Typical antipsychotic

Typical antipsychotics (also known as first generation antipsychotics, or FGAs) 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 phenothiazines, namely chlorpromazine which was discovered serendipitously.[1] Another prominent grouping of antipsychotics are the butyrophenones, an example of which would be haloperidol. The newer, second-generation antipsychotics, also known as atypical antipsychotics, have larger supplanted the use of typical antipsychotics as first-line agents due to the higher risk of movement disorders in the latter.

Typical antipsychotic
Drug class
Skeletal formula of chlorpromazine, the first neuroleptic drug
SynonymsFirst generation antipsychotics, conventional antipsychotics, classical neuroleptics, traditional antipsychotics, major tranquilizers
In Wikidata
Bottle containing loxapine capsules, a mid-potency typical antipsychotic.

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, internal restlessness, and other involuntary movements (e.g. tardive dyskinesia, which can persist after stopping the medication).[2] 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."[3] While typical antipsychotics are more likely to cause EPS, atypicals are more likely to cause metabolic side effects, such as weight gain and increase the risk for type II diabetes.[4]

Medical uses

Typical antipsychotics block the dopamine 2 receptor (D2) receptor, causing an antipsychotic effect.[5] It is thought that 60-80% of D2 receptors need to be occupied for antipsychotic effect.[5] For reference, the typical antipsychotic haloperidol tends to block about 80% of D2 receptors at doses ranging from 2 to 5 mg per day.[5] 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).[5] Typical antipsychotics can be used to treat, e.g., schizophrenia or severe agitation.[5] 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.[5]

Adverse effects

Side effects vary among the various agents in this class of medications, but common side effects include: dry mouth, muscle stiffness, muscle cramping, tremors, 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 patients develop rabbit syndrome while on typical antipsychotics.[6]

There is a low 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%.[7] There are few treatments that have consistently been shown to be effective for the treatment of tardive dyskinesia, though an VMAT2 inhibitor like valbenazine may help.[8] The atypical antipsychotic clozapine has also been suggested as an alternative antipsychotic for patients experiencing tardive dyskinesia.[9] Tardive dyskinesia may reverse upon discontinuation of the offending agent or it may be irreversible, withdrawal may also make tardive dyskinesia more severe.[10]

Neuroleptic malignant syndrome, or 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 retrospective cohort study from the New England Journal of Medicine on Dec. 1, 2005 showed an increase in risk of death with the use of typical antipsychotics that was on par with the increase shown with atypical antipsychotics.[11] 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:

PotencyExamples Adverse effect profile
highfluphenazine and haloperidolmore 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)
middleperphenazine and loxapineintermediate D2 affinity, with more off-target effects than high-potency agents
lowchlorpromazineless 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.[12]

A related concept to D2 potency is the concept of "chlorpromazine equivalence", which provides a measure of the relative effectiveness of antipsychotics.[13][14] 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.[15] 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.[15] DDD is primarily used for comparing the utilization of antipsychotics (e.g. in an insurance claim database), rather than comparing therapeutic effects between antipsychotics.[15] Maximum dose methods are sometimes used to compare between antipsychotics as well.[15] 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.[15]

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

Low potency

Medium potency

High potency

Where: † indicates products that have since been discontinued.[16]

Long-acting injectables

Some typical antipsychotics are available in a long-acting injectable (LAI), or "depot", formulation. The first LAI antipsychotics (often referred to as simply "LAIs") were the typical antipsychotics fluphenazine and haloperidol.[17] Both fluphenazile and haloperidol are formulated as decanoates, referring to the attachment of a decanoic acid group to the antipsychotic molecule.[17] These are then dissolved in an organic oil.[17] 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[18]).[17] Fluphenazine decanoate can be administered every 7 to 21 days (usually every 14 to 28 days)[18], while haloperidol decanoate can be administered every 28 days, though some people will require more or less frequent injections.[17] 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).[18]

Both of the typical antipsychotic LAIs are inexpensive in comparison to the atypical LAIs.[17] Atypical LAIs are usually preferred over typical LAIs due to the differences in side effects between typical and atypical antipsychotics in general.[18]

Pharmacokinetics of long-acting injectable antipsychotics
MedicationBrand nameClassVehicleDosageTmaxt1/2 singlet1/2 multiplelogPcRef
Aripiprazole lauroxilAristadaAtypicalWatera441–1064 mg/4–8 weeks24–35 days?54–57 days7.9–10.0
Aripiprazole monohydrateAbilify MaintenaAtypicalWatera300–400 mg/4 weeks7 days?30–47 days4.9–5.2
Bromperidol decanoateImpromen DecanoasTypicalSesame oil40–300 mg/4 weeks3–9 days?21–25 days7.9[19]
Clopentixol decanoateSordinol DepotTypicalViscoleob50–600 mg/1–4 weeks4–7 days?19 days9.0[20]
Flupentixol decanoateDepixolTypicalViscoleob10–200 mg/2–4 weeks4–10 days8 days17 days7.2–9.2[20][21]
Fluphenazine decanoateProlixin DecanoateTypicalSesame oil12.5–100 mg/2–5 weeks1–2 days1–10 days14–100 days7.2–9.0[22][23][24]
Fluphenazine enanthateProlixin EnanthateTypicalSesame oil12.5–100 mg/1–4 weeks2–3 days4 days?6.4–7.4[23]
FluspirileneImap, RedeptinTypicalWatera2–12 mg/1 week1–8 days7 days?5.2–5.8[25]
Haloperidol decanoateHaldol DecanoateTypicalSesame oil20–400 mg/2–4 weeks3–9 days18–21 days7.2–7.9[26][27]
Olanzapine pamoateZyprexa RelprevvAtypicalWatera150–405 mg/2–4 weeks7 days?30 days–
Oxyprothepin decanoateMeclopinTypical?????8.5–8.7
Paliperidone palmitateInvega SustennaAtypicalWatera39–819 mg/4–12 weeks13–33 days25–139 days?8.1–10.1
Perphenazine decanoateTrilafon DekanoatTypicalSesame oil50–200 mg/2–4 weeks??27 days8.9
Perphenazine enanthateTrilafon EnanthateTypicalSesame oil25–200 mg/2 weeks2–3 days?4–7 days6.4–7.2[28]
Pipotiazine palmitatePiportil LongumTypicalViscoleob25–400 mg/4 weeks9–10 days?14–21 days8.5–11.6[21]
Pipotiazine undecylenatePiportil MediumTypicalSesame oil100–200 mg/2 weeks???8.4
RisperidoneRisperdal ConstaAtypicalMicrospheres12.5–75 mg/2 weeks21 days?3–6 days–
Zuclopentixol acetateClopixol AcuphaseTypicalViscoleob50–200 mg/1–3 days1–2 days1–2 days4.7–4.9
Zuclopentixol decanoateClopixol DepotTypicalViscoleob50–800 mg/2–4 weeks4–9 days?11–21 days7.5–9.0
Note: All by intramuscular injection. Footnotes: a = Microcrystalline or nanocrystalline aqueous suspension. b = Low-viscosity vegetable oil (specifically fractionated coconut oil with medium-chain triglycerides). c = Predicted, from PubChem and DrugBank. Sources: Main: See template.

History
Main article: Antipsychotic § History
Advertisement for Thorazine (chlorpromazine) from the 1950s, reflecting the perceptions of psychosis, including the now-discredited perception of a tendency towards violence, from the time when antipsychotics were discovered[29]

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.[5] 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".[30]

Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs.[31] In the late 1950s the most widely used term was "neuroleptic", followed by "major tranquilizer" and then "ataraxic".[31] The word neuroleptic was coined in 1955 by Delay and Deniker after their discovery (1952) of the antipsychotic effects of chlorpromazine.[31] It is 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. It was often taken to refer also 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.[30] These terms are being abandoned in favor of "antipsychotic", which refers to the medication's desired effects.[31]

See also

References
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  2. "A Roadmap to Key Pharmacologic Principles in Using Antipsychotics". The Primary Care Companion to the Journal of Clinical Psychiatry. 9 (6): 444–54. 2007. doi:10.4088/PCC.v09n0607. PMC 2139919. PMID 18185824.
  3. Tyrer, Peter; Kendall, Tim (2009). "The spurious advance of antipsychotic drug therapy". The Lancet. 373 (9657): 4–5. doi:10.1016/S0140-6736(08)61765-1. PMID 19058841.
  4. "Not found". www.rcpsych.ac.uk. Archived from the original on 8 May 2018. Retrieved 8 May 2018.
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  12. Gitlin, Michael J. (1996). The psychotherapist's guide to psychopharmacology. New York: Free Press. p. 392. ISBN 0-684-82737-9.
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  23. Curry SH, Whelpton R, de Schepper PJ, Vranckx S, Schiff AA (April 1979). "Kinetics of fluphenazine after fluphenazine dihydrochloride, enanthate and decanoate administration to man". Br J Clin Pharmacol. 7 (4): 325–31. doi:10.1111/j.1365-2125.1979.tb00941.x. PMC 1429660. PMID 444352.
  24. Young. D.: Ereshefsky. L.: Saklad. S.R.; Jann. M.W. and Garcia. N.: Explaining the pharmacokinetics of fluphenazine through computer simulations. (Abstract.) Presented at the 19th Annual Midyear Clinical Meeting of the American Society of Hospital Pharmacists. Dallas. Texas (1984).
  25. Janssen PA, Niemegeers CJ, Schellekens KH, Lenaerts FM, Verbruggen FJ, van Nueten JM, Marsboom RH, Hérin VV, Schaper WK (November 1970). "The pharmacology of fluspirilene (R 6218), a potent, long-acting and injectable neuroleptic drug". Arzneimittelforschung. 20 (11): 1689–98. PMID 4992598.
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  29. 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."
  30. Pieters T, Majerus B (December 2011). "The introduction of chlorpromazine in Belgium and the Netherlands (1951-1968); tango between old and new treatment features". Studies in History and Philosophy of Biological and Biomedical Sciences. 42 (4): 443–52. doi:10.1016/j.shpsc.2011.05.003. PMID 22035718. Archived from the original on 9 July 2017.
  31. King C, Voruganti LN (May 2002). "What's in a name? The evolution of the nomenclature of antipsychotic drugs". Journal of Psychiatry & Neuroscience. 27 (3): 168–75. PMC 161646. PMID 12066446.
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