View source for Typical antipsychotic

{{Short description|Class of drugs}}
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| Image               = Chlorpromazine.svg
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| Caption             = [[Skeletal formula]] of [[chlorpromazine]], the first neuroleptic drug
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| Synonyms            = First generation antipsychotics, conventional antipsychotics, classical neuroleptics, traditional antipsychotics, major tranquilizers
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[[Image:Loxapine.jpg|thumb|right|Bottle containing capsules of loxapine, a mid-potency typical antipsychotic]]
'''Typical antipsychotics''' (also known as '''major [[tranquilizers]]''', and '''first generation antipsychotics''') are a class of [[antipsychotic]] drugs first developed in the 1950s and used to treat [[psychosis]] (in particular, [[schizophrenia]]).  Typical antipsychotics may also be used for the treatment of acute mania, agitation, and other conditions. The first typical antipsychotics to come into medical use were the [[phenothiazine]]s, namely [[chlorpromazine]] which was discovered [[serendipitously]].<ref>{{cite journal | vauthors = Shen WW | title = A history of antipsychotic drug development | journal = Comprehensive Psychiatry | volume = 40 | issue = 6 | pages = 407–14 | year = 1999 | pmid = 10579370 | doi = 10.1016/s0010-440x(99)90082-2 }}</ref> Another prominent grouping of antipsychotics are the [[butyrophenones]], an example of which is [[haloperidol]]. The newer, second-generation antipsychotics, also known as [[atypical antipsychotics]], have largely supplanted the use of typical antipsychotics as first-line agents due to the higher risk of movement disorders with typical antipsychotics.

Both generations of medication tend to block receptors in the brain's [[dopamine pathways]], but atypicals at the time of marketing were claimed to differ from typical antipsychotics in that they are less likely to cause [[extrapyramidal symptoms]] (EPS), which include unsteady [[Parkinson's disease]]-type movements, [[akathisia|internal restlessness]], and other involuntary movements (e.g. [[tardive dyskinesia]], which can persist after stopping the medication).<ref>{{cite journal | title = A roadmap to key pharmacologic principles in using antipsychotics | journal = Primary Care Companion to the Journal of Clinical Psychiatry | volume = 9 | issue = 6 | pages = 444–54 | year = 2007 | pmid = 18185824 | pmc = 2139919 | doi = 10.4088/PCC.v09n0607 }}</ref> More recent research has demonstrated the side effect profile of these drugs is similar to older drugs, causing the leading medical journal ''[[The Lancet]]'' to write in its editorial "the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction."<ref>{{cite journal | vauthors = Tyrer P, Kendall T | title = The spurious advance of antipsychotic drug therapy | journal = Lancet | volume = 373 | issue = 9657 | pages = 4–5 | date = January 2009 | pmid = 19058841 | doi = 10.1016/S0140-6736(08)61765-1 | s2cid = 19951248 | url = http://www.thelancet.com/journals/lancet/issue/current?tab=past | access-date = 2023-03-02 | archive-date = 2023-02-06 | archive-url = https://web.archive.org/web/20230206214800/https://www.thelancet.com/journals/lancet/issue/current?tab=past | url-status = dead }}</ref> While typical antipsychotics are more likely to cause EPS, atypicals are more likely to cause adverse metabolic effects, such as [[weight gain]] and increase the risk for [[type II diabetes]].<ref>{{cite web|url=http://www.rcpsych.ac.uk/healthadvice/treatmentswellbeing/antipsychoticmedication.aspx%7B%7Bfull%7D%7D|title=Not found|website=www.rcpsych.ac.uk|access-date=8 May 2018|url-status=live|archive-url=https://web.archive.org/web/20180508094647/https://www.rcpsych.ac.uk/healthadvice/treatmentswellbeing/antipsychoticmedication.aspx%7B%7Bfull%7D%7D|archive-date=8 May 2018}}</ref>

== Clinical uses ==
Typical antipsychotics block the [[Dopamine receptor D2|dopamine 2 receptor (D2)]] receptor, causing a tranquilizing effect.<ref name="Schatzberg 2019">{{cite book |title=Schatzberg's Manual of Clinical Psychopharmacology |date=2019 |publisher=American Psychiatric Association Publishing |isbn=978-1-61537-230-0 |edition=Ninth |url=https://www.appi.org/Products/Psychopharmacology/Schatzbergs-Manual-of-Clinical-Psychopharmacology}}</ref> It is thought that 60–80% of D2 receptors need to be occupied for antipsychotic effect.<ref name="Schatzberg 2019" /> For reference, the typical antipsychotic [[haloperidol]] tends to block about 80% of D2 receptors at doses ranging from 2 to 5&nbsp;mg per day.<ref name="Schatzberg 2019" /> On the aggregate level, no typical antipsychotic is more effective than any other, though people will vary in which antipsychotic they prefer to take based on individual differences in tolerability and effectiveness.<ref name="Schatzberg 2019" /> Typical antipsychotics can be used to treat, e.g., schizophrenia or severe agitation.<ref name="Schatzberg 2019" /> Haloperidol, due to the availability of a rapid-acting injectable formulation and decades of use, remains the most commonly used antipsychotic for treating severe agitation in the emergency department setting.<ref name="Schatzberg 2019" />

== Adverse effects ==
{{further|Phenothiazines}}

Adverse effects vary among the various agents in this class of medications, but common effects include: dry mouth, [[muscle]] stiffness, muscle cramping, [[tremor]]s, [[extrapyramidal symptom|EPS]] and [[weight]] gain. EPS refers to a cluster of symptoms consisting of [[akathisia]], [[parkinsonism]], and [[dystonia]]. Anticholinergics such as [[benztropine]] and [[diphenhydramine]] are commonly prescribed to treat the EPS. 4% of users develop [[rabbit syndrome]] while on typical antipsychotics.<ref name="2870650PMID">{{cite journal | vauthors = Yassa R, Lal S | title = Prevalence of the rabbit syndrome | journal = The American Journal of Psychiatry | volume = 143 | issue = 5 | pages = 656–7 | date = May 1986 | pmid = 2870650 | doi = 10.1176/ajp.143.5.656 }}</ref>

There is a risk of developing a serious condition called [[tardive dyskinesia]] as a side effect of antipsychotics, including typical antipsychotics. The risk of developing tardive dyskinesia after chronic typical antipsychotic usage varies on several factors, such as age and gender, as well as the specific antipsychotic used. The commonly reported incidence of TD among younger patients is about 5% per year.  Among older patients incidence rates as high as 20% per year have been reported. The average prevalence is approximately 30%.<ref>{{cite journal | vauthors = Llorca PM, Chereau I, Bayle FJ, Lancon C | title = Tardive dyskinesias and antipsychotics: a review | journal = European Psychiatry | volume = 17 | issue = 3 | pages = 129–38 | date = May 2002 | pmid = 12052573 | doi = 10.1016/S0924-9338(02)00647-8 | s2cid = 40761404 }}</ref>  There are few treatments that have consistently been shown to be effective for the treatment of tardive dyskinesia, though an [[Vesicular monoamine transporter 2|VMAT2]] inhibitor like [[valbenazine]] may help.<ref name="FDA approves valben">{{cite web | author = Office of the Commissioner |title=FDA approves first drug to treat tardive dyskinesia |url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-tardive-dyskinesia |website=FDA |access-date=18 June 2020 |language=en |date=24 March 2020}}</ref> The atypical antipsychotic [[clozapine]] has also been suggested as an alternative antipsychotic for patients experiencing tardive dyskinesia.<ref name="Pardis et al 2019">{{cite journal | vauthors = Pardis P, Remington G, Panda R, Lemez M, Agid O | title = Clozapine and tardive dyskinesia in patients with schizophrenia: A systematic review | journal = Journal of Psychopharmacology | volume = 33 | issue = 10 | pages = 1187–1198 | date = October 2019 | pmid = 31347436 | doi = 10.1177/0269881119862535 | s2cid = 198912192 }}</ref> Tardive dyskinesia may reverse upon discontinuation of the offending agent or it may be irreversible, withdrawal may also make tardive dyskinesia more severe.<ref>{{cite web |url=https://medlineplus.gov/ency/article/000685.htm |title=Tardive dyskinesia: MedlinePlus Medical Encyclopedia |access-date=2017-01-18 |url-status=live |archive-url=https://web.archive.org/web/20170131184044/https://medlineplus.gov/ency/article/000685.htm |archive-date=2017-01-31 }}{{full citation needed|date=September 2018}}</ref>

[[Neuroleptic malignant syndrome]] (NMS) is a rare, but potentially fatal side effect of antipsychotic treatment.  NMS is characterized by fever, muscle rigidity, autonomic dysfunction, and altered mental status.  Treatment includes discontinuation of the offending agent and supportive care.

The role of typical antipsychotics has come into question recently as studies have suggested that typical antipsychotics may increase the risk of death in elderly patients.  A 2005 retrospective cohort study from the ''New England Journal of Medicine'' showed an increase in risk of death with the use of typical antipsychotics that was on par with the increase shown with atypical antipsychotics.<ref>{{cite journal | vauthors = Wang PS, Schneeweiss S, Avorn J, Fischer MA, Mogun H, Solomon DH, Brookhart MA | title = Risk of death in elderly users of conventional vs. atypical antipsychotic medications | journal = The New England Journal of Medicine | volume = 353 | issue = 22 | pages = 2335–41 | date = December 2005 | pmid = 16319382 | doi = 10.1056/NEJMoa052827 | s2cid = 35202051 | doi-access = free }}</ref> This has led some to question the common use of antipsychotics for the treatment of agitation in the elderly, particularly with the availability of alternatives such as mood stabilizing and antiepileptic drugs.

== Potency ==
Traditional antipsychotics are classified as ''high-potency'', ''mid-potency'', or ''low-potency'' based on their potency for the D2 receptor:

{| class="wikitable"
! Potency !! Examples  !! Adverse effect profile
 |-
 |high|| [[fluphenazine]] and [[haloperidol]] ||  more [[Extrapyramidal system|extrapyramidal side effects]] (EPS) and less [[antihistaminic]] effects (e.g. [[sedation]]), [[alpha adrenergic]] antagonism (e.g. [[orthostatic hypotension]]), and [[anticholinergic]] effects (e.g. [[dry mouth]])
 |-
 |middle|| [[perphenazine]] and [[loxapine]] || intermediate D2 affinity, with more off-target effects than high-potency agents
 |-
 |low|| [[chlorpromazine]] ||  less risk of EPS but more antihistaminic effects, alpha adrenergic antagonism, and anticholinergic effects
|}

[[Prochlorperazine]] (Compazine, Buccastem, Stemetil) and [[Pimozide]] (Orap) are less commonly used to treat psychotic states, and so are sometimes excluded from this classification.<ref name="isbn0-684-82737-9">{{cite book | last = Gitlin | first = Michael J. | name-list-style = vanc |title=The psychotherapist's guide to psychopharmacology |publisher=Free Press |location=New York |year=1996 |page=392 |isbn=0-684-82737-9 }}</ref>

A related concept to D2 potency is the concept of "chlorpromazine equivalence", which provides a measure of the relative effectiveness of antipsychotics.<ref name="pmid12823080">{{cite journal | vauthors = Woods SW | title = Chlorpromazine equivalent doses for the newer atypical antipsychotics | journal = The Journal of Clinical Psychiatry | volume = 64 | issue = 6 | pages = 663–7 | date = June 2003 | pmid = 12823080 | doi = 10.4088/JCP.v64n0607 }}</ref><ref name="pmid14624195">{{cite journal | vauthors = Rijcken CA, Monster TB, Brouwers JR, de Jong-van den Berg LT | title = Chlorpromazine equivalents versus defined daily doses: how to compare antipsychotic drug doses? | journal = Journal of Clinical Psychopharmacology | volume = 23 | issue = 6 | pages = 657–9 | date = December 2003 | pmid = 14624195 | doi = 10.1097/01.jcp.0000096247.29231.3a | s2cid = 12939895 }}</ref> The measure specifies the amount (mass) in milligrams of a given drug that must be administered in order to achieve desired effects equivalent to those of 100 milligrams of chlorpromazine.<ref name="Patel et al 2013">{{cite journal | vauthors = Patel MX, Arista IA, Taylor M, Barnes TR | title = How to compare doses of different antipsychotics: a systematic review of methods | journal = Schizophrenia Research | volume = 149 | issue = 1–3 | pages = 141–8 | date = September 2013 | pmid = 23845387 | doi = 10.1016/j.schres.2013.06.030 | s2cid = 45642900 }}</ref> Another method is "defined daily dose" (DDD), which is the assumed average dose of an antipsychotic that an adult would receive during long-term treatment.<ref name="Patel et al 2013" /> DDD is primarily used for comparing the utilization of antipsychotics (e.g. in an insurance claim database), rather than comparing therapeutic effects between antipsychotics.<ref name="Patel et al 2013" /> Maximum dose methods are sometimes used to compare between antipsychotics as well.<ref name="Patel et al 2013" /> It is important to note that these methods do not generally account for differences between the tolerability (i.e. the risk of side effects) or the safety between medications.<ref name="Patel et al 2013" />

For a list of typical antipsychotics organized by potency, see below:

===Low potency===
{{div col|colwidth=25vw}}
* [[Chlorpromazine]] 
* [[Chlorprothixene]]
* [[Levomepromazine]]
* [[Mesoridazine]]
* [[Pericyazine|Periciazine]]
* [[Promazine]]
* [[Thioridazine]]†
{{end div col}}
===Medium potency===
{{div col|colwidth=25vw}}
* [[Loxapine]]
* [[Molindone]]
* [[Perphenazine]]
* [[Thiothixene]]
{{end div col}}
===High potency===
{{div col|colwidth=25vw}}
* [[Droperidol]] 
* [[Flupentixol]]
* [[Fluphenazine]]
* [[Haloperidol]]
* [[Pimozide]]
* [[Prochlorperazine]]
* [[Thioproperazine]]
* [[Trifluoperazine]]
* [[Zuclopenthixol]]
{{end div col}}
†: discontinued or withdrawn products<ref>{{cite book|title=Martindale: The Complete Drug Reference|publisher=The Royal Pharmaceutical Society of Great Britain|access-date=2 November 2013|year=2013|url=http://www.medicinescomplete.com/mc/martindale/current/}}</ref>

== Long-acting injectables ==
Some typical antipsychotics have been formulated as a long-acting injectable (LAI), or "[[Depot injection|depot]]", formulation. Depot injections are also used on persons under [[Outpatient commitment|involuntary commitment]] to force compliance with a court treatment order when the person would refuse to take daily oral medication. This has the effect of dosing a person who doesn't consent to take the drug. The United Nations Special Rapporteur On Torture has classified this as a human rights violation and cruel or inhuman treatment.<ref>{{cite web | url=https://www.madinamerica.com/wp-content/uploads/2013/03/torture.pdf | title=Special rapporteur on torture and other cruel, inhuman or degrading treatment or punishment | access-date=2024-02-07}}</ref>

The first LAI antipsychotics (often referred to as simply "LAIs") were the typical antipsychotics fluphenazine and haloperidol.<ref name="Kennedy 2012">{{cite journal | vauthors = Kennedy WK |title=When and how to use long-acting injectable antipsychotics |journal=Current Psychiatry |date=2012|volume=11 |issue=8 |pages=40–43 |url=https://www.mdedge.com/psychiatry/article/64796/schizophrenia-other-psychotic-disorders/when-and-how-use-long-acting |language=en}}</ref> Both fluphenazile and haloperidol are formulated as [[Decanoic acid|decanoates]], referring to the attachment of a decanoic acid group to the antipsychotic molecule.<ref name="Kennedy 2012" /> These are then dissolved in an organic oil.<ref name="Kennedy 2012" /> Together, these modifications prevent the active medications from being released immediately upon injection, attaining a slow release of the active medications (note, though, that the fluphenazine decanoate product is unique for reaching peak fluphenazine blood levels within 24 hours after administration<ref name="Carpenter et al 2018">{{cite journal | vauthors = Carpenter J, Wong KK |title=Long-acting injectable antipsychotics: What to do about missed doses |journal=Current Psychiatry |date=2018|volume=17 |issue=7 |pages=10–12, 14–19, 56 |url=https://www.mdedge.com/psychiatry/article/168776/schizophrenia-other-psychotic-disorders/long-acting-injectable |language=en}}</ref>).<ref name="Kennedy 2012" /> Fluphenazine decanoate can be administered every 7 to 21 days (usually every 14 to 28 days),<ref name="Carpenter et al 2018" /> while haloperidol decanoate can be administered every 28 days, though some people receive more or less frequent injections.<ref name="Kennedy 2012" /> If a scheduled injection of either haloperidol decanoate or fluphenazine decanoate is missed, recommendations for administering make-up injectable dose(s) or providing antipsychotics to be taken by mouth vary by, e.g., how long ago the last injection was and how many previous injections the person has received (i.e., if [[steady state levels]] of the medication have been reached or not).<ref name="Carpenter et al 2018" />

Both of the typical antipsychotic LAIs are inexpensive in comparison to the atypical LAIs.<ref name="Kennedy 2012" /> Doctors usually prefer atypical LAIs over typical LAIs due to the differences in adverse effects between typical and atypical antipsychotics in general.<ref name="Carpenter et al 2018" />

{{Pharmacokinetics of long-acting injectable antipsychotics}}

== History ==
{{Main|Antipsychotic#History}}
[[File:Thorazine advert.jpg|thumb|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<ref>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."</ref>]]

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]] after an initial report in 1952.<ref name="Schatzberg 2019" /> It was first used in psychiatric institutions because of its powerful tranquilizing effect; at the time it was advertised as a "pharmacological [[lobotomy]]".<ref name=pieters>{{cite journal | vauthors = Pieters T, Majerus B | title = The introduction of chlorpromazine in Belgium and the Netherlands (1951-1968); tango between old and new treatment features | journal = Studies in History and Philosophy of Biological and Biomedical Sciences | volume = 42 | issue = 4 | pages = 443–52 | date = December 2011 | pmid = 22035718 | doi = 10.1016/j.shpsc.2011.05.003 | url = http://orbilu.uni.lu/handle/10993/2251 | url-status = live | archive-url = https://web.archive.org/web/20170709194021/http://orbilu.uni.lu/handle/10993/2251 | df = dmy-all | archive-date = 9 July 2017 }}</ref> (Note that "tranquilizing" here only refers to changes in external behavior, while the experience a person has internally may be one of increased agitation but inability to express it.)<ref>{{Cite journal|last=Muench|first=John|date=1 March 2010|title=Adverse Effects Of Antipsychotics|url=https://www.aafp.org/afp/2010/0301/p617.html|access-date=23 March 2021|journal=American Family Physician|volume=81|issue=5|pages=617–622}}</ref>

Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs.<ref name="king">{{cite journal | vauthors = King C, Voruganti LN | title = What's in a name? The evolution of the nomenclature of antipsychotic drugs | journal = Journal of Psychiatry & Neuroscience | volume = 27 | issue = 3 | pages = 168–75 | date = May 2002 | pmid = 12066446 | pmc = 161646 }}</ref> In the late 1950s the most widely used term was "neuroleptic", followed by "major [[tranquilizer]]" and then "ataraxic".<ref name="king"/> The word ''neuroleptic'' was coined in 1955 by Delay and Deniker after their discovery (1952) of the antipsychotic effects of chlorpromazine.<ref name="king"/> It is derived from the {{langx|el|"[[wikt:νεῦρον|νεῦρον]]"}} (''neuron'', originally meaning "[[sinew]]" but today referring to the [[nerve]]s) and "[[wikt:λαμβάνω|λαμβάνω]]" (''lambanō'', meaning "take hold of"). Thus, the word means ''taking hold of one's nerves''. It was often taken to refer also to common effects such as reduced activity in general, as well as lethargy and impaired motor control. Although these effects are unpleasant and harmful, they were, along with akathisia, considered a reliable sign that the drug was working.<ref name=pieters /> These terms have been largely replaced by the term "antipsychotic" in medical and advertising literature, which refers to the medication's more-marketable effects.<ref name="king"/>

== See also ==
* [[Tranquilizer]]
* [[Atypical antipsychotic]]
* [[Tardive dyskinesia]]
* [[Schizophrenia]]
* [[Bipolar disorder]]
* [[Psychiatric survivors movement|Psychiatric survivors' movement]]
* [[Conditioned avoidance response test]]

== References ==
{{reflist}}

{{Antipsychotics}}
{{Dopaminergics}}

{{DEFAULTSORT:Typical Antipsychotic}}
[[Category:Typical antipsychotics| ]]
[[Category:Treatment of psychosis]]