Haloperidol Plasma Levels Research Articles

Rat brain CYP2D enzymatic metabolism alters acute and chronic haloperidol side-effects by different mechanisms

Risk for side-effects after acute (e.g. parkinsonism) or chronic (e.g. tardive dyskinesia) treatment with antipsychotics, including haloperidol, varies substantially among people. CYP2D can metabolize many antipsychotics and variable brain CYP2D metabolism can influence local drug and metabolite levels sufficiently to alter behavioral responses. Here we investigated a role for brain CYP2D in acutely and chronically administered haloperidol levels and side-effects in a rat model.Rat brain, but not liver, CYP2D activity was irreversibly inhibited with intracerebral propranolol and/or induced by seven days of subcutaneous nicotine pre-treatment. The role of variable brain CYP2D was investigated in rat models of acute (catalepsy) and chronic (vacuous chewing movements, VCMs) haloperidol side-effects.Selective inhibition and induction of brain, but not liver, CYP2D decreased and increased catalepsy after acute haloperidol, respectively. Catalepsy correlated with brain, but not hepatic, CYP2D enzyme activity. Inhibition of brain CYP2D increased VCMs after chronic haloperidol; VCMs correlated with brain, but not hepatic, CYP2D activity, haloperidol levels and lipid peroxidation. Baseline measures, hepatic CYP2D activity and plasma haloperidol levels were unchanged by brain CYP2D manipulations.Variable rat brain CYP2D alters side-effects from acute and chronic haloperidol in opposite directions; catalepsy appears to be enhanced by a brain CYP2D-derived metabolite while the parent haloperidol likely causes VCMs. These data provide novel mechanistic evidence for brain CYP2D altering side-effects of haloperidol and other antipsychotics metabolized by CYP2D, suggesting that variation in human brain CYP2D may be a risk factor for antipsychotic side-effects.

Determination of oxidative stress and activities of antioxidant enzymes in guinea pigs treated with haloperidol

Guinea pigs (Cavia porcellus) were treated with haloperidol (HP), and free radical (FR) and ferric reducing antioxidant power (FRAP) assays were used to determine oxidative stress levels. Furthermore, the superoxide dismutase (SOD), glutathione reductase (GR) and glutathione-S-transferase (GST) activity levels were detected and glucose levels and the reduced and oxidized glutathione (GSH/GSSG) ratio were measured in HP-treated and untreated guinea pigs. The present study demonstrated that the administration of HP causes significant oxidative stress in guinea pigs (P=0.022). In animals treated with HP, the activity of GST was significantly increased compared with a placebo (P= 0.007). The elevation of SOD and GR activity levels and increase in the levels of glutathione (GSH) in HP-treated animals were not statistically significant. In the HP-untreated animals, a significant positive correlation was observed between oxidative stress detected by the FR method and GST (r=0.88, P=0.008) and SOD (r=0.86, P= 0.01) activity levels, respectively. A significant negative correlation between the levels of plasma glucose and oxidative stress detected by the FRAP method was observed (r=−0.78, P=0.04). Notably, no significant correlations were observed in the treated animals. In the HP-treated group, two subgroups of animals were identified according to their responses to oxidative stress. The group with higher levels of plasma HP had higher enzyme activity and reactive oxygen species production compared with the group with lower plasma levels of HP. The greatest difference in activity (U/μl) between the two groups of animals was for GR.

No Association of a Set of Candidate Genes on Haloperidol Side Effects

We previously investigated a sample of patients during an active phase of psychosis in the search for genetic predictors of haloperidol induced side effects. In the present work we extend the genetic association analysis to a wider panel of genetic variations, including 508 variations located in 96 genes. The original sample included 96 patients. An independent group of 357 patients from the CATIE study served as a replication sample. Outcomes in the investigation sample were the variation through time of: 1) the ESRS and UKU total scores 2) ESRS and UKU subscales (neurologic and psychic were included) related to tremors and 3) ESRS and UKU subscales that do not relate to tremors. Outcome in the replication sample was the presence vs absence of motoric side effects from baseline to visit 1 (∼ one month of treatment) as assessed by the AIMS scale test. Rs2242480 located in the CYP3A4 was associated with a different distribution of the UKU neurologic scores through time (permutated p = 0.047) along with a trend for a different haloperidol plasma levels (lower in CC subjects). This finding was not replicated in the CATIE sample. In conclusion, we did not find conclusive evidence for a major association between the investigated variations and haloperidol induced motoric side effects

Lack of association between 71 variations located in candidate genes and response to acute haloperidol treatment

The antipsychotic pharmacological treatment effectiveness and side effects are at least partially driven by the genetic personal background. In the present study, 71 genetic variations located in 21 candidate genes were investigated as modulators of the haloperidol efficacy and side effects in a sample of 101 acutely ill psychotic patients. Patients were assessed at days0, 7, 14, 21, and 28 (Positive and Negative Syndrome Scale (PANSS) test) and days1, 3, 7, 14, 21, and 28 (UKU, BAS, and ESRS tests). Haloperidol plasma levels were measured at the same timepoints. None of the 71 variations were associated with response to treatment or with incidence of side effects passed a multiple testing threshold. A marginal association was detected between two haplotypes within the signal transducer and activator of transcription 4 gene and PANSS positive and dopamine beta-hydroxylase with PANSS negative scores (p = 0.004 and p = 0.008, respectively). In conclusion, no major association was observed between the investigated variations and the efficacy profile of haloperidol.

Sociodemographic and treatment related variables are poor predictors of haloperidol induced motor side effects

Age, haloperidol plasma levels and sex are associated with haloperidol induced motor side effects according to some lines of evidence, even though some conflicting findings mandate further research. We here report that age and sex were associated with dystonia during the early phases of treatment (p=0.0006 and p=0.008 respectively), but are overall poor predictors of the Extrapyramidal Symptom Rating Scale scores' variation over time (first month of treatment) in a sample of 60 acutely ill haloperidol treated psychotic patients. We conclude that age, sex and haloperidol plasma levels are not robust predictors of haloperidol induced motor side effects. Nonetheless, some limits of the study including the small sample size and the imputation of missing data could have diminished the power of detecting minor impacts of the investigated clinical predictors of the haloperidol induced motor side effects.

USE OF INTERMEDIATE PHENOTYPES IN PHARMACOGENETICS

Pharmacogenetic studies are hampered by the complexity of the drug response phenomenon. Therefore the optimal methodology for investigations should include a detailed clinical and sociodemographic data collection, plasma level of drugs, frequent measurements on various dimensions of the phenomenonwith appropriate genetic and statistical tools including pathway and gene coverage and epistatic events. As an example we report new data investigating a set of 50 SNPs located in 11 genes coding for subunits of glutamatergic receptors, as modulators of the efficacy of haloperidol in a sample of 101 schizophrenic patients. Furthermore, we investigated the possible impact on the motor side effect profile associated with haloperidol treatment. Patients were administered the PANSS and ESRS tests at baseline and at day 3, 7,14, 21 and 28. MANCOVA analysis for repeated measureswas applied alongwith the FDR correction formultiple tests. T/T genotype at rs472792 (GRIA1) was found to be associated with a better response to haloperidol treatment thanG/Tat PANSS positive at week 2 (f=6.18, p=0.001) after covaring for haloperidol plasma levels and influencing clinical variables. C/C genotype at rs1461231 (GRIA1) was found to be associated with a better response to treatment compared to G/G genotype at PANSS positive scores at week 1 (f=7.32, p=0.00032). Despite limitations linked to the small sample size, those findings provide an example of a detailed pharmacogenetic analysis in antipsychotic response possibly allowing a complex predictive model to be used in everyday clinical practice.

A comparison of haloperidol plasma levels among Japanese, Korean and Swedish psychiatric patients

Purpose: The purpose of this study is to compare the steady-state plasma levels of HAL between Japanese, Koreans and Swedes who were treated with HAL monotherapy per os. Method: The steady-state plasma levels of haloperidol (HAL) in 75 Japanese, 120 Korean, and 50 Swedish psychiatric patients treated orally with HAL were compared. Results: Significantly higher doses of HAL were used in the Koreans (mean dose = 21 mg/day) than in the Japanese (15 mg/day) or Swedes (9 mg/day) (one-way analysis of variance (ANOVA) (p<0.0001), Bonferroni's post test (p<0.001)). The mean concentration/daily dose ratio (C/D ratio) of HAL was 2.2 times higher in Korean patients (2.78 nmol/L/mg/day) and 1.5 times higher in Japanese patients (1.88 nmol/L/mg/day) than that in Swedish patients (1.24 nmol/L/mg/day). A significant difference in the C/D ratio was observed among the 3 ethnic groups (one-way ANOVA; p<0.0001). Discussion: The higher C/D ratio of HAL in Asians might be partly due to the higher frequency of the CYP2D6*10 allele in Asians; however, interethnic differences in the activity of other enzymes, such as CYP3A4, might have caused the differences in the present study, especially at the higher doses of HAL.

Interaction of haloperidol plasma level and antipsychotic effect in early phases of acute psychosis treatment

The definition of the best combination of “when” and “how much” of haloperidol dosing during acute psychotic illness still represents a challenge. Randomized controlled trials can hardly account for the high variability of dose × timing of dose increase strategies that can be applied in everyday practice. We conducted an observational study in order to study and evaluate the naturalistic strategies of haloperidol oral administration in a sample of 101 acutely ill psychotic patients. Out of this sample, 82 patients had complete data on PANSS scores and 50 patients had data on the haloperidol plasma levels. In accordance with previous evidence, we found that improvement during the first two weeks of treatment was a significant predictor of response ( t = 6.94, p = 2.11E−08). On this note, increasing the haloperidol doses over 6.64 ± 2.08 mg/day on average from the second to the third week of treatment in those patients who did not respond to treatment during the first two weeks of treatment was of no use for further amelioration. This cutoff was associated with treatment efficacy but not with the incidence of side effects. In conclusion a moderate dose of haloperidol is suggested in the first two weeks, in case of non response a dose increase is of no further benefit. This finding could contribute to tailor more individualized treatment and highlights the need for early detection of non-responders.

Adjunctive Treatment With a Dopamine Partial Agonist, Aripiprazole, for Antipsychotic-Induced Hyperprolactinemia: A Placebo-Controlled Trial

Hyperprolactinemia and associated side effects often occur with antipsychotics. The authors investigated the effect of adjunctive treatment with aripiprazole on hyperprolactinemia and psychopathology in patients with schizophrenia maintained with haloperidol. Fifty-six patients with hyperprolactinemia taking haloperidol were enrolled. Haloperidol dose was fixed; aripiprazole was dosed at 15 mg/day for the first 4 weeks, then 30 mg/day for the following 4 weeks. Serum prolactin, haloperidol, and aripiprazole levels were measured. Symptoms and side effects were assessed with the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms, Clinical Global Impression symptom scale, Simpson-Angus Rating Scale, and Barnes Akathisia Rating Scale at weeks 1, 2, 4, 6, and 8. Prolactin levels of patients receiving aripiprazole significantly decreased over time, demonstrating a significant time effect and a time-by-group interaction. In the aripiprazole group, 88.5% of patients at week 8 had prolactin levels normalize compared to 3.6% of patients receiving placebo. Among 11 female patients with menstrual disturbances randomly assigned to aripiprazole, seven patients regained menstruation during the study, whereas none receiving placebo did. Plasma levels of haloperidol were not significantly altered. No significant time effect and time-by-group interactions on BPRS, Scale for the Assessment of Negative Symptoms, and Simpson-Angus Rating Scale scores were noted. Adjunctive aripiprazole treatment reversed hyperprolactinemia in both sexes, resulting in reinstatement of menstruation in female patients, with no significant effects on psychopathology and extrapyramidal symptoms. Aripiprazole has higher affinity to dopamine D(2) receptors than haloperidol, which is the likely cause of this observation.

TDM and Pharmacogenetic Tests as Tools in Pharmacovigilance: Case Reports

Our hypothesis is, that: 1) a relevant number of Adverse Drug Reactions are dose dependent side effects (e.g. extrapyramidal side effects correlate with Dopamin2 receptor occupancy which correlates with plasma levels of haloperidol), 2) plasma levels of a given drug reflect better than its dose brain concentrations, 3) plasma levels are, amongst other, dependent on the pharmacogenetic status of the patient.

Haloperidol Half-life After Chronic Dosing

In normal subjects after a single oral dose, haloperidol half-life has been reported to range 14.5-36.7 hours (or up to 1.5 days). After chronic administration, half-lives of up to 21 days have been reported. The objective of this study was to evaluate specific factors that might account for differences in haloperidol half-life in patients taking haloperidol chronically, including gender, age, weight, race, CYP2D6 and CYP3A5 genotypes, comedication, and smoking.Thirty-one patients were administered haloperidol for 4 weeks followed by a 1-week washout before administration of clozapine. Haloperidol plasma levels were measured weekly for at least 2 months after discontinuation. The geometric mean for haloperidol half-life and detectable levels duration were 3.9 and 13.8 days, respectively. Within 31 subjects, 58% (18/31) had half-lives <3 days (1.2-2.3 days) and 42% (13/31) had half-lives > or =3 days. Two of 3 patients with half-lives longer than 30 days (720 hours) and levels detectable >2 months had received haloperidol decanoate. Five patients who received haloperidol decanoate in the prior year were excluded from a comparison between patients with long haloperidol half-lives (> or =3 days, n = 10) and patients with short half-lives (<3 days, n = 16). The only significant difference between the two groups was that African-Americans (n = 4) were all found to have a long haloperidol half-life (P = 0.014). CYP3A5 genotype did not appear to influence haloperidol half-life but the two CYP2D6 poor metabolizer had half-lives > or =3 days. This study suggests that haloperidol half-life following repeated drug administration is substantially more prolonged than what has been observed after acute haloperidol administration.

Effect of CYP2D6 genotypes on the metabolism of haloperidol in a Japanese psychiatric population.

We investigated the effect of CYP2D6 genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 88 Japanese schizophrenic inpatients being treated with HAL. Some subjects carrying CYP2D6*5 allele (CYP2D6*1/CYP2D6*5, CYP2D6*5/CYP2D6*10) showed extremely high concentrations of both HAL and RHAL, and the groups with CYP2D6*5 allele seemed to have higher plasma concentrations of HAL (1.14+/-0.69 ng/ml/mg) and RHAL (1.10+/-1.05 ng/ml/mg) than the other groups. Among those without CYP2D6*5 allele, there were no significant differences in plasma concentrations of HAL and RHAL between those without CYP2D6*10 allele (HAL=0.68+/-0.31 ng/ml/mg, RHAL=0.28+/-0.37 ng/ml/mg), those with one CYP2D6*10 (HAL=0.70+/-0.23 ng/ml/mg, RHAL=0.31+/-0.16 ng/ml/mg) and those with two CYP2D6*10 alleles (HAL=0.69+/-0.14 ng/ml/mg, RHAL=0.40+/-0.09 ng/ml/mg), although there was a tendency of higher plasma concentration of RHAL in those with two CYP2D6*10 alleles. At a lower daily dosage of HAL (<10 mg/day), the subjects with two or one CYP2D6*10 allele(s) showed significantly higher plasma concentrations of RHAL (0.43+/-0.23 ng/ml/mg, 0.34+/-0.16 ng/ml/mg) than those without CYP2D6*10 allele (0.18+/-0.16 ng/ml/mg). The results of this study indicate that CYP2D6*10 allele plays significant but modest role in HAL metabolism in Japanese; nevertheless, we should not lump CYP2D6*10 allele with CYP2D6*5 allele because these two mutated alleles seem to have different impacts in the metabolism of HAL.

Usefulness of Plasma Haloperidol Levels for Monitoring Clinical Efficacy and Side Effects in Alzheimer Patients With Psychosis and Behavioral Dyscontrol

This study investigated whether measurement of plasma levels may be useful in monitoring clinical efficacy and side effects during oral haloperidol (HL) treatment of psychosis and behavioral dyscontrol in patients with Alzheimer disease (AD). After a single-blind placebo period of 1 week, 71 outpatients with AD were randomized to a 6-week, double-blind, placebo-controlled trial of HL 2 mg-3 mg/day (standard dose), HL 0.5 mg-0.75 mg/day (low dose), or placebo, with plasma levels for HL drawn at the end of 6 weeks. Of the 40 patients who received active HL for 6 weeks, 35 had plasma levels drawn. Plasma levels were all below the lower limit of the postulated therapeutic range in schizophrenia. Nonetheless, HL plasma level significantly correlated with clinical efficacy as measured by reduction in Brief Psychiatric Rating Scale Total score, Psychosis factor, and Hostile-Suspiciousness factor, the Behavioral Syndromes Scale for Dementia Psychomotor Agitation scale, and with the severity of extrapyramidal side effects (EPS). Oral dose did not significantly correlate with any of these efficacy or side-effect measures. Plasma levels significantly correlated with HL dose. When both HL dose and HL plasma level were included as independent variables in linear-regression analyses, only HL plasma level was a significant predictor of efficacy and EPS. Measurement of HL plasma levels may have potential usefulness as an adjunct in monitoring treatment response to oral HL in AD patients with psychosis or disruptive behavior.

Lack of impact of CYP1A2 genetic polymorphism (C/A polymorphism at position 734 in intron 1 and G/A polymorphism at position −2964 in the 5′-flanking region of CYP1A2) on the plasma concentration of haloperidol in smoking male Japanese with schizophrenia

The impact of genetic polymorphism of CYP1A2 that are related to the induction of the isozyme on the plasma levels of haloperidol (HAL) in 40 male smokers with schizophrenia was investigated. A point mutation from C to A in intron 1 at position 734 and a point mutation from G to A at position −2964 in the 5′-flanking region of CYP1A2 were identified by polymerase chain-reaction-restricted fragment length polymorphism method. Regarding C/A polymorphism in intron 1 at position 734, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight among the subjects with A/A ( n=21), A/C ( n=14) and C/C ( n=5) genotypes (one-way analysis of variance: 63.1±18.5, 47.8±12.5 and 50.8±15.1 ng/ml/mg/kg, respectively, F(2,37)=2.556, P=.09). Regarding G/A polymorphism at position −2964 in the 5′-flanking region, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight between subjects with G/G ( n=24) and G/A ( n=15) (two-tailed t test: G/G and G/A=51.2±16.6 and 59.0±17.6 ng/ml/mg/kg, respectively, df=28, P=.22). The present study suggests that the genotyping of CYP1A2 cannot predict the steady state plasma levels of HAL in male smoking schizophrenics.

The impact of genetic polymorphism of CYP1A2 inducibility on the steady state plasma haloperidol levels in smokers

s: The 10th Annual Meeting of the Japanese Society of Clinical Neuropsychopharmacology, Tokyo, Japan, 15-16 November 2000

Effect of Chlorpromazine and Clozapine on Plasma Concentrations of Haloperidol in a Patient with Schizophrenia

A 40-year-old patient being treated for schizophrenia developed elevated plasma levels of haloperidol (HAL) in combination with chlorpromazine (CPZ) and during overlap treatment with clozapine. Competitive inhibition of HAL by first CPZ and then clozapine is discussed as a possible mechanism.

CYP2D6*10 alleles are not the determinant of the plasma haloperidol concentrations in Asian patients.

The authors we investigated the relationship between plasma levels of haloperidol (HAL) and the number of CYP2D6*10 (*10) alleles in 66 Japanese inpatients with schizophrenia (male = 61, female = 5) on HAL. Plasma HAL level was determined by an enzyme immunoassay method. Daily dose of HAL was 1.5-36 (mean +/- SD = 12.3 +/- 7.6) mg or 0.02-0.49 (0.21 +/- 0.13) mg/kg body weight. Plasma HAL levels ranged from 1.4 to 47.4 (12.4 +/- 9.5) ng/mL. No significant difference in the plasma HAL levels was observed between the subjects with no, one, and two *10 alleles (one-way analysis of variance: 56.1 +/- 20.3, 61.0 +/- 20.3, and 63.3 +/- 20.3 ng/mL/mg/kg, respectively, F(2,63) = 0.65, p = 0.52). These results are not supportive of the previous report that plasma HAL levels can be predicted by the number of *10 alleles in Asian patients.

The effect of cytochrome P450 2D6 genotypes on haloperidol metabolism: a preliminary study in a psychiatric population.

We investigated the effect of cytochrome P450 (CYP2D6) genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 47 Japanese male schizophrenic inpatients being treated with HAL. Mutation-specific polymerase chain reaction (PCR) analysis was used to detect CYP2D6*10 as the C188C1T mutation in exon 1. A long-PCR analysis method was used to detect CYP2D6*5. Allele frequencies of CYP2D6*5 and CYP2D6*10 were 4.3% and 34.0%, respectively. Plasma concentrations of HAL and RHAL were measured using high-performance liquid chromatography. The ranges of the plasma concentration of HAL and RHAL corrected to the dose were 0.28-1.60 (mean +/- SD, 0.66+/-0.25, n = 47) ng/mL/mg and 0.03-3.00 (mean+/-SD, 0.36+/-0.46, n = 47) ng/mL, respectively. Plasma RHAL/HAL ratios (R/H ratios) ranged from 0.06 to 1.88 (mean +/- SD, 0.48+/-0.32, n = 47). The analysis was performed among the four genotype groups: CYP2D6*1/CYP2D6*1 (n = 11), CYP2D6*1/CYP2D6*10 (n = 11), CYP2D6*10/CYP2D6*10 (n = 6) and those who have CYP2D6*5 allele (CYP2D6*1/ CYP2D6*5 or CYP2D6*5/CYP2D6*10 (n = 4). We observed significant tendency in effects of CYP2D6 genotypes on plasma concentration of HAL and significant effects on plasma concentration of RHAL, and R/H ratio. These results we obtained suggested that the plasma concentration of HAL and RHAL were determined partly by CYP2D6 polymorphic activity.

An investigation of ethnic and gender differences in the pharmacodynamics of haloperidol

The objective of this study was to examine neuroleptic effectiveness among Asians and Caucasians, and to investigate inter-ethnic pharmacodynamic differences. Asians and Caucasians suffering a first episode of psychosis were maintained on low oral doses of haloperidol (2 mg/day) for the first week of treatment. Doses were increased weekly until the optimal therapeutic dosage was achieved. This was defined as the point at which subjects: (a) experienced significant clinical improvement; or (b) developed extrapyramidal side effects. Plasma haloperidol and prolactin were measured at intake, at the end of first week of the treatment on haloperidol 2 mg/day, and at optimal therapeutic dosage. The average optimal dosage for Asians and Caucasians was equal. However, at the end of the first week of haloperidol at a fixed dose of 2 mg, Caucasian males had significantly lower plasma haloperidol levels than Asian males while no ethnic differences in haloperidol levels were found among females. There were no ethnicity or gender effects on plasma prolactin response after 1 week of treatment. Ethnicity and gender may affect haloperidol metabolism.

Change in plasma prolactin and clinical response to haloperidol in schizophrenia and schizoaffective disorder

There has been a long-standing interest in plasma prolactin as a potential in vivo indicator of blockade of tuberoinfundibular D 2 dopamine receptors. Potential relationships between prolactin response and neuroleptic treatment have been obscured by the use of high doses which have caused prolactin to plateau. With lower doses of neuroleptic now commonly in use, prolactin may be more valuable as a correlate of clinical response. In this study, 23 acutely exacerbated schizophrenic and schizoaffective patients were washed out for at least 6 days and were then treated with haloperidol to achieve fixed low to moderate plasma levels under double-blind conditions. Clinical response, plasma prolactin, and haloperidol plasma levels were measured weekly for 3 weeks. Clinical symptoms at endpoint were related to both prolactin change and final prolactin level during haloperidol treatment. Specifically, fewer symptoms at endpoint were associated with a greater increase in prolactin over time and a higher prolactin level at endpoint. Thus, prolactin increase caused by low to moderate doses of haloperidol may be a correlate of endpoint symptomatology. As lower doses of typical neuroleptics are now in use, prolactin response as a predictor of clinical response may have more clinical utility. Further study of prolactin and clinical response to typical neuroleptics should focus on low neuroleptic doses.