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Thioridazine


Thioridazine

Article Author:
Shana Feinberg
Article Author:
Kamron Fariba
Article Editor:
Abdolreza Saadabadi
Updated:
10/6/2020 3:22:04 PM
For CME on this topic:
Thioridazine CME
PubMed Link:
Thioridazine

Indications

Similar to other first-generation, or typical, antipsychotics, thioridazine is a medication FDA approved to treat schizophrenia and schizophrenia spectrum disorders. Other off-label uses include depression with psychotic features, pediatric behavioral disorders, and geriatric psychoneurotic manifestations. [1][2][3][4]

Mechanism of Action

Typical antipsychotics, including thioridazine, work to treat psychosis by blocking dopamine (DA) receptors. These medications are effective in treating the positive symptoms of schizophrenia, such as hallucinations, delusions, and disorganization. Positive symptoms are believed to manifest as a result of increased levels of dopamine in the mesolimbic pathway. More specifically, thioridazine blocks DA-2 receptors in the mesolimbic pathway, diminishing positive symptoms. Thioridazine is classified as a low potency first-generation antipsychotic, and as such is relatively sedating. Thioridazine is a substrate of the hepatic enzyme CYP450 2D6 and is also an inhibitor of the same enzyme. 

Administration

Thioridazine is an oral medication taken in tablet form. The tablets come in either 10 mg, 15 mg, 25 mg, 50 mg, 100 mg, 150 mg, or 200 mg. For schizophrenia, recommendations are to initiate thioridazine at 50 mg to 100 mg three times per day and gradually increase the dose as indicated, to a maximum of 800 mg per day. Of import is the risk of inducing dose-dependent QTc prolongation, and so it is suggested to start low and dose slow. Thioridazine also comes in liquid form at 30 mg/mL and 100 mg/mL. 

Adverse Effects

Extrapyramidal Side Effects (EPS)

Similar to other typical antipsychotics, thioridazine is associated with a risk of developing EPS. Because it is a low potency antipsychotic, however, the development of EPS occurs less frequently than with high potency antipsychotics. Extrapyramidal side effects include symptoms of dystonia, parkinsonism, and tardive dyskinesia. Dystonic reactions are muscle spasms that may occur early on and involve the eyes, tongue, or neck. Dystonic reactions precipitate in response to the decreased ratio of dopamine to acetylcholine, and thus are treatable by normalizing the ratio with anticholinergic medications, such as benztropine or diphenhydramine. It is essential to monitor patients for dystonia to avoid problems breathing, such as laryngospasm, which may require intubation. Parkinsonism results from DA antagonism and can manifest as resting tremor, cogwheel rigidity, postural instability, and shuffling gait. Parkinsonism is also treatable with benztropine or diphenhydramine, as well as the NMDA antagonist amantadine. And lastly, typical antipsychotics are associated with an even higher risk of tardive dyskinesia (TD) than atypical antipsychotics. TD is the result of the chronic administration of antipsychotics. The abnormal choreoathetoid movements seen in patients with tardive dyskinesia can affect the head, tongue, or face. Tardive dyskinesia is a serious adverse effect as it is not only embarrassing and uncomfortable for the patient, but it is mostly irreversible in nature. If a patient begins to develop tardive dyskinesia, the best treatment is to stop the antipsychotic medication and substitute thioridazine for an atypical antipsychotic with less risk.[5][6][7]

Neuroleptic Malignant Syndrome (NMS) 

NMS is another serious side effect of all antipsychotics and occurs more frequently with typical antipsychotics. This adverse effect may occur suddenly. The provider should monitor for unstable vital signs, such as tachycardia, fever, muscle rigidity, elevated white blood cell count, and creatinine phosphokinase. If the patient develops NMS, the clinician should immediately initiate hydration and supportive therapy. The antipsychotic should be discontinued as well. If necessary, further management is possible with dantrolene and bromocriptine.

ECG Changes

Thioridazine is associated with prolonged QTc intervals, which may have serious or even fatal consequences, such as Torsades de pointes. The recommendation is that patients with known prolonged QTc or arrhythmias avoid thioridazine. Before starting this medication, it would be wise to order an ECG and monitor for QTc prolongation or other ECG changes during treatment.

Other Side Effects

The development of pigmentary retinopathy is a unique adverse manifestation associated with thioridazine, and not with other antipsychotics. Patients may have nonspecific symptoms while taking thioridazine, such as dry mouth, dry eyes, sedation, weight gain, dizziness, erectile dysfunction, pruritus, photosensitivity, and constipation. Other rare and more unique side effects of thioridazine include irreversible retinal pigmentation, poikilothermia, and agranulocytosis.

Contraindications

There is a black-box warning for dementia-related psychosis because it may increase the risk of death secondary to cerebrovascular events in the elderly. Thioridazine is associated with a prolonged QT interval. Thus patients with long QT syndrome, QT intervals prolonged to more than 450, or taking concomitant medications known to prolong the QT interval should avoid thioridazine. Also, patients with known heart arrhythmias or hypotensive or hypertensive heart disease should avoid this medication, as well.

Because of drug-drug interactions, the clinician should be aware of the patient's medication profile. Thioridazine is metabolized by the hepatic enzyme CYP450 2D6. Medications that inhibit CYP450 2D6 should be used with caution when prescribing thioridazine. Medications that may affect thioridazine levels include but are not limited to fluoxetine, paroxetine, duloxetine, fluvoxamine, propranolol, citalopram, and pindolol.

Another rare, but serious, side effect of thioridazine is agranulocytosis. Each patient should be evaluated for abnormal white blood cell counts pre and post administration of thioridazine. [8]

Monitoring

Patients require monitoring for medication side effects during treatment, and it is often necessary to screen patients before treatment to obtain baseline results. Since thioridazine can cause significant ECG (electrocardiogram) changes and arrhythmias, it is important to get a baseline ECG and potassium level. Furthermore, an additional ECG is recommended for any change in dose and periodically after that. Another possible side effect of thioridazine is leucopenia, and thus routine complete blood counts are recommended over the course of the initial weeks. Opthomalogic exams should be implemented as well, as thioridazine can also cause irreversible retinal pigmentation over time. Studies are equivocal regarding the use of thioridazine in pregnancy, and so it may be advisable to get a pregnancy test before the administration of the drug. Thioridazine must be cautioned for use in the third trimester of pregnancy, as it may be associated with a risk of neonatal withdrawal symptoms and extrapyramidal side effects. Furthermore, thioridazine has a narrow therapeutic index, which means it is necessary to monitor each patient for adverse side effects carefully.[9][10]

Toxicity

Thioridazine is a low potency typical antipsychotic, like chlorpromazine. Unlike higher potency antipsychotics, thioridazine has a lower incidence of extrapyramidal side effects. However, lower potency antipsychotics are more likely to be associated with antimuscarinic, antihistaminic, and antiadrenergic side effects. Thioridazine is metabolized through the liver with a half-life of 24 hours and is excreted in the urine, bile, and feces. The hepatic cytochrome P450 CYP2D6 metabolism of thioridazine is important because it assists in identifying different drug-drug interactions. Thus, it is necessary to evaluate patients and identify medications that may increase or decrease levels of thioridazine. [11]

Enhancing Healthcare Team Outcomes

The use of thioridazine has declined significantly because of the availability of safer and more effective atypical antipsychotics. However, healthcare workers, including the primary care provider or nurse practitioner who prescribe thioridazine, should first consult with the psychiatrist for a better option. If the drug is prescribed, its adverse effects must be closely monitored. Further, the patient requires education about the side effects and potential drug interactions. Although a rare but serious side effect of thioridazine is agranulocytosis, each patient should be evaluated for abnormal white blood cell counts before use because this medication may exacerbate this problem.


References

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[4] Adams SA,Nasrallah HA, Multiple retinal anomalies in schizophrenia. Schizophrenia research. 2018 May;     [PubMed PMID: 28755877]
[5] Euwema MS,Swanson TJ, Deadly Single Dose Agents 2018 Jan;     [PubMed PMID: 28722879]
[6] Dean L, Thioridazine Therapy and {i}CYP2D6{/i} Genotypes 2012;     [PubMed PMID: 28520378]
[7] Tisdale JE, Drug-induced QT interval prolongation and torsades de pointes: Role of the pharmacist in risk assessment, prevention and management. Canadian pharmacists journal : CPJ = Revue des pharmaciens du Canada : RPC. 2016 May;     [PubMed PMID: 27212965]
[8] Thioridazine and severe cardiac arrhythmia. Prescrire international. 2001 Dec     [PubMed PMID: 11824444]
[9] Kristiansen JE,Dastidar SG,Palchoudhuri S,Roy DS,Das S,Hendricks O,Christensen JB, Phenothiazines as a solution for multidrug resistant tuberculosis: From the origin to present. International microbiology : the official journal of the Spanish Society for Microbiology. 2015 Mar;     [PubMed PMID: 26415662]
[10] Xiang YT,Chiu HF,Ungvari GS,Correll CU,Lai KY,Wang CY,Si TM,Lee EH,He YL,Yang SY,Chong MY,Kua EH,Fujii S,Sim K,Yong MK,Trivedi JK,Chung EK,Udomratn P,Chee KY,Sartorius N,Tan CH,Shinfuku N, QTc prolongation in schizophrenia patients in Asia: clinical correlates and trends between 2004 and 2008/2009. Human psychopharmacology. 2015 Mar;     [PubMed PMID: 25611192]
[11] Thanacoody RH, Thioridazine: the good and the bad. Recent patents on anti-infective drug discovery. 2011 May     [PubMed PMID: 21548877]