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Antipsychotic

April 08, 2023

Antipsychotics, also known as neuroleptics,[1] 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.[2][3] They are also the mainstay together with mood stabilizers in the treatment of bipolar disorder.[4]

Antipsychotic
Drug class
Olanzapine, an example of a second-generation (atypical) antipsychotic
Class identifiers
SynonymsNeuroleptics, major tranquilizers[1]
UsePrincipally: Schizophrenia, Schizoaffective disorder, Dementia, Tourette syndrome, Bipolar disorder, irritability in autism spectrum disorder
Clinical data
Drugs.comDrug Classes
External links
MeSHD014150
In Wikidata

Prior research has shown that use of any antipsychotic is associated with smaller brain tissue volumes,[5][6] including white matter reduction[7] and that this brain shrinkage is dose dependent and time dependent.[5][6] A more recent controlled trial suggests that second generation antipsychotics[8] combined with intensive psychosocial therapy[9] may potentially prevent pallidal brain volume loss in first episode psychosis.[10][7]

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, and tardive akathisia.

Prevention of these adverse effects is possible through concomitant medication strategies including use of beta-blockers. Currently, treatments for tardive diseases are not well established.

First-generation antipsychotics (e.g. chlorpromazine), known as typical antipsychotics, were first introduced in the 1950s, and others were developed until the early 1970s.[11] Second-generation antipsychotics, known as atypical antipsychotics, were introduced firstly with clozapine in the early 1970s followed by others (e.g. risperidone).[12] Both generations of medication block receptors in the brain for dopamine, 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.[13]

Medical uses

Antipsychotics are most frequently used for the following conditions:

  • Schizophrenia[2]
  • Schizoaffective disorder most commonly in conjunction with either an antidepressant (in the case of the depressive subtype) or a mood stabiliser (in the case of the bipolar subtype).
  • 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[14] and, according to a recent meta-analysis, they tend to have a lower liability for causing conversion from mania to depression.[15]
  • 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.[16]
  • Treatment resistant depression as an adjunct to standard antidepressant therapy.[16]

Antipsychotics are generally not recommended for treating behavioral problems associated with dementia, given that the risk of use tends to be greater than the potential benefit.[17] The same can be said for insomnia, in which they are not recommended as first-line therapy.[17] 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.[17]

Antipsychotics are used to treat tics associated with Tourette syndrome.[18] Aripiprazole, an atypical antipsychotic, is used as add-on medication to ameliorate sexual dysfunction as a symptom of Selective serotonin reuptake inhibitor antidepressants in women.[19]: 10  Quetiapine is used to treat generalized anxiety disorder.[20]

Schizophrenia

Main article: Schizophrenia § Medication

Antipsychotic drug treatment is a key component of schizophrenia treatment recommendations by the National Institute of Health and Care Excellence (NICE),[21] the American Psychiatric Association,[22] and the British Society for Psychopharmacology.[23] The main aim of treatment with antipsychotics is to reduce the positive symptoms of psychosis that include delusions and hallucinations.[2] 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 the cognitive symptoms (memory impairments, reduced ability to plan and execute tasks).[24][25] In general, the efficacy of antipsychotic treatment in reducing positive symptoms appears to increase with increasing severity of baseline symptoms.[26] 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.[27]

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 (a form of prophylaxis, maintenance therapy aims to maintain therapeutic benefit and prevent symptom relapse), and treatment of recurrent episodes of acute psychosis.[2][23]

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.[23] 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.[28]

First episode psychosis

First episode psychosis (FEP) is the first time that psychotic symptoms are presented. NICE recommends that all persons 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 are informed that combination treatment is more effective.[21] A diagnosis of schizophrenia is not made at this time as it takes longer to determine by both DSM-5 and ICD-11, and only around 60% of those presenting with a first episode psychosis will later be diagnosed with schizophrenia.[29]

The conversion rate for a first episode drug induced psychosis to bipolar disorder or schizophrenia are lower, with 30% of people converting to either bipolar disorder or schizophrenia.[30] NICE makes no distinction between a substance-induced psychosis, and any other form of psychosis. The rate of conversion differs for different classes of drug.[30]

Pharmacological options for the specific treatment of FEP have been discussed in recent reviews.[31][32] 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. Evidence that early treatment has a favorable effect on long term outcomes is equivocal.[21][23]

Recurrent psychotic episodes

Placebo-controlled trials of both first and second generation antipsychotic drugs consistently demonstrate the superiority of active drug to placebo in suppressing psychotic symptoms.[23] A large meta-analysis of 38 trials of antipsychotic drugs in schizophrenia acute psychotic episodes showed an effect size of about 0.5.[33] There is little or no difference in efficacy among approved antipsychotic drugs, including both first- and second-generation agents.[21][34] 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.[35]

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.[2][23]

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.[36] 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.[23]

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 stopped taking antipsychotics.[37] 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.[37]

A significant challenge in the use of antipsychotic drugs for the prevention of relapse is the poor rate of adherence.[2] 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.[36][38] If someone experiences psychotic symptoms due to nonadherence, they may be compelled to 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).[2][39] NICE advises LAIs be offered to patients when preventing covert, intentional nonadherence is a clinical priority.[40] LAIs are used to ensure adherence in outpatient commitment.[2][41] 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).[39]

Bipolar disorder

Main article: Bipolar disorder

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.[16][42] 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[42] before the full therapeutic effects are seen) and the comparatively rapid antimanic effects of antipsychotic drugs.[43] The antipsychotics have a documented efficacy when used alone in acute mania/mixed episodes.[14]

At least five atypical antipsychotics (lumateperone,[44] cariprazine,[45] lurasidone,[46] olanzapine,[47] and quetiapine[48]) have also been found to possess efficacy in the treatment of bipolar depression as a monotherapy, whereas only olanzapine[49] and quetiapine[50][51] 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.[52]

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.[53][54] 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.[55] Despite a lack of FDA approval and black-box warnings, atypical antipsychotics are very often prescribed to people with dementia.[55] An assessment for an underlying cause of behavior is needed before prescribing antipsychotic medication for symptoms of dementia.[56] 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.[57] Psychosocial interventions may reduce the need for antipsychotics.[58] In 2005, the FDA issued an advisory warning of an increased risk of death when atypical antipsychotics are used in dementia.[55] In the subsequent 5 years, the use of atypical antipsychotics to treat dementia decreased by nearly 50%.[55]

Major depressive disorder

A number of atypical antipsychotics have some benefits when used in addition to other treatments in major depressive disorder.[59][60] Aripiprazole, quetiapine extended-release, and olanzapine (when used in conjunction with fluoxetine) have received the Food and Drug Administration (FDA) labelling for this indication.[61] There is, however, a greater risk of side effects with their use compared to using traditional antidepressants.[59] 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.[62]

Other

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.[63] Evidence however does not support the use of atypical antipsychotics in eating disorders or personality disorder.[64] The atypical antipsychotic risperidone may be useful for obsessive–compulsive disorder.[63] 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.[64][65] Some of the more serious adverse effects may also occur at the low doses used, such as dyslipidemia and neutropenia,[66][67] 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.[68] Low dose antipsychotics may also be used in treatment of impulse-behavioural and cognitive-perceptual symptoms of borderline personality disorder.[69] 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.[70][71]

In children they may be used in those with disruptive behavior disorders, mood disorders and pervasive developmental disorders or intellectual disability.[72] Antipsychotics are only weakly recommended for Tourette syndrome, because although they are effective, side effects are common.[73] The situation is similar for those on the autism spectrum.[74] 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.[75] A UK review of unlicensed usage in children and adolescents reported a similar mixture of findings and concerns.[76] 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.[77]

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.[78]

Antipsychotics may be an option, together with stimulants, in people with ADHD and aggressive behavior when other treatments have not worked.[79] They have not been found to be useful for the prevention of delirium among those admitted to hospital.[80]

Typicals vs atypicals

It is unclear whether the atypical (second-generation) antipsychotics offer advantages over older, first generation antipsychotics.[2][25][81] Amisulpride, olanzapine, risperidone and clozapine may be more effective but are associated with greater side effects.[82] Typical antipsychotics have equal drop-out and symptom relapse rates to atypicals when used at low to moderate dosages.[83]

Clozapine is an effective treatment for those who respond poorly to other drugs ("treatment-resistant" or "refractory" schizophrenia),[84] but it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people.[85]

Due to bias in the research the accuracy of comparisons of atypical antipsychotics is a concern.[86]

In 2005, a US government body, the National Institute of Mental Health published the results of a major independent study (the CATIE project).[87] 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%).[14]

Atypical antipsychotics do not appear to lead to improved rates of medication adherence compared to typical antipsychotics.[88]

Many researchers question the first-line prescribing of atypicals over typicals, and some even question the distinction between the two classes.[89][90][91] 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.[92] 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.[93]

Adverse effects

For more detailed comparison of atypical antipsychotics, see Atypical antipsychotic § Adverse effects.

Generally, more than one antipsychotic drug should not be used at a time because of increased adverse effects.[94]

Some atypicals are associated with considerable weight gain, diabetes and the risk of metabolic syndrome.[95] Unwanted side effects cause people to stop treatment, resulting in relapses.[96]Risperidone (atypical) has a similar rate of extrapyramidal symptoms to haloperidol (typical).[95] 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.[97] 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.[98] Very rarely antipsychotics may cause tardive psychosis.[99]

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.[100][101]

Clozapine is also associated with thromboembolism (including pulmonary embolism), myocarditis, and cardiomyopathy.[102][103] 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.[103] 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.[100] 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).[104]

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.[105][106] Typical antipsychotics and atypical risperidone can have a side effect of sexual dysfunction.[107] Clozapine, olanzapine, and quetiapine are associated with beneficial effects on sexual functioning helped by various psychotherapies.[108]

By rate

Common (≥ 1% and up to 50% incidence for most antipsychotic drugs) adverse effects of antipsychotics include:[109]

  • Sedation (particularly common with asenapine, clozapine, olanzapine, quetiapine, chlorpromazine and zotepine[34])
  • 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
- 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[34])
  • Anticholinergic side-effects (common for olanzapine, clozapine; less likely on risperidone[110]) 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%.[111]

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.[112] Evidence suggests that females are more sensitive to the metabolic side effects of first-generation antipsychotic drugs than males.[113] Metabolic adverse effects appear to be mediated by the following mechanisms:
- Causing weight gain by antagonizing the histamine H1 and serotonin 5-HT2Creceptors[114] and perhaps by interacting with other neurochemical pathways in the central nervous system.[115]
- 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.)

Long-term effects

See also: List of long term side effects of antipsychotics

Some studies have found decreased life expectancy associated with the use of antipsychotics, and argued that more studies are needed.[117][118] Antipsychotics may also increase the risk of early death in individuals with dementia.[119] Antipsychotics typically worsen symptoms in people with depersonalisation disorder.[120] 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.[94][121] 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.[94][122] A meta-analysis of observational studies with over two million individuals has suggested a moderate association of antipsychotic use with breast cancer.[123]

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 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.[124] A second meta-analysis suggested that treatment with antipsychotics was associated with increased grey matter loss.[125] 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 over a 17–27 month period.[126]

The National Association of State Mental Health Program Directors said that antipsychotics are not interchangeable and it is recommend including trying at least one weight-neutral treatment for those patients with potential metabolic issues.[127]

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.[128]

Adverse effect on cognitive function[129][130][131] and increased risk of death in people with dementia along with worsening of symptoms has been described in the literature.[132][133]

Discontinuation

See also: Drug withdrawal § Prescription medicine

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[134] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[135] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[135] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[135] Symptoms generally resolve after a short period of time.[135]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[136] It may also result in recurrence of the condition that is being treated.[137] Rarely tardive dyskinesia can occur when the medication is stopped.[135]

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.[136][138]

Tardive dyskinesia may abate during withdrawal from the antipsychotic agent, or it may persist.[139]

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.[140] The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[141] 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.[142]

List of agents

 
Chlorpromazine
 
Haloperidol
 
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.[34]

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)

Main article: Typical antipsychotic

Butyrophenones

Main article: Butyrophenones

Diphenylbutylpiperidines

Phenothiazines

Main article: Phenothiazines

Thioxanthenes

Main article: 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)

Main article: Atypical antipsychotic

Benzamides

  • Amisulpride ‡ – 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.[143]
  • 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

  • Lumateperone – In December 2019, lumateperone received its first global approval in the USA for the treatment of schizophrenia in adults.[144] In 2020 and 2021 FDA approved for depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate.
  • Iloperidone – 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 – Primary, active metabolite of risperidone that was approved in 2006.
  • Perospirone † – Has a higher incidence of extrapyramidal side effects than other atypical antipsychotics.[145]
  • Risperidone – 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 – Approved in 2004[146] 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.

Butyrophenones

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

Tricyclics

  • Asenapine – Used for the treatment of schizophrenia and acute mania associated with bipolar disorder.
  • Clozapine – 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 – 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 – 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. It indirectly serves as a norepinephrine reuptake inhibitor by means of its active metabolite, norquetiapine.
  • Zotepine – An 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-HT2A 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 agonism as opposed to the D2 receptor antagonistic mechanism of both first-generation (typical) and second-generation (atypical) antipsychotic medications.[147]

Phenylpiperazines/quinolinones

Benzisoxazoles/benzisothiazoles
  • Lurasidone (Latuda) – Approved by the US FDA for schizophrenia and bipolar depression, and for use as schizophrenia treatment in Canada.

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.[149][150]

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.[151][152] Higher concentrations of 5-HT2A receptors in cortical and subcortical areas, in particular in the right caudate nucleus have been historically recorded.[151]

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.[153]

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.[154] 5-HT2A antagonism increases dopaminergic activity in the nigrostriatal pathway, leading to a lowered extrapyramidal side effect liability among the atypical antipsychotics.[154][155]

Comparison of medications

Pharmacokinetics of long-acting injectable antipsychotics
Medication Brand name Class Vehicle Dosage Tmax t1/2 single t1/2 multiple logPc Ref
Aripiprazole lauroxil Aristada Atypical Watera 441–1064 mg/4–8 weeks 24–35 days ? 54–57 days 7.9–10.0
Aripiprazole monohydrate Abilify Maintena Atypical Watera 300–400 mg/4 weeks 7 days ? 30–47 days 4.9–5.2
Bromperidol decanoate Impromen Decanoas Typical Sesame oil 40–300 mg/4 weeks 3–9 days ? 21–25 days 7.9 [240]
Clopentixol decanoate Sordinol Depot Typical Viscoleob 50–600 mg/1–4 weeks 4–7 days ? 19 days 9.0 [241]
Flupentixol decanoate Depixol Typical Viscoleob 10–200 mg/2–4 weeks 4–10 days 8 days 17 days 7.2–9.2 [241][242]
Fluphenazine decanoate Prolixin Decanoate Typical Sesame oil 12.5–100 mg/2–5 weeks 1–2 days 1–10 days 14–100 days 7.2–9.0 [243][244][245]
Fluphenazine enanthate Prolixin Enanthate Typical Sesame oil 12.5–100 mg/1–4 weeks 2–3 days 4 days ? 6.4–7.4 [244]
Fluspirilene Imap, Redeptin Typical Watera 2–12 mg/1 week 1–8 days 7 days ? 5.2–5.8 [246]
Haloperidol decanoate Haldol Decanoate Typical Sesame oil 20–400 mg/2–4 weeks 3–9 days 18–21 days 7.2–7.9 [247][248]
Olanzapine pamoate Zyprexa Relprevv Atypical Watera 150–405 mg/2–4 weeks 7 days ? 30 days –
Oxyprothepin decanoate Meclopin Typical ? ? ? ? ? 8.5–8.7
Paliperidone palmitate Invega Sustenna Atypical Watera 39–819 mg/4–12 weeks 13–33 days 25–139 days ? 8.1–10.1
Perphenazine decanoate Trilafon Dekanoat Typical Sesame oil 50–200 mg/2–4 weeks ? ? 27 days 8.9
Perphenazine enanthate Trilafon Enanthate Typical Sesame oil 25–200 mg/2 weeks 2–3 days ? 4–7 days 6.4–7.2 [249]
Pipotiazine palmitate Piportil Longum Typical Viscoleob 25–400 mg/4 weeks 9–10 days ? 14–21 days 8.5–11.6 [242]
Pipotiazine undecylenate Piportil Medium Typical Sesame oil 100–200 mg/2 weeks ? ? ? 8.4
Risperidone Risperdal Consta Atypical Microspheres 12.5–75 mg/2 weeks 21 days ? 3–6 days –
Zuclopentixol acetate Clopixol Acuphase Typical Viscoleob 50–200 mg/1–3 days 1–2 days 1–2 days 4.7–4.9
Zuclopentixol decanoate Clopixol Depot Typical Viscoleob 50–800 mg/2–4 weeks 4–9 days ? 11–21 days 7.5–9.0
Note: All by intramuscular injection. Footnotes: a = Microcrystalline or nanocrystalline aqueous suspension. b = Low-viscosity vegetable oil (specifically fractionated coconut oil with medium-chain triglycerides). c = Predicted, from PubChem and DrugBank. Sources: Main: See template.

History

 
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[250]

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".[251] 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.[252]

Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs.[13] In the late 1950s the most widely used term was "neuroleptic", followed by "major tranquilizer" and then "ataraxic".[13] The first recorded use of the term tranquilizer dates from the early nineteenth century.[253] 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.[254] The word neuroleptic was coined in 1955 by Delay and Deniker after their discovery (1952) of the antipsychotic effects of chlorpromazine.[13] It is derived from the Greek: "νεῦρον" (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.[251] 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.[255] This term derived from the Greek adjective "ἀτάρακτος" (ataraktos), which means "not disturbed, not excited, without confusion, steady, calm".[13] 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.[13] 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.[13] 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.[256][257] 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.[13]

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.[258][259]

Antipsychotics are a type of psychoactive or psychotropic medication.[260][261]

Sales

Antipsychotics were once among the biggest selling and most profitable of all drugs, generating $22 billion in global sales in 2008.[262] 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.[263] By 2008, sales in the US reached $14.6 billion, the biggest selling drugs in the US by therapeutic class.[264]

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.[265]

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.[266][267][268]

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.[269]

Recreational use

Certain second-generation antipsychotics are misused or abused for their sedative, tranquilizing, and (paradoxically) "hallucinogenic" effects.[270] The most commonly second-generation antipsychotic implicated is quetiapine.[270] 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.[270] Olanzapine, another sedating second-generation antipsychotic, has also been misused for similar reasons.[270] 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.[270]

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.[271]

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.[272] 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.[273][274] 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.[275]

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.[276] 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.[276] In addition, AstraZeneca faces numerous personal-injury lawsuits from former users of Seroquel (quetiapine), amidst federal[clarification needed] investigations of its marketing practices.[277] 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.[262]

Harvard University medical professor Joseph Biederman conducted research on bipolar disorder in children that led to an increase in such diagnoses. A 2008 Senate[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.[276]

Pharmaceutical companies have also been accused of attempting to set the mental health agenda through activities such as funding consumer advocacy groups.[278]

Special populations

It is recommended that persons with dementia who exhibit behavioral and psychological symptoms should not be given antipsychotics before trying other treatments.[279] 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.[279] 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.[279] Elderly persons often have their dementia treated first with antipsychotics and this is not the best management strategy.[280]

See also

Notes

  1. ^ Bolded drug names indicate drugs that are metabolites of clinically-marketed antipsychotics.

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April 08, 2023
antipsychotic, also, known, neuroleptics, class, psychotropic, medication, primarily, used, manage, psychosis, including, delusions, hallucinations, paranoia, disordered, thought, principally, schizophrenia, also, range, other, psychotic, disorders, they, also. Antipsychotics also known as neuroleptics 1 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 2 3 They are also the mainstay together with mood stabilizers in the treatment of bipolar disorder 4 AntipsychoticDrug classOlanzapine an example of a second generation atypical antipsychoticClass identifiersSynonymsNeuroleptics major tranquilizers 1 UsePrincipally Schizophrenia Schizoaffective disorder Dementia Tourette syndrome Bipolar disorder irritability in autism spectrum disorderClinical dataDrugs comDrug ClassesExternal linksMeSHD014150In WikidataPrior research has shown that use of any antipsychotic is associated with smaller brain tissue volumes 5 6 including white matter reduction 7 and that this brain shrinkage is dose dependent and time dependent 5 6 A more recent controlled trial suggests that second generation antipsychotics 8 combined with intensive psychosocial therapy 9 may potentially prevent pallidal brain volume loss in first episode psychosis 10 7 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 and tardive akathisia Prevention of these adverse effects is possible through concomitant medication strategies including use of beta blockers Currently treatments for tardive diseases are not well established First generation antipsychotics e g chlorpromazine known as typical antipsychotics were first introduced in the 1950s and others were developed until the early 1970s 11 Second generation antipsychotics known as atypical antipsychotics were introduced firstly with clozapine in the early 1970s followed by others e g risperidone 12 Both generations of medication block receptors in the brain for dopamine but atypicals tend to act on serotonin receptors as well Neuroleptic originating from Greek neῦron neuron and lambanw take hold of thus meaning which takes the nerve refers to both common neurological effects and side effects 13 Contents 1 Medical uses 1 1 Schizophrenia 1 1 1 Prevention of psychosis and symptom improvement 1 1 2 First episode psychosis 1 1 3 Recurrent psychotic episodes 1 1 4 Maintenance therapy 1 2 Bipolar disorder 1 3 Dementia 1 4 Major depressive disorder 1 5 Other 1 6 Typicals vs atypicals 2 Adverse effects 2 1 By rate 2 2 Long term effects 2 3 Discontinuation 3 List of agents 3 1 First generation typical 3 1 1 Butyrophenones 3 1 2 Diphenylbutylpiperidines 3 1 3 Phenothiazines 3 1 4 Thioxanthenes 3 2 Disputed unknown 3 2 1 Benzamides 3 2 2 Tricyclics 3 2 3 Others 3 3 Second generation atypical 3 3 1 Benzamides 3 3 2 Benzisoxazoles benzisothiazoles 3 3 3 Butyrophenones 3 3 4 Tricyclics 3 3 5 Others 3 4 Third generation 3 4 1 Phenylpiperazines quinolinones 3 4 1 1 Benzisoxazoles benzisothiazoles 4 Mechanism of action 5 Comparison of medications 6 History 7 Society and culture 7 1 Terminology 7 2 Sales 7 3 Overprescription 7 4 Legal 7 5 Formulations 7 6 Recreational use 7 7 Controversy 8 Special populations 9 See also 10 Notes 11 References 12 Further reading 13 External linksMedical uses EditAntipsychotics are most frequently used for the following conditions Schizophrenia 2 Schizoaffective disorder most commonly in conjunction with either an antidepressant in the case of the depressive subtype or a mood stabiliser in the case of the bipolar subtype 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 14 and according to a recent meta analysis they tend to have a lower liability for causing conversion from mania to depression 15 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 16 Treatment resistant depression as an adjunct to standard antidepressant therapy 16 Antipsychotics are generally not recommended for treating behavioral problems associated with dementia given that the risk of use tends to be greater than the potential benefit 17 The same can be said for insomnia in which they are not recommended as first line therapy 17 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 17 Antipsychotics are used to treat tics associated with Tourette syndrome 18 Aripiprazole an atypical antipsychotic is used as add on medication to ameliorate sexual dysfunction as a symptom of Selective serotonin reuptake inhibitor antidepressants in women 19 10 Quetiapine is used to treat generalized anxiety disorder 20 Schizophrenia Edit Main article Schizophrenia Medication Antipsychotic drug treatment is a key component of schizophrenia treatment recommendations by the National Institute of Health and Care Excellence NICE 21 the American Psychiatric Association 22 and the British Society for Psychopharmacology 23 The main aim of treatment with antipsychotics is to reduce the positive symptoms of psychosis that include delusions and hallucinations 2 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 the cognitive symptoms memory impairments reduced ability to plan and execute tasks 24 25 In general the efficacy of antipsychotic treatment in reducing positive symptoms appears to increase with increasing severity of baseline symptoms 26 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 27 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 a form of prophylaxis maintenance therapy aims to maintain therapeutic benefit and prevent symptom relapse and treatment of recurrent episodes of acute psychosis 2 23 Prevention of psychosis and symptom improvement Edit 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 23 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 28 First episode psychosis Edit First episode psychosis FEP is the first time that psychotic symptoms are presented NICE recommends that all persons 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 are informed that combination treatment is more effective 21 A diagnosis of schizophrenia is not made at this time as it takes longer to determine by both DSM 5 and ICD 11 and only around 60 of those presenting with a first episode psychosis will later be diagnosed with schizophrenia 29 The conversion rate for a first episode drug induced psychosis to bipolar disorder or schizophrenia are lower with 30 of people converting to either bipolar disorder or schizophrenia 30 NICE makes no distinction between a substance induced psychosis and any other form of psychosis The rate of conversion differs for different classes of drug 30 Pharmacological options for the specific treatment of FEP have been discussed in recent reviews 31 32 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 Evidence that early treatment has a favorable effect on long term outcomes is equivocal 21 23 Recurrent psychotic episodes Edit Placebo controlled trials of both first and second generation antipsychotic drugs consistently demonstrate the superiority of active drug to placebo in suppressing psychotic symptoms 23 A large meta analysis of 38 trials of antipsychotic drugs in schizophrenia acute psychotic episodes showed an effect size of about 0 5 33 There is little or no difference in efficacy among approved antipsychotic drugs including both first and second generation agents 21 34 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 35 Maintenance therapy Edit 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 2 23 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 36 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 23 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 stopped taking antipsychotics 37 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 37 A significant challenge in the use of antipsychotic drugs for the prevention of relapse is the poor rate of adherence 2 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 36 38 If someone experiences psychotic symptoms due to nonadherence they may be compelled to 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 2 39 NICE advises LAIs be offered to patients when preventing covert intentional nonadherence is a clinical priority 40 LAIs are used to ensure adherence in outpatient commitment 2 41 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 39 Bipolar disorder Edit Main article Bipolar disorder 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 16 42 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 42 before the full therapeutic effects are seen and the comparatively rapid antimanic effects of antipsychotic drugs 43 The antipsychotics have a documented efficacy when used alone in acute mania mixed episodes 14 At least five atypical antipsychotics lumateperone 44 cariprazine 45 lurasidone 46 olanzapine 47 and quetiapine 48 have also been found to possess efficacy in the treatment of bipolar depression as a monotherapy whereas only olanzapine 49 and quetiapine 50 51 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 52 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 53 54 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 Edit Psychosis and agitation develop in as many as 80 percent of people living in nursing homes 55 Despite a lack of FDA approval and black box warnings atypical antipsychotics are very often prescribed to people with dementia 55 An assessment for an underlying cause of behavior is needed before prescribing antipsychotic medication for symptoms of dementia 56 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 57 Psychosocial interventions may reduce the need for antipsychotics 58 In 2005 the FDA issued an advisory warning of an increased risk of death when atypical antipsychotics are used in dementia 55 In the subsequent 5 years the use of atypical antipsychotics to treat dementia decreased by nearly 50 55 Major depressive disorder Edit A number of atypical antipsychotics have some benefits when used in addition to other treatments in major depressive disorder 59 60 Aripiprazole quetiapine extended release and olanzapine when used in conjunction with fluoxetine have received the Food and Drug Administration FDA labelling for this indication 61 There is however a greater risk of side effects with their use compared to using traditional antidepressants 59 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 62 Other Edit 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 63 Evidence however does not support the use of atypical antipsychotics in eating disorders or personality disorder 64 The atypical antipsychotic risperidone may be useful for obsessive compulsive disorder 63 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 64 65 Some of the more serious adverse effects may also occur at the low doses used such as dyslipidemia and neutropenia 66 67 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 68 Low dose antipsychotics may also be used in treatment of impulse behavioural and cognitive perceptual symptoms of borderline personality disorder 69 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 70 71 In children they may be used in those with disruptive behavior disorders mood disorders and pervasive developmental disorders or intellectual disability 72 Antipsychotics are only weakly recommended for Tourette syndrome because although they are effective side effects are common 73 The situation is similar for those on the autism spectrum 74 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 75 A UK review of unlicensed usage in children and adolescents reported a similar mixture of findings and concerns 76 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 77 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 78 Antipsychotics may be an option together with stimulants in people with ADHD and aggressive behavior when other treatments have not worked 79 They have not been found to be useful for the prevention of delirium among those admitted to hospital 80 Typicals vs atypicals Edit It is unclear whether the atypical second generation antipsychotics offer advantages over older first generation antipsychotics 2 25 81 Amisulpride olanzapine risperidone and clozapine may be more effective but are associated with greater side effects 82 Typical antipsychotics have equal drop out and symptom relapse rates to atypicals when used at low to moderate dosages 83 Clozapine is an effective treatment for those who respond poorly to other drugs treatment resistant or refractory schizophrenia 84 but it has the potentially serious side effect of agranulocytosis lowered white blood cell count in less than 4 of people 85 Due to bias in the research the accuracy of comparisons of atypical antipsychotics is a concern 86 In 2005 a US government body the National Institute of Mental Health published the results of a major independent study the CATIE project 87 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 14 Atypical antipsychotics do not appear to lead to improved rates of medication adherence compared to typical antipsychotics 88 Many researchers question the first line prescribing of atypicals over typicals and some even question the distinction between the two classes 89 90 91 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 92 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 93 Adverse effects EditFor more detailed comparison of atypical antipsychotics see Atypical antipsychotic Adverse effects Generally more than one antipsychotic drug should not be used at a time because of increased adverse effects 94 Some atypicals are associated with considerable weight gain diabetes and the risk of metabolic syndrome 95 Unwanted side effects cause people to stop treatment resulting in relapses 96 Risperidone atypical has a similar rate of extrapyramidal symptoms to haloperidol typical 95 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 97 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 98 Very rarely antipsychotics may cause tardive psychosis 99 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 100 101 Clozapine is also associated with thromboembolism including pulmonary embolism myocarditis and cardiomyopathy 102 103 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 103 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 100 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 104 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 105 106 Typical antipsychotics and atypical risperidone can have a side effect of sexual dysfunction 107 Clozapine olanzapine and quetiapine are associated with beneficial effects on sexual functioning helped by various psychotherapies 108 By rate Edit Common 1 and up to 50 incidence for most antipsychotic drugs adverse effects of antipsychotics include 109 Sedation particularly common with asenapine clozapine olanzapine quetiapine chlorpromazine and zotepine 34 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 droolingHyperprolactinaemia rare for those treated with clozapine quetiapine and aripiprazole 16 34 which can cause Galactorrhoea the unusual secretion of breast milk Gynaecomastia abnormal growth of breast tissue Sexual dysfunction in both sexes OsteoporosisOrthostatic hypotension Weight gain particularly prominent with clozapine olanzapine quetiapine and zotepine 34 Anticholinergic side effects common for olanzapine clozapine less likely on risperidone 110 such as Blurred vision Constipation Dry mouth although hypersalivation may also occur Reduced perspirationTardive 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 30 111 Rare Uncommon lt 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 112 Evidence suggests that females are more sensitive to the metabolic side effects of first generation antipsychotic drugs than males 113 Metabolic adverse effects appear to be mediated by the following mechanisms Causing weight gain by antagonizing the histamine H1 and serotonin 5 HT2Creceptors 114 and perhaps by interacting with other neurochemical pathways in the central nervous system 115 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 116 QT interval prolongation more prominent in those treated with amisulpride pimozide sertindole thioridazine and ziprasidone 16 34 Torsades de pointes Seizures particularly in people treated with chlorpromazine and clozapine Thromboembolism Myocardial infarction StrokeLong term effects Edit See also List of long term side effects of antipsychotics Some studies have found decreased life expectancy associated with the use of antipsychotics and argued that more studies are needed 117 118 Antipsychotics may also increase the risk of early death in individuals with dementia 119 Antipsychotics typically worsen symptoms in people with depersonalisation disorder 120 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 94 121 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 94 122 A meta analysis of observational studies with over two million individuals has suggested a moderate association of antipsychotic use with breast cancer 123 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 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 124 A second meta analysis suggested that treatment with antipsychotics was associated with increased grey matter loss 125 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 over a 17 27 month period 126 The National Association of State Mental Health Program Directors said that antipsychotics are not interchangeable and it is recommend including trying at least one weight neutral treatment for those patients with potential metabolic issues 127 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 128 Adverse effect on cognitive function 129 130 131 and increased risk of death in people with dementia along with worsening of symptoms has been described in the literature 132 133 Discontinuation Edit See also Drug withdrawal Prescription medicine The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse 134 Symptoms of withdrawal commonly include nausea vomiting and loss of appetite 135 Other symptoms may include restlessness increased sweating and trouble sleeping 135 Less commonly there may be a feeling of the world spinning numbness or muscle pains 135 Symptoms generally resolve after a short period of time 135 There is tentative evidence that discontinuation of antipsychotics can result in psychosis 136 It may also result in recurrence of the condition that is being treated 137 Rarely tardive dyskinesia can occur when the medication is stopped 135 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 136 138 Tardive dyskinesia may abate during withdrawal from the antipsychotic agent or it may persist 139 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 140 The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse 141 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 142 List of agents Edit Chlorpromazine Haloperidol 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 34 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 Edit Main article Typical antipsychotic Butyrophenones Edit Main article Butyrophenones Benperidol Bromperidol Droperidol Haloperidol Moperone discontinued Pipamperone discontinued Timiperone Diphenylbutylpiperidines Edit Fluspirilene Penfluridol PimozidePhenothiazines Edit Main article Phenothiazines Acepromazine although it is mostly used in veterinary medicine Chlorpromazine 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 Edit Main article Thioxanthenes Chlorprothixene Clopenthixol Flupentixol Thiothixene Zuclopenthixol Disputed unknown Edit This category is for drugs that have been called both first and second generation depending on the literature being used Benzamides Edit Sulpiride Sultopride Veralipride Tricyclics Edit Carpipramine Clocapramine Clorotepine Clotiapine Loxapine Mosapramine Others Edit Molindone Second generation atypical Edit Main article Atypical antipsychotic Benzamides Edit Amisulpride 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 143 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 Edit Lumateperone In December 2019 lumateperone received its first global approval in the USA for the treatment of schizophrenia in adults 144 In 2020 and 2021 FDA approved for depressive episodes associated with bipolar I or II disorder bipolar depression in adults as monotherapy and as adjunctive therapy with lithium or valproate Iloperidone 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 Primary active metabolite of risperidone that was approved in 2006 Perospirone Has a higher incidence of extrapyramidal side effects than other atypical antipsychotics 145 Risperidone 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 Approved in 2004 146 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 Butyrophenones Edit Melperone Only used in a few European countries No English speaking country has licensed it to date LumateperoneTricyclics Edit Asenapine Used for the treatment of schizophrenia and acute mania associated with bipolar disorder Clozapine 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 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 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 It indirectly serves as a norepinephrine reuptake inhibitor by means of its active metabolite norquetiapine Zotepine An 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 Edit Blonanserin Approved by the PMDA in 2008 Used in Japan and South Korea Pimavanserin A selective 5 HT2A 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 Edit Third generation antipsychotics are recognized as demonstrating D2 receptor agonism as opposed to the D2 receptor antagonistic mechanism of both first generation typical and second generation atypical antipsychotic medications 147 Phenylpiperazines quinolinones Edit Aripiprazole Abilify Partial agonist at the D2 receptor Considered the prototypical third generation antipsychotic 148 Aripiprazole lauroxil Abilify Maintena Long acting version of aripiprazole for injection Brexpiprazole Partial agonist of the D2 receptor Successor of aripiprazole Cariprazine A D3 preferring D2 D3 partial agonist Benzisoxazoles benzisothiazoles Edit Lurasidone Latuda Approved by the US FDA for schizophrenia and bipolar depression and for use as schizophrenia treatment in Canada Mechanism of action EditAntipsychotic 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 149 150 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 151 152 Higher concentrations of 5 HT2A receptors in cortical and subcortical areas in particular in the right caudate nucleus have been historically recorded 151 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 153 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 154 5 HT2A antagonism increases dopaminergic activity in the nigrostriatal pathway leading to a lowered extrapyramidal side effect liability among the atypical antipsychotics 154 155 Comparison of medications EditOverviewGeneric name Class Type Brand name s Launch Developer Originator s RefsAmisulpride Benzamide Disputed Solian 1986 Sanofi Synthelabo 156 157 158 Aripiprazole Phenylpiperazine Quinolinone Atypical Abilify 2002 Otsuka Bristol Myers Squibb 156 159 Aripiprazole lauroxil Phenylpiperazine Quinolinone Atypical Aristada 2015 Alkermes 160 Asenapine Tricyclic Dibenzoxapinopyrrole Atypical Saphris Sycrest 2009 Organon Merck 156 161 Benperidol Butyrophenone Typical Anquil 1966 Janssen 156 Blonanserin Pyridinylpiperazine Atypical Lonasen 2008 Sumitomo Dainippon Mitsubishi Tanabe 156 162 Brexpiprazole Phenylpiperazine Quinolinone Atypical Rexulti 2015 Otsuka Lundbeck 163 Bromperidol Butyrophenone Typical Impromem 1981 Janssen 156 159 Cariprazine Phenylpiperazine Atypical Vraylar Reagila 2015 Gedeon Richter Actavis 164 Carpipramine Tricyclic Dibenzazepine Disputed Defecton Prazinil 1977 Pierre Fabre 156 Chlorpromazine Tricyclic Phenothiazine Typical Thorazine 1952 Rhone Poulenc GlaxoSmithKline 156 159 Chlorprothixene Tricyclic Thioxanthene Disputed Truxal 1959 Roche 156 159 165 Clocapramine Tricyclic Dibenzazepine Disputed Clofekton Padrasen 1974 Yoshitomi 166 Clopenthixol Tricyclic Thioxanthene Typical Sordinol Ciatyl 1961 Lundbeck 167 Clorotepine Tricyclic Dibenzothiepin Disputed Clotepin 1971 Spofa 168 169 Clotiapine Tricyclic Dibenzothiazepine Disputed Etumine 1966 Sandoz Wander 170 171 Clozapine Tricyclic Dibenzodiazepine Atypical Clozaril 1972 Sandoz Novartis 156 159 Cyamemazine Tricyclic Phenothiazine Disputed Tercian 1972 Aventis 156 172 Droperidol Butyrophenone Typical Dridol Droleptan Inapsine 1963 Janssen Cilag 156 173 Flupentixol Tricyclic Thioxanthene Typical Fluanxol 1965 Lundbeck 156 174 Fluphenazine Tricyclic Phenothiazine Typical Prolixin 1959 Bristol Myers Squibb 156 159 Fluspirilene Diphenylbutylpiperidine Typical Imap 1970 Janssen 156 Haloperidol Butyrophenone Typical Haldol 1959 Janssen 156 159 Iloperidone Benzisoxazole Atypical Fanapt 2010 Novartis 156 175 Levomepromazine Tricyclic Phenothiazine Disputed Nozinan Levoprome 1957 Rhone Poulenc 156 165 176 Levosulpiride Benzamide Disputed Levopraid 1987 Abbott 156 Loxapine Tricyclic Dibenzoxazepine Disputed Loxitane Loxapac 1975 Wyeth 156 159 177 Lurasidone Benzisothiazole Atypical Latuda 2010 Sumitomo Dainippon Sunovion 178 Melperone Butyrophenone Disputed Buronil 1967 Lundbeck 159 Mesoridazine Tricyclic Phenothiazine Typical Serentil 1967 Novartis Boehringer 159 Molindone Dihydroindolone Disputed Moban 1975 Abbott 159 Mosapramine Tricyclic Dibenzazepine Disputed Cremin 1991 Mitsubishi Pharma 156 Nemonapride Benzamide Disputed Emilace Emirace 1991 Yamanouchi 156 179 Olanzapine Tricyclic Thienobenzodiazepine Atypical Zyprexa 1996 Lilly 156 159 Paliperidone Benzisoxazole Atypical Invega 2007 Janssen Cilag Johnson amp Johnson 156 180 Paliperidone palmitate Benzisoxazole Atypical Invega Sustenna Xeplion 2009 Janssen Cilag Johnson amp Johnson 181 Penfluridol Diphenylbutylpiperidine Typical Semap 1973 Janssen 182 183 Perazine Tricyclic Phenothiazine Typical Taxilan 1958 Promonta 184 Periciazine Tricyclic Phenothiazine Typical Neuleptil Neulactil 1964 Rhone Poulenc 156 185 Perospirone Benzisothiazole Atypical Lullan 2001 Sumitomo Dainippon Mitsubishi Tanabe 156 186 Perphenazine Tricyclic Phenothiazine Typical Trilafon 1957 Schering Plough 156 159 Pimavanserin Dibenzylpiperidinylurea Atypical Nuplazid 2016 ACADIA Pharmaceuticals 187 Pimozide Diphenylbutylpiperidine Typical Orap 1969 Janssen 156 159 Pipamperone Butyrophenone Disputed Dipiperon 1961 Janssen 170 182 Pipotiazine Tricyclic Phenothiazine Typical Piportil 1973 Rhone Poulenc Aventis 156 188 Prochlorperazine Tricyclic Phenothiazine Typical Compazine 1956 Rhone Poulenc GlaxoSmithKline 156 159 176 Promazine Tricyclic Phenothiazine Typical Sparine 1956 Wyeth 156 Quetiapine Tricyclic Dibenzothiazepine Atypical Seroquel 1997 AstraZeneca 156 159 Remoxipride Benzamide Disputed Roxiam 1990 AstraZeneca 156 158 159 Risperidone Benzisoxazole Atypical Risperdal 1993 Janssen 156 159 Sertindole Imidazolidinone Atypical Serdolect 1996 Lundbeck 156 159 Spiperone Butyrophenone Typical Spiropitan 1969 Eisai 189 Sulpiride Benzamide Disputed Dogmatil 1968 Delagrange Fujisawa 156 158 159 Sultopride Benzamide Disputed Barnetil 1976 Delagrange Sanofi Synthelabo 156 190 Thioridazine Tricyclic Phenothiazine Typical Melleril 1958 Novartis 156 159 Tiapride Benzamide Disputed Tiapridal 1975 Sanofi Synthelabo 156 Tiotixene Tricyclic Thioxanthene Typical Navane 1967 Pfizer 156 159 191 Trifluoperazine Tricyclic Phenothiazine Typical Stelazine 1958 GlaxoSmithKline 156 159 Triflupromazine Tricyclic Phenothiazine Typical Vesprin 1957 Bristol Myers Squibb 156 Veralipride Benzamide Disputed Agreal 1980 Sanofi Synthelabo 156 Ziprasidone Benzisothiazole Atypical Geodon 2000 Pfizer 156 159 Zotepine Tricyclic Dibenzothiepin Atypical Zoleptil 1982 Fujisawa 156 159 Zuclopenthixol Tricyclic Thioxanthene Typical Clopixol Cisordinol 1978 Lundbeck 156 167 174 Tolerability as propensity for adverse effects Generic name 14 16 34 192 193 Discontinuation rate 34 OR with 95 CI Anticholinergic effects Sedation EPSE Weight Gain Metabolic AEs QTc prolongation ORs amp 95 CIs PE Hypotension Notes e g notable AEs Amisulpride 0 43 0 32 0 57 0 66 0 39 0 91 Torsades de Pointes common on overdose 194 Has a comparatively low penetrability of the blood brain barrier Amoxapine Amoxapine is also an antidepressant Very toxic in overdose due to the potential for renal failure and seizures Aripiprazole 0 61 0 51 0 72 akathisia mostly 0 01 0 13 to 0 15 can reduce prolactin levels Only clinically utilised antipsychotic that does not act by antagonising the D2 receptor and rather partially agonises this receptor Asenapine 0 69 0 54 0 86 0 30 0 04 to 0 65 Oral hypoesthesia Has a complex pharmacologic profile Blonanserin 195 196 0 7 Only used in a few East Asian countries Chlorpromazine 0 65 0 5 0 84 First marketed antipsychotic sort of the prototypical low potency first generation typical antipsychotic Clozapine 0 46 0 32 0 65 Notable AEs Agranulocytosis neutropaenia leukopaenia and myocarditis Dose dependent seizure risk 197 Overall the most effective antipsychotic on average Usually reserved for treatment resistant cases or highly suicidal patients Droperidol Mostly used for postoperative nausea and vomiting Flupenthixol Also used in lower doses for depression Fluphenazine 0 69 0 24 1 97 198 High potency first generation typical antipsychotic Haloperidol 0 8 0 71 0 90 0 11 0 03 0 19 Prototypical high potency first generation typical antipsychotic Iloperidone 0 69 0 56 0 84 0 34 0 22 0 46 Levomepromazine Also used as an analgesic agitation anxiety and emesis Loxapine 0 52 0 28 0 98 199 Lurasidone 0 77 0 61 0 96 0 10 0 21 to 0 01 May be particularly helpful in ameloriating the cognitive symptoms of schizophrenia likely due to its 5 HT7 receptor 200 Melperone 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 201 Is a butyrophenone low potency atypical antipsychotic that has been tried as a treatment for Parkinson s disease psychosis although with negative results Molindone 202 Withdrawn from the market Seems to promote weight loss which is rather unusual for an antipsychotic seeing how they tend to promote weight gain 202 Olanzapine 0 46 0 41 0 52 0 22 0 11 0 31 Paliperidone 0 48 0 39 0 58 dose dependent 0 05 0 18 to 0 26 Active metabolite of risperidone Perazine 0 62 0 4 1 10 203 Limited data available on adverse effects Periciazine Also used to treat severe anxiety Not licensed for use in the US Perospirone 204 205 Usually grouped with the atypical antipsychotics despite its relatively high propensity for causing extrapyramidal side effects 205 Perphenazine 0 30 0 04 2 33 206 Has additional antiemetic effects Pimozide 1 01 0 30 3 39 207 High potency first generation typical antipsychotic Pipotiazine Only available in the UK Prochlorperazine Primarily used in medicine as an antiemetic Quetiapine 0 61 0 52 0 71 0 17 0 06 0 29 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 Removed from the market amidst concerns about an alarmingly high rate of aplastic anaemia Risperidone 0 53 0 46 0 60 dose dependent 0 25 0 15 0 36 Sertindole 0 78 0 61 0 98 0 90 0 76 1 02 Not licensed for use in the US Sulpiride 1 00 0 25 4 00 208 Not licensed for use in the US Thioridazine 0 67 0 32 1 40 209 Dose dependent risk for degenerative retinopathies 210 Found utility in reducing the resistance of multidrug and even extensively resistant strains of tuberculosis to antibiotics Tiotixene Trifluoperazine 0 94 0 59 1 48 211 Ziprasidone 0 72 0 59 0 86 0 41 0 31 0 51 Zotepine 0 69 0 41 1 07 Dose dependent risk of seizures 212 Not licensed for use in the US Zuclopenthixol 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 Acronyms used AE Adverse effect OR Odds ratio CI Confidence Interval EPSE Extrapyramidal Side Effect QTc Corrected QT interval PE Prolactin elevation Legend very low propensity for this AE low propensity severity for this AE moderate propensity severity for this AE high propensity severity for this AEEfficacyGeneric drug name Schizophrenia 14 34 Mania 213 214 Bipolar depression 215 Bipolar maintenance 216 217 Adjunct in major depression 218 Amisulpride in dysthymia Aripiprazole prevents manic and mixed but not depressive episodes Asenapine Chlorpromazine Clozapine 219 220 221 Haloperidol Iloperidone Loxapine only in the treatment of agitation Lurasidone Melperone Olanzapine Paliperidone Perospirone 222 Quetiapine Risperidone Sertindole Ziprasidone Zotepine Binding affinityKi nM toward cloned human receptors unless otherwise specified Note 1 Drug name 114 223 SERT 5 HT1A 5 HT2A 5 HT2C 5 HT6 5 HT7 a1A a2A a2C NET D1 D2 D3 D4 5 HT2A D2 H1 M1 M3Amisulpride gt 10 000 gt 10 000 8 304 gt 10 000 4 154 73 5 gt 10 000 1 114 1 540 gt 10 000 gt 10 000 2 2 2 4 2 370 3774 5 gt 10 000 gt 10 000 gt 10 000Aripiprazole 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 678Asenapine 224 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 128Blonanserin 225 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 NDBrexpiprazole 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 gt 10 000N DEBN 195 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 NDChlorpromazine 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 0Clozapine 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 25Norclozapine 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 7cis 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 NDFluphenazine 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 441Haloperidol 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 gt 10 000 gt 10 000Iloperidone 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 gt 10 000Loxapine gt 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 33Amoxapine 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 000Lurasidone 225 226 ND 6 8 2 0 415 ND 0 5 48 1 6 10 8 ND 262 1 7 ND ND 1 18 gt 10 000 gt 10 000 gt 10 000Melperone 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 gt 10 000 gt 10 000Molindone ND 3 797 3773 gt 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 gt 10 000Olanzapine 3 676 2282 3 73 10 2 8 07 105 2 112 314 28 9 gt 10 000 70 33 34 23 47 0 14 33 0 109 2 19 2 5 56 33Paliperidone 3 717 616 6 0 71 48 2 414 2 7 2 5 17 35 7 35 gt 10 000 41 04 0 7 0 5 54 3 1 104 18 8 gt 10 000 gt 10 000Perphenazine ND 421 5 6 132 17 23 10 810 5 85 2 ND ND 0 14 0 13 17 40 8 1 500 1 848Pimozide ND 650 48 35 2 112 71 0 5 197 7 1 593 376 5 ND gt 10 000 1 45 0 25 1 8 33 34 692 2 800 HB 1 955Prochlorperazine 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 NDQuetiapine gt 10 000 394 2 912 1 843 948 75 307 6 22 3 630 28 85 gt 10 000 994 5 379 340 2 019 2 41 6 90 489 1631 5Norquetiapine 227 ND 45 48 107 ND 76 144 237 ND 12 99 8 RC 196 ND ND 0 245 3 5 38 3 RC NDRisperidone gt 10 000 422 88 0 17 12 2057 17 6 6 5 16 5 1 3 gt 10 000 243 53 3 57 2 0 4 66 0 0476 20 05 gt 10 000 gt 10 000Sertindole ND 280 0 39 0 9 5 4 28 1 8 640 450 ND ND 2 35 2 30 4 92 0 166 130 gt 5 000 2 692Sulpiride ND gt 10 000 gt 10 000 RC gt 10 000 RC 5 000 RC 4 000 RC gt 10 000 RB 4 893 RB ND ND gt 10 000 9 80 8 05 54 gt 1 000 gt 10 000 RB gt 10 000 RB gt 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 29Tiotixene 3 878 410 2 50 1355 5 245 47 15 25 11 5 79 95 51 95 gt 10 000 51 0 12 0 40 203 416 7 8 gt 10 000 gt 10 000Trifluoperazine ND 950 74 378 144 290 8 24 653 7 391 5 ND ND 1 12 ND 38 1 66 07 63 ND 1 001Ziprasidone 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 gt 10 000 gt 10 000Zotepine 151 470 5 2 7 3 2 6 12 7 208 106 530 71 25 6 4 18 0 108 3 21 18 73Acronyms used 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 desethylblonanserinPharmacokineticsDrug 228 229 230 231 Bioavailability t1 2 parent drug active metabolite Protein binding tmax Cmax Vd Excretion Routes Metabolism enzymes 114 Active metabolitesAmisulpride 48 12 h 16 3 4 h 54 4 ng mL 5 8 L kg Faeces 20 urine 50 when given IV Oral NoneAripiprazole 87 Oral 100 IM 75 h 94 h 99 3 5 h 4 9 L kg Faeces 55 urine 25 Oral IM including depot CYP2D6 CYP3A4 DehydroaripiprazoleAsenapine 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 NoneBlonanserin 195 196 232 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 desethylblonanserinChlorpromazine 20 30 h 92 97 20 L kg Urine Oral IM IV CYP2D6 Several active metabolitesClozapine 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 NorclozapineDroperidol 2 h 8 12 h Extensive 60 min IM 2 L kg adults 0 58 L kg children Urine 75 faeces 22 IM IV NoneFlupentixol 40 55 Oral 35 h 7 days depot 12 14 L kg Urine Oral IM including depot NoneFluphenazine 2 7 Oral 14 16 h 14 days depot 2 h Oral 8 10 h depot Urine faeces Oral IM including depot NoneHaloperidol 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 8 18 L kg Urine 30 faeces 15 Oral IM IV CYP3A4 NoneIloperidone 96 95 2 4 h 1340 2800 L Urine 45 58 faeces 20 22 Oral CYP3A4 CYP2D6 None notable Levomepromazine 30 h 2 3 h Urine faeces IM IV Methotrimeprazine sulfoxideLoxapine 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 Urine 56 70 faeces Only oral data available Oral IM Inhalation CYP1A2 CYP3A4 CYP2D6 Amoxapine a tricyclic antidepressant 7 OH loxapine 8 OH loxapineLurasidone 9 19 18 h 99 1 3 h 6173 L Urine 9 faeces 80 Oral CYP3A4 2 activeMelperone 233 54 Oral via syrup 65 Oral via tablets 87 IM 2 1 6 4 h Oral 6 6 3 7 h IM 50 1 6 2 4 h Oral tablets 1 h Oral syrup 1132 814 ng mL 25 mg orally 2228 3416 ng mL 50 mg orally 89539 37001 ng mL 100 mg orally 9 9 3 7 L kg 10 mg 7 1 61 L kg 20 mg Urine 70 as metabolites 5 5 10 4 as parent drug Oral IM NoneOlanzapine 87 Oral 30 h 93 6 h Oral 15 45 min short acting IM 7 days depot 4 20 4 mg mL 234 1000 L Urine 57 faeces 30 Oral IM including depot CYP1A2 NonePaliperidone 28 Oral 23 h Oral 25 49 days IM 74 24 h Oral 13 days IM 8 85 11 7 ng mL 235 390 487 L Urine 80 faeces 11 Oral IM depot CYP3A4 CYP2D6 NonePericiazine 12 h 2 h 150 ng mL Urine Oral Perospirone 145 1 9 2 5 h 92 1 5 h 5 7 ng mL Urine 0 4 as unchanged drug Oral NonePerphenazine 9 12 h 10 19 h 1 3 h 2 4 h metabolite 0 984 ng mL 0 509 ng mL Urine faeces Oral CYP2D6 7 OH perphenazinePimozide 40 50 55 h 6 8 h 4 19 ng mL dose dependent Urine Oral CYP3A4 CYP2D6 NoneProchlorperazine 12 5 6 8 9 h High 12 9 17 7 L h Urine bile Oral IM IV N desmethylprochlorperazineQuetiapine 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 236 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 1 2 L kg Urine 70 faeces 14 Oral IM including depot CYP2D6 PaliperidoneSertindole 3 days 99 5 10 h 20 L kg Urine 4 faeces 46 56 Oral CYP2D6 NoneSulpiride 237 27 9 8 h 40 3 6 h 2 72 0 66 L kg Urine faeces Oral NoneThioridazine 24 h 95 Oral CYP2D6 NoneTiotixene 24 h 90 Oral CYP1A2 NoneTrifluoperazine 24 h Oral NoneZiprasidone 60 Oral 100 IM 7 h Oral 2 5 h IM 99 6 8 h Oral 60 min IM 1 5 L kg Faeces 66 urine 20 Oral IM CYP3A4 CYP1A2 NoneZotepine 238 239 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 20 L kg Faeces urine 10 Oral IM including depot CYP2D6 Nonevte Pharmacokinetics of long acting injectable antipsychotics Medication Brand name Class Vehicle Dosage Tmax t1 2 single t1 2 multiple logPc RefAripiprazole lauroxil Aristada Atypical Watera 441 1064 mg 4 8 weeks 24 35 days 54 57 days 7 9 10 0Aripiprazole monohydrate Abilify Maintena Atypical Watera 300 400 mg 4 weeks 7 days 30 47 days 4 9 5 2Bromperidol decanoate Impromen Decanoas Typical Sesame oil 40 300 mg 4 weeks 3 9 days 21 25 days 7 9 240 Clopentixol decanoate Sordinol Depot Typical Viscoleob 50 600 mg 1 4 weeks 4 7 days 19 days 9 0 241 Flupentixol decanoate Depixol Typical Viscoleob 10 200 mg 2 4 weeks 4 10 days 8 days 17 days 7 2 9 2 241 242 Fluphenazine decanoate Prolixin Decanoate Typical Sesame oil 12 5 100 mg 2 5 weeks 1 2 days 1 10 days 14 100 days 7 2 9 0 243 244 245 Fluphenazine enanthate Prolixin Enanthate Typical Sesame oil 12 5 100 mg 1 4 weeks 2 3 days 4 days 6 4 7 4 244 Fluspirilene Imap Redeptin Typical Watera 2 12 mg 1 week 1 8 days 7 days 5 2 5 8 246 Haloperidol decanoate Haldol Decanoate Typical Sesame oil 20 400 mg 2 4 weeks 3 9 days 18 21 days 7 2 7 9 247 248 Olanzapine pamoate Zyprexa Relprevv Atypical Watera 150 405 mg 2 4 weeks 7 days 30 days Oxyprothepin decanoate Meclopin Typical 8 5 8 7Paliperidone palmitate Invega Sustenna Atypical Watera 39 819 mg 4 12 weeks 13 33 days 25 139 days 8 1 10 1Perphenazine decanoate Trilafon Dekanoat Typical Sesame oil 50 200 mg 2 4 weeks 27 days 8 9Perphenazine enanthate Trilafon Enanthate Typical Sesame oil 25 200 mg 2 weeks 2 3 days 4 7 days 6 4 7 2 249 Pipotiazine palmitate Piportil Longum Typical Viscoleob 25 400 mg 4 weeks 9 10 days 14 21 days 8 5 11 6 242 Pipotiazine undecylenate Piportil Medium Typical Sesame oil 100 200 mg 2 weeks 8 4Risperidone Risperdal Consta Atypical Microspheres 12 5 75 mg 2 weeks 21 days 3 6 days Zuclopentixol acetate Clopixol Acuphase Typical Viscoleob 50 200 mg 1 3 days 1 2 days 1 2 days 4 7 4 9Zuclopentixol decanoate Clopixol Depot Typical Viscoleob 50 800 mg 2 4 weeks 4 9 days 11 21 days 7 5 9 0Note All by intramuscular injection Footnotes a Microcrystalline or nanocrystalline aqueous suspension b Low viscosity vegetable oil specifically fractionated coconut oil with medium chain triglycerides c Predicted from PubChem and DrugBank Sources Main See template History Edit 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 250 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 251 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 252 Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs 13 In the late 1950s the most widely used term was neuroleptic followed by major tranquilizer and then ataraxic 13 The first recorded use of the term tranquilizer dates from the early nineteenth century 253 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 254 The word neuroleptic was coined in 1955 by Delay and Deniker after their discovery 1952 of the antipsychotic effects of chlorpromazine 13 It is derived from the Greek neῦron neuron originally meaning sinew but today referring to the nerves and lambanw 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 251 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 255 This term derived from the Greek adjective ἀtaraktos ataraktos which means not disturbed not excited without confusion steady calm 13 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 13 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 13 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 256 257 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 13 Society and culture EditTerminology Edit 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 258 259 Antipsychotics are a type of psychoactive or psychotropic medication 260 261 Sales Edit Antipsychotics were once among the biggest selling and most profitable of all drugs generating 22 billion in global sales in 2008 262 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 263 By 2008 sales in the US reached 14 6 billion the biggest selling drugs in the US by therapeutic class 264 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 265 Overprescription Edit 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 266 267 268 Legal Edit Antipsychotics are sometimes administered as part of compulsory psychiatric treatment via inpatient hospital commitment or outpatient commitment Formulations Edit 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 269 Recreational use Edit Certain second generation antipsychotics are misused or abused for their sedative tranquilizing and paradoxically hallucinogenic effects 270 The most commonly second generation antipsychotic implicated is quetiapine 270 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 270 Olanzapine another sedating second generation antipsychotic has also been misused for similar reasons 270 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 270 Controversy Edit 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 271 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 272 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 273 274 In the US the government has initiated legal action against the pharmaceutical company Johnson amp Johnson for allegedly paying kickbacks to Omnicare to promote its antipsychotic risperidone Risperdal in nursing homes 275 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 276 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 276 In addition AstraZeneca faces numerous personal injury lawsuits from former users of Seroquel quetiapine amidst federal clarification needed investigations of its marketing practices 277 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 262 Harvard University medical professor Joseph Biederman conducted research on bipolar disorder in children that led to an increase in such diagnoses A 2008 Senate 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 amp 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 276 Pharmaceutical companies have also been accused of attempting to set the mental health agenda through activities such as funding consumer advocacy groups 278 Special populations EditIt is recommended that persons with dementia who exhibit behavioral and psychological symptoms should not be given antipsychotics before trying other treatments 279 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 279 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 279 Elderly persons often have their dementia treated first with antipsychotics and this is not the best management strategy 280 See also EditList of investigational antipsychotics Antipsychotic switchingNotes Edit Bolded drug names indicate drugs that are metabolites of clinically marketed 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