposed to the D2 and 5HT-2A receptor antagonism of second-generation (atypical) antipsychotics and D2 antagonism of first-generation (typical) antipsychotics.
Butyrophenone(s)
Phenylpiperazines/quinolinones/benzoxazinones
Muscarinic agonists
Mechanism of action
Antipsychotic drugs such as haloperidol and chlorpromazine tend to block dopamine D2 receptors in the dopaminergic pathways of the Human 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. (1990). 9783805550505 ISBN 9783805550505
(2025). 9783642257605 ISBN 9783642257605
Comparison of medications
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Torsades de Pointes common on overdose. Has a comparatively low penetrability of the blood–brain barrier. Amoxapine is also an antidepressant. Very toxic in overdose due to the potential for renal failure and seizures. Only clinically utilised antipsychotic that does not act by antagonising the D2 receptor and rather partially agonises this receptor. Oral hypoesthesia. Has a complex pharmacologic profile. Only used in a few East Asian countries. First marketed antipsychotic, sort of the prototypical low-potency first-generation ( typical) antipsychotic. Notable AEs: Agranulocytosis, neutropaenia, leukopenia and myocarditis. Dose-dependent seizure risk. Overall the most effective antipsychotic, on average. Usually reserved for treatment-resistant cases or highly suicidal patients. Mostly used for postoperative nausea and vomiting. Also used in lower doses for depression. High-potency first-generation ( typical) antipsychotic. Prototypical high-potency first-generation ( typical) antipsychotic. ? Also used as an analgesic, agitation, anxiety and emesis. ? May be particularly helpful in ameloriating the cognitive symptoms of schizophrenia, likely due to its 5-HT7 receptor. 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. Is a butyrophenone, low-potency atypical antipsychotic that has been tried as a treatment for Parkinson's disease psychosis, although with negative results. Withdrawn from the market. Seems to promote weight loss (which is rather unusual for an antipsychotic seeing how they tend to promote weight gain). ? Active metabolite of risperidone. Limited data available on adverse effects. Also used to treat severe anxiety. Not licensed for use in the US. Usually grouped with the atypical antipsychotics despite its relatively high propensity for causing extrapyramidal side effects. Has additional antiemetic effects. High potency first-generation ( typical) antipsychotic. Only available in the UK. Primarily used in medicine as an antiemetic. 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. Removed from the market amidst concerns about an alarmingly high rate of aplastic anaemia. ? Not licensed for use in the US. Not licensed for use in the US. Dose-dependent risk for degenerative retinopathies. Found utility in reducing the resistance of multidrug and even extensively resistant strains of tuberculosis to antibiotics. ? ? ? Dose-dependent risk of seizures. Not licensed for use in the US. 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.
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>10,000 4,678 8,128 ND >10,000 ND 57.0 19.25 95.7 ND 1,441 >10,000 >10,000 211.33 1,000 >10,000 >10,000 >10,000 56.33 >10,000 1,848 1,955 ND 1631.5 ND >10,000 2,692 >10,000 (RB) 29 >10,000 1,001 >10,000 73 Acronyms used:
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None Dehydroaripiprazole None N-desethylblonanserin Several active metabolites Norclozapine None None None None None notable. Methotrimeprazine sulfoxide Amoxapine (a tricyclic antidepressant), 7-OH loxapine, 8-OH loxapine 2 active None None None ? None 7-OH perphenazine None N-desmethylprochlorperazine Norquetiapine (a norepinephrine reuptake inhibitor and 5-HT1A receptor partial agonist) Paliperidone None None None None None None Norzotepine (a norepinephrine reuptake inhibitor) None
History
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". 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 drug design.
(2025). 9780387347073, Springer US. ISBN 9780387347073 The word neuroleptic was coined in 1955 by Delay and Deniker after their discovery (1952) of the antipsychotic effects of chlorpromazine. It is derived from the ( neuron, originally meaning "sinew" but today referring to the ) and "" ( lambanō, meaning "take hold of"). Thus, the word means taking hold of one's nerves. It was often taken to refer also to common side effects such as reduced activity in general, as well as lethargy and impaired motor control. Although these effects are unpleasant and in some cases harmful, they were at one time, along with akathisia, considered a reliable sign that the drug was working. The term "ataraxy" was coined by the neurologist Howard Fabing and the classicist Alister Cameron to describe the observed effect of psychic indifference and detachment in patients treated with chlorpromazine. This term derived from the Greek adjective "" ( ), which means "not disturbed, not excited, without confusion, steady, calm". In the use of the terms "tranquilizer" and "ataractic", medical practitioners distinguished between the "major tranquilizers" or "major ataractics", which referred to drugs used to treat psychoses, and the "minor tranquilizers" or "minor ataractics", which referred to drugs used to treat neurosis. While popular during the 1950s, these terms are infrequently used today. They are being abandoned in favor of "antipsychotic", which refers to the drug's desired effects. Today, "minor tranquilizer" can refer to anxiolytic and/or hypnotic drugs such as the and nonbenzodiazepines, which are useful as generally short-term management for insomnia together with cognitive behavioral therapy for insomnia. (1997). 9780721652573, Saunders. ISBN 9780721652573 They are potentially addictive sedatives.
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. (2025). 9780781724685, Lippincott Williams & Wilkins. ISBN 9780781724685R. Elliott Ingersoll, Carl F. Rak (2015): Psychopharmacology for Mental Health Professionals: An Integrative Approach, Cengage Learning, Boston, pp. 150-186 and 342-349, .
Sales
Antipsychotics were once among the biggest selling and most profitable of all drugs, generating $22 billion in global sales in 2008. Pipelineantipsychotic drugs to drive next market evolution (2009). Healthcarefinancenews.com (7 August 2009). By 2003 in the US, an estimated 3.21 million patients received antipsychotics, worth an estimated $2.82 billion. Over 2/3 of prescriptions were for the newer, more expensive atypicals, each costing on average $164 per year, compared to $40 for the older types. By 2008, sales in the US reached $14.6 billion, the biggest selling drugs in the US by therapeutic class. 2008 U.S. Sales and Prescription Information: Top Therapeutic Classes by U.S. Sales (PDF) . Imshealth.com.
Overprescription
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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.
Recreational use
Certain second-generation antipsychotics are misused or Substance abuse for their sedative, tranquilizing, and (paradoxically) "hallucinogenic" effects. The most commonly implicated second-generation antipsychotic is quetiapine. In case reports, quetiapine has been abused in doses taken by mouth (which is how the drug is available from the manufacturer), but also crushed and insufflated or mixed with water for injection into a vein. Olanzapine, another sedating second-generation antipsychotic, has also been misused for similar reasons. There is no standard treatment for antipsychotic abuse, though switching to a second-generation antipsychotic with less abuse potential (e.g., aripiprazole) has been used.
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.
Special populations
It is recommended that persons with dementia who exhibit behavioral and psychological symptoms should not be given antipsychotics before trying other treatments., which cites
When taking antipsychotics this population has increased risk of cerebrovascular effects, parkinsonism or extrapyramidal symptoms, sedation, confusion and other cognitive adverse effects, weight gain, and increased mortality. Physicians and caretakers of persons with dementia should try to address symptoms including agitation, aggression, apathy, anxiety, depression, irritability, and psychosis with alternative treatments whenever antipsychotic use can be replaced or reduced. Elderly persons often have their dementia treated first with antipsychotics and this is not the best management strategy., which cites
American Psychiatric Association (2025). 9780890423363, American Psychiatric Association. ISBN 9780890423363
See also
Notes
Further reading
External links
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