Quantitation of Haloperidol, Fluphenazine, Perphenazine, and Thiothixene in Serum or Plasma Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).

Haloperidol, fluphenazine, perphenazine, and thiothixene are "typical" antipsychotic drugs that are used in the treatment of schizophrenia and other psychiatric disorders. The monitoring of the use of these drugs has applications in therapeutic drug monitoring and overdose situations. LC-MS/MS is used to analyze plasma/serum extracts with deuterated analog of imipramine as the internal standard to ensure accurate quantitation and control for any potential matrix effects. Positive ion electrospray is used to introduce the analytes into the mass spectrometer. Selected reaction monitoring of two product ions for each analyte allows for the calculation of ion ratios which ensures correct identification of each analyte, while a matrix-matched calibration curve is used for quantitation.

Correlation of initial thiothixene serum levels and clinical response. Comparison of fluorometric, gas chromatographic, and RBC assays.

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.

Tardive dyskinesia and steady-state serum levels of thiothixene.

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.

Inpatient violence and the schizophrenic patient: an inverse correlation between danger-related events and neuroleptic levels.

A correlational analysis of neuroleptic serum levels and measures of inpatient violence in 58 male schizophrenic patients is presented. Significant correlations were found between thiothixene (Navane) serum levels and several measures of inpatient violence including assault. The large variance noted with serum levels of neuroleptics on fixed doses may account for patients who have lower serum levels receiving less control of psychotic symptoms which may lead to violent behavior.

Serum level monitoring of thiothixene in schizophrenia: acute single-dose levels at fixed doses.

After establishing a strong correlation between steady-state thiothixene levels and levels drawn 2.5 hours after a 20-mg test dose, the authors examined the correlation between clinical improvement and serum levels drawn 2.5 hours after a single 20-mg test dose of thiothixene. For 30 male schizophrenic inpatients, improvement on the Brief Psychiatric Rating Scale was significantly correlated with the single test-dose levels. Serum levels were also positively correlated with age, which may explain the tendency of elderly patients to require lower neuroleptic doses and to exhibit a higher incidence of side effects. The results suggest that acute single-dose levels may be useful in predicting clinical response to thiothixene.

Plasma level monitoring of antipsychotic drugs. Clinical utility.

The steady-state plasma concentrations of antipsychotic drugs show large interpatient variations but remain relatively stable from day to day in each individual patient. Monitoring of antipsychotic drug concentrations in plasma might be of value provided the patients are treated with only 1 antipsychotic drug. Some studies have reported a relationship between therapeutic response and serum antipsychotic drug 'concentrations' as measured using the radioreceptor assay (RRA) method, which measures dopamine receptor-blocking activity in plasma. Most studies, however, have failed to demonstrate such a relationship, and the RRA does not seem to provide the generally useful tool for plasma concentration monitoring of antipsychotic drugs that was hoped for initially. A lack of correlation between dopamine receptor-blocking activity in plasma and therapeutic response may be due to differences in the blood-brain distribution of both antipsychotic drugs and their active metabolites. Chemical assay methods (e.g. GLC and HPLC) have been used in studies which examined the relationships between therapeutic response and antipsychotic drug concentrations in red blood cells and in plasma. It seems that for these drugs, measuring red blood cell concentrations does not offer any significant advantage over measuring plasma concentrations. Reasonably controlled studies of plasma concentration-response relationships using randomly allocated, fixed dosages of chlorpromazine, fluphenazine, haloperidol, perphenazine, sulpiride, thioridazine and thiothixene have been published but often involve relatively few patients. A correlation between therapeutic response and plasma concentrations of thioridazine and its metabolites has not been demonstrated, and plasma level monitoring of thioridazine and its metabolites therefore appears to have no clinical value. Clinical behavioural deterioration concomitant with high plasma concentrations of chlorpromazine and haloperidol have been reported. A dosage reduction might be considered after 2 to 4 weeks' treatment in non-responders who have plasma chlorpromazine concentrations above 100 to 150 micrograms/L or plasma haloperidol concentrations above 20 to 30 micrograms/L. Non-responders and good responders to chlorpromazine treatment, however, have plasma drug concentrations in the same range, and a therapeutic range of plasma chlorpromazine levels has not been defined. Therapeutic plasma haloperidol concentrations (i.e. 'window') in the range of 5 to 20 micrograms/L have been reported by some investigators, but others have found no such relationship.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

Thiothixene plasma levels and clinical response in acute schizophrenia.

Plasma levels of cis and trans thiothixene were compared to clinical response in 8 acutely schizophrenic inpatients. While absolute plasma levels did not appear to correlate with clinical condition, the data did suggest that increases or decreases in cis plasma levels correlated with corresponding improvements or deteriorations in clinical condition in thiothixene responsive patients. While the results are very preliminary, the authors suggest that future studies differentiate the cis and trans isomers, and analyze relative as well as absolute changes in plasma levels as compared to clinical changes.

Psychotropic blood levels: a guide to clinical response.

In the clinical use of psychotropic drugs, the value of blood level monitoring remains uncertain because, for most of these agents, consistent, predictable correlations between blood level and therapeutic response have not been established. In recent years productive work has been done in this area which suggests that, in certain clinical situations and with certain psychotropic agents, monitoring of blood levels may be a useful component of patient care. The literature regarding blood levels and therapeutic response to various psychotropic drugs is reviewed and some of the clinical settings in which blood levels are, in fact, predictive of therapeutic response in the management of psychiatric illness are discussed.

Blood levels of neuroleptics: state of the art.

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.

Correlation of thiothixene serum levels and age.

Two experiments are reported in which acute single test dose levels of thiothixene (Navane) were correlated with age. In the first study 20 mg oral doses were given to 28 male subjects and serum levels were drawn 2 h later. Mean age was 30 and correlation of serum level with age was 0.43, P less than 0.02. In a second older group with a mean age of 41, 10 mg oral doses were given to 25 subjects. A correlation with age of 0.41, P less than 0.05 was obtained with age. In prior work such acute levels have been found to correlate with steady-state serum levels and with clinical response to the medication. Few side-effects were seen in these populations and no correlations were obtained between serum levels and any side-effects.

Plasma levels of thiothixene by radioreceptor assay: clinical usefulness.

Thirty-four newly admitted schizophrenic patients were treated with a fixed dose of thiothixene (0.44 mg/kg) for 4 weeks. Thiothixene and its active metabolites were measured by a new radioreceptor assay. Improvement occurred over the entire range of recorded plasma levels, but the chances of substantial improvement appear greater above 40 neuroleptic units (n.u.). The data do not support the notion of a "therapeutic window", in that higher plasma levels were not associated with side effects or clinical deterioration (although at extreme plasma levels this must of course be so). In 11 nonresponders dosage could not be increased because of side effects. If a non-responder with troublesome side effects has a low plasma level (less than 40 n.u.), it would seem prudent to switch to another antipsychotic drug.

Serum neuroleptic concentrations and clinical response: a radioreceptor assay investigation of acutely psychotic patients.

Twenty-two acutely psychotic patients were rigorously assessed for psychopathology at baseline and after 14 days of neuroleptic treatment. The neuroleptic radioreceptor assay (NRRA) was used to determine serum neuroleptic concentrations. Serum neuroleptic concentration was significantly, nonlinearly related to changes in BPRS Total Score, and BPRS Factor Scores for Thought Disturbance and Anxiety-Depression. Clinical improvement was associated with intermediate (11-50, 51-126 ng/ml haloperidol equivalents) while poor clinical outcome was related to both low (less than or equal to 10 ng/ml) or high (greater than 125 ng/ml) serum levels. The results are discussed in terms of a possible "therapeutic window" for the neuroleptics and the implications this might have for clinical practice.

Plasma levels and clinical effects of thioridazine and thiothixene.

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.

Correlates of dangerous behavior by schizophrenics in hospital.

An evaluation of correlates of inpatient dangerous behavior in a schizophrenic population is presented. Potential correlates included: neuroleptic serum levels, admission schizophrenic symptoms on the Brief Psychiatric Rating Scale (BPRS), act leading to admission, military experience, and childhood discipline. A multiple regression analysis indicated that the best correlate of inpatient physical assaults, verbal assaults, and total number of inpatient dangerous acts in our population was low neuroleptic serum levels. The best predictor of seclusion and restraint was severity of Vietnam combat. Additional significant correlates included degree of schizophrenic symptoms on the BPRS and history of violence prior to admission. Three factors: neuroleptic serum level, degree of schizophrenic symptoms, and violence prior to admission accounted for 49% of the sample variance for inpatient assaults.

Neuroleptic plasma levels.

There is enormous variation in plasma levels of most neuroleptics in patients on the same dose. Much of the past research on the relation between plasma levels of antipsychotic drugs and clinical change, however, has been difficult to interpret. It does appear that decreased bioavailability, at least in public institutions, is rarely the cause of treatment failure. Aberrantly low plasma levels are more likely due to surreptitious noncompliance or drug interactions with enzyme inducers such as carbamazepine. Therapeutic plasma level ranges, in which good antipsychotic effect occurs without undue side effects, have been tentatively identified for perphenazine, haloperidol, fluphenazine, and chlorpromazine. The extent to which aberrantly high plasma levels are associated with inferior antipsychotic response is unclear. Antipsychotic plasma levels may be most useful when the distinction between side effects and worsening psychosis is unclear. The utility of high neuroleptic plasma levels in the treatment-resistant patient is unclear.

Acute thiothixene overdose.

An acute thiothixene intoxication is presented. Blood thiothixene concentration of 0.52 mg/L was detected before it declined to 0.047 mg/L in 12 hrs. Analysis was by thin layer chromatography, ultraviolet spectrophotometry, and fluorescence spectrophotometry.

Flow-injection chemiluminometric determination of some thioxanthene derivatives in pharmaceutical formulations and biological fluids using the [Ru(dipy)3(2+)]-Ce(IV) system.

A flow-injection (FI) methodology using tris(2,2'-dipyridyl)ruthenium(II), [Ru(dipy)3(2+)], chemiluminescence (CL) was developed for the rapid and sensitive determination of three thioxanthene derivatives, namely zuclopenthixol hydrochloride, flupentixol hydrochloride and thiothixene. The method is based on the CL reaction of the studied thioxanthenes with [Ru(dipy)3(2+)] and Ce(IV) in a sulfuric acid medium. Under the optimum conditions, calibration graphs were obtained over the concentration ranges 0.002-6 migrograms/ml for zuclopenthixol hydrochloride, 0.5-15 micrograms/ml for flupentixol hydrochloride and 0.05-7.5 micrograms/ml for thiothixene. The limits of detection (s/n = 3) were 4.2 x 10(-9) mol/l zuclopenthixol hydrochloride, 2 x 10(-8) mol/l flupentixol hydrochloride and 4.5 x 10(-8) mol/l thiothixene. The method was successfully applied to the determination of these compounds in dosage forms and biological fluids.

[Relations between the levels of neuroleptics and the doses, the therapeutic effects and the side effects]. / Relation des taux des neuroleptiques avec les doses, les actions thérapeutiques et les effets secondaires.

The mass fragmentography and the gas-liquid chromatography are available actually for quantitation of very low levels of neuroleptics. The Radio-immunological assay is full of promise. Their plasma levels are not correlated with their dosage in a man to another, but, for some of them, there is lineary relation for one person. A correlation between their levels and their clinical efficacy is not certainly demonstrated for thioridazine and non transformed chlorpromazine; it could be possible for his sulphoxide metabolite and for butaperazine. The sides-effects are relatively correlated with their levels in the begining of the therepautic. The antiparkinsonian drugs, the antidepressants and the lithium could influenced them.

Injectable long-term control-released in situ gels of hydrochloric thiothixene for the treatment of schizophrenia: preparation, in vitro and in vivo evaluation.

Hydrochloric thiothixene (HT) is an antipsychotic drug used in the treatment of various psychoses including schizophrenia, mania, polar disorder, and in behavior disturbances. However, because the psychotics often could not control their behaviors, the independent administration of antipsychotic drug based on medical order was difficult. The omissions of the administration often brought an unsatisfactory therapeutic efficacy. A novel injectable long-term control-released in situ gel of HT for the treatment of schizophrenia was developed based on biodegradable material polylactic acid (PLA). The optimum formulation of the injectable PLA-based HT in situ gel containing 15% (w/w) HT and 45% (w/w) PLA with benzyl benzoate was used as a gelling solvent. The results of the in vitro and in vivo studies showed that this in situ gel had a long-term period of drug release for several weeks and a good histocompatibility without any remarkable inflammatory reactions.