|Systematic (IUPAC) name|
|Licence data||US Daily Med:|
|Pregnancy cat.||C (AU) C (US)|
|Legal status||Prescription Only (S4) (AU) ℞-only (US) Withdrawn by the manufacturer in the UK, Canada and Australia|
|Metabolism||hepatic (at least partly mediated by CYP2D6)|
| (what is this?)
Thioridazine (Mellaril (DE, BD, ET, ID, BR), Melleril (withdrawn worldwide in 2005), Sonapax (RU), Thioril (IN)) is a piperidine typical antipsychotic drug belonging to the phenothiazine drug group and was previously widely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 Due to concerns about cardiotoxicity and retinopathy at high doses this drug has been withdrawn in many countries (including the UK and Australia) and in other countries it is not commonly prescribed, reserved for patients who have failed to respond to,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. Its perceived atypical effects (namely its comparatively low propensity for extrapyramidal side effects) are likely the result of its potent anticholinergic effects.
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 Consequently it was withdrawn from the UK and Canada in July 2005.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.
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.
Thioridazine has the following binding profile:
|Biologic Protein||Binding affinity (Ki[nM])||Binding affinity of Mesoridazine (Ki [nM])||Binding affinity of Sulforidazine (Ki [nM])||Notes|
|5-HT2A||27.67||4.76 (HB)||ND||The ratio of 5-HT2A to D2 receptor binding is believed to dictate whether or not most antipsychotics are atypical or typical. In thioridazine's case its ratio of 5-HT2A to D2 receptor binding is below the level that's believed to be required for atypicality despite its relatively low extrapyramidal side effect liability in practice.|
|5-HT2C||53||157||ND||Believed to play a role in the weight gain-promoting effects of antipsychotics.|
|α1A||3.15||2 (HB)||ND||Likely the receptor responsible for the orthostatic hypotension known to occur in individuals on thioridazine.|
|M1||12.8||10||ND||This receptor is believed to be the chief receptor responsible for the anticholinergic side effects of thioridazine (e.g. dry mouth, constipation, blurred vision, etc.). Likely plays a role in thioridazine's low extrapyramidal side effect liability as anticholinergic drugs such as benzatropine are routinely given to treat extrapyramidal side effects resulting from antipsychotic treatment.|
|D2||0.4||4.3||0.25||Believed to be the receptor responsible for the therapeutic effects of antipsychotics.|
|hERG||191||ND||ND||Likely involved in thioridazine's cardiac effects.|
|H1||16.5||1.81 (HB)||ND||Likely responsible for the sedating effects of thioridazine.|
|H2||136||ND||ND||Regulates the release of hydrochloric acid into the stomach.|
Note: The Binding affinities given are towards cloned human receptors unless otherwise specified
HB - Human brain receptor.
RC - Cloned rat receptor.
ND - No data.
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.
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 10–75 mg per day for mild cases to 600–800 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 (10–50 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
|“||For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status and by some measures improved functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this possibility must be weighed against the unwanted effects of therapy. The current study helps to inform a clinical management strategy for current practice, but the considerable risks of maintenance therapy highlight the urgency of further work to find, develop, and implement safer and more effective treatment approaches for neuropsychiatric symptoms in people with AD.||”|
|This section requires expansion. (June 2008)|
Thioridazine, (±)-(10-[2-(1-methyl-2-piperidyl)ethyl]-2-(methylthio)phenothiazine) is synthesized by alkylating 2-methylthiophenothiazine with 2-(2-chloroethyl)-1-methylpiperidine.
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