Search

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.

A randomized cross-over trial was conducted in 30 restless mentally subnormal patients by increasing the dosage of haloperidol from 10 to 60 mg and that of thioridazine from 100 to 600 mg daily. The clinical effects of drug holidays on placebo and serum drug levels were also examined. There were more relative drug-responders than nonresponders or negative responders. Correlation between clinical response and drug serum levels was poor, probably owing to the heterogeneity of disorders treated. Mesoridazine and other metabolites had 5-6 times higher serum levels than the parent compound, and relatively high serum levels are achieved already with moderate doses. The observed differences between haloperidol and thioridazine treatment were surprisingly few. Serum cholesterol was higher (P less than 0.05) at the end of thioridazine than of the haloperidol administration.

One of the leading current theories of the etiology of schizophrenia is excessive activity of some brain dopaminergic tracts. One of the major objections to the theory is that thioridazine is clinically as effective a treatment of schizophrenia as other neuroleptic drugs but appears to have much less dopamine-blocking properties than these agents in man and laboratory animals. Serum prolactin levels are increased by dopamine receptor-blocking drugs. We have found that thioridazine is as effective as chlorpromazine, trifluperazine, and prolixin enanthate in increasing serum prolactin levels in unmediated schizophrenic patients, indicating it is an effective dopamine-blocking agent.

Two agitated patients with Alzheimer's disease who either failed to respond or worsened with conventional low-dose neuroleptic and other pharmacologic treatment are described. Both patients demonstrated sustained improvement with very low-dose neuroleptics, one with haloperidol 0.125 mg and the other with thioridazine 5 mg. Clinical, pharmacokinetic, and pharmacodynamic factors that may have accounted for this response are discussed.

Eleven residents receiving long-term thioridazine treatment were studied while receiving their previous dose, standardized low and high doses (1.25 and 2.50 mg/kg per day), and placebo conditions. For theoretical reasons, subjects were also classified by degree of stereotypic behavior on the Fairview Problem Behavior Checklist (Barron & Sandman, 1983). Ratings of hyperactivity and self-injury were significantly lower during the higher as compared with the lower dose condition. Subjects classified as in the high-stereotypy group had significantly and substantially higher levels of maladaptive behavior on several other clinical variables. When all four drug conditions were compared, no significant drug effects were detected. However, high-stereotypy subjects responded significantly better to the drug than low-stereotypy subjects on ratings of Lethargy/Social Withdrawal and Hyperactivity on the Aberrant Behavior Checklist (Aman, Singh, Stewart, & Field, 1985a). The findings were related to previous dosage research and the literature on stereotypic behavior.

A four-week, double-blind study compared the effectiveness of thioridazine and diazepam in 40 geriatric patients with various symptoms of senility. Patients' progress was evaluated with the Hamilton Anxiety Rating Scale, a Modified Nurses' Observation Scale for Inpatient Evaluation (NOSIE), a global rating of degree of illness, and a global rating of degree of overall change. The data indicate that thioridazine was superior to diazepam inrelieving troublesome symptoms of senility.

The authors examined the effect of combined thioridazine (THI) and desipramine (DMI) for an early antidepressant response in 14 patients with a DSM III diagnosis of major depressive disorder with melancholia. All 14 patients received a constant dose of 200 mg DMI/day for 21 days while 7 patients received 100 mg THI/day for only the first 7 days. A significantly greater improvement from baseline Hamilton Depression Scale (HDS) scores occurred during the first 7 days in patients receiving both drugs. Possible mechanisms for this early antidepressant action are discussed.

Plasma levels of thioridazine and four of its metabolites were determined in a series of fifteen young acute schizophrenics; Consistent individually different metabolic patterns were detected in a group of patients who had the same value for the sum of thioridazine plus metabolites. The apparent volume of distribution and half life were calculated. Clinical evolution tended to correlate best with the level of mesoridazine.

Dose proportionality in some pharmacokinetic parameters for thioridazine and its two active metabolites (mesoridazine and sulforidazine) was investigated in 11 healthy human subjects following oral administration of three single doses (25, 50, and 100 mg) of thioridazine hydrochloride separated in each case by an interval of two weeks. Also, after a further two weeks, another 100-mg dose of thioridazine (divided as 5 mg every 0.5 h) was administered to all the volunteers to investigate the effect of a slow rate of dosage input on the pharmacokinetic parameters of this drug. An HPLC method was used to measure concentrations of thioridazine, mesoridazine, and sulforidazine in plasma samples collected up to 72 h following each dose. Dose proportionality for the three single doses of thioridazine was observed for all three analytes in the area under the plasma concentration versus time curves (AUC infinity 0 or AUCt0) and the maximum plasma concentration (Cmax) in that the relationships between the dose and these parameters were each describable by an equation for a straight line (r2 greater than or equal to 0.8). However, the mean apparent distribution and elimination rate constants for thioridazine and mesoridazine and the mean apparent oral clearance for thioridazine decreased significantly with increasing dose. This suggests nonlinear trends in the elimination kinetics at high doses of thioridazine. When a 100-mg divided oral dose of thioridazine was administered, no statistically significant differences between single and divided doses were observed in the mean AUC infinity 0 or AUCt0 for thioridazine or sulforidazine. A significant decrease in the mean AUC infinity 0 or AUCt0 was observed for mesoridazine after the administration of the divided dose.(ABSTRACT TRUNCATED AT 250 WORDS)

The phenothiazines have exhibited a history of problems associated with the bioequivalence of solid oral dosage forms. The more recent availability of chemically equivalent forms of thioridazine has raised new and interesting questions about the appropriateness of generic product interchange, even among brands that have been designated "therapeutically equivalent" by the Food and Drug Administration. The scrutiny that has accompanied the consideration of thioridazine products for inclusion into various state generic substitution formularies has offered an opportunity to examine issues involving bioequivalency in considerable detail. Specific bioequivalency concerns relate to: correct analysis of drug in biological fluids; the importance of evaluating active metabolites: single-dose vs. multiple-dose crossover studies; appropriate statistical power analysis; the "70/70" rule, and comparison of product variabilities. Examples of problems are cited to illustrate that significant questions still remain about the appropriate factors that should be used to establish bioequivalency.

The cardiovascular and respiratory effects of an intravenous overdose of thioridazine (125 mg kg-1 h-1) were examined in either spontaneously breathing or artificially ventilated urethane-anaesthetized rats. In both groups PO2, heart rate and mean arterial pressure decreased and atrioventricular and intraventricular conduction time, as well as QT time, increased similarly. PCO2 and pH did not differ significantly except in spontaneously breathing rats where a severe acidosis occurred at the end of the experiments. Haemolysis was suspected. The same dose was administered intravenously to artificially ventilated rats. Plasma concentrations of the drug and its main metabolites, haematocrit and free plasma Hb were determined in separate groups. A severe haemolysis was observed. Thioridazine administered in the same doses intragastrically, intraduodenally or intraperitoneally resulted in lower plasma values than after intravenous administration and there was no haemolysis. Much higher oral doses produced haemolysis at 36 h, at which time plasma concentrations were not higher than those recorded after administration via the other non-intravenous routes. It is probable that the observed changes in cardiovascular and respiratory parameters are partly the result of haemolysis following thioridazine administration.

Neuroleptic drugs were gradually reduced from 25 hospitalized chronic schizophrenics while 23 such patients were maintained on matched dosages of neuroleptics. At the end of 15 weeks, 74% of the drug-reduced subjects and 80% of the drug-maintained subjects were rated to have decompensated. Drug-reduced patients decompensated while receiving a mean of 75 mg equivalent of chlorpromazine. Clinical stability was obtained at 150 mg equivalent of chlorpromazine. Twenty-six percent of the drug-reduced patients showed no signs of clinical relapse at the end of the 15-week trial and were receiving a mean of 8 mg equivalent of chlorpromazine. The results suggest that gradual and successive reductions in maintenance antipsychotic drugs can be implemented with minimal risk to the clinical status of the chronic mental patient.

A well-documented association exists between the phenothiazines and the tricyclic antidepressants and such alarming side effects as cardiac arrhythmias, ECG changes, and even sudden death. Most disturbing is the fact that major and possibly fatal arrhythmias can occur in young adults without antecedent heart disease who are receiving therapeutic dosages of these psychotropic drugs (especially thioridazine). Further study of the cardiovascular side effects of psychotropic drugs is needed to clarify the association. In the meantime, it is mandatory that physicians individualize treatment programs that include these drugs and carefully monitor patient response.

Over the past decade a variety of studies have been carried out in the Department of Psychiatry and Human Behavior at the University of California, Irvine, investigating the pharmacokinetics of some psychoactive pharmacological agents and the relationships of these pharmacokinetics to certain clinical responses. This report summarizes and provides an overview of these studies.

The authors conducted a two-part study of the effects of thioridazine and withdrawal dyskinesias on the workshop performance of mentally retarded young adults. In part 1, 80 mentally retarded subjects were divided into five groups of 16 according to administration, discontinuation, or nonadministration of thioridazine. The major finding was that thioridazine can impair the workshop performance of mentally retarded individuals. In part 2, 28 subjects were divided into four matched groups of 7 subjects each whose thioridazine dose was abruptly or gradually discontinued and who did or did not have withdrawal dyskinesias. Workshop performance declined with the onset of the dyskinesias and improved as the dyskinesias subsided.

The phenothiazines are among the most widely used drugs to treat symptoms commonly associated with acute and chronic psychoses. One of the commonly prescribed compounds within this class of drugs is thioridazine, available both as a generic product as well as the innovator product, Mellaril. Each of these products is coded as bioequivalent and consequently therapeutically equivalent by the Food and Drug Administration (FDA). A recent issue of this journal contained an article that raised a number of questions concerning the bioequivalence of the generic versions of thioridazine that have been approved by the FDA. Their article was based in part on information obtained from the FDA as well as information supplied to the authors by Sandoz, Inc., the manufacturer of the original thioridazine drug product Mellaril. The FDA has reviewed its original decision of bioequivalence. Based on this reassessment, the FDA strongly rejects the assertion by the authors that several of the approved generic thioridazine products are not bioequivalent. The rationale behind the FDA decisions and the FDA's viewpoint on the bioequivalence of generic thioridazine drug products is discussed in detail.

Thioridazine, unlike most other effective antipsychotic drugs, appears to be only a weak dopamine antagonist in various regions of the brain. We decided to test, indirectly, thioridazine's effects on another brain dopaminergic system, the tuberoinfundibular tract, which regulates prolactin secretion by stimulating hypothalamic secretion of prolactin-inhibiting factor. Chlorpromazine and several other phenothiazines have been shown to stimulate prolactin secretion. Five healthy men ingested 50 mg of chlorpromazine concentrate on one occasion, and 50 mg of thioridazine concentrate on another. Both drugs noticeably stimulated prolactin secretion within two hours. It is concluded that thioridazine is a potent dopamine antagonist in the tuberoinfundibular system, and it is suggested that this system's regulation of prolactin secretion may provide a useful method for studying antipsychotic drug effects in man.

Difficulties in developing techniques to measure plasma levels of neuroleptic drugs have included the presence of metabolites, as well as cross-reactivity not only between these metabolites and the parent compound but between drugs (e.g., a phenothiazine and a tricyclic). Although newer techniques have minimized some of these problems, interpretation of published data must also recognize such design limitations as variable dose, small sample size, etc. The literature is reviewed on the relationship between therapeutic response and plasma levels of chlorpromazine, thioridazine, thiothixene, fluphenazine, butaperazine, and haloperidol. It is suggested that additional studies, carefully designed, on dosage and plasma levels could help in achieving the lowest possible therapeutic dosage and thus in minimizing side effects.

The effects of therapeutic and toxic doses of thioridazine (Mellaril) (10 and 50 mg/kg body weight, respectively) on ventricular electrophysiologic properties were studied in 12 anesthetized dogs. Threshold pacing currents (diastolic threshold), effective refractory period and conduction time were significantly increased, and idioventricular automaticity was suppressed after administration of 10 mg/kg of thioridazine; the effects were much more pronounced after administration of 50 mg/kg. Rapidly repetitive responses or tachycardia could be induced in the ventricle by two early premature beats in 9 of the 12 dogs after the 50 mg/kg dose, but they did not occur before drug administration or after the 10 mg/kg dose. These results indicate that the antiarrhythmic and arrhythmogenic effects of thioridazine are dose-dependent and that careful monitoring with frequent electrocardiograms is needed for patients receiving large doses of this drug.

A randomized cross-over trial was conducted in 30 restless mentally subnormal patients by increasing the dosage of haloperidol from 10 to 60 mg and of thioridazine from 100 to 600 mg daily. The effects of drug holidays and serum drug levels were also examined. Mesoridazine had 5-6 times higher serum levels than the parent compound and relatively high serum levels are achieved already with moderate doses. The observed differences between haloperidol and thioridazine treatment were surprisingly few. Serum cholesterol was higher (P < 0.05) at the end of the thioridazine administration. Drug holidays may benefit may patients.

The efficacy of oral concentrate in the rapid tranquilization of 159 acutely disturbed patients in a psychiatric emergency service was evaluated. Patients were randomly assigned to 1 of 10 treatment groups: 7 oral groups and 3 comparison intramuscular groups. Although intramuscular medication produced a faster response, concentrate also proved to be effective for rapid tranquilization. Side effects were benign and minimal. Age, sex, race, and diagnosis had no effect on outcome. The use of concentrate as a paradigm for treating acutely psychotic patients is discussed.

Thioridazine-tricyclic antidepressant combination is frequently used in clinical practice. One reason for the choice of this combination may be its anticipated effectiveness in depressions which show both retarded and anxious features. Because both of these drugs have an adverse effect on cardiac repolarization, this may be a particularly hazardous combination. Two cases are presented illustrating life-threatening ventricular arrythmia in patients who have ingested both thioridazine and tricyclic antidepressants.

Senile itching, a peculiar clinical situation consisting of a cutaneous senile involution associated with a relevant neurogenic component, still keeps being a difficult therapeutic problem. For the purpose, a clinical trial, carried out with a combination of thioridazine and dihydroergotoxine on 19 patients carriers of the affection, could show a relevant decrease in all parameters assessed, ie itching, muscle tension and skin temperature measured by biofeedback. The combination also showed a good tolerance.

After oral administration of thioridazine or mesoridazine to man, faecal extracts contained mainly unconjugated 7-hydroxy-thioridazine and its demethylated analogue, together with some 3-hydroxy-thioridazine, and 7-hydroxy derivatives of sulphoridazine and desmethyl sulphoridazine. In contrast, urine contained free 7-hydroxy-mesoridazine, and no free 7-hydroxy-thioridazine was detectable. Conjugates of all these phenols were also found. After oral sulphoridazine administration (thioridazine side-chain sulphone), urine contained mainly 7-hydroxy-sulphoridazine and faeces both 7-hydroxy-sulphoridazine and its desmethyl analogue. Sulphoridazine metabolism is therefore much simpler than that of thioridazine. This different elimination pattern in faeces and urine may be due to reduction of sulphoxides but not sulphones by intestinal bacteria.

Polypharmacy with psychoactive drugs was surveyed in 1276 elderly psychiatric patients from 12 Veterans Administration hospitals. One out of every six patients received two or more psychoactive agents. No specific combination of drugs was overly popular. The most frequently administered combinations, thioridazine plus phenobarbital and chlorpromazine plus phenobarbital, were administered to only 13 patients each (1% of the sample). The large majority of the combinations involved antipsychotic agents. One antipsychotic drug, thioridazine, was a component of nearly one-third of the combinations. The most frequent pairings were an antipsychotic drug plus and antidepressant, two antipsychotic drugs, and an antipsychotic drug plus an antianxiety agent or sedative-hypnotic. The use of polypharmacy was significantly related to patient age. One out of every four patients 60 to 65 years of age received two or more psychoactive drugs compared to only one out of eight over 75 years of age. The implications of these findings for treatment and research are discussed.

The influence of the central nervous system in the production of phenothiazine-induced arrhythmia and death was examined in this study. In a series of cats, spinal cords were transected at the atlanto-occipital junction prior to the 1 mg/kg/min, i.v. infusion of chlorpromazine or thioridazine. No protection against drug-induced arrhythmia or death was afforded by this procedure. In other cats, 6OH-dopamine was administered prior to intravenous injection of atropine and infusion of chlorpromazine, 1 mg/kg/min. In these in situ denervated heart preparations, there was no protection against chlorpromazine-induced arrhythmia or death. In alpha-chloralose anesthetized cats, 0.5 mg chlorpromazine administered intracerebroventricularly did not induce arrhythmia or death, although blood pressure decreased initially. Thus, chlorpromazine or thioridazine do not appear to produce arrhythmia or death via a central locus and may instead be acting directly on myocardial conduction to produce arrhythmia and death.

A Tourette-like syndrome (TLS) may occur after long-term neuroleptic treatment. A review of 11 cases reported in the literature is given. We describe the onset of a TLS in a 13-year old boy with childhood schizophrenia after short term, low-dose treatment with thioridazine. The syndrome resolved 5 months after neuroleptic withdrawal. Subsequent exposure to neuroleptics (mainly perphenazine) induced a recurrence of motor tics and involuntary vocalizations which resolved on drug discontinuation. Awareness that neuroleptics may induce a TLS may lead to prompt recognition and avoidance of labelling the manifestations as symptoms of the underlying psychosis or attention-seeking behaviour.

Toxic effects on the retina by oral administration of thioridazine was investigated by electroretinography (ERG) using male Wistar rats. An obvious reduction followed by a disappearance in the O2 component of the oscillatory potentials of the ERG was seen in a dose-dependent manner. The minimum dosage given to produce the above change was 3 mg/kg/day for 7 days' administration. This change seemed to be permanent, whereas a and b waves as well as other oscillatory potentials, e.g., O1, O3, were normal throughout the experiment. The significance of the data is discussed.

The hypothesis that the anticholinergic properties of thioridazine can account for its ability to enhance amphetamine-induced stereotyped behaviors was tested. In one experiment, scopolamine-induced repetitive head movements were shown to be potentiated by thioridazine. In another experiment, subthreshold doses of scopolamine and thioridazine interacted to potentiate amphetamine-induced repetitive head movements. The data suggest that thioridazine, in addition to its neuroleptic activity, has significant anticholinergic effects in vivo and these effects may account for its potentiation of amphetamine-induced stereotypy.