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.
Notable and relatively common adverse effects of antipsychotics include extrapyramidal symptoms (which involve motor control) and hyperprolactinaemia primarily in typicals and weight gain and metabolic abnormalities mostly in atypicals. Temporary withdrawal symptoms including insomnia, agitation, psychosis, and motor disorders may occur during dosage reduction of antipsychotics, and can be mistaken for the return of the underlying condition.
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 seeing how 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. Bipolar depression can be treated with quetiapine, olanzapine or lurasidone. As for bipolar maintenance several atypical antipsychotics have demonstrated efficacy in preventing manic/mixed relapse but few (with the exception of quetiapine and olanzapine) have demonstrated efficacy in preventing manic, mixed and depressive relapse as a monotherapy)
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. Two different antipsychotics should not typically be used in the same person.
In people with schizophrenia less than half (41%) showed any therapeutic response to an atypical antipsychotic, compared to 24% on placebo, there is a decline in treatment response over time, and potentially a biases in the literature in favor of these medication.Risperidone (an atypical antipsychotic), shows only slight benefit compared with placebo and that, despite its widespread use, evidence remains limited, poorly reported and probably biased in favor of risperidone due to pharmaceutical company funding of trials.
Some doubts have been raised about the long-term effectiveness of antipsychotics for schizophrenia, in part because two World Health Organization studies found individuals diagnosed with schizophrenia tend to have better long-term outcomes in developing countries (where there is lower availability and use of antipsychotics and mental health problems are treated with more informal, community-led methods only) than in developed countries.
Some argue 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. Evidence from comparison studies indicates that at least some individuals with schizophrenia recover from psychosis without taking antipsychotics, and may do better in the long term than those that do take antipsychotics. Some argue that, overall, the evidence suggests that antipsychotics only help if they are used selectively and are gradually withdrawn as soon as possible and have referred to the "Myth of the antipsychotic".
The methods used in trials of antipsychotics, despite stating that the overall quality is "rather good," reported issues with the selection of participants (including that, in schizophrenia trials, in general up to 90% of people that are suitable do not meet the elaborate inclusion and exclusion criteria, and that negative symptoms have not been properly assessed despite companies marketing the newer antipsychotics for these); issues with the design of trials (including pharmaceutical company funding of most of them, and inadequate experimental "blinding" so that trial participants could sometimes tell whether they were on placebo or not); and issues with the assessment of outcomes (including the use of a minimal reduction in scores to show "response," lack of assessment of quality of life or recovery, a high rate of discontinuation, selective highlighting of favorable results in the abstracts of publications, and poor reporting of side-effects).
While flupenthixol, an injectable form of antipsychotic that is given every few weeks, is extensively used, there is little evidence to support this use. There is little long term data on the benefits of antipsychotics (beyond two to three years). It is recommended that if a person is without symptoms for a year stopping the use of antipsychotics be considered.
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 Clinical 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.
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.
A number of second-generation (or atypical) antipsychotics have proven to be effective adjuncts in the treatment of major depressive disorder of which aripiprazole, quetiapine, and olanzapine (when used in conjunction with fluoxetine) have received FDA labelling for this indication. Quetiapine has also proven effective as a monotherapy in major depressive 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 in autism spectrum disorder. 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. Recently, risperidone was approved by the US FDA for the treatment of irritability in children and adolescents with autism.
Aggressive challenging behavior in adults with intellectual disability is often treated with antipsychotic drugs despite lack of an evidence base. A recent randomized controlled trial, however, found no benefit over placebo and recommended that the use of antipsychotics in this way should no longer be regarded as an acceptable routine treatment.
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 effectiveClozapine has appeared to be more effective than other atypical antipsychotics, although it has previously been banned due to its potentially lethal side effects. While controlled clinical trials of atypicals reported that extrapyramidal symptoms occurred in 5–15% of patients, a study of bipolar disorder in a real world clinical setting found a rate of 63%, questioning the generalizability of the trials. 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 44 pounds (20 kg) over 18 months) 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.
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.
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)
Extrapyramidal side effects (particularly common in patients on first-generation antipsychotics), which includes:
- Akathisia — an often distressing sense of inner restlessness.
- 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:
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 said to be a common practice but not necessarily evidence-based or recommended, and there have been 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.
Chronic treatment with antipsychotics may reduce amounts of brain tissue and potentially cause some of the symptoms believed to be due to schizophrenia According to studies in macaque monkeys cell loss only affects the number of glial cells and not the numbers of neuronal cells. Continuous use of neuroleptics has been shown to decrease the total brain volume by 10% in macaque monkeys. The effects may differ for typical versus atypical antipsychotics and may interact with different stages of disorders. Such effects were not clearly tested for by pharmaceutical companies prior to obtaining approval for placing the drugs on the market.
A loss of brain tissue has been reported in schizophrenics treated with antipsychotics. Brain volume was negatively correlated with both duration of illness and antipsychotic dosage. No association was found with severity of illness or abuse of other substances. An accompanying editorial said: "The findings should not be construed as an indication for discontinuing the use of antipsychotic medications as a treatment for schizophrenia. But they do highlight the need to closely monitor the benefits and adverse effects of these medications in individual patients, to prescribe the minimal amount needed to achieve the therapeutic goal [and] to consider the addition of nonpharmacological approaches that may improve outcomes."
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-related psychosis from antipsychotics is called "supersensitivity psychosis", and is attributed to increased number and sensitivity of brain dopamine receptors, due to blockade of dopaminergic receptors by the antipsychotics, which often leads to exacerbated symptoms in the absence of neuroleptic medication. Efficacy of antipsychotics may likewise be reduced over time, due to this development of drug tolerance.
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
Clinically used antipsychotic medications are listed below by drug group. Trade names appear in parentheses.
† 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.
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.
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 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), recently approved by the 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.
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.
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.
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.
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 recently discontinued.†
Alstonine, an indole alkaloid that is found in a number of different plants and that serves as a 5-HT2C receptor agonist. Attenuates MK-801-induced hyperlocomotion, social withdrawal and working memory deficits.
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.
* 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-HT2A receptors. Different alleles of the 5-HT2A receptor have been associated with schizophrenia and other psychoses, including depression. Higher concentrations of 5-HT2A receptors 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 of the unwanted side effects that the typical antipsychotics can produce (see above). They were commonly classified on a spectrum of low potency to high potency, where potency referred to the ability of the drug to bind to dopamine receptors, and not to the effectiveness of the drug. High-potency antipsychotics such as haloperidol, in general, have doses of a few milligrams and cause less sleepiness and calming effects than low-potency antipsychotics such as chlorpromazine and thioridazine, which have dosages of several hundred milligrams. The latter have a greater degree of anticholinergic and antihistaminergic activity, which can counteract dopamine-related side-effects.
Atypical antipsychotic drugs have a similar blocking effect on D2 receptors, however, most also act on serotonin receptors, especially 5-HT2A and 5-HT2C receptors. Both clozapine and quetiapine appear to bind just long enough to elicit antipsychotic effects but not long enough to induce extrapyramidal side effects and prolactin hypersecretion. 5-HT2A antagonism increases dopaminergic activity in the nigrostriatal pathway, leading to a lowered extrapyramidal side effect liability among the atypical antipsychotics.
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.
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.
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.
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.
Antipsychotic drugs are now the top-selling class of pharmaceuticals in America, generating annual revenue of about $14.6 billion.
Society and culture
Antipsychotics are 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. The number of prescriptions for children and adolescents doubled to 4.4 million between 2003 and 2006, in part because of increases in diagnoses of bipolar disorder.
According to The Guardian newspaper: "At the heart of years of dissent against psychiatry through the ages has been its use of drugs, particularly antipsychotics, to treat distress. Do such drugs actually target any "psychiatric condition"? Or are they chemical control—a socially-useful reduction of the paranoid, deluded, distressed, bizarre and odd into semi-vegetative zombies?"
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.
^Bolded drug names indicates drugs that are metabolites of clinically-marketed antipsychotics
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^The text reads: "When the patient lashes out against 'them' - THORAZINE (brand of chlorpromazine) quickly puts an end to his violent outburst. 'Thorazine' is especially effective when the psychotic episode is triggered by delusions or hallucinations. At the outset of treatment, Thorazine's combination of antipsychotic and sedative effects provides both emotional and physical calming. Assaultive or destructive behavior is rapidly controlled. As therapy continues, the initial sedative effect gradually disappears. But the antipsychotic effect continues, helping to dispel or modify delusions, hallucinations and confusion, while keeping the patient calm and approachable. SMITH KLINE AND FRENCH LABORATORIES leaders in psychopharmaceutical research."