The term '''antipsychotic''' is applied to a group of [[Medication|drugs]] commonly but not exclusively used to treat [[psychosis]]. Common conditions with which antipsychotics might be used include [[schizophrenia]], [[bipolar disorder]], [[mania]] and [[delusional disorder]].

==Terminology==

Antipsychotics are also referred to as '''neuroleptic drugs''', '''neuroleptics'''. The word ''neuroleptic'' is derived from [[Greek language|Greek]]: "νεύρο" referring to the [[nerve]]s and "λαμβάνω" meaning ''take hold of''. Thus, the word means ''taking hold of one's nerves''. This term reflects the drugs' ability to make movement more difficult and sluggish, which clinicians believed indicated that a dose was high enough.{{Fact|date=August 2007}} The lower doses used currently have resulted in reduced incidence of motor side-effects and sedation, and the term is less commonly used than in the past.

Antipsychotics are broadly divided into two groups, the [[Typical antipsychotic|typical or first-generation antipsychotics]] and the [[Atypical antipsychotic|atypical or second-generation antipsychotics]]. There are also [[dopamine partial agonists]], which are often categorized as atypicals.

Typical antipsychotics are also sometimes referred to as '''major tranquilizers''', because some of them can tranquilize and sedate. This term is increasingly disused, as the terminology implies a connection with [[benzodiazepine]]s ("minor" tranquilizers) when none exists.

== Usage ==
Common conditions with which antipsychotics might be used include [[schizophrenia]], [[mania]] and [[delusional disorder]]. They might be used to counter psychosis associated with a wide range of other diagnoses. Antipsychotics may also be used in [[mood disorder]] (e.g. [[bipolar disorder]]) even when no signs of psychosis are present. In addition, these drugs are used to treat non-psychotic disorders. For example, some antipsychotics ([[haloperidol]], [[pimozide]]) are used [[Off-label use|off-label]] to treat [[Tourette syndrome]]; while [[abilify]] is prescribed in some cases of [[Asperger's syndrome]].

In routine clinical practice, antipsychotics may be used as part of risk management, and to control difficult patients, although this is controversial.

==History==
The original antipsychotic drugs were happened upon largely by chance and were tested empirically for their effectiveness.

The first antipsychotic was [[chlorpromazine]], which was developed as a surgical [[anesthetic]]. It was first used on psychiatric patients in the belief that it would have a calming effect. However, the drug soon appeared to reduce psychosis beyond this calming effect, and now some believe that it causes a reduction of psychosis unrelated to the sedating effect of the medication. It was introduced for the treatment of psychosis during the period when [[lobotomy]] was a common treatment and was hailed as a "cure" for schizophrenia. It was then touted to provide a "chemical lobotomy," causing similar neurological effects without requiring surgery.

The newer atypical antipsychotics are supposedly [[rational drug design|rationally designed drugs]] in which a theoretical understanding of both the condition to be treated and the effect of certain molecules on the body is used to develop potential new drug candidates. However, continued off-label use of the newer drugs indicates that old-fashioned empirical drug discovery is still important in evaluating this class of medication.

== Common antipsychotic drugs ==
[[Image:Chlorpromazine-2D-skeletal.png|thumb|Chlorpromazine.]]
[[Image:Haloperidol.svg|thumb|Haloperidol.]]
[[Image:Quetiapine.png|thumb|Quetiapine.]]
Commonly used antipsychotic medications are listed below by drug group. Trade names appear in parentheses.

===[[Typical antipsychotic]]s===
====[[Phenothiazines]]====
* [[Chlorpromazine]] (Thorazine)
* [[Fluphenazine]] (Prolixin) - Available in decanoate (long acting) form
* [[Perphenazine]] (Trilafon)
* [[Prochlorperazine]] (Compazine)
* [[Thioridazine]] (Mellaril)
* [[Trifluoperazine]] (Stelazine)
* [[Mesoridazine]]
* [[Promazine]]
* [[Triflupromazine]] (Vesprin)
* [[Levomepromazine]] (Nozinan)
====[[Thioxanthenes]]====
* [[Chlorprothixene]]
* [[Flupenthixol]] (Depixol and Fluanxol)
* [[Thiothixene]] (Navane)
* [[Zuclopenthixol]] (Clopixol and Acuphase)
====[[Butyrophenones]]====
* [[Haloperidol]] (Haldol) - Available in decanoate (long acting) form
* [[Droperidol]]
* [[Pimozide]] (Orap) - Used to treat [[Tourette syndrome]]
* [[Melperone]]

===[[Atypical antipsychotic]]s===
* [[Clozapine]] (Clozaril) - Requires weekly to biweekly [[complete blood count|CBC (FBC)]] because of risk of [[agranulocytosis]] (a severe decrease of [[white blood cells]]).
* [[Olanzapine]] (Zyprexa) - Used to treat psychotic disorders including schizophrenia, acute manic episodes, and maintenance of bipolar disorder. Dosing 2.5 mg to 20 mg per day. Comes in a form that quickly dissolves in the mouth (Zyprexa Zydis). May cause appetite increase, weight gain and altered glucose metabolism leading to an increased risk of diabetes mellitus.
* [[Risperidone]] (Risperdal) - Dosing 0.25 to 6 mg per day and is titrated upward; divided dosing is recommended until initial titration is completed at which time the drug can be administered once daily. Available in long-acting form (Risperdal Consta that is administered every 2 weeks; usual dose is 25 mg). Comes in a form that quickly dissovles in the mouth (Risperdal M-Tab). Used off-label to treat [[Tourette Syndrome]].
* [[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 (if it's used to treat sleep disorders and is not effective at 200 mg, it is not going to be effective in this regard). Dosing starts at 25 mg and continues up to 800 mg maximum per day, depending on the severity of the symptom(s) being treated. Users typically take smaller doses during the day for the neuroleptic properties and larger dose at bedtime for the sedative effects, or divided in two equally high doses every 12 hours (75-400mg bid).
* [[Ziprasidone]] (Geodon) - Now (2006) approved to treat bipolar disorder. Dosing 20 mg twice daily initially up to 80 mg twice daily. Prolonged [[QT interval]] a concern; watch closely with patients who have heart disease; when used with other drugs that prolong QT interval potentially life-threatening.
*[[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 [[anti-depressant]] and [[anxiolytic]] effects in non-schizophrenic patients, leading to its use in [[dysthymia]] and [[social anxiety disorder]]. In one particular study, amisulpride was found to have greater efficacy than [[fluoxetine]] in decreasing anxiety. Currently, amisulpride is approved in Europe, Australia and other countries for use in schizophrenia, and is approved and marketed in lower dosages in some countries for treating [[dysthymia]] (such as in Italy as [[Deniban]]). Amisulpride has not been approved by the FDA for use in the United States.
*[[Paliperidone]] (Invega) - Derivative of risperidone. Approved in December 2006.
* Dopamine [[partial agonist]]s:
* [[Aripiprazole]] (Abilify) - Dosing 5 mg up to maximum of 30 mg has been used. Mechanism of action is thought to reduce susceptibility to metabolic symptoms seen in some other atypical antipsychotics.<ref>{{cite journal |last=Swainston |first=Harrison T. |coauthors=Perry, C.M. |year=2004 |title=Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder. |journal=Drugs |volume=64 |issue=15 |pages=1715-1736 |accessdate= 2007-11-08}}PMID 15257633</ref>
* Under clinical development - [[Bifeprunox]]; [[norclozapine]] (ACP-104).
===Other options===
* Symbyax - A combination of [[olanzapine]] and [[fluoxetine]] used in the treatment of bipolar depression.
* [[Tetrabenazine]] (Nitoman in Canada and Xenazine in New Zealand and some parts of Europe) is similar in function to antipsychotic drugs, though isn't generally considered an antipsychotic itself. This is likely due to its main usefulness being the treatment of hyperkinetic [[movement disorder]]s 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]] that most antipsychotics have, tetrabenazine can actually be an effective ''treatment'' for the condition.
*[[Cannabidiol]] One of the main psychoactive components of [[cannabis]]. A recent study has shown cannabidiol to be as effective as atypical antipsychotics in treating schizophrenia. <ref>{{cite journal
| last = Zuardi
| first = A.W
| coauthors = J.A.S. Crippa, J.E.C. Hallak, F.A. Moreira, F.S. Guimarães
| title = Cannabidiol as an antipsychotic drug
| journal = Brazilian Journal of Medical and Biological Research
| date = 2006
| volume = 39
| pages = 421-429
| url = http://www.scielo.br/pdf/bjmbr/v39n4/6164.pdf
| issn = ISSN 0100-879X }}</ref>

The most common typical antipsychotic drugs are now [[Patent|off-patent]], meaning any pharmaceutical company is legally allowed to produce cheap [[generic drug|generic]] versions of these medications. While this makes them cheaper than the atypical drugs which are still manufactured under patent constraints, atypical drugs are preferred as a first line treatment because they are believed to have fewer side effects and seem to have additional benefits for the 'negative symptoms' of [[schizophrenia]], a typical condition for which they might be prescribed.

'''"''LY2140023''"'''

A new [[schizophrenia]] [[drug]] "''LY2140023''" yielded promising results, as it targets in the [[brain]] – [[glutamate]] receptors rather than [[dopamine]] and had few side effects. The [[Nature Medicine]] study, by drug firm [[Eli Lilly]] found it promising and Dr.Sandeep Patil's team proved that LY2140023 appear to work as antipsychotics when tested upon [[rodents]].<ref>[http://news.bbc.co.uk/2/hi/health/6971037.stm BBC NEWS, Schizophrenia trials 'promising']</ref>

== Drug action ==
All antipsychotic drugs tend to block [[Dopamine receptor|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 which 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 [[Adverse effect (medicine)|side effects]] that the typical antipsychotics can produce (see below).
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]] typically 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.<ref>{{cite journal |last=Murphy |first=B.P. |coauthors=Chung YC, Park TW, McGorry PD |year=2006 |month=12 |title=Pharmacological treatment of primary negative symptoms in schizophrenia: a systematic review |journal=Schizophrenia Research |volume=88 |issue=1-3 |pages=5-25 |accessdate=2007-11-08}}PMID 16930948</ref>

== Side effects ==
Antipsychotics are associated with a range of side-effects. It is well recognized that many people (around two thirds in controlled drug trials) discontinue antipsychotics, partly due to adverse effects.

[[Extrapyramidal side-effect|Extrapyramidal]] reactions include acute [[dystonia]]s, [[akathisia]], [[parkinsonism]] (rigidity and [[tremor]]), [[tardive dyskinesia]], [[tachycardia]], [[hypotension]], [[impotence]], lethargy, [[seizure]]s, and [[hyperprolactinaemia]].

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 that, frequently, can be life threatening.

[[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.

One of the more serious of these side effects is [[tardive dyskinesia]],<ref>Photos and videos of tardive dyskinesia can be seen [http://www.yoism.org/?q=node/120 here].</ref> in which the sufferer may show repetitive, involuntary, purposeless movements 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.
It is believed by some that the risk of tardive dyskinesia can be reduced by combining the anti-psychotics with [[diphenhydramine]] or [[benztropine]], though this has not been established. [[Central nervous system]] damage is also associated with irreversible tardive [[akathisia]] and/or [[tardive dysphrenia]].

Another antipsychotic side-effect is deterioration of teeth due to a lack of saliva.

A potentially serious side effect of many antipsychotics is that they tend to lower an individuals seizure threshold. Chlorpromazine and clozapine particularly, 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]]).

Another serious side effect is [[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.

Another problematic side effect of antipsychotics is [[dysphoria]].

Some people suffer few of the obvious side effects from taking antipsychotic medication, while others may have serious adverse effects. Some side effects, such as subtle cognitive problems, may go unnoticed.

==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 and for preventing relapse.<ref>American Psychiatric Association (2004) Practice Guideline for the Treatment of Patients With Schizophrenia. Second Edition.</ref><ref>The Royal College of Psychiatrists & The British Psychological Society (2003). [http://www.nice.org.uk/download.aspx?o=289559 ''Schizophrenia. Full national clinical guideline on core interventions in primary and secondary care''] (PDF). London: Gaskell and the British Psychological Society.</ref> 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.

Antipsychotic [[polypharmacy]]&mdash;prescribing two or more antipsychotics at the same time for an individual&mdash;is said to be a frequent practice but not necessarily evidence-based.<ref>Patrick V, Levin E, Schleifer S. (2005) Antipsychotic polypharmacy: is there evidence for its use? ''J Psychiatr Pract.'' 2005 Jul;11(4):248-57. PMID 16041235</ref>

Some doubts have been raised about the long-term effectiveness of antipsychotics 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) than in developed countries.<ref>{{cite journal |author=Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper J, Day R, Bertelsen A |title=Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization ten-country study |journal=Psychol Med Monogr Suppl |volume=20 |issue= |pages=1-97 |year= |pmid=1565705}}</ref><ref>Hopper K, Wanderling J (2000). Revisiting the developed versus developing country distinction in course and outcome in schizophrenia: results from ISoS, the WHO collaborative followup project. International Study of Schizophrenia. ''Schizophrenia Bulletin'', 26 (4), 835–46. PMID 11087016</ref> The reasons for the differences are not clear, however, and various explanations have been suggested.

Some argue that the evidence for antipsychotics from withdrawal-relapse studies may be flawed, because they do not take into account that antipsychotics may sensitize the brain and provoke psychosis if discontinued.<ref>Moncrieff J. (2006) Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. ''Acta Psychiatr Scand.'' Jul;114(1):3-13. PMID 16774655</ref> Evidence from comparison studies indicates that at least some individuals recover from psychosis without taking antipsychotics, and may do better than those who do take antipsychotics.<ref>Harrow M, Jobe TH. (2007) Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications: a 15-year multifollow-up study. ''J Nerv Ment Dis.'' May;195(5):406-14. PMID 17502806</ref> Some argue that, overall, the evidence suggests that antipsychotics only help if they used selectively and are gradually withdrawn as soon as possible.<ref>Whitaker R. (2004) The case against antipsychotic drugs: a 50-year record of doing more harm than good. ''Med Hypotheses.'' 2004;62(1):5-13. PMID 14728997</ref>

A dose response effect has been found in one study from 1971 between increasing neuroleptic dose and increasing number of psychotic breaks.<ref>{{cite journal |author=Prien R, Levine J, Switalski R |title=Discontinuation of chemotherapy for chronic schizophrenics |journal=Hosp Community Psychiatry |volume=22 |issue=1 |pages=4-7 |year=1971 |pmid=4992967}}</ref>{{Verify source|date=July 2007}}

== Typical versus atypical ==
While the atypical, second-generation medications were marketed as offering greater efficacy in reducing psychotic symptoms while reducting side effects (and extra-pyramidal symptoms in particular) than typical medications, these results showing these effects often lack robustness. To remediate this problem, the [[NIMH]] conducted a recent multi-site, double-blind, study (the CATIE project), which was published in 2005.<ref>{{cite journal |author=Lieberman J et al |title=Effectiveness of antipsychotic drugs in patients with chronic schizophrenia |journal=N Engl J Med |volume=353 |issue=12 |pages=1209-23 |year=2005 |pmid=16172203 |url=http://content.nejm.org/cgi/content/abstract/353/12/1209}}</ref> This study compared several atypical antipsychotics to an older typical antipsychotic, [[perphenazine]], among 1493 persons with schizophrenia. Perphenazine was chosen because of its lower potency and moderate side-effect profile. The study found that only [[olanzapine]] outperformed perphenazine in the researchers' principal outcome, the discontinuation rate. The authors also noted the apparent superior efficacy of olanzapine to the other drugs for greater reduction in psychopathology, longer duration of successful treatment, and lower rate of hospitalizations for an exacerbation of schizophrenia. In contrast, no other atypical studied ([[risperidone]], [[quetiapine]], and [[ziprasidone]]) did better than the typical perphenazine on those measures. Olanzapine, however, was associated with relatively severe metabolic effects: subjects with olanzapine showed a major weight gain problem and increases in glucose, cholesterol, and triglycerides. The average weight gain (1.1 kg/month, or 44 pounds for the 18 months that lasted the study) casts serious doubt on the potentiality of long-term use of this drug. Perphenazine did not create more extrapyramidal side-effect as measured by rating scales (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 percent vs. 2 percent to 4 percent, P=0.002).

A phase 2 part of this study roughly replicated these findings.<ref>{{cite journal |author=Stroup T et al |title=Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic |journal=Am J Psychiatry |volume=163 |issue=4 |pages=611-22 |year=2006 |pmid=16585435}}</ref> This phase consisted on a second randomization of the patients who discontinuated the taking of 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, in part to the decrease of power. Perphenazine again did not create more extrapyramidal effects.

A subsequent phase was conducted. <ref>{{cite journal |author=McEvoy J et al |title=Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment |journal=Am J Psychiatry |volume=163 |issue=4 |pages=600-10 |year=2006 |pmid=16585434}}</ref> This phase innovated in allowing clinicians to offer [[clozapine]]. Clozapine indeed proved to be more effective at reducing medication drop-outs than other neuroleptic agents. Researchers also observed a trend showing clozapine with a greater reduction of symptoms. However, the potential of clozapine to cause toxic side effects, including agranulocytosis, limits the prescription to persons with schizophrenia.

==See also==
* [[Dopamine]]
* [[Dopamine hypothesis of schizophrenia]]
* [[Psychosis]]
* [[Schizophrenia]]
* [[Tardive dysphrenia]]

==References==
{{reflist}}
* [http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12356650&dopt=Abstract Jones, H. M., & Pilowsky, L. S. (2002)] Dopamine and antipsychotic drug action revisited. ''British Journal of Psychiatry'', 181, 271-275.
* Jablensky, A. (1992). Schizophrenia: manifestations, incidence and course in different cultures, A World Health Organization ten-country study, Psychological Medicine, 20 1-95.
* Prien, R. , Levine, J., & Switalski, R. (1971). Discontinuation of chemotherapy for chronic schizophrenics. Hospital & Community Psychiatry, 22(1), 4-7.

==External links==
* [http://www.mcmanweb.com/article-178.htm Bipolar Meds - The Antipsychotics]
* [http://www.fda.gov/bbs/topics/ANSWERS/2005/ANS01350.html FDA Public Health Advisory] - Public Health Advisory for Antipsychotic Drugs used for Treatment of Behavioral Disorders in Elderly Patients
* [http://www.medicina.ufrj.br/cursos/JBP%202%20COLUNAS%20-%20com%20referencia%20completa%20&%20foto%20-%20AGONISTAS%20PARCIAIS%20NO%20ARMAMENTARIUM.pdf 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 available here]
* [http://www.medicina.ufrj.br/cursos/FROTA%20LIVRO%20I%20&%20II.pdf 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. Free full-text on Portuguese available online here]

{{Antipsychotics}}
{{Major Drug Groups}}

[[Category:Antipsychotics|*]]
[[Category:Psychiatry]]

[[af:Antipsigotikum]]
[[cs:Antipsychotika]]
[[da:Antipsykotika]]
[[de:Neuroleptikum]]
[[es:Neuroléptico]]
[[fr:Neuroleptique]]
[[io:Neuroleptiko]]
[[it:Neurolettico]]
[[hu:A skizofrénia gyógyszerei]]
[[nl:Antipsychoticum]]
[[ja:抗精神病薬]]
[[no:Antipsykotika]]
[[pl:Leki przeciwpsychotyczne]]
[[pt:Antipsicótico]]
[[ru:Антипсихотические препараты]]
[[sk:Neuroleptikum]]
[[fi:Antipsykoottinen lääke]]
[[sv:Neuroleptikum]]
[[zh:抗精神病药]]