antipsychotic

• adj.

• 抗精神病の

• n.

• 統合失調症治療薬、抗精神病薬、抗精神病剤、抗精神薬

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/08/14 17:51:30」(JST)

wiki en

[Wiki en表示]

Olanzapine (Zyprexa), an example of a second-generation antipsychotic

Antipsychotics (also known as neuroleptics or major tranquilizers) are a class of psychiatric medication primarily used to manage psychosis (including delusions, hallucinations, or disordered thought), in particular in schizophrenia and bipolar disorder, and are increasingly being used in the management of non-psychotic disorders (ATC code N05A). The word neuroleptic originates from the Greek word "νεῦρον", neuron ("nerve") and lepsis ("seizure" or "fit").

First-generation antipsychotics, known as typical antipsychotics, were discovered in the 1950s. Most second-generation drugs, known as atypical antipsychotics, have been developed more recently, although the first atypical antipsychotic, clozapine, was discovered in the 1950s and introduced clinically in the 1970s. Both generations of medication tend to block receptors in the brain's dopamine pathways, but atypicals tend to act on serotonin receptors as well.

The superiority of antipsychotics to placebo in the treatment of schizophrenia, bipolar disorder, and certain other psychiatric disorders is well-established, but their efficacy is suboptimal and their use is associated with important side effects, most notably movement disorders and weight gain.

Medical uses

Antipsychotics are most frequently used for the following conditions:

• Schizophrenia
• 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 and, according to a recent meta-analysis, they tend to have a lower liability for causing conversion from mania to depression.
• Psychotic depression. In this indication it is a common practice for the attending psychiatrist to prescribe a combination of an atypical antipsychotic and an antidepressant as this practice is best supported by the evidence.
• Treatment-resistant (and not necessarily psychotic) major depression as an adjunct to standard antidepressant therapy.

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

Schizophrenia

Main article: Schizophrenia

Anti-psychotic drug treatment is a key component of schizophrenia treatment algorithms recommended by the National Institute of Health and Clinical Excellence (NICE), the American Psychiatric Association, and the British Society for Psychopharmacology. The main effect of treatment with antipsychotics is to reduce the so called "positive" symptoms, including delusions and hallucinations. There is little evidence to support any significant impact of antipsychotic use on negative symptoms (such as apathy, lack of emotional affect, and lack of interest in social interactions) or on the cognitive symptoms (disordered thinking, reduced ability to plan and execute tasks) of schizophrenia.

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

Prevention of frank psychosis and symptom amelioration in those showing prodromal symptoms of schizophrenia

Test batteries such as the PACE (Personal Assessment and Crisis Evaluation Clinic) and COPS (Criteria of Prodromal Syndromes), which measure low level psychotic symptoms, and others focused on cognitive disturbances (Basic symptoms"), are used to evaluate people with early, low level symptoms of psychosis. Used in combination with family history information, these tests can identify a "high risk" group having a 20-40% risk of progression to frank psychosis within 2 years. These patients are often treated with low doses of antipsychotic drugs with the goal of reducing their symptoms and preventing progression to frank psychosis. While generally useful for reducing symptoms, the clinical trials performed to date provide little evidence that early use of antipsychotics, alone or in combination with cognitive-behavioral therapy, provides improved long term outcomes in those with prodromal symptoms.

Treatment of first episode psychosis

NICE recommends that all persons presenting with a first episode of frank psychosis be treated with both an anti-psychotic drug and cognitive-behavioral therapy (CBT). NICE further recommends that those expressing a preference for CBT alone be informed that combination treatment is more efficacious. A diagnosis of schizophrenia is not normally made at this time, as up to 25% of those presenting with first episode psychosis are eventually found to suffer from bipolar disorder instead. The goals of treatment of these patients include reducing symptoms and potentially improving long-term treatment outcomes. Randomized clinical trials have provided strong evidence for the efficacy of antipsychotic drugs in achieving the former goal, with first-generation and second generation anti-psychotics showing about equal effiacy. Evidence that early treatment has a favorable effect on long term outcomes is equivocal.

Treatment of 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. A large meta analysis of 38 trials of antipsychotic drugs in schizophrenia acute psychotic episodes showed an effect size of about 0.5. There is little or no difference in effiacy among approved antipsychotic drugs, including both first- and second-generation agents. The efficacy of such drugs is suboptimal. Few patients achieve complete resolution of symptoms. Response rates, calculated using various cutoff values for symptom reduction, are low and their interpretation is complicated by high placebo response rates and selective publication of clinical trial results.

Maintenance therapy

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

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

A significant challenge in the use of antipsychotic drugs for the prevention of relapse is the poor rate of compliance. In spite of the relatively high rates of adverse effects associated with these drugs, some evidence, including higher dropout rates in placebo arms compared to treatment arms in randomized clinical trials, suggest that most patients who discontinue treatment do so because of suboptimal efficacy.

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

Three atypical antipsychotics (lurasidone, olanzapine and quetiapine) have also been found to possess efficacy in the treatment of bipolar depression as a monotherapy. Whereas only olanzapine and quetiapine have been proven to be effective broad-spectrum (i.e. against all three types of relapse— manic, mixed and depressive) prophylactic (or maintenance) treatments in patients with bipolar disorder. A recent Cochrane review also found that olanzapine had a less favourable risk/benefit ratio than lithium as a maintenance treatment for bipolar disorder.

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

Dementia

Antipsychotics in old age dementia showed a modest benefit compared to placebo in managing aggression or psychosis, but this is combined with a significant increase in serious adverse events. Thus, antipsychotics should not be used routinely to treat dementia with aggression or psychosis, but may be an option in a few cases where there is severe distress or risk of physical harm to others. Psychosocial interventions may reduce the need for antipsychotics.

Unipolar Depression

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

Other

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

In children they may be used in those with disruptive behavior disorders, mood disorders and pervasive developmental disorders or intellectual disability. Antipsychotics are only weakly recommended for Tourette syndrome as well they are effective side effects are common. The situation is similar for those on the autism spectrum. Much of the evidence for the off-label use of antipsychotics (for example, for dementia, OCD, PTSD, Personality Disorders, Tourette's) was of insufficient scientific quality to support such use, especially as there was strong evidence of increased risks of stroke, tremors, significant weight gain, sedation, and gastrointestinal problems. A UK review of unlicensed usage in children and adolescents reported a similar mixture of findings and concerns. A survey of children with pervasive developmental disorder found that 16.5% were taking an antipsychotic drug, most commonly for irritability, aggression, and agitation. Risperidone has been approved by the US FDA for the treatment of irritability in autistic children and adolescents.

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.

Typicals versus atypicals

While the atypical (second-generation) antipsychotics were marketed as offering greater efficacy and reduced side effects than typical medications this may not be true. One review concluded there were no differences while another found that atypicals were "only moderately more efficacious". These conclusions were, however, questioned by another review, which found that clozapine, amisulpride, and olanzapine and risperidone were more effective Clozapine has appeared to be more effective than other atypical antipsychotics, although it requires close monitoring of patients due to its association with potentially fatal angranulocytosis. Due to bias in the research the accuracy of comparisons of atypical antipsychotics is a concern.

In 2005, the US government body National Institute of Mental Health published the results of a major independent (not funded by the pharmaceutical companies) multi-site, double-blind study (the CATIE project). This study compared several atypical antipsychotics to an older typical antipsychotic, perphenazine, among 1493 persons with schizophrenia. The study found that only olanzapine outperformed perphenazine in discontinuation rate (the rate at which people stopped taking it due to its effects). The authors noted an apparent superior efficacy of olanzapine to the other drugs in terms of reduction in psychopathology and rate of hospitalizations, but olanzapine was associated with relatively severe metabolic effects such as a major weight gain problem (averaging 9.4 lbs) and increases in glucose, cholesterol, and triglycerides. The mean and maximal doses used for olanzapine were considerably higher than standard practice, and this has been postulated as a biasing factor that may explain olanzapine's superior efficacy over the other atypical antipsychotics studied, where doses were more in line with clinically relevant practices. 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%).

Compliance has not been shown to be different between the two types.

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

The re-evaluation of the evidence has not necessarily slowed the bias toward prescribing the atypicals.

Adverse effects

Antipsychotics are associated with a range of side effects. It is well-recognized that many people stop taking them (around two-thirds even in controlled drug trials) due in part to adverse effects.

More than one antipsychotic drug should not be used at a time except under unusual circumstances. Among the reasons for this are the increased number and harm from adverse effects of the drug when multiple drugs are used.

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

• Sedation (particularly common in patients on clozapine, olanzapine, quetiapine, chlorpromazine and zotepine)
• Headaches
• Dizziness
• Diarrhea
• Anxiety
• Extrapyramidal side effects (particularly common in patients on first-generation antipsychotics), which includes:

- Akathisia — an often distressing sense of inner restlessness.

- Dystonia

- Parkinsonism

- Tremor

• Hyperprolactinaemia (rare for those on clozapine, quetiapine and aripiprazole), which can cause:

- Galactorrhoea — unusual secretion of breast milk.

- Gynaecomastia

- Sexual dysfunction (in both sexes)

- Osteoporosis

• Orthostatic hypotension
• Weight gain (particularly prominent in patients on clozapine, olanzapine, quetiapine and zotepine)
• Anticholinergic side-effects (common for olanzapine, clozapine; less likely on risperidone ) such as:

- Amnesia (although this is not a common adverse effect in patients on antipsychotics)

- Angle-closure glaucoma (also rare in patients on antipsychotics)

- Blurred vision

- Constipation

- Dry mouth (although hypersalivation may also occur)

- Reduced perspiration

• Tardive dyskinesia appears to be more frequent in those on high-potency first-generation antipsychotics such as haloperidol and tends to appear after chronic and not acute treatment. It is characterised 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).

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

• Blood dyscarias (e.g., agranulocytosis, leukopaenia, 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. Evidence suggests that females are more sensitive to the metabolic side effects of first-generation antipsychotic drugs than males. Metabolic adverse effects appears to be mediated by the following mechanisms:

- Blocking the M₃ muscarinic acetylcholine receptor, which is responsible for regulating the release of insulin.

- Inappropriately changing the body's energy source from carbohydrates to lipids.

- Causing weight gain by antagonising the histamine H₁ and serotonin 5-HT_2Creceptors and perhaps by interacting with other neurochemical pathways in the central nervous system.

• Neuroleptic malignant syndrome a potentially fatal condition characterised by:

- Autonomic instability, which can manifest itself with tachycardia, nausea, vomiting, diaphoresis, etc.

- Hyperthermia — elevated body temperature.

- Mental status change (confusion, hallucinations, coma, etc.)

- Muscle rigidity

- Laboratory abnormalities (e.g., elevated creatinine kinase, reduced iron plasma levels, electrolyte abnormalities, etc.)

• Pancreatitis
• Pharyngitis
• QT interval prolongation — more prominent in patients on amisulpride, pimozide, sertindole, thioridazine and ziprasidone.
• Seizures, which is particularly common in patients on chlorpromazine and clozapine.
• Thromboembolism
• Myocardial infarction
• Stroke
• Torsades de Pointes

Some studies have found decreased life expectancy associated with the use of antipsychotics, and argued that more studies are needed. Antipsychotics may also increase the risk of early death in individuals with dementia. In individuals without psychosis, doses of antipsychotics can produce the "negative symptoms" of schizophrenia such as amotivation. Antipsychotics typically worsen symptoms in people who suffer from depersonalisation disorder. Antipsychotic polypharmacy (prescribing two or more antipsychotics at the same time for an individual) is a common practice but not evidence-based or recommended, and there are initiatives to curtail it. Similarly, the use of excessively high doses (often the result of polypharmacy) continues despite clinical guidelines and evidence indicating that it is usually no more effective but is usually more harmful.

Other

Loss of grey matter and other brain structural changes over time are observed in schizophrenia. Meta analyses of the effects of antipsychotic treatment on the course of grey matter loss and structural changes have reached conflicting conclusions. A 2012 meta analysis concluded that grey matter loss is greater in patients treated with first generation antipsychotics relative to those treated with atypicals, and hypothesized a protective effect of atypicals as one possible explanation. A second meta analyses suggested that treatment with antipsychotics was associated with increased grey matter loss.

Subtle, long-lasting forms of akathisia are often overlooked or confused with post-psychotic depression, in particular when they lack the extra pyramidal aspect that psychiatrists have been taught to expect when looking for signs of akathisia. Part of the reason for underdiagnosis is the erroneous belief that second-generation antipsychotics rarely cause akathisia.

Withdrawal

Withdrawal symptoms from antipsychotics may emerge during dosage reduction and discontinuation. Withdrawal symptoms can include nausea, emesis, anorexia, diarrhea, rhinorrhea, diaphoresis, myalgia, paresthesia, anxiety, agitation, restlessness, and insomnia. The psychological withdrawal symptoms can include psychosis, and can be mistaken for a relapse of the underlying disorder. Conversely, the withdrawal syndrome may also be a trigger for relapse. Better management of the withdrawal syndrome may improve the ability of individuals to discontinue antipsychotics.

Tardive dyskinesia may abate during withdrawal from the antispsychotic agent, or it may persist.

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

List of agents

Chlorpromazine.

Haloperidol.

Quetiapine.

Clinically used antipsychotic medications are listed below by drug group. Trade names appear in parentheses.

Notes:

† indicates drugs that are no longer marketed in English-speaking countries.

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

# denotes drugs that have been withdrawn worldwide.

First-generation

Main article: Typical antipsychotic

Butyrophenones

Main article: Butyrophenones

• Benperidol (Anguil, Benguil, Frenactil, Glianimon)^‡
• Bromperidol (Bromodol, Impromen)^†
• Droperidol (Droleptan, Inapsine)^‡
• Haloperidol (Haldol, Serenace)
• Moperone (Luvatren (discontinued))^†
• Pipamperone (Dipiperon, Piperonil (discontinued))^†
• Timiperone (Celmanil, Tolopelon)^†

Diphenylbutylpiperidine

• Fluspirilene (Imap)
• Penfluridol (Semap)
• Pimozide (Orap)

Phenothiazines

Main article: Phenothiazines

• Acepromazine (Plegicil)^† — although it is mostly used in veterinary medicine.
• Chlorpromazine (Largactil, Thorazine (discontinued))
• Cyamemazine (Tercian)^†
• Dixyrazine (Esucos)^†
• Fluphenazine (Modecate, Permitil (discontinued), Prolixin (discontinued)) – Available in decanoate (long-acting) form
• Levomepromazine (Levinan, Levoprome (discontinued), Nozinan)^‡
• Mesoridazine (Lidanil, Serentil (discontinued))^†
• Perazine (Peragal, Perazin, Pernazinum, Taxilan)
• Pericyazine (Neulactil, Neuleptil)^‡
• Perphenazine (Trilafon)
• Pipotiazine (Lonseren, Piportil)^‡
• Prochlorperazine (Compazine)
• Promazine (Prozine, Sparine (discontinued))
• Promethazine (Avomine, Phenergan)
• Prothipendyl (Dominal)^†
• Thioproperazine (Majeptil)^‡ (only English-speaking country it is available in is Canada)
• Thioridazine (Aldazine (discontinued), Mellaril (discontinued), Melleril (discontinued))
• Trifluoperazine (Stelazine)
• Triflupromazine (Vesprin (discontinued))^†

Thioxanthenes

Main article: Thioxanthenes

• Chlorprothixene (Cloxan, Taractan, Truxal)^†
• Clopenthixol (Sordinol)
• Flupentixol (Depixol, Fluanxol)^‡
• Tiotixene (Navane, Thixit)
• Zuclopenthixol (Acuphase, Cisordinol, Clopixol)^‡

Others

• Clotiapine (Entumine, Etomine, Etumine)^‡
• Loxapine (Adasuve, Loxitane)
• Prothipendyl (Dominal)^†

Disputed/Unknown

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

• Carpipramine (Defekton, Prazinil)^†
• Clocapramine (Clofekton, Padrasen)^†
• Molindone (Moban)^#
• Mosapramine (Cremin)^†
• Sulpiride (Meresa)^‡
• Sultopride (Barnetil, Topral)^†
• Veralipride (Agreal)^†

Second-generation

Main article: Atypical antipsychotic

• Amisulpride (Solian)^‡– 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.
• Amoxapine (Asendin), active metabolite of loxapine, that's most frequently used as a tricyclic antidepressant and has, in a few clinical trials, been found to possess atypical antipsychotic effects.
• Aripiprazole (Abilify) – Partial agonist at the D₂ receptor unlike all other clinically-utilised antipsychotics.
• Asenapine (Saphris, Sycrest) is a 5-HT2A- and D2-receptor antagonist developed for the treatment of schizophrenia and acute mania associated with bipolar disorder.
• Clozapine (Clozaril) – Requires 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.
• Blonanserin (Lonasen)^† — an antipsychotic that is used in Japan and Korea. May have a beneficial effect on cognition via its antagonism of the 5-HT₆ receptor.
• Iloperidone (Fanapt, Fanapta, and previously known as Zomaril) – 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.
• Lurasidone (Latuda), approved by the US FDA for schizophrenia and bipolar depression. Given once daily, it has shown mixed Phase III efficacy results but has a relatively well-tolerated side effect profile. It is also licensed for use as schizophrenia treatment in Canada. Not yet licensed elsewhere, however. Has procognitive effects via its antagonism of the 5-HT₇ receptor.
• Melperone (Buronil, Buronon, Eunerpan, Melpax, Neuril)^†, an atypical antipsychotic that is only used in a few European countries. No English-speaking country has licensed it to date.
• Nemonapride (Emilace)^†
• Olanzapine (Zyprexa) – Used to treat psychotic disorders including schizophrenia, acute manic episodes, and maintenance of bipolar disorder. Used as an adjunct to antidepressant therapy, especially to fluoxetine treatment in the form of Symbyax.
• Paliperidone (Invega)– Primary Metabolite of risperidone that was approved in 2006, it offers a controlled releaseonce-daily dose, or a once-monthly depot injection.
• Perospirone (Lullan)^† — has a higher incidence of extrapyramidal side effects than other atypical antipsychotics.
• Quetiapine (Seroquel) – Used primarily to treat bipolar disorder and schizophrenia. Also used and licensed in a few countries (including Australia, UK and US) 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.
• Remoxipride (Roxiam)^# 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.
• Risperidone (Risperdal) – Divided dosing is recommended until initial titration is completed, at which time the drug can be administered once daily. Used off-label to treat Tourette syndrome and anxiety disorder.
• Sertindole (Serdolect, Serlect)^‡. Sertindole was 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.
• Trimipramine (Surmontil)
• Ziprasidone (Geodon, Zeldox) – Approved in 2004 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.
• Zotepine (Lodopin, Losizopilon, Nipolept, Setous) – 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.^†

Investigational agents

• Alstonine, an indole alkaloid that is found in a number of different plants and that serves as a 5-HT_2C receptor agonist. Attenuates MK-801-induced hyperlocomotion, social withdrawal and working memory deficits.
• Bifeprunox^‡‡

• Bitopertin a GlyT₁ inhibitor. Being investigated as a treatment for mostly negative and cognitive symptoms.
• Brexpiprazole a D₂/5-HT_1A partial agonist.
• Cannabidiol (CBD), one of the active constituents of cannabis that has antipsychotic effects, unlike the chief active constituent of cannabis, namely, tetrahydrocannabinol, which has psychotomimetic effects.

• Cariprazine a D3-selective D2/D3 partial agonist.
• Pimavanserin a 5-HT_2A inverse agonist. Being investigated as an adjunct to antipsychotics in schizophrenia and as a monotherapy for Parkinson's disease psychosis.
• Pomaglumetad methionil^‡‡ a mGluR_2/3-selective agonist; development has been ceased due to negative phase III trial results both as a monotherapy and as an adjunct to antipsychotics.

• Vabicaserin^‡‡ a 5-HT_2C full agonist.
• Xanomeline^‡‡ a M₁ & M₄ agonist.

• Zicronapine

* where ^‡‡ indicates drugs for which development has ceased

Mechanism of action

All antipsychotic drugs tend to block D₂ receptors in the dopamine 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. It has also been proven less dopamine released in the prefrontal cortex in the brain, and excess dopamine released from all other pathways, has also been linked to psychotic experiences, caused by abnormal dopaminergic function as a result of patients suffering from schizophrenia or bipolar disorder. Various neuroleptics such as haloperidol and chlorpromazine suppress dopamine chemicals throughout its pathways, in order for dopamine receptors to function normally.

In addition of the antagonistic effects of dopamine, antipsychotics (in particular atypical neuroleptics) also antagonize 5-HT_2A receptors. Different alleles of the 5-HT_2A receptor have been associated with schizophrenia and other psychoses, including depression. Higher concentrations of 5-HT_2A receptors in cortical and subcortical areas, in particular in the right caudate nucleus have been historically recorded. This is the same receptor that psychedelic drugs agonize to various degrees, which explains the correlation between psychedelic drugs and schizophrenia.

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

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

Comparison of medications

Tolerability
Generic name	Discontinuation rate (OR with 95% CI in brackets)	Anticholinergic effects	Sedation	EPSE	Weight Gain	Metabolic AEs	QTc prolongation (ORs & 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. 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 [–0.13-0·15])	- (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 [–0.04-0.65])	+	+	Oral hypoesthesia. Has a complex pharmacologic profile.
Blonanserin	~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. 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)	++	+	+++	+	+	+	+++	+	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)	+	++	+++	+	+/-	?	+++	++	?
Lurasidone	0.77 (0.61-0.96)	-	-	++/+	-	-	- (–0.10 [–0.21-0.01])	++/+	-	May be particularly helpful in ameloriating the cognitive symptoms of schizophrenia, likely due to its 5-HT7 receptor.
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. Is a butyrophenone, low-potency atypical antipsychotic that has been tried as a treatment for Parkinson's disease psychosis, although with negative results.
Molindone	?	-	++/+	+	-	-	?	+++	+/-	Withdrawn from the market. Seems to promote weight loss (which is rather unique for an antipsychotic seeing how they tend to promote weight gain).
Olanzapine	0.46 (0.41-0.52)	+	++	+	+++	+++	+ (0.22 [0.11-0.31])	+	+	?
Paliperidone	0.48 (0.39-0.58)	-	-	++/+ (dose-dependent)	++	+	- (0.05 [–0.18-0.26])	+++	++	Active metabolite of risperidone.
Perazine	0.62 (0.35-1.10)	?	?	?	?	?	?	?	?	Limited data available on adverse effects.
Pericyazine	?	+++	+++	+	++	+	?	+++	++	Also used to treat severe anxiety. Not licensed for use in the US.
Perospirone	?	+/-	+	++/+	+/-	?	-	++/+	-	Usually grouped with the atypical antipsychotics despite its relatively high propensity for causing extrapyramidal side effects.
Perphenazine	0.40 (0.08-1.90)	+	+	+++	+	+	+	+++	+	Has additional antiemetic effects.
Pimozide	0.66 (0.45-0.98)	+	+	+	+	+	+++	+++	+	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)	-	-	+	+	+/-	+	+++/++	-	Not licensed for use in the US.
Thioridazine	0.67 (0.32-1.40)	+++	+++	+	++	++	+++	+++	+++	Dose-dependent risk for degenerative retinopathies. 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)	+/-	+	+++	+	+/-	?	+++	+	?
Ziprasidone	0.72 (0.59 to 0.86)	-	++	+	-	-	++ (0.41 [0.31 to 0.51])	++/+	+	?
Zotepine	0.69 (0.41 to 1.07)	+	+++	++	+++/++	+++/++	++	+++	++	Dose-dependent risk of seizures. 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 AE

Efficacy
Generic drug name	Schizophrenia	Mania	Bipolar depression	Bipolar maintenance	Adjunct in major depression
Amisulpride	+++	?	?	?	? (+++ in dysthymia)
Aripiprazole	++	++	-	++ (prevents manic and mixed but not depressive episodes)	+++
Asenapine	++/+	++	?	++	?
Chlorpromazine	++	?	?	?	?
Clozapine	+++	?	?	?	?
Haloperidol	++	+++	?	?	?
Iloperidone	+	?	?	?	?
Loxapine	+++/++	+++ (only in the treatment of agitation)	?	?	?
Lurasidone	+	?	+++	?	?
Melperone	+++	?	?	?	?
Olanzapine	+++	+++/++	++	++ (most effective at preventing manic/mixed relapse)	++
Paliperidone	++	+++/++	?	?	?
Perospirone	+	?	?	?	?
Quetiapine	++	++	+++	+++	++
Risperidone	+++	+++	-	++	+++
Sertindole	++	?	?	?	?
Ziprasidone	++/+	+	?	+	?
Zotepine	++	?	?	?	?

Binding affinity
Ki [nM] toward cloned human receptors (unless otherwise specified)
Generic drug name	SERT	5-HT1A	5-HT2A	5-HT2C	5-HT6	5-HT7	α1A	α2A	α2C	NET	D1	D2	D3	D4	5-HT2A/D2	H1	M1	M3
Amisulpride	>10,000	>10,000	8,304	>10,000	4,154	73.5	>10,000	1,114	1,540	>10,000	>10,000	2.2	2.4	2,370	3774.5	>10,000	>10,000	>10,000
Aripiprazole	1,081	5.6	8.7	22.4	642.4	9.97	25.85	74.1	37.63	2091.5	1,173.5	1.64	5.35	514	5.3	27.93	6,778	4,678
Asenapine	ND	2.5	0.06	0.03	0.25	0.13	1.2	1.2	1.2	ND	1.4	1.3	0.42	1.1	0.0462	1.0	8,128	8,128
Blonanserin	ND	804	0.812	26.4	41.9	183	26.7 (RB)	530 (RC)	ND	ND	1,070	0.142	0.494	150	5.72	765	100	ND
N-DEBN	ND	ND	1.28	4.50	5.03	206 (RC)	ND	ND	ND	ND	1,020	1.38	0.23	ND	0.93	ND	ND	ND
Chlorpromazine	1,296	2,115.5	4.5	15.6	17.0	28.4	0.28	184	46	2,443	76.3	1.40	4.65	5.33	3.21	3.09	32.3	57.0
Clozapine	1,624	123.7	5.35	9.44	13.5	17.95	1.62	37	6.0	3,168	266.3	157	269.1	26.4	0.0341	1.13	6.17	19.25
Norclozapine	316.6	13.9	10.9	11.9 (RC)	11.6	60.1	104.8	137.6	117.7	493.9	14.3	94.5	153	63.94	0.115	3.4	67.6	95.7
cis-Flupenthixol	ND	8,028	87.5 (HFC)	102.2 (RC)	ND	ND	ND	ND	ND	ND	3.5	0.35	1.75	66.3	250	0.86	ND	ND
Fluphenazine	5,950	1,039.9	37.93	982.5	34.67	8.00	6.45	314.1	28.9	3,076	17.33	0.30	1.75	40.0	126.4	14.15	1,095	1,441
Haloperidol	3,256	2,066.83	56.81	4,801	5,133	377.6	12.0	801.5	403	2,112	121.8	0.7	3.96	2.71	81.2	1698	>10,000	>10,000
Iloperidone	ND	93.21	1.94	147	63.09	112	0.3	160	16.2	1479	129.32	10.86	10.55	13.75	0.179	12	4,898	>10,000
Loxapine	>10,000	2,456	6.63	13.25	31.0	87.6	31.0	150.9	80.0	5,698	54	28.1	19.33	7.80	0.236	4.90	119.45	211.33
Amoxapine	58	ND	0.5	2.0 (RC)	50	40.21	50	ND	ND	16	ND	20.8	21.0	21.0	0.0240	25	1,000	1,000
Lurasidone	ND	6.8	2.0	415	ND	0.5	48	1.6	10.8	ND	262	1.7	ND	ND	1.18	>10,000	>10,000	>10,000
Melperone	ND	2,200 (HB)	230	2,100 (HB)	1,254 (RC)	578 (HB)	180 (HB)	150 (HB)	ND	ND	ND	194	8.95	555	1.186	580	>10,000	>10,000
Molindone	ND	3,797	3773	>10,000	1,008	3,053	2,612	1,097	172.6	ND	ND	6.0	72.5	2,950	628.83	2,130	ND	>10,000
Olanzapine	3,676	2282	3.73	10.2	8.07	105.2	112	314	28.9	>10,000	70.33	34.23	47.0	14.33	0.109	2.19	2.5	56.33
Paliperidone	3,717	616.6	0.71	48	2,414	2.7	2.5	17.35	7.35	>10,000	41.04	0.7	0.5	54.3	1.104	18.8	>10,000	>10,000
Perphenazine	ND	421	5.6	132	17	23	10	810.5	85.2	ND	ND	0.14	0.13	17	40	8	1,500	1,848
Pimozide	ND	650	48.35	2,112	71	0.5	197.7	1,593	376.5	ND	>10,000	1.45	0.25	1.8	33.34	692.2	800 (HB)	1,955
Prochlorperazine	ND	5,900 (HC)	15 (HC)	122	148 (RC)	196 (RC)	23.8 (HB)	1,694.91 (HB)	ND	ND	ND	0.65	2.90	5.40	23.1	18.86 (HB)	555.55 (HB)	ND
Quetiapine	>10,000	394.2	912	1,843	948.75	307.6	22	3,630	28.85	>10,000	994.5	379	340	2,019	2.41	6.90	489	1631.5
Norquetiapine	ND	45	48	107	ND	76	144	237	ND	12	99.8 (RC)	196	ND	ND	0.245	3.5	38.3 (RC)	ND
Risperidone	>10,000	422.88	0.17	12	2057.17	6.6	5	16.5	1.3	>10,000	243.53	3.57	2.0	4.66	0.0476	20.05	>10,000	>10,000
Sertindole	ND	280	0.39	0.9	5.4	28	1.8	640	450	ND	ND	2.35	2.30	4.92	0.166	130	>5,000	2,692
Sulpiride	ND	>10,000	>10,000 (RC)	>10,000 (RC)	5,000 (RC)	4,000 (RC)	>10,000 (RB)	4,893 (RB)	ND	ND	>10,000	9.80	8.05	54	>1,000	>10,000 (RB)	>10,000 (RB)	>10,000 (RB)
Thioridazine	1,259	144.35	27.67	53	57.05	99	3.15	134.15	74.9	842	94.5	2.20	1.50	6.00	12.58	16.5	12.8	29
Thiothixene	3,878	410.2	50	1355.5	245.47	15.25	11.5	79.95	51.95	>10,000	51	0.12	0.40	203	416.7	8	>10,000	>10,000
Trifluoperazine	ND	950	74	378	144	290.8	24	653.7	391.5	ND	ND	1.12	ND	38.1	66.07	63	ND	1,001
Ziprasidone	112	54.67	0.73	13	60.95	6.31	18	160	68	44	30	4.35	7.85	52.9	0.1678	62.67	>10,000	>10,000
Zotepine	151	470.5	2.7	3.2	6	12	7	208	106	530	71	25	6.4	18	0.108	3.21	18	73
Acronyms used: 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-deethylblonanserin

Pharmacokinetics
Drug	Bioavailability	t1/2 parent drug (active metabolite)	Protein binding	tmax	Cmax	Vd	Excretion	Routes of administration	Metabolising enzymes	Active metabolites
Amisulpride	48%	12 h	16%	3-4 h	54 ± 4 ng/mL	5.8 L/kg	Faeces (20%), urine (50%, when given IV)	Oral	?	None
Aripiprazole	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	Dehydroaripiprazole
Asenapine	35% (sublingual)	24 h	95%	0.5-1.5 h	4 ng/mL	20-25 L/kg	Urine (50%), faeces (40%)	Sublingual	CYP1A2, UGT1A4, CYP2D6	None
Blonanserin	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-deethylblonanserin
Chlorpromazine	20%	30 h	92-97%	?	?	20 L/kg	Urine	Oral, IM, IV	CYP2D6	Several active metabolites
Clozapine	50-60%	12 h	97%	1.5-2.5 h	102-771 ng/mL	4.67 L/kg	Urine (50%), faeces (30%)	Oral	CYP1A2, CYP2D6, CYP3A4	Norclozapine
Droperidol	?	2 h (8-12 h)	Extensive	60 min (IM)	?	2 L/kg (adults), 0.58 L/kg (children)	Urine (75%), faeces (22%)	IM, IV	?	None
Flupentixol	40-55% (Oral)	35 h	?	7 days (depot)	?	12-14 L/kg	Urine	Oral, IM (including depot)	?	None
Fluphenazine	2.7% (Oral)	14-16 h, 14 days (depot)	?	2 h (Oral), 8-10 h (depot)	?	?	Urine, faeces	Oral, IM (including depot)	?	None
Haloperidol	60-70% (Oral)	10-20 h (short-acting IM), 3 weeks (depot)	92%	2-6 h (Oral), 10-20 min (short-acting IM), 6–7 days (depot)	?	8-18 L/kg	Urine (30%), faeces (15%)	Oral, IM, IV	CYP3A4	None
Iloperidone	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 sulfoxide
Loxapine	High	6-8 h (Inhaled), 4-12 h (Oral)	96.6%	2 min (inhaled), 2 h (oral), 5 h (IM)	257 ng/mL (inhaled), 6-13 ng/mL (Oral)	?	Urine (56-70%), faeces [Only oral data available]	Oral, IM, Inhalation	CYP1A2, CYP3A4, CYP2D6	Amoxapine (a tricyclic antidepressant), 7-OH loxapine, 8-OH loxapine
Lurasidone	9-19%	18 h	99%	1-3 h	?	6173 L	Urine (9%), faeces (80%)	Oral	CYP3A4	2 active
Melperone	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	?	None
Olanzapine	87% (Oral)	30 h	93%	6 h (Oral), 15-45 min (short-acting IM), 7 days (depot)	4-20.4 mg/mL	1000 L	Urine (57%), faeces (30%)	Oral, IM (including depot)	CYP1A2	None
Paliperidone	28% (Oral)	23 h (Oral), 25–49 days (IM)	74%	24 h (Oral), 13 days (IM)	8.85-11.7 ng/mL	390-487 L	Urine (80%), faeces (11%)	Oral, IM (depot)	CYP3A4, CYP2D6	None
Periciazine	?	12 h	?	2 h	150 ng/mL	?	Urine	Oral	?	?
Perospirone	?	1.9-2.5 h	92%	1.5 h	5.7 ng/mL	?	Urine (0.4% as unchanged drug)	Oral	?	None
Perphenazine	?	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 perphenazine
Pimozide	40-50%	55 h	?	6-8 h	4-19 ng/mL (dose-dependent)	?	Urine	Oral	CYP3A4, CYP2D6	None
Prochlorperazine	12.5%	6.8-9 h	High	?	?	12.9-17.7 L/h	Urine, bile	Oral, IM, IV	?	N-desmethylprochlorperazine
Quetiapine	100%	6 h (IR), 7 h (XR); active metabolite: 12 h	83%	1.5 h (IR), 6 h (XR)	@ 250 mg q8hr 778 ng/mL (male), 879 ng/mL (female)	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	Paliperidone
Sertindole	?	3 days	99.5%	10 h	?	20 L/kg	Urine (4%), faeces (46-56%)	Oral	CYP2D6	None
Sulpiride	27 ± 9%	8 h	40%	3-6 h	?	2.72 ± 0.66 L/kg	Urine, faeces	Oral	?	None
Thioridazine	?	24 h	95%	?	?	?	?	Oral	CYP2D6	None
Tiotixene	?	24 h	90%	?	?	?	?	Oral	CYP1A2	None
Trifluoperazine	?	24 h	?	?	?	?	?	Oral	?	None
Ziprasidone	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	None
Zotepine	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	None

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

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

The discovery of chlorpromazine's psychoactive effects in 1952 led to greatly reduced use of restraint, seclusion, and sedation in the management of agitated patients, and also 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.

Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs. In the late 1950s the most widely used term was "neuroleptic", followed by "major tranquilizer" and then "ataraxic". The first recorded use of the term tranquilizer dates from the early nineteenth century. In 1953 Frederik F. Yonkman, a chemist at the Swiss based Cibapharmaceutical company, first used the term tranquilizer to differentiate reserpine from the older sedatives. The wordneuroleptic was 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. This may refer to common side effects such as reduced activity in general, as well as lethargy and impaired motor control. Although these effects are unpleasant and in some cases harmful, they were at one time, along with akathisia, considered a reliable sign that the drug was working. The term "ataraxy" was coined by the neurologist Howard Fabing and the classicist Alister Cameron to describe the observed effect of psychic indifference and detachment in patients treated with chlorpromazine. This term derived from the Greek adjective "ἀτάρακτος" (ataraktos), which means "not disturbed, not excited, without confusion, steady, calm". In the use of the terms "tranquilizer" and "ataractic", medical practitioners distinguished between the "major tranquilizers" or "major ataractics", which referred to drugs used to treat psychoses, and the "minor tranquilizers" or "minor ataractics", which referred to drugs used to treat neuroses. While popular during the 1950s, these terms are infrequently used today. They are being abandoned in favor of "antipsychotic", which refers to the drug's desired effects. Today, "minor tranquilizer" can refer to anxiolytic and/or hypnotic drugs such as the benzodiazepines and nonbenzodiazepines, which have some antipsychotic properties and are recommended for concurrent use with antipsychotics, and are useful for insomnia or drug-induced psychosis. They are powerful (and potentially addictive) sedatives.

Antipsychotics are broadly divided into two groups, the typical or first-generation antipsychotics and the atypical or second-generation antipsychotics. The typical antipsychotics are classified according to their chemical structure while the atypical antipsychotics are classified according to their pharmacological properties. These include serotonin-dopamine antagonists (seedopamine antagonist and serotonin antagonist), multi-acting receptor-targeted antipsychotics (MARTA, those targeting several systems), and dopamine partial agonists, which are often categorized as atypicals.

Society and culture

Sales

Antipsychotics were once among the biggest selling and most profitable of all drugs, generating $22 billion in global sales in 2008. 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 compared to $40 for the older types. By 2008, sales in the US reached $14.6 billion, the biggest selling drugs in the US by therapeutic class.

Formulations

Antipsychotics are sometimes administered as part of compulsory psychiatric treatment via inpatient (hospital) commitment or outpatient commitment. They may be administered orally or, in some cases, through long-acting (depot) injections administered in the dorsgluteal, ventrogluteal or deltoid muscle.

Controversy

Joan 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. Moncreiff has further argued that the evidence for antipsychotics from discontinuation-relapse studies may be flawed, because they do not take into account that antipsychotics may sensitize the brain and provoke psychosis if discontinued, which may then be wrongly interpreted as a relapse of the original condition.

Use of this class of drugs has a history of criticism in residential care. As the drugs used can make patients calmer and more compliant, critics claim that the drugs can be overused. Outside doctors can feel under pressure from care home staff. In an official review commissioned by UK government ministers it was reported that the needless use of anti-psychotic medication in dementia care was widespread and was linked to 1800 deaths per year. In the US, the government has initiated legal action against the pharmaceutical company Johnson & Johnson for allegedly paying kickbacks to Omnicare to promote its antipsychotic risperidone (Risperdal) in nursing homes.

There is some controversy over maintenance therapy for schizophrenia. A review of studies about maintenance therapy concluded that long-term antipsychotic treatment was superior to placebo in reducing relapse in individuals with schizophrenia, although some of the studies were small. A review of major longitudinal studies in North America found that a moderate number of patients with schizophrenia were seen to recover over time from their symptoms, raising the possibility that some patients may not require maintenance medication. It has also been argued that much of the research into long-term antipsychotic maintenance may be flawed due to failure to take into account the role of antipsychotic withdrawal effects on relapse rates.

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

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

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

Special populations

Antipsychotics are intended to treat psychotic disorders. However, they are frequently used as a first-line treatment for other conditions in vulnerable populations.

Evidence indicates that antipsychotics should not be used in children or adolescents as a first-line treatment for anything other than a psychotic disorder. In a concerning trend, in the United States since 2000 the usage of these drugs in young people has greatly increased especially among children from low-income families. Evidence for the efficacy and tolerability of antipsychotic medications is not sufficient to be able to anticipate all the risks, which include young peoples' tendency toward weight gain, metabolic side effects, and cardiovascular changes.

It is recommended that persons with dementia who exhibit behavioral and psychological symptoms should not be given antipsychotics before trying other treatments. When taking antipsychotics this population has increased risk of cerebrovascular effects, parkinsonism or extrapyramidal symptoms, sedation, confusion and other cognitive adverse effects, weight gain, and increased mortality. Physicians and caretakers of persons with dementia should try to address symptoms including agitation, aggression, apathy, anxiety, depression, irritability, and psychosis with alternative treatments whenever antipsychotic use can be replaced or reduced. Elderly persons often have their dementia treated first with antipsychotics and this is not best.

Notes

References

External links

• Are atypical antipsychotics advantageous? - the case for, Australian Prescriber 2005 (note: pharmaceutical company conflict of interest statement at the end)
• Are atypical antipsychotics advantageous? - the case against, Australian Prescriber 2005
• First Generation Antipsychotics: An Introduction, Psychopharmacology Institute, 2012
• Bipolar Meds - The Antipsychotics, mcmanweb.com
• FDA Public Health Advisory - Public Health Advisory for Antipsychotic Drugs used for Treatment of Behavioral Disorders in Elderly Patients, fda.gov
• FROTA LH. Partial Agonists in the Schizophrenia Armamentarium. Tardive Dysphrenia: The newest challenge to the last generation atypical antipsychotics drugs? J Bras Psiquiatr 2003; Vol 52 Supl 1;14-24. Free full-text in Portuguese with Abstracts in English, medicina.ufrj.br
• Antipsychotic Medication - information from mental health charity The Royal College of Psychiatrists
• (Portuguese) FROTA LH. Fifty Years of Antipsychotic Drugs in Psychiatry. "Cinqüenta Anos de Medicamentos Antipsicóticos em Psiquiatria." 1st ed; Ebook: CD-Rom/On-Line Portuguese, ISBN 85-903827-1-0, File .pdf (Adobe Acrobat) 6Mb, Informática, Rio de Janeiro, August 2003, 486pp., medicina.ufrj.br

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. 第2世代抗精神病剤：薬理学、投与、および副作用の比較 second generation antipsychotic medications pharmacology administration and comparative side effects
• 2. 第1世代抗精神病剤：薬理学、投与、および副作用の比較 first generation antipsychotic medications pharmacology administration and comparative side effects
• 3. 第一世代（定型）抗精神病剤中毒 first generation typical antipsychotic medication poisoning
• 4. 第二世代（非定型）抗精神病薬中毒 second generation atypical antipsychotic medication poisoning
• 5. 統合失調症に対する薬物療法：持効性抗精神病薬注射製剤 pharmacotherapy for schizophrenia long acting injectable antipsychotic drugs

English Journal

• Penetration enhancer-containing spanlastics (PECSs) for transdermal delivery of haloperidol: in vitro characterization, ex vivo permeation and in vivo biodistribution studies.

• Fahmy AM1, El-Setouhy DA1, Ibrahim AB2, Habib BA1, Tayel SA1, Bayoumi NA2.
• Drug delivery.Drug Deliv.2018 Nov;25(1):12-22. doi: 10.1080/10717544.2017.1410262.
• PMID 29219628

• Neurosteroid pregnenolone sulfate, alone, and as augmentation of lurasidone or tandospirone, rescues phencyclidine-induced deficits in cognitive function and social interaction.

• Rajagopal L1, Soni D1, Meltzer HY2.
• Behavioural brain research.Behav Brain Res.2018 Sep 17;350:31-43. doi: 10.1016/j.bbr.2018.05.005. Epub 2018 May 24.
• PMID 29763637

• Vascular endothelial growth factor in patients with schizophrenia: A systematic review and meta-analysis.

• Misiak B1, Stramecki F2, Stańczykiewicz B3, Frydecka D2, Lubeiro A4.
• Progress in neuro-psychopharmacology & biological psychiatry.Prog Neuropsychopharmacol Biol Psychiatry.2018 Aug 30;86:24-29. doi: 10.1016/j.pnpbp.2018.05.005. Epub 2018 May 26.
• PMID 29772306

Japanese Journal

• せん妄の診断と治療をめぐる課題と展望

• 臨床精神薬理 20(2), 119-123, 2017-02
• NAID 40021097540

• 回避・制限性食物摂取障害にrisperidoneが有効であった1例

• 精神医学 = Clinical psychiatry 59(1), 91-94, 2017-01
• NAID 40021064336

• Olanzapine治療に関連した糖尿病症例の特徴と経過 : 21例のcase series

• 臨床精神薬理 20(1), 69-78, 2017-01
• NAID 40021063130

Related Links

• Antipsychotic | Define Antipsychotic at Dictionary.com

Another surprise was the large number of inmates who blamed their crime on antipsychotic medicine. Being condemned to a lifetime of harsh antipsychotic drugs seems a far cry from a runny nose and fever. ...

• antipsychotic - definition of antipsychotic by Medical dictionary

antipsychotic /an·ti·psy·chot·ic/ (-si-kot´ik) effective in the treatment of psychotic disorders; also, an agent that so acts. Antipsychotics are a chemically diverse but pharmacologically similar class of drugs; besides psychotic ...

---

★リンクテーブル★

リンク元	「抗精神病剤」「抗精神病」「抗精神薬」
拡張検索	「atypical antipsychotics」

「抗精神病剤」

　　[★]

英

antipsychotic drug、antipsychotic

関

抗精神病薬、神経遮断薬、メジャートランキライザー、抗精神薬、抗精神病、統合失調症治療薬

「抗精神病」

　　[★]

英

antipsychotic

関

抗精神病薬、抗精神薬、抗精神病剤、統合失調症治療薬

「抗精神薬」

　　[★]

英

antipsychotic

関

抗精神病薬、抗精神病、抗精神病剤、統合失調症治療薬

「atypical antipsychotics」

　　[★] 非定型抗精神病薬, AAP