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The spontaneous photooxidation of thiothixen (Navane) to 2-(N,N-dimethyl-sulfonamido)-9-thioxanthone is described. The corresponding sulfoxide is demonstrated to be the fluorescent species obtained upon permanganate oxidation of thiothixene in the fluorometric assay procedure of Mjörndal and Oreland.
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OBJECTIVE: In this study healthy volunteers received thiothixene with and without a 3-day pretreatment with paroxetine to determine if paroxetine decreased the clearance of thiothixene. METHOD: Ten healthy medication-free volunteers (4 women and 6 men, mean age 38 +/- 12 years) were randomized to receive a single 20 mg oral dose of thiothixene on two separate occasions. On one occasion thiothixene was given concurrently, and following 3 days of pre-treatment with oral paroxetine (20 mg/day). On the other occasion thiothixene was given without paroxetine pre-treatment. The two study days were separated by a minimum period of 2 weeks. On both study days, after the administration of thiothixene, 10 ml blood samples were collected over the next 72 h. RESULTS: None of the pharmacokinetic parameters of thiothixene were significantly altered by a 3-day treatment with paroxetine. DISCUSSION: It is likely that the CYP2D6 isoenzyme is not responsible for a high proportion of thiothixene clearance, but one cannot exclude the possibility that a longer paroxetine pretreatment might have caused some inhibition of thiothixene clearance.
A 24-week double-blind study was conducted to compare haloperidol and thiothixene for efficacy and safety in 46 schizophrenic outpatients. In addition to the standard psychiatric rating scales, Brief Psychiatric Rating Scale (BPRS), Nurses' Observation Scale for Inpatient Evaluation (NOSIE), and Evaluation of Social Functioning Rating (ESFR), two scales more sensitive to the incidence of treatment emergent depression were utilized. They were the Hamilton Depression Scale (HPRSD) and the Zung Self-rating Depression Scale (ZUNG). On the BPRS factors, haloperidol was significantly superior to thiothixene in Thought Disturbance and Hostility-Suspiciousness, and in Total symptomatology. Haloperidol was also significantly superior to thiothixene in Cognitive Disturbance on the HPRSD. Results of global evaluations suggested haloperidol produced slightly more rapid relief of symptoms than did thiothixene. The inclusion of the depression scales was useful in following patients who exhibited depressive symptoms; clinically significant depression was seen in 5 patients receiving haloperidol and 3 receiving thiothixene. A high incidence of akathisia in the thiothixene group was responsible for a statistically significant difference between groups in the number of central nervous system symptoms. Mean doses of test drugs were 17.5 mg/day for haloperidol an 31.8 mg/day for thiothixene. The study showed that haloperidol was equal to and in some parameters superior to thiothixene in producing improvement in the symptoms of psychosis.
Fifty-nine plasma thiothixene concentrations were measured in 42 patients as part of routine therapeutic drug monitoring. Data collection included concomitant medications, smoking history, and demographic variables. A retrospective analysis was performed to assess the effect of these parameters on oral thiothixene clearance. When groups of patients were categorized by concomitant medications (i.e., no interacting drugs, enzyme/clearance inducers, and enzyme/clearance inhibitors), thiothixene clearance was found to be significantly increased by enzyme inducing drugs (e.g., anticonvulsants) and decreased by clearance inhibiting agents (e.g., cimetidine). Tobacco smoking significantly increased the hepatic clearance of thiothixene within the no interactions and inhibitor groups, but not in the inducer group. Significantly more patients in the inducer group had nondetectable plasma concentrations of thiothixene than the other groups. When the entire patient population was dichotomized by age, patients less than 50 years old had a significantly greater mean clearance (48.2 +/- 37.8 liters/min) versus those greater than or equal to 50 (20.0 +/- 12.6 liters/min). Men in this cohort exhibited a significantly higher clearance (49.2 +/- 38.7 liters/min) than did the women (22.0 +/- 13.5 liters/min). By taking into account these potential sources of pharmacokinetic variability when monitoring plasma thiothixene concentrations, more appropriate dosing of thiothixene may be achieved. Controlled, prospective studies are needed to validate these findings.
Psychotic women with schizophrenic symptoms were treated with melperone 100 mg X 3 (n = 29) or thiothixene 10 mg X 3 (N = 34) USING A DOUBLE-BLIND PROCEDURE. Before and during treatment, levels of HVA, MOPEG, and 5-HIAA, the major metabolites of DA, NE, and 5-HT, were determined in lumbar cerebrospinal fluid by a mass fragmentographic technique. Both treatments resulted in an elevation of the HVA levels after 2 weeks, thiothixene having a more marked effect. The effect of thiothixene but not of melperone persisted after 4 weeks. Thiothixene did not influence the MOPEG level, but melperone reduced it after 4 weeks of treatment. The 5-HIAA levels were not significantly altered by the drugs. The HVA/MOPEG and the HVA/5-HIAA ratios were highly significantly elevated by both drugs after 2 as well as 4 weeks. Thiothixene induced a significantly greater change of these ratios than melperone. The results supply evidence that thiothixene accelerates central dopamine metabolism in man, presumably by blocking DA receptors. Melperone appears to act similarly, but has an effect which is weaker and/or of shorter duration. During long-term treatment with melperone the receptors develop tolerance to it. The acceleration in DA metabolism declines and the effect of melperone switches instead to central NA metabolism. The results indicate that both drugs cause long-term changes in the activity ratios of central monoamine systems. It is suggested that such changes in several systems rather than single biochemical events may be related to the antipsychotic effects of neuroleptic drugs. This study also demonstrated the versatility of using monoamine metabolite analysis of the CSF as a tool for the quantification of biochemical effects of neuroleptic drugs on the human CNS.
A high-performance liquid chromatographic procedure is described for the separation of cis and trans isomers of thiothixene, a thioxanthene derivative used as an antipsychotic agent. A radial compression module (RCM-100) was used with both silica and cyanopropyl cartridges. A fixed-wavelength UV detector (254 nm) was used in these studies for quantitation. Mesoridazine is used as an internal standard because of its separation characteristics and reproducible quantitation. C18 Sep-Pak cartridges are used for biological sample clean-up. Plasma samples from patients treated with thiothixene (Navane) were assayed for cis and trans-thiothixene. No trans-thiothixene was detectable and cis-thiothixene concentrations ranged from 0 to 22.5 ng/ml.
Fifty outpatients with borderline and/or schizotypal personality disorder were randomly allocated to thiothixene (Navane) or placebo treatment that was continued for 12 weeks. The mean daily dosage of thiothixene hydrochloride in the final week of the study was 8.7 mg, a lower dosage than is used in outpatient schizophrenics. Significant drug-placebo differences were found, regardless of diagnosis, on "illusions," "ideas of reference," "psychoticism," "obsessive-compulsive symptoms," and "phobic anxiety," but not on "depression." Thiothixene seems to have more than an antipsychotic effect. Since response to treatment studies are a means for reformulating diagnostic concepts, we suggest a subdiagnosis defined by those symptoms that are drug-responsive, some of which are not included in current diagnostic criteria. Patients with borderline and schizotypal disorder without the foregoing symptoms probably would not profit from thiothixene and might needlessly be placed at risk for adverse drug effects.
The effects of thioridazine and thiothixene were studied by a double-blind technique on 40 schizophrenic patients. The doses were adjusted for optimal clinical and therapeutic effects and side effects were rated after three and eight weeks of treatment. No statistically significant differences were observed between the two drugs or between either of the two drugs and the previous medication. Plasma levels were estimated by a fluorometric technique after three and eight weeks of treatment. No correlation was found between plasma levels and clinical effects for either thioridazine or thiothixene. Plasma levels of both drugs were clearly correlated to dosage after three weeks of treatment. After eight weeks this correlation persisted for thioridazine but not for thiothixene. By that time plasma levels of thiothixene had decreased to about 30 per cent of the initial value, indicating strong enzyme induction.
This study compares the effects of two neuroleptic drugs with different pharmacologic characteristics (thiothixene and haloperidol) on cerebral glucose utilization in chronic schizophrenic inpatients. Positron emission tomographic (PET) scans were obtained from all subjects in a neuroleptic-free condition and again after 4-6 weeks of neuroleptic treatment. Eight subjects were treated with thiothixene and 12 with haloperidol. Thiothixene and haloperidol had different metabolic effects. For example, all thiothixene-treated subjects showed increased whole brain glucose utilization; all but one haloperidol-treated subject showed decreased utilization. Different patterns of relative prefrontal and striatal metabolism were also observed. These results highlight the importance of controlling for the effects of neuroleptic treatment and indicate the difficulty of interpreting data from studies with complex or poorly defined drug regimens.
The effects of melperone and thiothixene on the concentrations of monoamine metabolites in brain and prolactin in the serum of rats and mice were determined. Both drugs increased brain concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in a dose-dependent manner. 5-Hydroxyindoleacetic acid (5-HIAA) was unaffected. The effect of thiothixene was longer lasting and about 5 times greater than that of melperone. Melperone, but not thiothixene, increased levels of 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG). Several hours after administration of melperone, levels of HVA and MOPEG were diminished. Both drugs increased prolactin concentrations in rat serum. Thiothixene was about 10 times more potent than melperone. Of two urinary metabolites of melperone investigated, one caused the same qualitative effects on monoamine metabolism as melperone itself but with reduced potency. The other metabolite was ineffective.
Twelve patients with schizophrenia received positron emission tomography scans with 18F-deoxyglucose before and after 4 to 6 weeks of treatment with clozapine or thiothixene. Both stereotaxic and magnetic resonance image template methods were used to position regions of interest for metabolic rate analysis. Clozapine increased and thiothixene decreased metabolic rates in the basal ganglia; these effects were most marked on the right side. Within the basal ganglia, a superior to inferior gradient in drug effect was found for thiothixene but not clozapine. This gradient resembled in some respects observations on regional differences in D2 receptors in human autoradiography. Baseline metabolic rates also predicted clinical medication response, with right inferior caudate metabolic rates differentiating clozapine and thiothixene responders. Larger sample studies are needed to replicate and extend these initial findings.
The authors examined plasma levels of thiothixene and clinical response in 19 DSM-III diagnosed inpatient schizophrenics, using an improved methodology. A significant curvilinear correlation was demonstrated between clinical response and plasma levels for thiothixene (p less than 0.02). Optimal clinical response to thiothixene appears to be associated with plasma levels from 2.0 to 15.0 ng/ml (p less than 0.05). These findings suggest that laboratory measurement of thiothixene levels may assist in determining the minimum effective dose for individual patients.
The hemodynamic effects and plasma levels of noradrenaline were studied in schizophrenic patients at rest and during exercise after long-term treatment with chlorpromazine (150-600 mg daily) and thiothixene (60-80 mg daily). The results are compared with those from previous studies in untreated patients and patients receiving very large doses of chlorpromazine. The effects of thiothixene on the different hemodynamic variables were very moderate, and the observed differences between this group and the control group may be due to the different patient materials. In the two groups of patients receiving chlorpromazine, the heart rate at rest and durng exercise tended to be higher than in the control group. There was also a tendency towards a lower stroke volume after this drug and thiothixene during exercise. The noradrenaline levels in plasma were highest after the high dose of chlorpromazine both at rest and during exercise, while they were lower after the moderate chlorpromazine dose. After thiothixene, the values were between those of the group on the low chlorpromazine dose and those of the control group.
A series of three experiments addressed major problems concerning the use of serum levels as predictors of clinical response to thiothixene (Navane) hydrochloride in schizophrenia: correlation of initial test doses with clinical response; comparison of fluorescence spectrophotometry with gas chromatography in relation to clinical response; and comparison of serum levels with RBC levels in relation to clinical response. All assays correlated (near r = .5) with Brief Psychiatric Rating Scale improvement during hospitalization, except RBC levels seemed to have superior correlations (.64) in patients with lower serum levels. These correlations are similar to those obtained with steady state levels. The different methods of determining thiothixene concentrations were highly intercorrelated as well. Thus, single-dose serum levels give important clinical correlations regardless of which assay is used for thiothixene determination.
The purpose of this investigation was to determine the relationship between serum levels of the neuroleptic agent thiothixene and tardive dyskinesia in schizophrenics of a wide age range. Forty-one male schizophrenic subjects, 21 with tardive dyskinesia and 20 without, were given a fixed dosage of thiothixene hydrochloride (10 mg orally four times daily) after a drug-free period of one week. Higher steady-state serum levels of thiothixene (obtained after five days of a fixed-dosage schedule) were associated with greater degrees of tardive dyskinesia. This relationship was independent of the relationship between tardive dyskinesia and age.
An HPLC methodology is described which enables the quantitation of thiothixene (N,N-dimethyl-9-[3-(4-methyl-1-piperazinyl)-propylidene]thioxanthe ne-2- sulfonamide) in bulk drug, finished product, and dissolution samples using a single analytical column (SiAl: a mixture of silica and alumina). The Z (cis) and the less pharmacologically active E (trans) isomers of thiothixene, as well as synthetic precursors and degradants, are well resolved within a short chromatographic run. A minor modification of the mobile phase allows direct injection and quantitation of low-concentration samples in a simulated gastric fluid (SGF) dissolution medium. The method is capable of supplanting the three separate procedures currently included in the thiothixene monograph of the U.S. Pharmacopeia XXI.
Zotepine and thiothixene were compared for clinical efficacy and safety in a double-blind trial. Using overall improvement ratings and Gorham's BPRS, zotepine rated higher improvement in motor retardation, suspiciousness, mannerisms and posturing symptoms, suggesting that it has both activating and antipsychotic activities. Thiothixene produced higher improvement ratings in symptoms such as hallucinatory behavior, somatic concerns, anxiety, guilt feelings, tension, depressive mood and uncooperativeness. As for side effects, there was a significantly lower frequency of dry mouth and insomnia with zotepine when compared with thiothixene. The lower incidence of insomnia is interesting in view of zotepine's clinical activating effects. There were no abnormal laboratory findings.