Acute mania: haloperidol dose and augmentation with lithium or lorazepam

Antipsychotic dosing for acute mania has not been well studied. Combined treatment with lithium and an antipsychotic is the most common treatment, but additional antimanic efficacy of a lithium-antipsychotic combination beyond that of an antipsychotic alone has not been well demonstrated. Furthermore, the possibility that lithium could affect antipsychotic dose requirement is believed to have never been studied. In this study, 63 acutely psychotic bipolar manic inpatients were randomly assigned to receive double-blind treatment with 1 of 2 haloperidol doses, 25 mg/day or 5 mg/day, for 21 days. In addition to haloperidol, subjects were randomly assigned to receive concomitant treatment with placebo, standard lithium, or lorazepam 4 mg/day. The high haloperidol dose produced greater improvement and more side effects than did the low dose. Lithium added to the low dose produced a markedly greater clinical response than did the low dose alone. Lorazepam did not improve the outcome for the patients receiving low-dose haloperidol. The clinical response produced by high-dose haloperidol was not enhanced by adding either lithium or lorazepam. All treatment effects emerged by the fourth day of treatment and persisted. Used alone, a haloperidol dose of 5 mg/day is too low for most manic patients, but concomitant lithium produces a dose-dependent enhancement of haloperidol response. Lorazepam 4 mg/day was insufficient to produce an advantage when added to low-dose haloperidol.     

Carbamazepine augmentation in lithium-refractory bipolar patients: a prospective study on long-term prophlyactic effectiveness

Twenty-two patients affected by bipolar or schizoaffective disorder, in whom carbamazepine was added to lithium after recurrence when on maintenance with lithium alone, were followed up prospectively for 2 to 13 years. The number of episodes, hospitalizations, and cumulative affective morbidity was markedly reduced after carbamazepine augmentation. Seventeen patients presented a better course during combined treatment than during lithium alone, and of these 15 had no further recurrences. Four patients did not appear to improve after carbamazepine augmentation, whereas one featured reemergence of affective episodes after having derived satisfactory benefit from combination for 7 years (delayed tolerance). Carbamazepine augmentation was associated with a reduction of lithium doses in some patients, including a subgroup who had not tolerated lithium at usual therapeutic levels. Carbamazepine significantly reduced serum thyrotropin concentrations, which were abnormally high in approximately one half of patients when on lithium alone. Total serum thyroxine concentrations were also decreased after carbamazepine augmentation, but free thyroid hormone concentrations did not change. Other significant carbamazepine-induced changes in laboratory tests included increases in total cholesterol concentrations and decreases in white blood cell counts.     

Effect of combination of aripiprazole with carbamazepine and fluvoxamine on liver functions in experimental animals

Objectives:

Aripiprazole, a new atypical antipsychotic drug extensively metabolized by enzyme CYP3A4, is found to produce asymptomatic elevation of serum transaminase levels on long-term treatment. The present study aims to evaluate the hepatotoxic effect of aripiprazole when coprescribed with carbamazepine and fluvoxamine.

Materials and Methods:

The rats were subjected to chronic treatment with two different doses, therapeutic dose (TD) and maximum therapeutic dose (MTD), of aripiprazole in combination with carbamazepine and fluvoxamine. The changes in hepatic function was assessed by various biochemical liver enzyme markers like serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), total bilirubin, histological studies, and physical parameters (liver weight, liver volume, and body weight).

Results:

The combination of aripiprazole with fluvoxamine at both TD and MTD showed the hepatic damage and significant elevation in serum transaminase level which is supported by histological reports. The coadministration of aripiprazole with carbamazepine leads to significant decrease in blood concentration of aripiprazole possibly due to induction of enzyme CYP3A4 resulting in loss or reduction of clinical efficacy.

Conclusions:

There would be an accumulation of aripiprazole when coadministered with fluvoxamine, a known inhibitor of CYP3A4, leading to hepatic damage and reduction in aripiprazole when administered along with carbamazepine. Therefore, aripiprazole with fluvoxamine and carbamazepine should be coprescribed with caution. The patients should be monitored for signs of adverse effects like hepatic damage or decreased efficacy of these drugs.KEY WORDS: Aripiprazole, antipsychotic drug, carbamazepine, drug-drug interaction, fluvoxamine, hepatotoxicity     

Use of carbamazepine in psychiatric disorders

Use of carbamazepine for the treatment of psychiatric disorders is reviewed. Carbamazepine's mechanism of action may be related to inhibition of kindling (repeated subtherapeutic electrical stimulation) in the temporal lobe and limbic system. In most published studies, carbamazepine was useful in affective disorders, especially in patients with bipolar manic disorders. In controlled, double-blind studies in patients with primary affective or schizoaffective disorders, carbamazepine significantly decreased manic symptoms and showed some antidepressant effect. Synergistic effects have been observed when carbamazepine is used with lithium. Carbamazepine has been reported to decrease symptoms in patients with aggression, dyscontrol syndromes, schizophrenia, and alcohol withdrawal syndrome, but few of these studies have been controlled, comparative trials; carbamazepine may be useful in patients with these disorders who do not respond to conventional therapies. Beneficial effects of carbamazepine in psychiatric disorders are usually observed with doses of 400-1600 mg/day and serum concentrations of 8-12 micrograms/mL. Carbamazepine is useful alone or in combination with other agents for bipolar affective disorders, especially in patients who are intolerant of or unresponsive to lithium. Serum carbamazepine concentration, hematological profile, and serum electrolytes should be monitored carefully to minimize the risk of toxicity.     

Use of lithium, carbamazepine, and valproic acid in a state-operated psychiatric hospital.

OBJECTIVE: To examine the prescribing of mood stabilizers (lithium, carbamazepine, and valproic acid) in a 500-bed state-operated psychiatric hospital in New York. METHODS: All 129 inpatients receiving mood stabilizers were identified and their medical records reviewed using a standardized drug use evaluation form. Diagnosis, other indications, and prior experience with mood stabilizers were examined, as well as outcome and adverse effects. RESULTS: Approximately one-quarter of the inpatient population received a mood stabilizer. The frequency of carbamazepine use exceeded the use of lithium, with 72 patients receiving carbamazepine and only 62 receiving lithium. Twenty-eight patients received valproic acid. Indications found most frequently for carbamazepine use included assaultive or aggressive behavior (70% for those receiving carbamazepine as the only mood stabilizer). Of those patients with bipolar or schizoaffective disorder and receiving either lithium, carbamazepine, or valproic acid, 36% were prescribed carbamazepine (10% as a first-line agent) and 50% lithium (26% as a first-line agent). None of these indications for carbamazepine has been approved by the Food and Drug Administration. In general, positive outcomes were documented but without supporting objective measures. Significant adverse effects were documented in the medical record in one-quarter of the patients. CONCLUSIONS: There was widespread use of the three mood stabilizers examined, singly and in combination, for a variety of indications. Lithium and valproic acid remain more frequently prescribed for the treatment of bipolar and schizoaffective disorders. Monotherapy with carbamazepine or valproic acid results in statistically significantly fewer adverse effects than lithium or combination therapy (p values between p = 0.00038 and p = 0.006). Current clinical practice has endorsed the use of carbamazepine for aggressive or assaultive behavior, although there does not appear to be sufficient proof of effectiveness in the literature. Formal studies of carbamazepine's antiagressive effects should be conducted.     

The lithium concentration of the blood plasma in combined therapy with lithium carbonate and carbamazepine]

In view of the fact that therapy of affective psychoses with the combination of lithium carbonate with carbamazepine has been becoming ever common, the question arises about the influence of carbamazepine on plasma lithium concentration. On the material of 125 blood samples by using the method of dispersion analysis it was shown that carbamazepine exerts no effect on this parameter. Therefore when carbamazepine is added to lithium therapy it is not advisable to decrease lithium dose as it can result in a reduction of the therapeutic effect.     

Tetraspan protein CD151: a common target of mood stabilizing drugs?

The latency in onset of antimanic and mood stabilizing effects of lithium suggest that long-term neuronal adaptations mediated by changes in gene expression may be important to the therapeutic action of lithium treatment. Using differential display-polymerase chain reaction, several novel, hitherto unexpected lithium-regulated genes have been isolated, all of which would not have been predicted with the candidate gene approach. During the process of characterizing one of these novel genes, we have identified a cDNA clone, a homolog of human/mouse transmembrane-4-superfamily (also known as tetraspan) protein, CD151, the expression of which was significantly decreased in rat frontal cortex following chronic (five weeks) lithium treatment. The reduction of CD151 mRNA levels was also observed following chronic administration of carbamazepine and valproate. Conversely, the expression of CD151 was not altered by short-term (one week) lithium treatment and by chronic administration of the tricyclic antidepressant, imipramine, or the typical antipsychotic, haloperidol, further demonstrating time dependence and pharmacological specificity of this effect. Our studies, thus, indicate that CD151 may represent a therapeutically relevant target common to lithium and the anticonvulsant mood stabilizing drugs, carbamazepine and valproate.     

Effects of carbamazepine on plasma haloperidol levels

Plasma haloperidol levels were monitored in three schizophrenic patients when carbamazepine was either added or discontinued. The percent decrease in plasma haloperidol levels due to concomitant carbamazepine therapy was between 59% and 61%. The effects of carbamazepine on plasma haloperidol levels were noted to occur in 2 to 3 weeks. Although no adverse effects occurred in the patients during therapy, careful monitoring of clinical symptoms and plasma haloperidol levels is recommended.     

Addition of lithium to haloperidol in non-affective,antipsychotic non-responsive schizophrenia: a double blind,placebo controlled,parallel design clinical trial

This double-blind placebo controlled, parallel design clinical trial compared the therapeutic effects of the addition of lithium or placebo to haloperidol in 21 seriously ill state hospital patients with DSM-III-R schizophrenia, who did not have concurrent affective disorders and who had not responded to previous trials of conventional antipsychotic medication. During a baseline period of 6 weeks, patients were switched to a stable dose of haloperidol (mean ± SD dose=13.6±8.1 mg/day). Patients were then randomized to receive either lithium or placebo in addition to haloperidol for 8 weeks (mean ± SD lithium level =0.98±0.13 mEq/1). Symptoms and side effects were assessed weekly. Improvement in symptoms correlated with the non-blind adjustment of antipsychotic dose, but not with lithium or placebo treatment. Side effects ratings did not differ between the two groups, but one patient developed a reversible delirium associated with combined lithium/haloperidol treatment. For these long-term, severely ill patients, combined treatment afforded no advantage over treatment with haloperidol alone.Supported by Grant MH 46700 from the National Institute for Mental Health. Lithium and lithium placebo capsules were supplied by Lilly Pharmaceuticals     

Significant dose effect of carbamazepine on reduction of steady-state plasma concentration of haloperidol in schizophrenic patients

A reduction in haloperidol concentration induced by carbamazepine coadministration has been consistently reported. However, the degree of this reduction is very different among individuals treated with various doses of carbamazepine. Thus, we investigated dose effect of carbamazepine on the steady-state plasma concentration of haloperidol. Eleven excited schizophrenic inpatients, despite receiving haloperidol 12 mg/d, were treated with incremental doses of carbamazepine for 6 weeks (100, 300, 600 mg/d for 2 weeks each). Plasma drug concentrations were monitored together with clinical assessments before and after each phase of the 3 carbamazepine doses. Mean haloperidol concentrations during coadministration of carbamazepine 100, 300, and 600 mg/d were 75%, 39%, and 15%, respectively, of corresponding variables before carbamazepine coadministration. Negative linear correlations were observed between dose or plasma concentration of carbamazepine and the degree of reduction in haloperidol concentration. Mean carbamazepine dose and plasma carbamazepine concentrations at 50% reduction of haloperidol concentration were 240 mg/d and 3.5 microg/mL, respectively. Scores in total and excitement symptoms were significantly reduced after carbamazepine coadministration, whereas no changes were observed in other clinical symptoms or any of the subgroup side effects. Therefore, this study indicates that carbamazepine decreases plasma haloperidol concentration in a dose-dependent or concentration-dependent manner, and that reduction in haloperidol concentration is apparent even at subtherapeutic dose of carbamazepine.     

Individual differences in serum levels of lithium in human subjects receiving fixed doses of lithium carbonate. relation to renal lithium clearance and body weight

Summary Serum levels of lithium were determined in ten healthy subjects receiving a fixed dose regimen of lithium carbonate for eight days. A steady state level of the morning serum lithium concentration was obtained after 6 to 8 days, and this level varied up to 3-fold between subjects. The lithium levels in serum were significantly correlated with the renal lithium clearances (p<0.05). There was a highly significant correlation (p<0.001) between the steady state level and the product of lithium clearance and body weight. No correlation was found between renal lithium and creatinine clearances.     

Effects of carbamazepine on serum antidepressant concentrations in psychiatric patients.

The combination of carbamazepine and an antidepressant (doxepin, amitriptyline, mianserin) was given to 22 psychiatric inpatients with 29 measurements of their serum antidepressant concentrations. For comparison, sex-, age-, and dose-matched inpatients, treated with the antidepressant but not with carbamazepine, were selected as controls (N = 29). All the patients were treated with their routine daily dose for at least 7 days before the gas-chromatographic measurement of serum predose concentrations of the antidepressants. In patients with carbamazepine, serum doxepin and doxepin + nordoxepin concentrations (N = 17) were decreased significantly (p less than 0.05), on average to 46% and 45%, respectively, as compared to that in subjects without carbamazepine. Also in carbamazepine + amitriptyline patients, serum nortriptyline and amitriptyline + nortriptyline concentrations (N = 8) were significantly lower than in those not receiving carbamazepine (p less than 0.05). The mean serum antidepressant levels were decreased to 42% and 40%, respectively. The serum mianserin concentration of carbamazepine patients (N = 4) was reduced to 30% of that in patients not treated with carbamazepine (p less than 0.01). The percentage fractions of demethylated metabolites (nordoxepin, nortriptyline) from the total antidepressant levels were not influenced by carbamazepine. In patients treated with carbamazepine, serum total antidepressant concentrations remained more often below the suggested therapeutic ranges than in those patients without carbamazepine. The results suggest that serum antidepressant concentrations are reduced by concurrent carbamazepine therapy, and that the concentrations should be carefully monitored when carbamazepine is added to the antidepressant regimen.     

碳酸锂对甲状腺机能亢进患者摄碘率的影响

目的　通过对甲状腺机能亢进症 (甲亢 )患者服用碳酸锂前、后甲状腺摄碘率变化的观察 ,了解碳酸锂对甲状腺摄碘率的影响。方法　 2 0例甲亢患者口服碳酸锂 0 .2 5g ,tid ,共 4周 ,分别在用药前、后进行甲状腺摄碘率和甲状腺激素水平的测定 ,并比较两次差别。结果　 2 0例患者在服用碳酸锂后甲状腺的摄碘率比服用前明显升高 ,具有统计学差异 (P <0 .0 1) ;而甲状腺激素水平无明显变化。结论　碳酸锂能够提高甲亢患者的甲状腺摄碘率 ,在一定程度上减少了放射性13 1I的治疗用量。     

Modification of the radioreceptor assay technique for estimation of serum neuroleptic drug levels leads to improved precision and sensitivity

This report describes a series of modifications in the radioreceptor assay procedure for monitoring of serum neuroleptic levels which resulted in a substantial increase in precision and in a higher sensitivity than is the case with existing assays. The use of a dopamine receptor preparation from pig striatum yielded a lower limit of sensitivity for haloperidol of 0.08 ng/ml, when 0.5 ml serum was used in the assay; the intra- and inter-assay coefficients of variation were 3 and 9%, respectively. The relative antipsychotic potency of various neuroleptics correlated with their optimal daily dosage. Anticonvulsants (carbamazepine, phenytoin, barbiturates), anxiolytics (diazepam, bromazepam), as well as other drugs or hormones such as lithium, chloral hydrate, l-tryptophan or l-thyroxine did not interfere with the assay. Simultaneous determination of haloperidol by the radioreceptor assay and radioimmunoassay in serum showed good correlation (r=0.994). Good correlation was also noted between the average optimal clinical daily dose of the neuroleptics and their affinity to the dopamine receptor of the porcine striatum (r=0.891). Cross-laboratory assessment indicated good correlation between the estimation of haloperidol by a dopamine receptor preparation from bovine caudata and porcine striata (r=0.830). The sensitivity of the present assay was improved about 30-fold compared to those previously reported.     

The use of drug level measurements in adult patients receiving theophylline, anti-epileptic drugs and amikacin.

This prospective study was conducted to determine how frequently measurement of drug levels was used in the management of adult patients receiving theophylline, phenytoin, phenobarbitone, carbamazepine or aminoglycosides in a large hospital. Fifty consecutive outpatients with asthma and 40 with epilepsy were interviewed and their records reviewed to determine which drugs had been prescribed and whether a level of the appropriate drug had been measured in the previous six months. Also, the records of 40 in-patients who were currently receiving amikacin were studied to determine whether serum levels had been measured at any stage during therapy with this drug. Serum theophylline levels were measured in only four (eight pc) patients who were taking this drug and were below the target range in two patients. Serum levels had been measured in 21 (52.5 pc) of 40 patients who were receiving 45 anti-epileptic drugs and were within the target in only nine. Serum amikacin levels were measured in 15 (37.5 pc) patients; blood had been taken for both peak and trough levels in 10 patients and found to exceed the target range in two patients. This study revealed that measurement of serum concentrations of theophylline, anti-epileptic drugs and amikacin was underutilised in the management of adult patients receiving these drugs at this hospital.     

锂盐与氟哌啶醇合用治疗躁狂症131例回顾分析

本文比较锂盐与氟哌啶醇合用组(86例)和其它药物组(45例)的各种副反应。研究发现2组之间锥外系反应发生率无明显差别(P>0.05)。无1例有神经中毒症状。研究表明,只要剂量适中、严密观察,锂盐和氟哌啶醇合用是安全的。     

A comparison of the effects of quetiapine ('seroquel') and haloperidol in schizophrenic patients with a history of and a demonstrated, partial response to conventional antipsychotic treatment. PRIZE Study Group

Quetiapine ('Seroquel') is a well-tolerated, novel, atypical antipsychotic with consistent efficacy in the treatment of schizophrenia. To date, no clinical studies have evaluated the effect of quetiapine in patients who only partially respond to conventional antipsychotics, yet this type of patient is most frequently seen by psychiatrists. Therefore, this international, multicentre, double-blind study was conducted to compare the efficacy and tolerability of 8 weeks' treatment of quetiapine 600 mg/day with haloperidol 20 mg/day in 288 patients who had a history of partial response to conventional antipsychotics and displayed a partial or no response to 1 month of fluphenazine (20 mg/day) treatment. Patients on quetiapine tended to have greater improvement than those on haloperidol in the primary efficacy measure, mean Positive and Negative Symptom Scale (PANSS) score, after 4 weeks' treatment (-9.05, -5.82, respectively, P = 0.061) and at study end (-11.50, -8.87, respectively, P = 0.234). Similarly, there was a trend towards patients on quetiapine demonstrating greater improvements in the secondary efficacy measures (Clinical Global Impression, PANSS subscale and Brief Psychiatric Rating Scale scores) [week 4 (baseline) to week 12 (end)], but the difference between treatments did not reach significance. Significantly more patients on quetiapine than on haloperidol showed a clinical response-patient response rates, defined as > 20% reduction in PANSS total score between weeks 4 and 12, were 52.2% for quetiapine and 38.0% for haloperidol (P = 0.043). Patients receiving quetiapine required less anticholinergic medication (P < 0.011), had greater reduction in extrapyramidal symptoms (EPS) (P = 0.005) and fewer treatment-emergent EPS-related adverse events compared to those on haloperidol (P < 0.001). Serum prolactin concentrations were elevated at the end of fluphenazine treatment in 73% of patients. Between weeks 4 and 12, elevated serum prolactin concentrations significantly decreased in quetiapine-treated patients compared to those receiving haloperidol (P < 0.001). At the end of quetiapine treatment, 83% of patients had normal prolactin levels while only 21% of patients receiving haloperidol were within the normal range. These results suggest that quetiapine may make a valuable contribution to the management of patients with a history of partial response to conventional antipsychotics.     

Effect of chronic lithium treatment with or without haloperidol on number and sizes of neurons in rat neocortex

The present study used stereological methods to determine whether long-term administration of lithium, with or without haloperidol, affects the number and average volume of neocortical neurons. Twenty-five rats were divided into three groups and given no treatment, lithium, or lithium combined with haloperidol. Serum lithium levels ranged from 0.5 to 0.8 mmol/l. Haloperidol was injected intraperitoneally at a daily dose of 1 mg/kg. After 30 weeks of treatment, the animals were killed and the brains were prepared. Neocortical volume, density of neurons, total number of neurons and mean volume of neurons were estimated. As no differences were found between the groups, the present study provides no evidence for quantitative morphological changes in the cerebral cortex due to long-term therapeutic levels of lithium, with or without haloperidol.     

Antipsychotic drugs, lithium, carbamazepine, and abnormal diurnal weight gain in psychosis

Diurnal weight gain was abnormal among 149 institutionalized chronically psychotic patients. We weighed patients weekly for 3 weeks at 7 A.M. and 4 P.M. and then normalized the diurnal weight gain (NDWG) as a percentage by subtracting the 7 A.M. weight from the 4 P.M. weight, multiplying the difference by 100, and dividing the result by the 7 A.M. weight. The NDWG was 2.026% +/- 1.399% for patients and 0.511% +/- 0.351% for normals. The NDWG related (Spearman rho = 0.328, p less than 0.0001) to chlorpromazine equivalent dose. The absence of lithium and carbamazepine, lithium alone, carbamazepine alone, and the combination of lithium and carbamazepine did not alter NDWG. Our data suggest that antipsychotic drugs may contribute to abnormal weight gain in chronic psychosis but that lithium and carbamazepine do not.