Limitations of the Anticholinergic Activity Assay and Assay-Based Anticholinergic Drug Scales.

OBJECTIVE: The anticholinergic activity (AA) assay is a common method to determine a patient's anticholinergic load. Several limitations, however, are expected when applying the AA assay to patients or using drug scales to estimate anticholinergic burden based on AA levels. This study aims to demonstrate common pitfalls in an experimental setting and outline their clinical consequences. METHODS: The AA was analyzed for five drugs with reported interaction with muscarinic receptors. Concentration-response curves were constructed for furosemide (weak anticholinergic), diphenhydramine (moderate anticholinergic), the strong anticholinergic amitriptyline and its metabolite nortriptyline, and the cholinergic pilocarpine. The Combination Index (CI) was used to assess the interaction of three drug combinations with amitriptyline. RESULTS: All compounds displaced the radioactive tracer from its receptor binding site in a concentration-dependent manner, and full displacement was reached for all compounds except furosemide (Emax 16%). The CI indicated that amitriptyline and thioridazine have antagonistic effects (CI = 1.46) at low and synergistic effects (CI = 0.88) at higher concentrations (p < 0.0001), whereas synergistic effects (CI = 0.47-0.48) were observed for amitriptyline in any concentration combined with pilocarpine (p < 0.001). CONCLUSION: When the patient's anticholinergic load is estimated using AA levels, the actual exposure, combination of anticholinergic drugs, their active metabolites, and also drugs with an opposite pharmacologic action will contribute to AA levels, whereas weak anticholinergic drugs in therapeutic concentrations are rather negligible.

Combined therapy with thioridazine decreases plasma levels of quetiapine inTaiwanese schizophrenic patients.

BACKGROUND: In this study, the authors studied the effect of thioridazine (TDZ) on the pharmacokinetic profile of quetiapine (QTP) in Taiwanese patients with schizophrenia. METHODS: Sixteen subjects with schizophrenia were recruited for this study. The authors pretreated 8 patients with TDZ 50 mg daily continuously given until the end of the study. QTP was administered to all the participants, and their doses were escalated to 300 mg once daily over a 7-day period and maintained for another week. On day 15, blood samples were collected at 12 time points within an 8-hour interval. The authors assayed the plasma levels of QTP with a high-performance liquid chromatography system coupled with ultraviolet detector. RESULTS: Significantly decreased plasma levels of QTP after oral administration were observed in patients comedicated with TDZ compared with the QTP monotherapy group at 1.5, 2, and 2.5 hours, and the P values were 0.046, 0.001, and 0.005, respectively. The Cmax of QTP was significantly lower in the group comedicated with TDZ (776.9 ± 175.2 versus 1452.3 ± 707.5 ng/mL; P = 0.002). The oral clearance of QTP was significantly higher in the combined group than in the monothreapy group (123.3 ± 66.8 versus 60.3 ± 28.5 L/h; P = 0.03). Other pharmacokinetic parameters were not significantly different. CONCLUSIONS: The coadministration of TDZ significantly decreased plasma QTP level and significantly increased the oral clearance of QTP. Although TDZ is switched to QTP, choosing larger doses of QTP for titration may be necessary to avoid the emergence of psychotic symptoms among schizophrenic patients.

An optical sensor with specific binding sites for the detection of thioridazine hydrochloride based on ZnO-QDs coated with molecularly imprinted polymer.

Here, an optical sensor with specific binding sites for sensitive and selective detection of thioridazine hydrochloride (THZ) was prepared. The optosensor was developed based on ZnO quantum dots (QDs) coated with molecularly imprinted polymers (MIPs). Initially, ZnO quantum dots (QDs) were synthesized by precipitation from Zn(CH3COO)2 and NaOH then, reverse microemulsion method was applied for fixing the MIPs layer on the surface of QDs. It was perceived that the fluorescence intensity of the QDs-MIPs quenched with increasing THZ concentration. Several parameters affect the optical sensor response were studied and optimized. Under the optimal conditions, THZ could be determined with a linear dynamic range of 4-120 nmol L-1 and with a low detection limit of 0.43 nmol L-1. The relative standard deviations for 25 and 60 nmol L-1 of THZ were obtained as 4.9% and 3.1%, respectively (three times measurement). High selectivity, simplicity, and cost-efficient for THZ measurement are the most important advantages of the fluorimetric sensor.

Rapid determination of some psychotropic drugs in complex matrices by tandem dispersive liquid-liquid microextraction followed by high performance liquid chromatography.

Simple and rapid determinations of some psychotropic drugs in some pharmaceutical wastewater and human plasma samples were successfully accomplished via the tandem dispersive liquid-liquid microextraction combined with high performance liquid chromatography-ultraviolet detection (TDLLME-HPLC-UV). TDLLME of the three psychotropic drugs clozapine, chlorpromazine, and thioridazine was easily performed through two consecutive dispersive liquid-liquid microextractions. By performing this convenient method, proper sample preconcentrations and clean-ups were achieved in just about 7min. In order to achieve the best extraction efficiency, the effective parameters involved were optimized. The optimal experimental conditions consisted of 100µL of CCl4 (as the extraction organic solvent), and the pH values of 13 and 2 for the donor and acceptor phases, respectively. Under these optimum experimental conditions, the proposed TDLLME-HPLC-UV technique provided a good linearity in the range of 5-3000ngmL-1 for the three psychotropic drugs with the correlation of determinations (R2s) higher than 0.996. The limits of quantification (LOQs) and limits of detection (LODs) obtained were 5.0ngmL-1 and 1.0-1.5ngmL-1, respectively. Also the proper enrichment factors (EFs) of 96, 99, and 88 for clozapine, chlorpromazine, and thioridazine, respectively, and good extraction repeatabilities (relative standard deviations below 9.3%, n=5) were obtained.

Postmortem redistribution of two antipsychotic drugs, haloperidol and thioridazine, in the rat.

Antipsychotic drugs may be associated with arrhythmia, ventricular fibrillation, or torsades de pointes, which can result in sudden death. These drugs could therefore be found in postmortem toxicological analyses of autopsy specimens following unexplained sudden death. The drug concentrations in tissues and body fluids change between the death and postmortem specimens collection because of postmortem redistribution. For this reason, it is often difficult to interpret the postmortem analysis. The aim of this study was to investigate postmortem redistribution of the two cardiotoxic antipsychotic drugs, haloperidol and thioridazine, in order to interpret the postmortem analysis. We have chosen the rat as an animal model. The rats received 1 mg/kg of haloperidol and 5 mg/kg of thioridazine by intraperitoneal injection. They were sacrificed and left at room temperature for 2, 6, 12, 24, or 48 h, at which times blood and tissue samples were taken. The drug analyses in tissues and blood were done using a liquid chromatography- tandem mass spectrometry method. Our results show that there is a redistribution of the two drugs from the lung to the cardiac blood. The concentration of the antipsychotic drugs in the lung decreased rapidly, whereas in the cardiac blood, this concentration increased within the first 2 h postmortem. By 48 h after death, the concentrations of the antipsychotic drugs were about twice as high as the initial concentrations in the cardiac blood. For the lungs, a decrease of 50% was observed between 0 and 48 h. Only myocardium and muscle concentrations did not change with the postmortem delay.

Antipsychotic-related fatal poisoning, England and Wales, 1993-2013: impact of the withdrawal of thioridazine.

CONTEXT: Use of second generation antipsychotics in England and Wales has increased in recent years whilst prescription of first generation antipsychotics has decreased. METHODS: To evaluate the impact of this change and of the withdrawal of thioridazine in 2000 on antipsychotic-related fatal poisoning, we reviewed all such deaths in England and Wales 1993-2013 recorded on the Office for National Statistics drug poisoning deaths database. We also reviewed antipsychotic prescribing in the community, England and Wales, 2001-2013. Use of routine mortality data: When an antipsychotic was recorded with other drug(s), the death certificate does not normally say if the antipsychotic caused the death rather than the other substance(s). A second consideration concerns intent. A record of "undetermined intent" is likely to have been intentional self-poisoning, the evidence being insufficient to be certain that the individual intended to kill. A record of drug abuse/dependence, on the other hand, is likely to have been associated with an unintentional death. Accuracy of the diagnosis of poisoning: When investigating a death in someone prescribed antipsychotics, toxicological analysis of biological samples collected post-mortem is usually performed. However, prolonged attempts at resuscitation, or diffusion from tissues into blood as autolysis proceeds, may serve to alter the composition of blood sampled after death from that circulating at death. With chlorpromazine and with olanzapine a further factor is that these compounds are notoriously unstable in post-mortem blood. Deaths from antipsychotics: There were 1544 antipsychotic-related poisoning deaths. Deaths in males (N = 948) were almost twice those in females. For most antipsychotics, the proportion of deaths in which a specific antipsychotic featured either alone, or only with alcohol was 30-40%, but for clozapine (193 deaths) such mentions totalled 66%. For clozapine, the proportion of deaths attributed to either intentional self-harm, or undetermined intent was 44%, but for all other drugs except haloperidol (20 deaths) the proportion was 56% or more. The annual number of antipsychotic-related deaths increased from some 55 per year (1.0 per million population) between 1993 and 1998 to 74 (1.5 per million population) in 2000, and then after falling slightly in 2002 increased steadily to reach 109 (1.9 per million population) in 2013. Intent: The annual number of intentional and unascertained intent poisoning deaths remained relatively constant throughout the study period (1993: 35 deaths, 2013: 38 deaths) hence the increase in antipsychotic-related deaths since 2002 was almost entirely in unintentional poisoning involving second generation antipsychotics. Clozapine, olanzapine, and quetiapine were the second generation antipsychotics mentioned most frequently in unintentional poisonings (99, 136, and 99 deaths, respectively). Mentions of diamorphine/morphine and methadone (67 and 99 deaths, respectively) together with an antipsychotic were mainly (84 and 90%, respectively) in either unintentional or drug abuse-related deaths. Deaths and community prescriptions: Deaths involving antipsychotics (10 or more deaths) were in the range 11.3-17.1 deaths per million community prescriptions in England and Wales, 2001-2013. Almost all (96%) such deaths now involve second generation antipsychotics. This is keeping with the increase in annual numbers of prescriptions of these drugs overall (<1 million in 2000, 7 million in 2013), largely driven by increases in prescriptions for olanzapine and quetiapine. In contrast, deaths involving thioridazine declined markedly (from 40 in 2000 to 10 in 2003-2013) in line with the fall in prescriptions for thioridazine from 2001. CONCLUSIONS: The removal of thioridazine has had no apparent effect on the incidence of antipsychotic-related fatal poisoning in England and Wales. That such deaths have increased steadily since 2001 is in large part attributable to an increase in unintentional deaths related to (i) clozapine, and (ii) co-exposure to opioids, principally diamorphine and methadone.

Successful suicides with thioridazine and mesoridazine: a result of probable cardiotoxicity.

Five cases of successful suicides from thioridazine and mesoridazine occurred. The clinical course and management are outlined. A sixth case of reversible total heart block associated with thioridazine is presented giving further evidence that the deaths from overdose probably resulted from drug cardiotoxicity.

Low serum neuroleptic levels predict relapse in schizophrenic patients.

Relapse occurs in a substantial proportion of schizophrenic patients treated with neuroleptics. The determinants of relapse have been elusive. In our study, low serum neuroleptic levels identified patients who had a relapse during a six-month period. Neuroleptic levels were measured by radioreceptor assay in 61 schizophrenic men and their clinical status was assessed in the subsequent six months. Ten patients had relapses, four showing a worsening of chronic psychotic symptoms and six showing eruption of psychotic symptoms after a period of remission. These ten patients had significantly lower normalized neuroleptic levels than those whose conditions remained stable. The lowest neuroleptic levels occurred in patients who had relapses after a period of remission. Serum neuroleptic levels in drug-responsive patients appear to be a critical determinant of remission. If these observations are replicated, a rational basis may be provided for prescribing and monitoring neuroleptic treatment and perhaps for preventing relapse.

Blood levels of neuroleptic drugs in nonresponding chronic schizophrenic patients.

Blood levels of butaperazine were measured in schizophrenic patients who were chronic nonresponders to their psychotropic medication. The blood levels were compared with those in patients who had shown a better clinical response to this neuroleptic. Nonresponders had two to seven times lower levels of butaperazine in plasma and RBCs after a single dose or chronic dosing. Some of the patients later treated with thioridazine or haloperidol had lower plasma levels of these neuroleptics also. No significant differences were found between nonresponders and relative responders in either the alpha- or beta-phase half-life of butaperazine in plasma and RBCs after administration of a single dose of the drug. Butaperazine and thioridazine levels were not related to previously administered amounts of neuroleptic drugs. These findings do not support the hypothesis that low blood levels are the result of faster systemic metabolism of the drug after it reaches the central circulation. Our results suggest that low blood levels of neuroleptics may be one important factor in the poor clinical response of some chronic schizophrenic patients.

Practical application of guinea pig telemetry system for QT evaluation.

The purpose of this study was to evaluate a telemetry system for examining QT evaluation in the conscious free-moving guinea pig using 10 reference compounds whose effects on human QT interval are well established: 8 positive references (bepridil, terfenadine, cisapride, haloperidol, pimozide, quinidine, E-4031 and thioridazine), and 2 negative references (propranolol and nifedipine). Pharmacokinetic experiments were also performed for the 8 positive references. Telemetry transmitters were implanted subcutaneously in male Hartley guinea pigs, and the RR and QT intervals were measured. All 8 positive references prolonged QTc (QTc = k x QT/RR(1/2)) 10% or more during the 60 min observation period. When the values of the QTc changes were plotted against the serum concentrations, the resulting curves exhibited an anticlockwise hysteresis loop for all 8 references. In guinea pigs treated with haloperidol, changes of the T-wave shape from positive to flat were observed. The 2 negative references did not prolong the QTc. These findings suggest that the present telemetry guinea pig model is useful for QT evaluation in the early stages of drug development, because of the small body size of guinea pigs and their action potential configuration, which is similar to that of humans.

Influence of the antiparkinsonian drugs on the plasma level of neuroleptics.

The interaction between various neuroleptics and antiparkinsonian drugs was analyzed by measuring the neuroleptic plasma level before and after withdrawal of antiparkinsonian drugs. The population completing the study consisted of 32 chronic schizophrenics treated with chlorpromazine (8), levomepromazine (14), thioridazine (6), or haloperidol (4). Twenty-five were also receiving benztropine; 4, trihexyphenidyl; and 3, procyclidine. During the first 4 weeks patients remained on neuroleptics and antiparkinsonians, the latter being withdrawn during the 5th week, and the neuroleptics alone being administered during 16 following weeks. The plasma level of neuroleptics was assayed by gas liquid chromatography, once weekly in the morning at two different times. The analysis of variance showed a significant difference in neuroleptic plasma level when patients took neuroleptics only versus the period they had received neuroleptics and antiparkinsonians. The multiple comparison based on Studentized range Q0-05 revealed a significant progressive increase of neuroleptic plasma level during 12 weeks after withdrawal of antiparkinsonian drugs after which a plateau was reached. The hypothetical mechanisms of action of antiparkinsonians on neuroleptic plasma level are discussed.

Plasma levels of thioridazine and metabolites are influenced by the debrisoquin hydroxylation phenotype.

The pharmacokinetics of thioridazine and its metabolites were studied in 19 healthy male subjects: 6 slow and 13 rapid hydroxylators of debrisoquin. The subjects received a single 25 mg oral dose of thioridazine, and blood samples were collected during 48 hours. Concentrations of thioridazine and metabolites in serum were measured by HPLC. Slow hydroxylators of debrisoquin obtained higher serum levels of thioridazine with a 2.4-fold higher Cmax and a 4.5-fold larger AUC(0-infinity) associated with a twofold longer half-life compared with that of rapid hydroxylators. The side-chain sulphoxide (mesoridazine) and sulphone (sulphoridazine), which are active metabolites, appeared more slowly in serum and had lower Cmax values, but comparable AUC. The thioridazine ring-sulphoxide attained higher Cmax and 3.3-fold higher AUC in slow hydroxylators than in rapid hydroxylators of debrisoquin. Thus the formation of mesoridazine from thioridazine and the 4-hydroxylation of debrisoquin seem to be catalyzed by the same enzyme, whereas the formation of thioridazine ring-sulphoxide is probably formed mainly by another enzyme.

Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizers of dextromethorphan and mephenytoin.

Concentrations of total (R) + (S) and of the enantiomers (R) and (S) of thioridazine and metabolites were measured in 21 patients who were receiving 100 mg thioridazine for 14 days and who were comedicated with moclobemide (450 mg/day). Two patients were poor metabolizers of dextromethorphan and one was a poor metabolizer of mephenytoin. Cytochrome P450IID6 (CYP2D6) is involved in the formation of thioridazine 2-sulfoxide (2-SO) from thioridazine and also probably partially in the formation of thioridazine 5-sulfoxide (5-SO), but not in the formation of thioridazine 2-sulfone (2-SO2) from thioridazine 2-SO. Significant correlations between the mephenytoin enantiomeric ratio and concentrations of thioridazine and metabolites suggest that cytochrome P450IIC19 could contribute to the biotransformation of thioridazine into yet-unknown metabolites, other than thioridazine 2-SO, thioridazine 2-SO2, or thioridazine 5-SO. An enantioselectivity and a large interindividual variability in the metabolism of thioridazine have been shown: measured (R)/(S) ratios of thioridazine, thioridazine 2-SO fast eluting (FE), thioridazine 2-SO slow eluting (SE), thioridazine 2-SO (FE+SE), thioridazine 2-SO2, thioridazine 5-SO(FE), and thioridazine 5-SO(SE) were (mean +/- SD) 3.48 +/- 0 .93 (range, 2.30 to 5.80), 0.45 +/- 0.22 (range, 0.21 to 1.20), 2.27 +/- 8.1 (range, 6.1 to 40.1), 4.64 +/- 0.68 (range, 2.85 to 5.70), 3.26 +/- 0.58 (range, 2.30 to 4.30), 0.049 +/- 0.019 (range, (0.021 to 0.087), and 67.2 +/- 66.2 (range, 16.8 to 248), respectively. CYP2D6 is apparently involved in the formation of (S)-thioridazine 2-SO(FE), (R)-thioridazine 2-SO(SE), and also probably (S)-thioridazine 5-SO(FE) and (R)-thioridazine 5-SO(SE).

Concentration-related pharmacodynamic effects of thioridazine and its metabolites in humans.

OBJECTIVE: To measure cardiac and other effects of thioridazine and relate these to the plasma concentration of the parent drug and its principal metabolites. METHODS: A double-blind, randomized-order crossover study involving nine healthy male subjects compared the effects of single doses of thioridazine (10 mg and 50 mg) with placebo. Plasma concentrations of thioridazine and its ring sulfoxide, side-chain sulfoxide, and side-chain sulfone metabolites were measured, together with effects on the ECG, blood pressure, salivary flow, and a batch of psychomotor tests for 72 hours after administration. RESULTS: Thioridazine, 50 mg, reduced standing systolic blood pressure (mean peak changes from baseline [95% CI] -32 mm Hg [-55, 10 mm Hg]; p < 0.01 versus placebo) and diastolic blood pressure (-14 mm Hg [-26, -2 mm Hg]; p < 0.05), increased standing heart rate (7 beats/min [-1, 16 beats/min]; p < 0.05), impaired psychomotor function, and prolonged the JT (20 ms1/2 [7, 34 ms1/2]; p < 0.05), QTa (22 ms1/2 [8, 36 ms1/2]; p < 0.05), and QTc (22 ms1/2 [11, 33 ms1/2]; p < 0.01) intervals, but had no effect on QT dispersion (-12 ms1/2 [-31, 6 ms1/2]). Thioridazine, 1.0 mg, also significantly increased QTc, but the effect was less marked (9 ms1/2 [-1, 19 ms1/2]; p < 0.05). Plasma thioridazine and metabolite concentrations did not correlate significantly with these effects. Maximum effects on QTc occurred after peak concentrations of thioridazine but before peak concentrations of the ring sulfoxide and side-chain sulfone metabolites. CONCLUSIONS: These data suggest that thioridazine has dose-related effects on ventricular repolarization and that the parent drug causes an important proportion of these effects, although its metabolites may also contribute.

Elevation of thioridazine plasma levels by propranolol.

As part of a pilot study to assess the efficacy of propranolol in the treatment of aggression in psychiatric patients, drug interactions of propranolol with other agents were estimated by blood level monitoring. In the two patients taking a standard oral dose of thioridazine, the addition of propranolol caused a threefold and fivefold increase of plasma thioridazine levels, which placed them in a potentially toxic range. Although neither patient exhibited a toxic effect, these levels may be associated with an increased risk of thioridazine-induced irreversible pigmentary retinopathy, cardiac arrhythmias, and tardive dyskinesia. The authors suggest precautionary monitoring of thioridazine plasma and other relevant levels and clinical assessments when thioridazine and propranolol are used in combination.

Effect of anticonvulsants on plasma haloperidol and thioridazine levels.

Patients who had therapeutic plasma levels of phenobarbital and/or diphenylhydantoin had significantly lower plasma levels of haloperidol and mesoridazine, the active metabolite of thioridazine, than patients who did not receive anticonvulsants. Plasma thioridazine levels per se were not affected by concomitant anticonvulsant treatment. Biperiden, an antimuscarinic, antiparkinsonian agent, did not affect the plasma levels of these three neuroleptics.

Calcium channel blockade: possible explanation for thioridazine's peripheral side effects.

The authors show that thioridazine possesses calcium antagonist activity which may relate to its cardiac and sexual side effects. Binding sites associated with voltage-operated calcium channels were labeled by 3H-nitrendipine. Thioridazine influenced this binding of 3H-nitrendipine in a fashion similar to known calcium antagonists such as verapamil. Thioridazine also antagonized potassium-induced, calcium-dependent contractions of rat vas deferens, with similar potency. Thioridazine concentrations that exert calcium channel antagonist effects correspond to blood levels at therapeutic doses.

Interaction between phenobarbital and thioridazine.

The effects of thioridazine (TDZ) on serum phenobarbital (PB) and phenytoin (PHT) were studied in mentally retarded persons. Persons taking these drug combinations were identified and matched on the basis of age, sex, body weight, and antiepileptic drug (AED) dosage with persons from the same population who were taking only the AEDs. Trough, steady state serum levels were obtained as part of regular AED monitoring schedules. Serum level of PB per unit dose was significantly less with concomitant administration of TDZ (100 to 200 mg/day) than when PB was given alone. This effect seemed to be TDZ dose-responsive. TDZ had no consistent effects on serum PHT.

Plasma level monitoring of antipsychotic drugs.

Psychotic patients treated with identical doses of antipsychotic drugs have been shown to have great interindividual differences in their steady state plasma concentration. Therefore, monitoring treatment by dosage adjustment alone is of little value. If antipsychotic blood levels can be related to clinical response then their routine measurement may well result in well defined guidelines to individualised optimal dosage. Despite the considerable effort expended in this field and the many interesting testable hypotheses generated, little substantive evidence for an acceptable plasma level monitoring guide has been reported to date. Work on metabolite level profiles, intra- and extracellular drug concentration differences, more detailed clinical rating scales, and improved experimental design, all show great promise for the future. Investigation of the pharmacokinetics and the elucidation of the often complex metabolic pathways of individual antipsychotic drugs are generating the data base required for the rational pharmacotherapy of these most severely ill patients. Until more data are available, routine monitoring of antipsychotic drug plasma levels remains of research interest.

Pharmacokinetics and metabolism of thioridazine during co-administration of tricyclic antidepressants.

1. Because of serious side-effects of thioridazine and tricyclic antidepressants (cardiotoxicity), a possible influence of imipramine and amitriptyline on the pharmacokinetics and metabolism of thioridazine was investigated in a steady state (2-week treatment) in rats. 2. Imipramine and amitriptyline (5 and 10 mg kg(-1) i.p., respectively) elevated 30 and 20 fold, respectively, the concentration of thioridazine (10 mg kg(-1) i.p.) and its metabolites (N-desmethylthioridazine, 2-sulphoxide, 2-sulphone, 5-sulphoxide) in blood plasma. Similar, yet weaker increases in the thioridazine concentration were found in the brain. Moreover, an elevation of thioridazine/metabolite ratios was observed. 3. Imipramine and amitriptyline added to control liver microsomes in vitro inhibited the metabolism of thioridazine via N-demethylation (an increase in K(m)), mono-2-sulphoxidation (an increase in K(m) and a decrease in V(max)) and 5-sulphoxidation (mainly a decrease in V(max)). Amitriptyline was a more potent inhibitor than imipramine of the thioridazine metabolism. 4. The varying concentration ratios of antidepressant/thioridazine in vivo appear to be more important to the final result of the pharmacokinetic interactions than are relative direct inhibitory effects of the antidepressants on thioridazine metabolism observed in vitro. 5. Besides direct inhibition of the thioridazine metabolism, the decreased activity of cytochrome P-450 towards 5-sulphoxidation, produced by chronic joint administration of thioridazine and the antidepressants, seems to be relevant to the observed in vivo interaction. 6. The obtained results may also point to inhibition of another, not yet investigated, metabolic pathway of thioridazine, which may be inferred from the simultaneous elevation of concentrations of both thioridazine and the measured metabolites.