Search

This study investigated to what extent fluvoxamine affects the pharmacokinetics of thioridazine (THD) in schizophrenic patients under steady-state conditions. Concentrations of THD, mesoridazine, and sulforidazine were measured in plasma samples obtained from 10 male inpatients, aged 36 to 78 years, at three different time points: A, during habitual monotherapy with THD at 88 +/-54 mg/day; B, after addition of a low dosage of fluvoxamine (25 mg twice a day) for 1 week; and C, 2 weeks after fluvoxamine discontinuation. After the addition of fluvoxamine, THD concentrations relative to time point A significantly increased approximately threefold from 0.40 to 1.21 micromol/L (225%) (p < 0.002), mesoridazine concentrations increased from 0.65 to 2.0 micromol/L (219%) (p < 0.004), and sulforidazine levels increased from 0.21 to 0.56 micromol/L (258%) (p < 0.004). The THD-mesoridazine and THD-sulforidazine ratios remained unchanged during the study. Mean plasma THD, mesoridazine, and sulforidazine levels decreased at time point C, but despite fluvoxamine discontinuation for 2 weeks, three patients continued to exhibit elevated concentrations of THD and its metabolites. In conclusion, fluvoxamine markedly interferes with the metabolism of THD, probably at the CYP2C19 and/or CYP1A2 enzyme level. Therefore, clinicians should be aware of the potential for a clinical drug interaction between both compounds, and careful monitoring of THD levels is valuable to prevent the accumulation of the drug and resulting toxicity.

In a double-blind comparison of haloperidol and mesoridazine in the treatment of 39 recently hospitalized schizophrenic patients, the two drug treatment groups showed comparable antipsychotic effects, though they did differ in side effects in expected manners. Analysis of the Brief Psychiatric Rating Scale to calculate an index of dysphoric response previously found predictive of poor ultimate outcome failed to predict outcome in this 4-week trial though patients with a dysphoric response to neuroleptics did prove to include a higher proportion of process schizophrenics, who might ultimately show poorer outcome, than did nondysphoric responders.

Available data on the clinical effectiveness and side effects of mesoridazine are reviewed, and an attempt is made to relate clinical efficacy to phenothiazine pharmacokinetics. Both controlled and open-label clinical studies have attested to the efficacy of mesoridazine in schizophrenia, as well as certain other psychiatric disorders. Clinical observations of the effectiveness of mesoridazine in patients refractory to treatment with thioridazine and other neuroleptics may be related to its slow rate of inactivation and to the relatively large proportion of free mesoridazine that is available for penetration to the target sites in the brain.

Self-injury is a severe behavioral problem commonly observed in institutionalized mentally retarded individuals. While several forms of therapy are available, pharmacological treatment is most often used in institutions to control this behavior. This paper evaluated the clinical and experimental literature on the effects of pharmacotherapy for self-injury. Few general conclusions could be drawn mainly due to the small number of studies and the general lack of methodological rigor of these studies. However, there was some indication that antipsychotics and antimanics may prove to be useful in the treatment of self-injury and warrant further investigation. Several areas of future research were discussed.

Among 1,152 psychiatric inpatients who received a phenothiazine, a butyrophenone, or a thioxanthene, 116 developed dystonia attributed to one or more of these drugs. The highest frequencies of dystonia occurred among recipients of haloperidol and the long-acting injectable fluphenazines. For all patients at risk, dystonia was more common in men and in younger patients. For chlorpromazine, high doses, male sex, and low age were each positively associated with dystonia.

Before and after a double-blind trial of haloperidol vs. mesoridazine, 24 hospitalized schizophrenics performed visual perception tasks designed to assess function of the cerebral hemispheres. Tasks involved identifying as "same" or "different" two images (either letters, digits, or unfamiliar shapes) projected tachistoscopically to the right or left visual field or to both together. Multivariate analysis of variance related response latency and accuracy to task type, hemisphere stimulated, and pre- vs. posttreatment testing. Both before and after treatment, subjects responded most slowly and least accurately to letter-matching. Bilateral presentation of stimuli resulted in faster and more accurate responses, except on shape-matching. Neuroleptic treatment improved speed and accuracy overall, though not under certain task conditions. Results accorded more with an impairment in verbal processing and interhemispheric coordination than with a specific left-hemispheric deficit in schizophrenia.

A double-blind study vs. placebo was carried out over a 6-week period in thirty adolescent patients to determine the efficacy and safety of mesoridazine, in the form of 10 mg tablets, in the treatment of symptoms associated with various personality disorders. The average daily dose for the 15 patients in the mesoridazine group was 27.3 mg in the first and 44.7 mg in the sixth week. Mesoridazine relieved anxiety to a highly significant degree when compared with placebo and proved significantly more effective than placebo also in terms of mean improvement scores for depression and hostility. Significant reductions were likewise achieved in the overall severity of the disorders and in the severity of nearly all the other symptoms. The incidence of adverse reactions did not differ significantly from that following placebo administration. No extrapyramidal symptoms were noted.

The phenothiazine derivatives, particularly chlorpromazine and thioridazine, are known to produce significant electrocardiographic abnormalities. Until now, documented life-threatening arrhythmias have not been reported following large doses of mesoridazine, the besylate salt of a metabolite of thioridazine and a relatively recent addition to the phenothiazine group. We describe such a case in which alterations in both impulse conduction (first-degree atrioventricular block, prolonged QRS duration, and right axis deviation) and impulse formation (supraventricular and ventricular tachycardia) were noted following a suicidal ingestion of mesoridazine. The electrophysiologic mechanisms underlying phenothiazine-induced arrhythmogenesis are reviewed.

A spectral analysis technique for quantifying dyskinesia in patients with diagnosis of Hungtington's Disease (chorea) (H.D.) is described. Spectral analysis involves computation of the magnitude of abnormal involuntary movements (AIMS) and of their distribution in frequency. It has the advantage of providing an objective measure of such movements. Three H.D. patients under different drug regimens and three age-matched controls have been evaluated and representative time records and power spectra are presented. Analysis established marked differences in the amplitude and shape of the normal and patient spectra. In addition, spectral analysis proved sensitive to differences in drug treatments among patients suggesting its additional use in evaluating the efficacy of therapeutic agents in the treatment of movement disorders.

Mesoridazine besylate (Serentil) was evaluated in an eight-week open-label trial in 12 male and 41 female patients with chronic schizophrenia who had ceased to progress beyond a certain level of functioning despite continued psychotropic medication not including Serentil. After a ten-day washout period the patients received Serentil in I.M. doses of 25-150 mg daily on the first ten study days, followed by daily tablet doses ranging from 25 to 400 mg until the final day of the study. Observations were made before and after the washout period as well as on days 3, 10, 14, 28 and 56 of the study, and results were expressed in terms of the Nurses' Observation Scale for Inpatient Evaluation (NOSIE) and the Brief Psychiatric Rating Scale (BPRS). The NOSIE ratings showed that the patients were significantly "less mentally ill" at the end of the washout period and underwent a statistically highly significant further improvement in the course of the Serentil treatment. These improvements occurred in irritability, manifest psychosis, retardation, and depressive manifestations, and social competence. Only two BPRS items improved significantly during the washout period. Treatment with Serentil led to improvement in thinking disturbances as well as in psychomotor, paranoid and depressive disturbances. In fact, between baseline and day 56 of the treatment period, all BPRs items except guilt feelings and all BPRS factors were improved to a highly significant (p less than 0.01) degree. Rating for mental illness from study day 10 onward showed that patients in a subgroup of depressive disturbances showed significantly greater improvement than patients in another subgroup, psychomotor disturbances. Adverse reactions were experienced by a total of 13 patients; in 7 of these a dosage adjustment became necessary for this reason. All patients completed the study program.

The report presents a method developed to analyze strip chart records generated by a system previously described and termed cineseismography which makes available quantitative records of abnormal involuntary movements in the human. In this report, method for converting measurements made on the strip chart record is described. Application of the method is made in three cases with diagnosis of Huntington's disease (chorea). Case histories are presented for each subject detailing the medications and dosage, and the quantitative data together with the histograms derived are provided. Preliminary trials indicate that movement decomposition, as in ataxia, can also be detected and quantified.

Seven schizophrenic (according to DSM-III criteria) inpatients completed a two-phase study; each phase had a 1-week drug-free period followed by 6 weeks of a drug trial. The first phase uniformly involved treatment with chlorpromazine, and in the second phase patients received either mesoridazine (N = 3) or thioridazine (N = 4). Clinical ratings (Brief Psychiatric Rating Scale and Clinical Global Impressions) and neuroleptic blood levels were obtained weekly throughout the study. Whereas patients failed to respond to chlorpromazine 1800 mg/day, response to mesoridazine 400 mg/day and to thioridazine 800 mg/day was established on all Brief Psychiatric Rating Scale factors except for anxiety-depression. A higher neuroleptic blood level was achieved with mesoridazine or thioridazine at less than half the reference chlorpromazine dosage. Correlations between neuroleptic blood level and clinical response were positive for mesoridazine, negative for chlorpromazine, and nonsignificant for thioridazine. These findings are consistent with earlier research. We conclude that drug-resistant schizophrenics seem to improve clinically with mesoridazine or thioridazine, unlike with chlorpromazine, and that for mesoridazine this difference may be a function of selective dopamine receptor blockade.