Antipsychotics, also known as neuroleptics or major tranquilizers,^[2] are a class of medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia and bipolar disorder. Antipsychotics are usually effective in relieving symptoms of psychosis in the short term.

The long-term use of antipsychotics is associated with adverse effects such as involuntary movement disorders, gynecomastia, impotence, weight gain and metabolic syndrome.

First-generation antipsychotics, known as typical antipsychotics, were discovered in the 1950s. Most second-generation drugs, known as atypical antipsychotics, have been developed more recently, although the first atypical antipsychotic, clozapine, was discovered in the 1960s and introduced clinically in the 1970s.^[3] Both generations of medication tend to block receptors in the brain's dopamine pathways, but atypicals tend to act on serotonin receptors as well. Neuroleptic, originating from Greek: νεῦρον (neuron) and λαμβάνω (take hold of) – thus meaning "which takes the nerve" – refers to both common neurological effects and side effects.^[4]

Antipsychotics are most frequently used for the following conditions:

They are not recommended for dementia or insomnia unless other treatments have not worked.^[8] They are not recommended in children unless other treatments are not effective or unless the child has psychosis.^[8]

The World Health Organization provides a description of recommendations for the prescription of antipsychotics for the purposes of the treatment of psychosis.^[9]

Antipsychotic drug treatment is a key component of schizophrenia treatment algorithms recommended by the National Institute of Health and Care Excellence (NICE),^[10] the American Psychiatric Association,^[11] and the British Society for Psychopharmacology.^[12] The main effect of treatment with antipsychotics is to reduce the so-called "positive" symptoms, including delusions and hallucinations. There is mixed evidence to support a significant impact of antipsychotic use on negative symptoms (such as apathy, lack of emotional affect, and lack of interest in social interactions) or on the cognitive symptoms (disordered thinking, reduced ability to plan and execute tasks) of schizophrenia.^[13][14] In general, the efficacy of antipsychotic treatment in reducing both positive and negative symptoms appears to increase with increasing severity of baseline symptoms.^[15] 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 so than conventional antipsychotics, although the reasoning and mechanics of this are still unclear to researchers.^[16]

Applications of antipsychotic drugs in the treatment of schizophrenia include prophylaxis in those showing symptoms that suggest that they are at high risk of developing psychosis, treatment of first episode psychosis, maintenance therapy, and treatment of recurrent episodes of acute psychosis.^[12]

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 others focused on cognitive disturbances (Basic symptoms"), are used to evaluate people with early, low level symptoms of psychosis. Used in combination with family history information, these tests can identify a "high risk" group having a 20–40% risk of progression to frank psychosis within 2 years.^[12] 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, the clinical trials performed to date provide little evidence that early use of antipsychotics, alone or in combination with cognitive-behavioral therapy, provides improved long term outcomes in those with prodromal symptoms.^[17]

NICE recommends that all persons presenting with a first episode of frank 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 efficacious.^[10] A diagnosis of schizophrenia is not normally made at this time, as up to 25% of those presenting with first episode psychosis are eventually found to suffer from bipolar disorder instead. The goals of treatment of these patients 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. Evidence that early treatment has a favorable effect on long term outcomes is equivocal.^[10][12]

Placebo-controlled trials of both first and second generation antipsychotic drugs consistently demonstrate the superiority of active drug to placebo in suppressing psychotic symptoms.^[12] A large meta-analysis of 38 trials of antipsychotic drugs in schizophrenia acute psychotic episodes showed an effect size of about 0.5.^[18] There is little or no difference in efficacy among approved antipsychotic drugs, including both first- and second-generation agents.^[10][19] 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.^[20]

The majority of patients treated with an antipsychotic drug will experience a response within 4 weeks. The goals of continuing treatment are to maintain suppression of symptoms, prevent relapse, improve quality of life, and support engagement in psychosocial therapy.^[12]

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.^[21] 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.^[12]

A significant challenge in the use of antipsychotic drugs for the prevention of relapse is the poor rate of compliance. 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, suggest that most patients who discontinue treatment do so because of suboptimal efficacy.^[21][22]

Antipsychotics are routinely used, often in conjunction with mood stabilisers such as lithium/valproate, as a first-line treatment for manic and mixed episodes associated with bipolar disorder.^[7][23] The reason for this combination is the therapeutic delay of the aforementioned mood stabilisers (for valproate therapeutic effects are usually seen around five days after treatment is commenced whereas lithium usually takes at least a week^[23] before the full therapeutic effects are seen) and the comparatively rapid antimanic effects of antipsychotic drugs.^[24] The antipsychotics have a documented efficacy when used alone in acute mania/mixed episodes.^[5]

Three atypical antipsychotics (lurasidone,^[25] olanzapine^[26] and quetiapine^[27]) have also been found to possess efficacy in the treatment of bipolar depression as a monotherapy, whereas only olanzapine^[28] and quetiapine^[29][30] 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.^[31]

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.^[32][33] 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.

An assessment for an underlying cause of behavior is needed before prescribing antipsychotic medication for symptoms of dementia.^[34] 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.^[35] Psychosocial interventions may reduce the need for antipsychotics.^[36]

A number of atypical antipsychotics have some benefits when used in addition to other treatments in major depressive disorder.^[37][38] Aripiprazole, quetiapine, and olanzapine (when used in conjunction with fluoxetine) have received the Food and Drug Administration (FDA) labelling for this indication.^[39] There is, however, a greater risk of side effects with their use.^[37]

Besides the above uses antipsychotics may be used for obsessive–compulsive disorder, posttraumatic stress disorder, personality disorders, Tourette syndrome, autism and agitation in those with dementia.^[40] Evidence however does not support the use of atypical antipsychotics in eating disorders or personality disorder.^[41] Risperidone may be useful for obsessive–compulsive disorder.^[40] The use of low doses of antipsychotics for insomnia, while common, is not recommended as there is little evidence of benefit and concerns regarding adverse effects.^[41][42] Low dose antipsychotics may also be used in treatment of impulse-behavioural and cognitive-perceptual symptoms of borderline personality disorder.^[43]

In children they may be used in those with disruptive behavior disorders, mood disorders and pervasive developmental disorders or intellectual disability.^[44] Antipsychotics are only weakly recommended for Tourette syndrome, because although they are effective, side effects are common.^[45] The situation is similar for those on the autism spectrum.^[46] 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.^[47] A UK review of unlicensed usage in children and adolescents reported a similar mixture of findings and concerns.^[48] A survey of children with pervasive developmental disorder found that 16.5% were taking an antipsychotic drug, most commonly for irritability, aggression, and agitation. Risperidone has been approved by the US FDA for the treatment of irritability in autistic children and adolescents.^[49]

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.^[50]

Antipsychotics may be an option, together with stimulants, in people with ADHD and aggressive behavior when other treatments have not worked.^[51]

It is unclear whether the atypical (second-generation) antipsychotics offer advantages over older, first generation antipsychotics.^[14][52] Amisulpride, olanzapine, risperidone and clozapine may be more effective but are associated with greater side effects.^[53] Typical antipsychotics have equal drop-out and symptom relapse rates to atypicals when used at low to moderate dosages.^[54]

Clozapine is an effective treatment for those who respond poorly to other drugs ("treatment-resistant" or "refractory" schizophrenia),^[55] but it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people.^[56]

Due to bias in the research the accuracy of comparisons of atypical antipsychotics is a concern.^[57]

In 2005, a US government body, the National Institute of Mental Health published the results of a major independent study (the CATIE project).^[58] No other atypical studied (risperidone, quetiapine, and ziprasidone) did better than the typical perphenazine on the measures used, nor did they produce fewer adverse effects than the typical antipsychotic perphenazine, although more patients discontinued perphenazine owing to extrapyramidal effects compared to the atypical agents (8% vs. 2% to 4%).^[5]

Compliance has not been shown to be different between the two types.^[59]

Many researchers question the first-line prescribing of atypicals over typicals, and some even question the distinction between the two classes.^[60][61][62] 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.^[63] 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.^[64]

Biperiden is prescribed for acute extrapyramidal side effects of antypsychotic therapy, such as akathisia.^[65]

Generally, more than one antipsychotic drug should not be used at a time because of increased adverse effects.^[66]

Very rarely antipsychotics may cause tardive psychosis.^[67]

Some studies have found decreased life expectancy associated with the use of antipsychotics, and argued that more studies are needed.^[76][77] Antipsychotics may also increase the risk of early death in individuals with dementia.^[78] Antipsychotics typically worsen symptoms in people who suffer from depersonalisation disorder.^[79] 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.^[66][80] 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.^[66][81]

Loss of grey matter and other brain structural changes over time are observed in schizophrenia. Meta-analyses of the effects of antipsychotic treatment on the course of grey matter loss and structural changes have reached conflicting conclusions. 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.^[82] A second meta-analysis suggested that treatment with antipsychotics was associated with increased grey matter loss.^[83]

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.^[84]

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.^[85] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.^[86] Other symptoms may include restlessness, increased sweating, and trouble sleeping.^[86] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.^[86] Symptoms generally resolve after a short period of time.^[86]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.^[87] It may also result in reoccurrence of the condition that is being treated.^[88] Rarely tardive dyskinesia can occur when the medication is stopped.^[86]

Unexpected psychotic episodes have been observed in patients withdrawing from clozapine. This is referred to as supersensitivity psychosis, not to be equated with tardive psychosis.^[87]

Tardive dyskinesia may abate during withdrawal from the antipsychotic agent, or it may persist.^[89]

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.^[90] The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.^[91] The process of cross-titration involves gradually increasing the dose of the new medication while gradually decreasing the dose of the old medication.^[70]

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.^[19]

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.

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

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.^[96][97] In addition to the antagonistic effects of dopamine, antipsychotics (in particular atypical neuroleptics) also antagonize 5-HT2A receptors. Different alleles of the 5-HT2A receptor have been associated with schizophrenia and other psychoses, including depression.^[98][99] Higher concentrations of 5-HT2A receptors in cortical and subcortical areas, in particular in the right caudate nucleus have been historically recorded.^[98]

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.^[100] 5-HT2A antagonism increases dopaminergic activity in the nigrostriatal pathway, leading to a lowered extrapyramidal side effect liability among the atypical antipsychotics.^[100][101]