Antipsychotic

Advertisement for Thorazine (chlorpromazine) from the 1950s^[1]

An antipsychotic (or neuroleptic) is a tranquilizing psychiatric medication primarily used to manage psychosis (including delusions or hallucinations, as well as disordered thought), particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s. Most of the drugs in the second generation, 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 antipsychotic drugs encompass a wide range of receptor targets.

A number of harmful and undesired (adverse) effects have been observed, including lowered life expectancy, weight gain, decrease in brain volume, enlarged breasts and milk discharge in men and women (hyperprolactinaemia), lowered white blood cell count (agranulocytosis), involuntary repetitive body movements (tardive dyskinesia), diabetes, an inability to sit still or remain motionless (akathisia), sexual dysfunction, a return of psychosis requiring increasing the dosage due to cells producing more neurochemicals to compensate for the drugs (tardive psychosis), and a potential for permanent chemical dependence leading to psychosis much worse than before treatment began, if the drug dosage is ever lowered or stopped (tardive dysphrenia).^{[citation needed]}

Temporary withdrawal symptoms including insomnia, agitation, psychosis, and motor disorders may occur during dosage reduction of antipsychotics, and can be mistaken for a return of the underlying condition.^[2][3]

The development of new antipsychotics with fewer of these adverse effects and with greater relative effectiveness as compared to existing antipsychotics (efficacy), is an ongoing field of research.

History

The original antipsychotic drugs were happened upon largely by chance and then tested for their effectiveness. The first, chlorpromazine, was developed as a surgical anesthetic. It was first used on psychiatric patients because of its powerful calming effect; at the time it was regarded as a "chemical 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 the extreme lobotomy-like sedation it was known for. 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,^{[citation needed]} 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.^[4]

Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs.^[5] In the late 1950s the most widely used term was "neuroleptic", followed by "tranquilizer" and then "ataraxic".^[5] The first recorded use of the term tranquilizer dates from the early nineteenth century.^[6] In 1953 Frederik F. Yonkman, a chemist at the Swiss based Ciba pharmaceutical company, first used the term tranquilizer to differentiate reserpine from the older sedatives.^[7] The word neuroleptic 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, lethargy, and impaired motor control. Although these effects are unpleasant and in some cases harmful, they were at one time considered a reliable sign that the drug was working.^{[citation needed]} 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.^[8] This term derived from the Greek adjective Greek: "ἀτάρακτος" (ataraktos) which means "not disturbed, not excited, without confusion, steady, calm".^[5] 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.^[5] 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.^[5] Today, "minor tranquilizer" can refer to anxiolytic and/or hypnotic drugs such as the benzodiazepines and nonbenzodiazepines which, despite not having antipsychotic properties, 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 (see dopamine antagonist and serotonin antagonist), multi-acting receptor-targeted antipsychotics (MARTA, those targeting several systems), and dopamine partial agonists, which are often categorized as atypicals.^[9]

Medical uses

Common conditions with which antipsychotics might be used include schizophrenia, bipolar disorder and delusional disorder. Antipsychotics might also be used to counter psychosis associated with a wide range of other diagnoses, such as psychotic depression. However, not all symptoms require heavy medication and hallucinations and delusions should only be treated if they distress the patient or produce dangerous behaviors. ^[10]

In addition, "antipsychotics" are increasingly used to treat non-psychotic disorders. For example, they are sometimes used off-label to manage aspects of Tourette syndrome or autism spectrum disorders. They have multiple off-label uses as an augmentation agent (i.e. in addition to another medication), for example in "treatment-resistant" depression^[11] or OCD.^[12] Despite the name, the off-label use of "antipsychotics" is said to involve deploying them as antidepressants, anti-anxiety drugs, mood stabilizers, cognitive enhancers, anti-aggressive, anti-impulsive, anti-suicidal and hypnotic (sleep) medications.^[13]

Antipsychotics have also been increasingly used off-label in cases of dementia in older people, and for various disorders and difficulties in children and teenagers. A survey of children with pervasive developmental disorder found that 16.5% were taking an antipsychotic drug, most commonly to alleviate mood and behavioral disturbances characterized by irritability, aggression, and agitation. Recently, risperidone was approved by the US FDA for the treatment of irritability in children and adolescents with autism.^[14]

Antipsychotics are sometimes used as part of compulsory treatment via inpatient (hospital) commitment or outpatient commitment. This may involve various methods to persuade a person to take the medication, or actual physical force. Administration may rely on an injectable form of the drug rather than tablets. The injection may be of a long-lasting type known as a depot injection, usually applied at the top of the buttocks. Those that are available in injectable form are haloperidol, olanzapine, and ziprasidone while those available as depot are haloperidol, flupenthixol, clopenthixol, and risperidone.

Antipsychotics are among the biggest selling and most profitable of all drugs, generating $22 billion in global sales in 2008.^[15] 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.^[16] By 2008, sales in the US reached $14.6 billion, the biggest selling drugs in the US by therapeutic class.^[17] 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.^[18]

Due to the chronic nature of the treated disorders, antipsychotic medications, once started, are seldom discontinued, and the aim of the treatment is often to gradually reduce dosage to a minimum safe maintenance dose that is enough to control the symptoms. Only when the side-effects have become too severe and/or a patient have been symptom-free for a long periods of time is discontinuation carefully attempted. Improper discontinuation or abrupt restarting of neuroleptics have been shown to cause dysfunction in regions of the brainstem as well as dysfunction of the autonomic nervous system.

Side 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.^[19] Extrapyramidal reactions include acute dystonias, akathisia, parkinsonism (rigidity and tremor), tardive dyskinesia, tachycardia, hypotension, impotence, lethargy, seizures, intense dreams or nightmares, and hyperprolactinaemia.^[20] Side effects from antipsychotics can be managed by a number of different drugs. For example, anticholinergics are often used to alleviate the motor side effects of antipsychotics.^[21] Some of the side-effects will appear after the drug has been used only for a long time.

Some studies have found decreased life expectancy associated with the use of antipsychotics, and argued that more studies are needed.^[22][23] In Feb. 2011, a minor loss of brain tissue was reported in schizophrenics treated with antipsychotics.^[24][25] 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."^[24][26] Continuous use of neuroleptics has been shown to decrease the total brain volume by 10% in macaque monkeys.^[27]

In "healthy" individuals without psychosis, doses of antipsychotics can produce the so-called "negative symptoms" (e.g. emotional and motivational difficulties) associated with schizophrenia.^[28]

From a subjective perspective, antipsychotics heavily influence one's perceptions of pleasurable sensations, causing a severe reduction in feelings of desire, motivation, pensive thought, and awe. This does not coincide with the apathy and lack of motivation experienced by the negative symptoms of schizophrenia. Detrimental effects on short term memory, which affect the way one figures and calculates (although this also may be purely subjective), may also be observed on high enough dosages. These are all the reasons why they are thought to affect "creativity". Also, for some individuals with schizophrenia, too much stress may cause "relapse".

Following are details concerning some of the side effects of antipsychotics:

• Antipsychotics, particularly atypicals, appear to cause diabetes mellitus and fatal diabetic ketoacidosis, especially (in US studies) in African Americans.^[29][30]
• Antipsychotics may cause pancreatitis.^[31]
• The atypical antipsychotics (especially olanzapine) seem to cause weight gain more commonly than the typical antipsychotics. The well-documented metabolic side effects associated with weight gain include diabetes, which can be life-threatening.^[32]
• Antipsychotics increase the likelihood of a fatal heart attack, with the risk of death increasing with dose and the length of time on the drug.^[33]
• Clozapine also has a risk of inducing agranulocytosis, a potentially dangerous reduction in the number of white blood cells in the body. Because of this risk, patients prescribed clozapine may need to have regular blood checks to catch the condition early if it does occur, so the patient is in no danger.^[34]
• One of the more serious of these side effects is tardive dyskinesia, in which the sufferer may show repetitive, involuntary, purposeless movements (that are permanent and have no cure) often of the lips, face, legs, or torso. It is believed that there is a greater risk of developing tardive dyskinesia with the older, typical antipsychotic drugs, although the newer antipsychotics are now also known to cause this disorder.
• A potentially serious side effect of many antipsychotics is that they tend to lower an individual's seizure threshold. Chlorpromazine and clozapine, in particular, have a relatively high seizurogenic potential. Fluphenazine, haloperidol, pimozide and risperidone exhibit a relatively low risk. Caution should be exercised in individuals that have a history of seizurogenic conditions such as epilepsy, or brain damage.
• Neuroleptic malignant syndrome, in which the drugs appear to cause the temperature regulation centers to fail, resulting in a medical emergency, as the patient's temperature suddenly increases to dangerous levels.
• Dysphoria.
• Drug-induced parkinsonism due to dopamine D2 receptor blockade may mimic idiopathic parkinsonism. The typical antipsychotics are more prone to cause this, compared to the atypical antipsychotics.
• Sexual dysfunction, which may rarely continue after withdrawal, similar to Post-SSRI sexual dysfunction (PSSD).
• Dystonia, a neurological movement disorder in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures.
• Hyperprolactinaemia. The breasts may enlarge and discharge milk, in both men and women due to abnormally-high levels of prolactin in the blood. Prolactin secretion in the pituitary is normally suppressed by dopamine. Drugs that block the effects of dopamine at the pituitary or deplete dopamine stores in the brain may cause the pituitary to secrete prolactin.
• There is evidence that exposure may cause demyelinating disease in laboratory animals.^[35]
• Following controversy over possible increased mortality (death) related to antipsychotics in individuals with dementia, warnings have been added to packaging.^[36]

Some people suffer few apparent side effects from taking antipsychotic medication, whereas others may have serious adverse effects.^[vague] Some side effects, such as subtle cognitive problems, may go unnoticed.

There is a possibility that the risk of tardive dyskinesia can be reduced by combining the anti-psychotics with diphenhydramine or benzatropine, although this remains to be established. Central nervous system damage is also associated with irreversible tardive akathisia and/or tardive dysphrenia.

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.^[2][3]

Tardive dyskinesia can emerge as a physical withdrawal symptom, and may either gradually abate during the withdrawal phase, or become persistent.^[37] 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,^[38] which often leads to exacerbated symptoms in the absence of neuroleptic medication.^[39] Efficacy of antipsychotics may likewise be reduced over time, due to this development of drug tolerance.^[3]

Withdrawal effects may also occur when switching a person from one antipsychotic to another, (presumably 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.^[40] The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.^[41]

Efficacy

There have been a large number of studies of the efficacy of typical antipsychotics, and an increasing number on the more recent atypical antipsychotics.

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.^[42][43] 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.

Nevertheless, a 2009 systematic review and meta-analysis of trials in people diagnosed with schizophrenia found that less than half (41%) showed any therapeutic response to an antipsychotic, compared to 24% on placebo, and that there was a decline in treatment response over time, and possibly a bias in which trial results were published.^[44] In addition, a 2010 Cochrane Collaboration review of trials of Risperidone, one of the biggest selling antipsychotics and the first of the new generation to become available in generic form, found only marginal 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.^[45] Another Cochrane review in 2009, of bipolar disorder, found the efficacy and risk/benefit ratio better for the traditional mood stabilizer lithium than for the antipsychotic Olanzapine as a first line maintenance treatment.^[46]

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.^[47] 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.^[48]

A review by the US Agency for Healthcare Research and Quality found that much of the evidence for the off-label use of antipsychotics (for example, for depression, 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.^[49] A UK review of unlicensed usage in children and adolescents reported a similar mixture of findings and concerns.^[50]

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.^[51]

A 2006 Cochrane Collaboration review of controlled trials of antipsychotics in old age dementia reported that one or two of the drugs showed a modest benefit compared to placebo in managing aggression or psychosis, but that this was combined with a significant increase in serious adverse events. They concluded that this confirms that antipsychotics should not be used routinely to treat dementia patients with aggression or psychosis, but may be an option in the minority of cases where there is severe distress or risk of physical harm to others.^[52]

Some doubts have been raised about the long-term effectiveness of antipsychotics for schizophrenia, in part because two large international 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.^[53][54]

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.^[55] 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.^[56] Some argue that, overall, the evidence suggests that antipsychotics only help if they are used selectively and are gradually withdrawn as soon as possible^[57] and have referred to the "Myth of the antipsychotic".^[58]

A review of 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 up to 90% of people who are generally 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).^[59]

Typicals versus atypicals

While the atypical (second-generation) antipsychotics were marketed as offering greater efficacy in reducing psychotic symptoms while reducing side effects (and Extrapyramidal symptoms in particular) than typical medications, the results showing these effects often lacked robustness, and the assumption was increasingly challenged even as atypical prescriptions were soaring.^[60] One review concluded there were no differences^[9] while another^[61] found that atypicals were "only moderately more efficacious".^[9] These conclusions were, however, questioned by another review, which found that clozapine, amisulpride, and olanzapine and risperidone were more effective^[9][62] Clozapine has appeared to be more effective than other atypical antipsychotics,^[9][63] 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.^[64]

In 2005 the US government body NIMH published the results of a major independent (not funded by the pharmaceutical companies) multi-site, double-blind study (the CATIE project).^[65] 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.^[66] 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 (a result supported by a meta-analysis by Dr. Leucht published in Lancet), although more patients discontinued perphenazine owing to extrapyramidal effects compared to the atypical agents (8% vs. 2% to 4%, P=0.002).

A phase 2 part of this CATIE study roughly replicated these findings.^[67] This phase consisted of a second randomization of the patients that discontinued taking medication in the first phase. Olanzapine was again the only medication to stand out in the outcome measures, although the results did not always reach statistical significance (which means they were not reliable findings) due in part to the decrease of power. The atypicals again did not produce fewer extrapyramidal effects than perphenazine. A subsequent phase was conducted^[68] that allowed clinicians to offer clozapine which was more effective at reducing medication drop-outs than other neuroleptic agents. However, the potential for clozapine to cause toxic side effects, including agranulocytosis, limits its usefulness.

It had been hoped that patient adherence to antipsychotics would be higher with the atypicals, but a 2008 review found that the data have failed to substantiate the notion that novel antipsychotic drug use leads to improved medication compliance and favorable clinical outcomes.^[69]

Overall evaluations of the CATIE and other studies have led many researchers to question the first-line prescribing of atypicals over typicals, or even to question the distinction between the two classes.^[70][71] In contrast, other researchers point to the significantly higher risk of tardive dyskinesia and EPS 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.^[66][72] 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 towards prescribing the atypicals, however.^[73]

Common antipsychotics

Chlorpromazine.

Haloperidol.

Quetiapine.

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

First generation antipsychotics

Main article: Typical antipsychotic

Butyrophenones

Main article: Butyrophenones

• Haloperidol (Haldol, Serenace)
• Droperidol (Droleptan)

Phenothiazines

Main article: Phenothiazines

• Chlorpromazine (Thorazine, Largactil)
• Fluphenazine (Prolixin) - Available in decanoate (long-acting) form
• Perphenazine (Trilafon)
• Prochlorperazine (Compazine)
• Thioridazine (Mellaril, Melleril)
• Trifluoperazine (Stelazine)
• Mesoridazine
• Periciazine
• Promazine
• Triflupromazine (Vesprin)
• Levomepromazine (Nozinan)
• Promethazine (Phenergan)
• Pimozide (Orap)
• Cyamemazine (Tercian)

Thioxanthenes

Main article: Thioxanthenes

• Chlorprothixene (Cloxan, Taractan, Truxal)
• Clopenthixol (Sordinol)
• Flupenthixol (Depixol, Fluanxol)
• Thiothixene (Navane)
• Zuclopenthixol (Cisordinol, Clopixol, Acuphase)

Second generation antipsychotics

Main article: Atypical antipsychotic

• Clozapine (Clozaril) - Requires weekly to biweekly complete blood count due to risk of agranulocytosis.
• Olanzapine (Zyprexa) - Used to treat psychotic disorders including schizophrenia, acute manic episodes, and maintenance of bipolar disorder
• 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.
• Quetiapine (Seroquel) - Used primarily to treat bipolar disorder and schizophrenia, and "off-label" to treat chronic insomnia and restless legs syndrome; it is a powerful sedative.
• Ziprasidone (Geodon) - Approved in 2004^[74] 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.
• 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. Amisulpride has not been approved for use by the Food and Drug Administration in the United States.
• Asenapine (Saphris) is a 5-HT2A- and D2-receptor antagonist under development for the treatment of schizophrenia and acute mania associated with bipolar disorder.
• Paliperidone (Invega) - Derivative of risperidone that was approved in 2006.
• Iloperidone (Fanapt) - Approved by the FDA on May 6, 2009.
• Zotepine (Nipolept, Losizopilon, Lodopin, Setous)- An atypical antipsychotic indicated for acute and chronic schizophrenia. It was approved in Japan circa 1982 and Germany in 1990, respectively.
• Sertindole (Serdolect, and Serlect in Mexico). 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.
• Lurasidone (Latuda), a recently FDA approved once daily antipsychotic with a favorable efficacy and safety profile.

Third generation antipsychotics

• Aripiprazole (Abilify) - Mechanism of action is thought to reduce susceptibility to metabolic symptoms seen in some other atypical antipsychotics.^[75] The extent to which these effects differ from other atypical antipsychotics is debated.^[76]
• Partial agonists of dopamine.

Other options

• Cannabidiol is one of the main components of Cannabis sativa. Cannabidiol differs from the active drug in cannabis, tetrahydrocannabinol, in that cannabidiol lacks the typical intoxicating and recreational effects. One study has suggested that cannabidiol may be as effective as atypical antipsychotics in treating schizophrenia.^[77] Some further research has supported these results, and found fewer side effects with cannabidiol than with amisulpride.^[78][78]
• Tetrabenazine is similar in function to antipsychotic drugs, though is not, in general, considered an antipsychotic itself. Its main usefulness is the treatment of hyperkinetic movement disorders such as Huntington's disease and Tourette syndrome, rather than for conditions such as schizophrenia. Also, rather than having the potential to cause tardive dyskinesia, which most antipsychotics have, tetrabenazine can be an effective treatment for the condition.
• Metabotropic glutamate receptor 2 agonism has been seen as a promising strategy in the development of novel antipsychotics.^[79][80][81] When tested in patients, the research substance LY2140023 yielded promising results and had few side effects. The active metabolite of this prodrug targets the brain glutamate receptors mGluR2/3 rather than dopamine receptors.^[82]
• Glycine transporter 1 inhibition. RG1678 has been shown in phase 2 clinical trials to be selectively effective for the negative symptoms of schizophrenia.^[83]
• A placebo-controlled trial has suggested that adding L-theanine, an amino acid found in green tea and available as supplement, to ongoing antipsychotic medication may be helpful in reducing some symptoms of schizophrenia.^[84]

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 is the blockade of dopamine receptors in this pathway that is thought to control psychotic experiences.

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. Some also block or partially block serotonin receptors (particularly 5HT_{2A, C} and 5HT_1A receptors):ranging from risperidone, which acts overwhelmingly on serotonin receptors, to amisulpride, which has no serotonergic activity. The additional effects on serotonin receptors may be why some of them can benefit the "negative symptoms" of schizophrenia.^[85]

Structural effects

Many studies now indicate that chronic treatment with antipsychotics affects the brain at a structural level, for example increasing the volume of the basal ganglia (especially the caudate nucleus), and reducing cortical grey matter volume in different brain areas. The effects may differ for typical versus atypical antipsychotics and may interact with different stages of disorders.^[86][87] Death of neurons in the cerebral cortex, especially in women, has been linked to the use of both typical and atypical antipsychotics for individuals with Alzheimers.^[88]

Recent studies on macaque monkeys have found that administration of haloperidol or olanzapine for about two years led to a significant overall shrinkage in brain tissue,^[89] in both gray and white matter across several brain areas, with lower glial cell counts,^[90] due to a decrease in astrocytes and oligodendrocytes,^[91] and increased neuronal density. It has been said that these studies require serious attention and that such effects were not clearly tested for by pharmaceutical companies prior to obtaining approval for placing the drugs on the market.^[92]

Controversy

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?"^[93]

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.^[94] 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.^[95][96] 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.^[97]

There is some controversy over maintenance therapy for schizophrenia.^[3][98] 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.^[99] 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.^[98] 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.^[3]

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. For example in the US, Eli Lilly and Company recently pleaded guilty to violating US laws for over a decade in regard to Zyprexa (olanzapine), and was ordered to pay $1.42 billion to settle criminal and civil allegations, including the biggest criminal fine for an individual corporation ever imposed in US history; while Astrazeneca is facing about 9,000 personal-injury lawsuits from more than 15,000 former users of Seroquel (quetiapine), amidst federal investigations of its marketing practices.^[100] 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.^[15]

Some critics have also analyzed the use of alleged front organizations and conflicted patient "advocacy" groups funded by pharmaceutical companies that seek to set the mental health agenda, including the use of the law to force people to take antipsychotics against their will, often justified by claims about risk of violence.^[101]

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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
• 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