Thioridazine (Mellaril (DE, BD, ET, ID, BR), Melleril (withdrawn worldwide in 2005), Sonapax (RU), Thioril (IN)) is a piperidine typical antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis. Due to concerns about cardiotoxicity and retinopathy at high doses this drug has been withdrawn in many countries (including the UK and Australia) and in other countries it is not commonly prescribed, reserved for patients who have failed to respond to, or have contraindications for, more widely used antipsychotics.
In older references, it is sometimes described as atypical, but more recently it is usually described as typical, with the term "atypical" usually reserved for agents showing D4 selectivity or serotonin antagonism. The atypicality of second generation agents is not clearly defined. Some believe it's low D2 affinity, quick dissociation, 5-HT2A receptor antagonism, or all of the above. Its perceived atypical effects (namely its comparatively low propensity for extrapyramidal side effects) are likely the result of its potent anticholinergic effects.
Indications
Its primary use in medicine is in the treatment of schizophrenia. It has also been tried with some success as a treatment for various psychiatric symptoms seen in patients with dementia.
Thioridazine is known to kill intracellular extensively drug-resistant (XDR) Mycobacterium tuberculosis and both inhibit MRSA directly but also increase the susceptibility of MRSA to β-lactam antibiotics at clinical concentrations. It also appears to increase the efficacy of standard antimicrobial agents (even ones to which the strain in question is resistant) in treating XDR-tuberculosis (XDR-TB) via inhibiting bacterial efflux pumps.
The product Melleril® has been voluntarily discontinued by its manufacturer, Novartis, worldwide. Consequently it was withdrawn from the UK and Canada in July 2005. Stocks of Melleril ran out in Australia in August 2007.
Side effects
For further information see: Phenothiazine
Thioridazine prolongs the QTc interval in a dose-dependent manner. It produces significantly less extrapyramidal side effects than most first-generation antipsychotics. Its use, along with the use of other typical antipsychotics, has been associated with degenerative retinopathies. It has a higher propensity for causing anticholinergic side effects coupled with a lower propensity for causing extrapyramidal side effects and sedation than chlorpromazine, but also has a higher incidence of hypotension and cardiotoxicity. It is also known to possess a relatively high liability for causing orthostatic hypotension compared to other antipsychotics. Similarly to other first-generation antipsychotics it has a relatively high liability for causing prolactin elevation. It is moderate risk for causing weight gain. As with all antipsychotics thioridazine has been linked to cases of tardive dyskinesia (an often permanent neurological disorder characterised by slow, repetitive, purposeless and involuntary movements, most often of the facial muscles, that is usually brought on by years of continued treatment with antipsychotics, especially the first-generation (or typical) antipsychotics such as thioridazine) and neuroleptic malignant syndrome (a potentially fatal complication of antipsychotic treatment). Blood dyscrasias such as agranulocytosis, leukopenia and neutropenia are possible with thioridazine treatment.
Pharmacology
Thioridazine has the following binding profile:
Note: The Binding affinities given are towards cloned human receptors unless otherwise specified
Acronyms used
HB - Human brain receptor.
RC - Cloned rat receptor.
ND - No data.
Metabolism
Thioridazine is a racemic compound with two enantiomers, both of which are metabolized, according to Eap et al., by CYP2D6 into (S)- and (R)-thioridazine 2-sulfoxide, better known as mesoridazine, and into (S)- and (R)-thioridazine-5-sulfoxide. Mesoridazine is in turn metabolized into sulforidazine. Thioridazine is an inhibitor of CYP1A2 and CYP3A2.
History
The manufacturer Novartis/Sandoz/Wander of the brands of thioridazine, Mellaril in the USA and Canada and Melleril in Europe, discontinued the drug worldwide in June 2005.
The usual dosage was 10â€"75 mg per day for mild cases to 600â€"800 mg per day for severely disturbed patients.
Thioridazine is still available from other manufacturers as a generic drug with the precaution that it is used only in psychotic patients refractory to other forms of drug treatment. ECG-monitoring and frequent white blood cell counts are required before initiating therapy and in close intervals afterwards. Low-dose thioridazine (10â€"50 mg per day) is somewhat popular in Russia for the treatment of somatoform disorders, panic attacks, hyperactive-impulsive type of ADHD and insomnia associated with alcohol withdrawal.
A multi-year UK study by the Alzheimer's Research Trust suggested that this and other neuroleptic anti-psychotic drugs commonly given to Alzheimer's patients with mild behavioural problems often make their condition worse. The study concluded that
Synthesis
- Mesoridazine
References
External links
- PubChem Substance Summary: Thioridazine National Center for Biotechnology Information,.
- Antipsychotic Mellaril Removed from Market Schizophrenia Daily News Blog.
- U.S. National Library of Medicine: Drug Information Portal - Thioridazine