Perphenazine

Overview

Perphenazine is a typical antipsychotic drug. Chemically, it is classified as a piperazinyl phenothiazine. Originally marketed in the United States as Trilafon, it has been in clinical use for decades. WP

Perphenazine is roughly ten times as potent as chlorpromazine at the dopamine-2 (D2) receptor; thus perphenazine is considered a medium-potency antipsychotic.[1][2][3] WP

Uses, dosage and effects

Medical uses

In low doses it is used to treat agitated depression (together with an antidepressant). Fixed combinations of perphenazine and the tricyclic antidepressant amitriptyline in different proportions of weight exist (see Etrafon below). When treating depression, perphenazine is discontinued as fast as the clinical situation allows. Perphenazine has no intrinsic antidepressive activity. Several studies show that the use of perphenazine with fluoxetine (Prozac) in patients with psychotic depression is most promising, although fluoxetine interferes with the metabolism of perphenazine, causing higher plasma levels of perphenazine and a longer half-life. In this combination the strong antiemetic action of perphenazine attenuates fluoxetine-induced nausea and vomiting (emesis), as well as the initial agitation caused by fluoxetine. Both actions can be helpful for many patients. WP⚠ Wikipedia itself has flagged this text: citation needed.

Perphenazine has been used in low doses as a 'normal' or 'minor' tranquilizer in patients with a known history of addiction to drugs or alcohol, a practice which is now strongly discouraged. WP⚠ Wikipedia itself has flagged this text: citation needed.

Perphenazine has sedating and anxiolytic properties, making the drug useful for the treatment of agitated psychotic patients. WP

A valuable off-label indication is the short-time treatment of hyperemesis gravidarum, in which pregnant women experience violent nausea and vomiting. This problem can become severe enough to endanger the pregnancy. As perphenazine has not been shown to be teratogenic and works very well, it is sometimes given orally in the smallest possible dose. WP

Effectiveness

Perphenazine is used to treat psychosis (e.g. in people with schizophrenia and the manic phases of bipolar disorder and OCD). Perphenazine effectively treats the positive symptoms of schizophrenia, such as hallucinations and delusions, but its effectiveness in treating the negative symptoms of schizophrenia, such as flattened affect and poverty of speech, is unclear. Earlier studies found the typical antipsychotics to be ineffective or poorly effective in the treatment of negative symptoms, but two recent, large-scale studies found no difference between perphenazine and the atypical antipsychotics. A 2015 systematic review compared perphenazine with other antipsychotic drugs:[4][5] WP⚠ A table follows this text in the source and is not copied here. Open the source to see it.

Risks and side effects

Side effects

As a member of the phenothiazine type of antipsychotics, perphenazine shares in general all allergic and toxic side-effects of chlorpromazine. A 2015 systematic review of the data on perphenazine conducted by the Cochrane Collaboration concluded that "there were no convincing differences between perphenazine and other antipsychotics" in the incidence of adverse effects. Perphenazine causes early and late extrapyramidal side effects more often than placebo, and at a similar rate to other medium-potency antipsychotics and the atypical antipsychotic risperidone.[6–9] WP

When used for its strong antiemetic or antivertignosic effects in cases with associated brain injuries, it may obscure the clinical course and interferes with the diagnosis. High doses of perphenazine can cause temporary dyskinesia. As with other typical antipsychotics, permanent or lasting tardive dyskinesia is a risk. WP

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.[10][11] WP

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.[11][12][13] WP

Interactions

Interactions

Fluoxetine causes higher plasma levels and a longer elimination half-life of perphenazine, therefore a dose reduction of perphenazine might be necessary. WP

Perphenazine intensifies the central depressive action of drugs with such activity (tranquilizers, hypnotics, narcotics, antihistaminics, OTC-antiemetics etc.). A dose reduction of perphenazine or the other drug may be necessary. WP

In general, all neuroleptics may lead to seizures in combination with the opioid tramadol (Ultram). WP

Perphenazine may increase the insulin needs of diabetic patients. Monitor blood glucose levels of insulin-dependent patients regularly during long-term treatment. WP

Pharmacology

Pharmacodynamics

Perphenazine has the following binding profile towards cloned human receptors unless otherwise specified:[14][15] WP⚠ A table follows this text in the source and is not copied here. Open the source to see it.

Acronyms: RS — Rat striatum receptor. RB — Rat brain receptor. WP

Mechanisms WP

Perphenazine is a typical antipsychotic medication of midrange or moderate potency (the 15-fold of a chlorpromazine dosage, also a typical antipsychotic medication). Compared with the high potent typical antipsychotic drug haloperidol (50-fold), it despite is considered by some to have similar extrapyramidal side-effects. This is probably because it has similar affinity values at the D2/3 receptors (0.7, 0.3). Compared to other substance types of antipsychotics of the phenothiazine family, perphenazine does have comparable greater behavioral effects in respective to its antipsychotic potency (compared to other phenothiazines), so it could be considered to be favorable or efficient as add-on if the adherence of the patient to the daily clinical life is somehow too missing or not really sufficient.[16–19] WP

There exists a distinction to separate the type an antipsychotic is blocking into pure (silent) antagonists and inverse agonists (but with both, antagonists and inverse agonists inducing the same therapeutic effect, in case of antipsychotics) where it seems to tend out that inverse agonists at least occurs very often at exactly this from a specific neuroleptic's bindingsite which is weightened the most potent and therapeutic effect initiating bindingsite of each neuroleptic's individuall affinityprofile (e.g. 5HT2A in Clo- and Olanzapine, H1 in Olanzapine, D2 in Haloperidole). Perphenazine here makes an exception being a normal antagonist in its most important bindingsite (D2).[20–23] WP

Like other phenothiazine derivatives, it also inhibits tubulin polymerization.[24] WP

Pharmacokinetics

Perphenazine has an oral bioavailability of approximately 40% and a half-life of 8 to 12 hours (up to 20 hours), and is usually given in 2 or 3 divided doses each day. It is possible to give two-thirds of the daily dose at bedtime and one-third during breakfast to maximize hypnotic activity during the night and to minimize daytime sedation and hypotension without loss of therapeutic activity. WP

Chemistry

Formula

C21H26ClN3OS PC

CAS number

58-39-9 PC

Molar mass (g/mol)

404.0 PC

IUPAC name (computed by PubChem)

2-[4-[3-(2-chlorophenothiazin-10-yl)propyl]piperazin-1-yl]ethanol PC

SMILES

C1CN(CCN1CCCN2C3=CC=CC=C3SC4=C2C=C(C=C4)Cl)CCO PC

InChIKey

RGCVKNLCSQQDEP-UHFFFAOYSA-N PC

PubChem CID

4748

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

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2. Journal / agency Ascher-Svanum H, Zhu B, Faries D, Landbloom R, Swartz M, Swanson J. Time to discontinuation of atypical versus typical antipsychotics in the naturalistic treatment of schizophrenia. BMC Psychiatry. February 2006. doi:10.1186/1471-244X-6-8 · PMID 16504026 · PMC1402287
3. Other Freudenreich O. Psychotic disorders. 2007
4. Journal / agency King DJ. Drug treatment of the negative symptoms of schizophrenia. European Neuropsychopharmacology. February 1998. doi:10.1016/S0924-977X(97)00041-2 · PMID 9452938
5. Journal / agency Lieberman JA. Comparative effectiveness of antipsychotic drugs. A commentary on: Cost Utility Of The Latest Antipsychotic Drugs In Schizophrenia Study (CUtLASS 1) and Clinical Antipsychotic Trials Of Intervention Effectiveness (CATIE). Archives of General Psychiatry. October 2006. doi:10.1001/archpsyc.63.10.1069 · PMID 17015808
6. Journal / agency Hartung B, Sampson S, Leucht S. Perphenazine for schizophrenia. The Cochrane Database of Systematic Reviews. March 2015. doi:10.1002/14651858.CD003443.pub3 · PMID 25749632 · PMC7173727
7. Other Kelsey JE, Newport DJ, Nemeroff CB. Principles of psychopharmacology for mental health professionals. 2006
8. Journal / agency Schillevoort I, de Boer A, Herings RM, Roos RA, Jansen PA, Leufkens HG. Antipsychotic-induced extrapyramidal syndromes. Risperidone compared with low- and high-potency conventional antipsychotic drugs. European Journal of Clinical Pharmacology. July 2001. doi:10.1007/s002280100302 · PMID 11549212
9. Journal / agency Høyberg OJ, Fensbo C, Remvig J, Lingjaerde O, Sloth-Nielsen M, Salvesen I. Risperidone versus perphenazine in the treatment of chronic schizophrenic patients with acute exacerbations. Acta Psychiatrica Scandinavica. December 1993. doi:10.1016/S0149-2918(98)80046-5 · PMID 7508675
10. Other British National Formulary. March 2009
11. Other Haddad P, Haddad PM, Dursun S, Deakin B. Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. 2004
12. Journal / agency Moncrieff J. Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta Psychiatrica Scandinavica. July 2006. doi:10.1111/j.1600-0447.2006.00787.x · PMID 16774655
13. Other Sacchetti E, Vita A, Siracusano A, Fleischhacker W. Adherence to Antipsychotics in Schizophrenia. 2013
14. Other PDSP Database - UNC
15. Journal / agency Sweet RA, Pollock BG, Mulsant BH, Rosen J, Sorisio D, Kirshner M, Henteleff R, DeMichele MA. Pharmacologic profile of perphenazine's metabolites. Journal of Clinical Psychopharmacology. April 2000. doi:10.1097/00004714-200004000-00010 · PMID 10770456
16. Other Perphenazin
17. Journal / agency Tardy M, Huhn M, Kissling W, Engel RR, Leucht S. Haloperidol versus low-potency first-generation antipsychotic drugs for schizophrenia. The Cochrane Database of Systematic Reviews. July 2014. doi:10.1002/14651858.CD009268.pub2 · PMID 25007358 · PMC10898321
18. Harm reduction site Perphenazine
19. Journal / agency Johanson CE, Kandel DA, Bonese K. The effects of perphenazine on self-administration behavior. Pharmacology, Biochemistry, and Behavior. 1976. doi:10.1016/0091-3057(76)90059-9 · PMID 819940
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21. Journal / agency Gaitonde SA, Avet C, de la Fuente Revenga M, Blondel-Tepaz E, Shahraki A, Pastor AM, Talagayev V, Robledo P, Kolb P, Selent J, González-Maeso J, Bouvier M. Pharmacological fingerprint of antipsychotic drugs at the serotonin 5-HT2A receptor. Molecular Psychiatry. 2024. doi:10.1038/s41380-024-02531-7 · PMID 38561467 · PMC11420065
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23. Journal / agency Sullivan LC, Clarke WP, Berg KA. Atypical Antipsychotics and Inverse Agonism at 5-HT2 Receptors. Current Pharmaceutical Design. 2015. doi:10.2174/1381612821666150605111236 · PMID 26044975 · PMC5543701
24. Journal / agency Baksheeva VE, La Rocca R, Allegro D, Derviaux C, Pasquier E, Roche P, Morelli X, Devred F, Golovin AV, Tsvetkov PO. NanoDSF Screening for Anti-tubulin Agents Uncovers New Structure–Activity Insights. Journal of Medicinal Chemistry. 2025. doi:10.1021/acs.jmedchem.5c01008

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