Doses Of Haloperidol Research Articles

Haloperidol prophylaxis in critically ill patients with a high risk for delirium

IntroductionDelirium is associated with increased morbidity and mortality. We implemented a delirium prevention policy in intensive care unit (ICU) patients with a high risk of developing delirium, and evaluated if our policy resulted in quality improvement of relevant delirium outcome measures.MethodsThis study was a before/after evaluation of a delirium prevention project using prophylactic treatment with haloperidol. Patients with a predicted risk for delirium of ≥ 50%, or with a history of alcohol abuse or dementia, were identified. According to the prevention protocol these patients received haloperidol 1 mg/8 h. Evaluation was primarily focused on delirium incidence, delirium free days without coma and 28-day mortality. Results of prophylactic treatment were compared with a historical control group and a contemporary group that did not receive haloperidol prophylaxis mainly due to non-compliance to the protocol mostly during the implementation phase.ResultsIn 12 months, 177 patients received haloperidol prophylaxis. Except for sepsis, patient characteristics were comparable between the prevention and the historical (n = 299) groups. Predicted chance to develop delirium was 75 ± 19% and 73 ± 22%, respectively. Haloperidol prophylaxis resulted in a lower delirium incidence (65% vs. 75%, P = 0.01), and more delirium-free-days (median 20 days (IQR 8 to 27) vs. median 13 days (3 to 27), P = 0.003) in the intervention group compared to the control group. Cox-regression analysis adjusted for sepsis showed a hazard rate of 0.80 (95% confidence interval 0.66 to 0.98) for 28-day mortality. Beneficial effects of haloperidol appeared most pronounced in the patients with the highest risk for delirium. Furthermore, haloperidol prophylaxis resulted in less ICU re-admissions (11% vs. 18%, P = 0.03) and unplanned removal of tubes/lines (12% vs. 19%, P = 0.02). Haloperidol was stopped in 12 patients because of QTc-time prolongation (n = 9), renal failure (n = 1) or suspected neurological side-effects (n = 2). No other side-effects were reported. Patients who were not treated during the intervention period (n = 59) showed similar results compared to the untreated historical control group.ConclusionsOur evaluation study suggests that prophylactic treatment with low dose haloperidol in critically ill patients with a high risk for delirium probably has beneficial effects. These results warrant confirmation in a randomized controlled trial.Trial registrationclinicaltrial.gov Identifier: NCT01187667.

Dr Mittal and Colleagues Reply

To the Editor: We thank Dr Zamani for taking the time and interest to pose these important questions about our article.1 First, we would like to clarify that the article is based on a case report and is not a formal study. We will address the questions and concerns in the same order as received. “They have interestingly attributed the patient’s signs and symptoms to the contents of the detoxification kit.” Response: We merely established a temporal association between the consumption of the detoxification compound and the development of psychotic symptoms. We did not establish any causative associations. “They treated the patient with haloperidol and lorazepam.” Response: The patient was given haloperidol and lorazepam only in the emergency room once for agitation. The medications were not repeated during the patient’s stay on the inpatient unit. Also, 1 dose of haloperidol and lorazepam is unlikely to treat a patient with psychotic illness secondary to cannabis abuse. As we mentioned in the case report, the psychotic symptoms resolved after discontinuation of the detoxification compound without any treatment. “No side effects have been reported for proprietary blend.” Dr Zamani provides a reference for an acai berry product with a proprietary blend. Response: The proprietary blend is the undisclosed ingredients in any product. So, it would be unjustified to compare 2 different compounds with proprietary blends, which can very well be different. Our response is that we do not know what ingredients are included in the proprietary blend, so any comment on its effects or side effects could not be justified. Dr Zamani provides a statement about the side effects of creatine. Response: We provided references for isolated case reports of psychosis with consumption of large amounts of creatine. Dr Zamani has presented a review of the side effects of the ingredients of the detoxification compound. As mentioned in our article, we completed an extensive review of the ingredients using not only the information Web sites such as www.webmd.com and information sites for the respective compounds, but also case reports and any ongoing research about these compounds, with special focus on psychotic symptoms. “How do the authors know that his symptoms were not due to acute cannabis intoxication? Response: As we mentioned in the original article, cannabis intoxication has been shown to be only a component cause of psychosis.3 In our patient, the cannabis intoxication was chronic with no history of psychotic symptoms in the past. There was no family history of psychotic illness, and psychotic symptoms resolved within 2 to 3 days without using antipsychotics, except for the single dose of haloperidol. The patient denied any psychotic symptoms at a follow-up appointment 6 months after his hospitalization. On the basis of these facts, it is unlikely that his psychosis was a direct effect of acute cannabis intoxication.

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Introduction: SCCM guidelines suggest haloperidol as the agent of choice for delirium management, yet the optimal dosing regimen is not well defined. Within our SICUs, two prescriber-dependent dosing strategies have emerged; a “conservative” strategy utilizing doses of 2mg or less given as a scheduled regimen and a “traditional” strategy utilizing larger doses above 2mg given as needed. Hypothesis: A difference in resolution of delirium and patient outcomes will be observed. Methods: This retrospective review included SICU patients that received at least one dose of haloperidol. Primary outcome measures: time to resolution of delirium, length of treatment, median dose per day of haloperidol and adjunctive treatment (hydromorphone or lorazepam equivalents), length of ICU and hospital stay. Secondary outcomes: delirium recognition, over-sedation and QTc prolongation. Data collected: demographics, APACHE II score, drug regimens, CAM score, treatment outcomes, length of stay, SAS score and QTc. Results: The study included 164 patients, with 82% in the conservative strategy group. There were an equal number of men and women, a mean age of 78 years and 69 in the conservative and traditional groups, respectively, and median APACHE II scores of 16 and 14. Time to delirium resolution was not different (5d v. 7, p=0.2). The conservative group received a longer duration of haloperidol treatment (3d v. 2, p=0.2) and less haloperidol per day (1.3mg v. 6.3, p <0.01). More opioids (2.3mg v 1.6, p=0.7) and benzodiazepines (1.2mg v. 1, p=0.5) were given to those in the traditional group, while more patients in the conservative group received adjunctive anti-psychotics (28% v. 19%, p=0.6). More patients in the traditional group had positive CAM scores at haloperidol initiation versus the conservative group (63% v. 57%, p=0.9). Hospital and SICU LOS, adjunctive treatment, over-sedation and QTc prolongation were not impacted by dosing strategy. Conclusions: The dosing strategy did not significantly impact time to resolution of delirium, delirium treatment length, adjunctive treatment, length of SICU or hospital stay, delirium recognition, over-sedation or QTc prolongation.

Cognitive Effects of a Single Dose of Atypical Antipsychotics in Healthy Volunteers Compared With Placebo or Haloperidol

Cognitive dysfunction in patients with schizophrenia is a strong correlate of poor outcome than any other symptom domain. To have greater knowledge about the effects of antipsychotics on cognitive function, subjects of this study were healthy volunteers who had no confounding variables typically found in patients with schizophrenia. The cognitive function of healthy volunteers in response to single doses of haloperidol, risperidone, aripiprazole, and amisulpride in a double-blind placebo-controlled trial was investigated. Assessments for the computerized neurocognitive test, mental and physical sedation, and extrapyramidal symptoms were performed within 1 week before (baseline) and approximately 4 hours after drug administration. Compared to the placebo, single administration of amisulpride at 400 mg in healthy volunteers enhanced word fluency test performance and remained intact after controlling for sedation and extrapyramidal symptoms. Significant improvement in some measurements of the computerized neurocognitive test was also observed in each antipsychotic-treated group but may have been related to practice effect. These findings suggest that amisulpride may have cognitive-enhancing effects in healthy volunteers.

Parkinsonism in Elderly Users of Haloperidol

Factors that influence the variation in occurrence of antipsychotic-induced parkinsonism (AIP) in the elderly have not been well elucidated. The aim of this study was to investigate the association between parkinsonism in elderly users of haloperidol and prescribed dose, plasma concentration, and duration of use of haloperidol in a cross-sectional design. This study included 150 inpatients aged 65 years and older who were treated with haloperidol. Parkinsonism assessed by the Simpson Angus Scale was present in 46% of the included patients. Prescribed haloperidol dose varied from 0.3 to 5 mg/d. Plasma concentration ranged from 0.13 to 4.11 μg/L, with one outlying measurement (21.43 μg/L). Dose is moderate but significantly associated with haloperidol plasma concentration (weighted R2 = 0.32; P < 0.001). Variability in the total score on the Simpson Angus Scale could not be explained by the variability in dose, concentration (respectively R2 = 0.003 and 0.001) nor duration of use of haloperidol. Smoking showed to be not significantly protective in the development of AIP (crude odds ratio, 0.39; 95% confidence interval, 0.15-0.997; and adjusted odds ratio, 0.44; 95% confidence interval, 0.17-1.17). In a clinical practice-setting dose, neither plasma concentration nor duration of use of haloperidol is associated with an increased occurrence of AIP. This study does not support the hypothesis of the peripheral pharmacokinetic explanation for the high prevalence of AIP and differences in AIP sensitivity in the elderly during treatment with haloperidol.

New insights into pharmacological profile of LASSBio-579, a multi-target N-phenylpiperazine derivative active on animal models of schizophrenia

Previous behavioral and receptor binding studies on N-phenylpiperazine derivatives by our group indicated that LASSBio-579, LASSBio-580 and LASSBio-581 could be potential antipsychotic lead compounds. The present study identified LASSBio-579 as the most promising among the three compounds, since it was the only one that inhibited apomorphine-induced climbing (5mg/kg p.o.) and apomorphine-induced hypothermia (15mg/kg p.o.). Furthermore, LASSBio-579 (0.5mg/kg p.o.) was effective in the ketamine-induced hyperlocomotion test and prevented the prepulse inhibition deficits induced by apomorphine, DOI and ketamine with different potencies (1mg/kg, 0.5mg/kg and 5mg/kg p.o., respectively). LASSBio-579 also induced a motor impairment, catalepsy and a mild sedative effect but only at doses 3–120 times higher than those with antipsychotic-like effects. In addition, LASSBio-579 (0.5 and 1mg/kg p.o.) reversed the catalepsy induced by WAY 100,635, corroborating its action on both dopaminergic and serotonergic neurotransmission and pointing to the contribution of 5-HT1A receptor activation to its pharmacological profile. Moreover, co-administration of sub-effective doses of LASSBio-579 with sub-effective doses of clozapine or haloperidol prevented the apomorphine-induced climbing without induction of catalepsy. In summary, our results characterize LASSBio-579 as a multi-target ligand active in pharmacological animal models of schizophrenia, confirming that this compound could be included in development programs aiming at a new drug for treating schizophrenia.

Effect of haloperidol dosing frequencies on the duration and severity of delirium in elderly hip fracture patients. A prospective randomized trial

Effect of haloperidol dosing frequencies on the duration and severity of delirium in elderly hip fracture patients. A prospective randomized trial

Role of the Dopaminergic System in the Acquisition, Expression and Reinstatement of MDMA-Induced Conditioned Place Preference in Adolescent Mice

BackgroundThe rewarding effects of 3,4-methylenedioxy-metamphetamine (MDMA) have been demonstrated in conditioned place preference (CPP) procedures, but the involvement of the dopaminergic system in MDMA-induced CPP and reinstatement is poorly understood.Methodology/Principal FindingsIn this study, the effects of the DA D1 antagonist SCH 23390 (0.125 and 0.250 mg/kg), the DA D2 antagonist Haloperidol (0.1 and 0.2 mg/kg), the D2 antagonist Raclopride (0.3 and 0.6 mg/kg) and the dopamine release inhibitor CGS 10746B (3 and 10 mg/kg) on the acquisition, expression and reinstatement of a CPP induced by 10 mg/kg of MDMA were evaluated in adolescent mice. As expected, MDMA significantly increased the time spent in the drug-paired compartment during the post-conditioning (Post-C) test, and a priming dose of 5 mg/kg reinstated the extinguished preference. The higher doses of Haloperidol, Raclopride and CGS 10746B and both doses of SCH 23390 blocked acquisition of the MDMA-induced CPP. However, only Haloperidol blocked expression of the CPP. Reinstatement of the extinguished preference was not affected by any of the drugs studied. Analysis of brain monoamines revealed that the blockade of CPP acquisition was accompanied by an increase in DA concentration in the striatum, with a concomitant decrease in DOPAC and HVA levels. Administration of haloperidol during the Post-C test produced increases in striatal serotonin, DOPAC and HVA concentrations. In mice treated with the higher doses of haloperidol and CGS an increase in SERT concentration in the striatum was detected during acquisition of the CPP, but no changes in DAT were observed.Conclusions/SignificanceThese results demonstrate that, in adolescent mice, the dopaminergic system is involved in the acquisition and expression of MDMA-induced CPP, but not in its reinstatement.

Effect of antipsychotic drugs on cortical thickness. A randomized controlled one-year follow-up study of haloperidol, risperidone and olanzapine

BackgroundImaging evidence indicates that brain alterations are primary to the full-blown onset of schizophrenia and seem to progress across time. The potential effects of antipsychotic medication on brain structure represent a key factor in understanding brain changes in psychosis. We aimed to investigate the effects of low doses of haloperidol, risperidone and olanzapine on cortical thickness. MethodWe investigated the effects of risperidone (N=16), olanzapine (N=18) and low doses of haloperidol (N=18) in cortical thickness changes during 1-year follow-up period in a large and heterogeneous sample of schizophrenia spectrum patients. The relationship between cortical thickness changes and clinical and cognitive outcome was also assessed. A group of 45 healthy volunteers was also longitudinally evaluated. Magnetic resonance imaging brain scans (1.5T) were obtained and images were analyzed by using BRAINS2. ResultsThere were no significant effects of time (F1,47<1.66; P>0.204), treatment group (F2,47<1.47; P>0.242) or group-by-time interaction (F2,47<1.82; P>0.174) for any of the cortical thickness variables. When the group of healthy controls was included in the analyses, it is of note that group-by-time interaction showed a significant result for the frontal lobe at trend level (F3,81=2.686; P=0.052). After the Bonferroni adjustment for multiple comparisons, there were no significant associations between changes in cortical thickness and clinical and cognitive outcome. ConclusionsLow doses of haloperidol, risperidone, and olanzapine seem to equally affect gray matter cortical thickness, overall and lobes, at the medium-term (1year). The clinical effectiveness of treatments was not significantly related to changes in cortical thickness.

Parametric studies of antipsychotic-induced sensitization in the conditioned avoidance response model

Repeated haloperidol and olanzapine treatment produces an enhanced disruption of avoidance responding, a validated measure of antipsychotic activity. Experimental parameters affecting this sensitization-like effect have not been thoroughly examined. The present study investigated the role of three parameters (number of injections, dose, and interval between initial exposure and challenge) in antipsychotic sensitization in the conditioned avoidance response paradigm. Well-trained Sprague-Dawley rats received different numbers of drug treatment (1-5 days) or different doses of haloperidol (0.025-0.10 mg/kg, subcutaneously) or olanzapine (0.5-2.0 mg/kg, subcutaneously). After certain time intervals (4, 10 or 17 days), they were tested for the expression of haloperidol or olanzapine sensitization in a challenge test in which all rats were injected with a lower dose of haloperidol (0.025 mg/kg) or olanzapine (0.5 mg/kg). Throughout the drug-treatment period, both haloperidol and olanzapine dose-dependently enhanced their disruption of avoidance responding. Three days later, the sensitization induced by a low dose of haloperidol (0.025 mg/kg) or olanzapine (0.5 mg/kg) was only apparent in rats that received treatment for 5 days, but not in those that received treatment for 1-4 days. The sensitization induced by the medium and high doses of haloperidol (0.05 and 0.10 mg/kg) or olanzapine (1.0 and 2.0 mg/kg) was still robust even with only 3 days of treatment. The sensitization induced by a 3-day haloperidol (0.10 mg/kg) and olanzapine (2.0 mg/kg) treatment was long-lasting, still detectable 17 days after the last drug treatment. This study suggests that antipsychotic sensitization is a robust behavioral phenomenon. Its induction and expression are strongly influenced by parameters such as number of drug exposures, drug dose, and test-retest interval. Given the importance of antipsychotic sensitization in the maintenance of antipsychotic effects in the clinic, this study introduces a paradigm that can be used to investigate the behavioral and neurobiological mechanisms underlying antipsychotic sensitization.

Combination Therapy of Zonisamide With Aripiprazole on ECT- and Benzodiazepine-Resistant Periodic Catatonia

Combination Therapy of Zonisamide With Aripiprazole on ECT- and Benzodiazepine-Resistant Periodic Catatonia

Haloperidol-loaded polysorbate-coated polymeric nanocapsules decrease its adverse motor side effects and oxidative stress markers in rats

Haloperidol is the most widely used antipsychotic drug in the treatment of psychiatric disorders. Despite its satisfactory therapeutic effect, its chronic use is related to severe motor side effects. Here, we investigate the incidence of motor side effects of haloperidol-loaded nanocapsules when compared to free haloperidol and the relation with oxidative stress (OS) development. Both vehicle (B-NcFO) and haloperidol loaded polysorbate-coated nanocapsules suspension (H-NcFO) prepared with fish oil as core showed uniform and rounded particles, nanometric size, negative zeta potential, low polydispersity indices and high encapsulation efficiency. Wistar rats received a single dose of free haloperidol (FH), B-NcFO or H-NcFO (0.2mg/kg ip) and were submitted to acute motor side effects evaluation 1h after the injection. Lower catalepsy time and oral dyskinesia were observed in H-NcFO-treated group than in FH group; however, both formulations decreased animals’ locomotor activity. In a experiment performed subchronically, rats injected daily with H-NcFO (0.2mg/kg-ip) for 28days showed decreased oral dyskinesia frequency and catalepsy time and no impairment on locomotor activity as compared to FH group (0.2mg/kg-ip). FH group showed higher OS, as observed by increased lipid peroxidation and reduced glutathione levels and catalase activity in extrapyramidal region. Our findings showed that nanocapsules may be an efficient form to prevent or minimize haloperidol motor side effects, which are related to OS development, ameliorating psychiatric patients’ quality of life.

Treatment of depression in first episode of schizophrenia: Results from EUFEST

Depressive symptomatology is an important target of treatment in first episode schizophrenia. This reanalysis of the European First Episode Schizophrenia Trial (EUFEST) describes the depressive symptomatology and the effect of antipsychotic treatment in patients suffering from first episode schizophrenia and schizophreniform disorder randomized to treatment with low dose haloperidol (n=103), amisulpride (n=104), olanzapine (n=105), quetiapine (n=104) or ziprasidone (n=82) for one year. At baseline, the mean score on the Calgary Depression Scale for Schizophrenia (CDSS) was 5.1 (±4.9) with 38.3% of patients having a CDSS score≥6, i.e. clinically relevant depressive symptom severity. During treatment depression scores decreased, the mean CDSS score being 1.1 (±2.1) and 3.0% of patients having a CDSS≥6 at 52 weeks. The proportion of patients using antidepressants during the complete trial was 18.5% in the haloperidol group, 28.6% in the olanzapine group compared to 5.8% in the quetiapine group, 12.5% in the amisulpride group, and 9.8% in the ziprasidone group. There were no differences over time in the probability of being depressed (CDSS≥6) between the 5 treatment groups after adjustment for antidepressant use, nor in a sub analysis of patients who did not take any antidepressant. Depression scores at baseline or during the trial had no effect on treatment discontinuation or on the reduction of positive symptoms. In summary, the results of EUFEST did not demonstrate a differential effect of the antipsychotics studied on depressive symptomatology in patients with first episode schizophrenia.

“Holes in My Head”

To the Editor: Delusional parasitosis is a somatic type delusional disorder in which sufferers maintain a fixed false belief that they are infested with parasites. Secondary forms of delusional parasitosis are addressed by treating the primary associated psychological or physical condition. We present a case of primary delusional parasitosis in a patient with end-stage renal disease. Case report. Mr A, a 63-year-old African American man, was admitted in 2010 to the medical floor from the dialysis unit after making some bizarre statements during a dialysis session. Psychiatry consult was requested by the medical team after the patient continued to endorse a fixed delusion that he had had 2 holes in his forehead for 2 months, which appeared intermittently and were reported by the patient to have closed before he was interviewed by the psychiatric consult team. Mr A also stated that he was not sure if any worms were crawling around in his head (pointing to his head) and was in the hospital to get the condition investigated. Upon further interview, the patient reported feeling that bugs were crawling on his skin, and he explained that insects were the reason for his severe pruritus and chronic skin condition. The patient also had a past history of increased confusion and making bizarre statements during dialysis sessions. His medical history was significant for diabetes mellitus with retinopathy, end-stage renal disease, anemia, glaucoma with partial blindness, and cutaneous lymphocytosis as well as chronic pruritus treated by glucocorticoid. Findings of head computed tomography without contrast were within normal limits, except for mild age-related generalized atrophy. Significant laboratory values included serum PO4 level of 6.2 mg/dL, serum magnesium level of 1.6 mg/dL, serum chloride level of 95 mg/dL, random blood glucose level of 375 mg/dL, blood urea nitrate level of 32 mg/dL, serum creatinine level of 5.5 mg/dL, and estimated glomerular filtration rate 13 mL/h. Differential diagnosis included chronic delirium due to dialysis and polypharmacy, delusional parasitosis, and cognitive disorder not other specified. Psychiatric consultants recommended optimization of medications and reduction of polypharmacy: Mr A was using clobetasol topical cream twice a day, fluocinonide topical twice a day, and terbinafine topical cream twice a day and taking triamcinolone 80 mg 4 times a day, finasteride 5 mg at night, clonidine 0.3 mg 3 times a day, furosemide 80 mg twice a day, hydralazine 20 mg 4 times a day, heparin 5,000 mg subcutaneously 3 times a day, labetalol 400 mg 3 times a day, isosorbide mononitrate 60 mg daily, ropinirole 1 mg at night, sliding scale insulin, pravastatin 20 mg at night, sodium bicarbonate 650 mg 3 times a day, diazepam 5 mg every 8 hours as needed, and zolpidem 12.5 mg at night. The patient was prescribed a number of sedating medications, including diazepam, zolpidem, clonidine, and hydroxyzine. Both ropinirole and hydralazine have been shown to cause psychotic symptoms.1,2 The patient’s diazepam was discontinued. His medical team was also advised to start a low dose of haloperidol, 1 mg twice a day, for delusions. The medical team was advised to premedicate with an antipsychotic, adjust the patient’s dialysis schedule, and consider changing dialysate to help reduce delirium; although dialysate was not changed, the other 2 changes were implemented as recommended. Confusion and delusions subsided after 4 days, at which time he was discharged from the hospital. Delusional parasitosis is usually diagnosed as a subtype of delusional disorder. The mean age at onset is 56.9 years, and the male-to-female ratio is 1:1.5.1 Patients describe a parasitic invasion on or inside the skin; they may bring in objects such as hair, lint, or skin—the “matchbox sign”—as proof of the infestation despite normal findings on examination.2 Patients rarely seek the help of a psychiatrist; rather, because of their belief in a somatic complaint, patients often see primary care physicians or dermatologists for treatment.1,2 Management initially involves ruling out a general medical condition and excluding the use of drugs, illicit or prescribed. Traditionally, treatment is pimozide, a dopamine antagonist, although some patients may respond to neuroleptics such as haloperidol or risperidone. Duration of treatment varies from 2 weeks to 3 months before use is tapered, but compliance can be challenging.1,3,4 Careful strategy is required to convince patients with delusional parasitosis of the importance of a psychiatric referral.

Assessment of dopaminergic involvement in cocaine‐induced conditioned taste aversions

Although cocaine induces conditioned taste aversions (CTA), little is known about the mechanisms underlying this effect. It has been suggested that cocaine's actions as a nonselective monoamine transport inhibitor may be mediating this suppression. Given the role of dopamine (DA) in cocaine reward, this neurotransmitter system is of particular interest. The present experiments used direct pharmacological antagonism (with the DA antagonist haloperidol) to determine a role, if any, of DA in the induction of CTAs by cocaine. Following the determination of behaviorally active doses of haloperidol with no aversive effects on their own (Experiment 1), animals were given 1 mg/kg haloperidol prior to various doses of cocaine in a taste aversion procedure (Experiment 2). Under these conditions, haloperidol blocked cocaine‐induced CTAs (at the 18 and 32 mg/kg doses). These results suggest that DA has a role in cocaine‐induced CTAs. These data are discussed in the context of previous work demonstrating roles for both norepinephrine and serotonin in cocaine‐induced taste aversion learning as well as current research investigating DA transporter inhibitors and cocaine within the cross‐drug preexposure preparation.

Clozapine is underutilized.

I read the piece by Wang and Li[1] with great interest. The issues surrounding the use of clozapine in China and the United States provide an interesting contrast. Wang and Li suggest that clozapine is over-utilized in China both as a first-line treatment and (in low doses) to augment other antipsychotic agents. The situation in the United States is that clozapine is grossly underutilized as a treatment for patients with refractory schizophrenia and clinically significant suicidality. Despite the evidence that 25-40% of patients with schizophrenia would be candidates for clozapine based on labeled indications, approximately 5% of patients with schizophrenia are receiving it. Clozapine was approved by the Food and Drug Administration in the United States in 1989 following a large-scale clinical trial we conducted in 1988[2] demonstrating clozapine's superiority over chlorpromazine in carefully selected treatment refractory patients who had undergone a prospective trial of high dose haloperidol in order to confirm their lack of response. Over the subsequent two decades clozapine's superiority has been confirmed in several government-funded studies.[3]–[5] Despite the introduction of other so called ‘atypical’ or second generation antipsychotics, no other compound—even those with similar chemical structures—has consistently replicated clozapine's effects. Although clozapine has been shown to be superior in patients who have failed on other medications, there is no evidence that clozapine is superior as a first-line medication. At the same time, however, it is possible that waiting until a patient fails adequate trials of three different medications is too conservative an approach; these patients may be waiting too long to try an effective treatment. Unfortunately, there is insufficient research to establish the optimum point in an individual's treatment history to introduce clozapine. It is certainly possible that the introduction of clozapine after one fully adequate failed trial of an antipsychotic medication (with confirmed adherence and therapeutic blood levels) would be sufficient. If this proved true it would be particularly valuable in the first episode of illness or in the first years after onset of illness as it would increase the likelihood of a timely treatment response. Clozapine's use has been somewhat constrained by the requirement for weekly blood monitoring in order to detect the presence of agranulocytosis. The risk of true agranulocytosis appears to have declined since the early years of clozapine use, and new methods for managing this condition has reduced fatality rates enormously. Nevertheless, the management of clozapine's side effects continues to be a challenge. Though progress is being made in identifying individuals at high risk for agranulocytosis[6] this still remains an obstacle for some physicians and patients. The risk of metabolic side effects is also very real and needs to be considered in any management plan. The appropriate or optimum dosing of clozapine also remains a challenge. Dosage patterns vary considerably from country to country. Though some studies provide guidance regarding therapeutic blood levels it is likely that there are ethnic differences in these relationships as well. Clearly, as suggested by Wang and Li,[1] more research is necessary to achieve the goals of personalized medicine in the use of a drug like clozapine, where both the potential rewards and risks are higher than usual. Some clinicians and policy makers attribute the underutilization of clozapine to its side effect profile and, therefore, patient resistance to its use. However, it is often the case that physicians project their own concerns about the possible serious side effects of clozapine onto patients and make assumptions about patients' desires without an appropriate process of shared decision-making. Moreover, many physicians in the United States and in China appear more comfortable with antipsychotic drug polypharmacy than with clozapine monotherapy, despite the fact that polypharmacy has not been adequately established as an appropriate strategy for the treatment of refractory patients. The fact that clozapine utilization varies as much as it does from country to country underscores the variety of factors that contribute to its use. Many clinicians are inadequately informed about the evidence base for the use of clozapine and about the strategies necessary for managing its potential adverse effects. Further training about clozapine is necessary. But there is also a need for research on implementation. How can the field of psychiatry better succeed at promulgating the use of evidence-based practices?

Hyperhidrosis under combination of zotepine and haloperidol alleviated by aripiprazole

HYPERHIDROSIS IS A possible side-effect of antipsychotics. We report a case developing hyperhidrosis under combination of zotepine and haloperidol, in which the sweating subsided after switching from zotepine to aripiprazole. Mrs C, a 55-year-old woman, was diagnosed as having schizophrenia at age 30 and diabetes mellitus at age 45. From 6 months before admission, because of refractory auditory hallucinations, the antipsychotics were gradually increased from zotepine 200 mg/day and haloperidol l5 mg/day; however her compliance was doubtful. After admission, zotepine 350 mg/day and haloperidol 15 mg/day were regularly administered. The concurrent medication included propranolol 60 mg/day, biperiden 6 mg/day, metformin 1000 mg/day, and glimepiride 2 mg/day. During the first 2 weeks of admission, excessive sweating was noticed. The sweating was generalized, with the most severe location in the trunk, and it was aggravated at night. The patient had no history of hyperhidrosis. The patient showed parkinsonism on neurological examination. Blood examination revealed fasting glucose 116 mg/dL and glycated hemoglobin A1c 7.3%, which were similar to her past data. Thyroid and adrenal functions were within normal limits. Antipsychotics-associated hyperhidrosis was suspected. During the third week of admission, we tapered zotepine to 200 mg/day and raised aripiprazole to 15–30 mg/day. The patient reported less sweating after that. There was no more evidence of excessive sweating at the end of the 6th week when we completely discontinued zotepine. Mrs C showed less auditory hallucination under a combination of aripiprazole and haloperidol, though mild rigidity could still be observed. Concurrent medications were not adjusted. This is the first report demonstrating hyperhydrosis associated with a combination of zotepine and haloperidol. The hyperhidrosis of Mrs C had two possible mechanisms. The first was via the cholinergic pathway. A report by Richardson et al. states that sweating induced by clozapine is related to cholinergic effect and is reversible under biperiden.1 But in our case, biperiden did not work in preventing hyperhidrosis. Second, depleted dopamine in hypothalamus influences thermoregulatory function. Mrs C received a high dose of zotepine and haloperidol. Her extrapyramidal syndrome implied low dopamine activity in nigrostriatal region, which is compatible with dopamine-related thermoregulatory disturbance. Aripiprazole was prescribed when tapering zotepine. Under aripiprazole, the depleted dopamine may be corrected to a regular activating level due to its feature as a dopamine partial agonist. Aripiprazole has higher D2 affinity (Ki = 0.95 nM) than haloperidol (Ki = 2 nM) or zotepine (Ki = 25 nM).2 Therefore, the D2 partial agonist property of aripiprazole can still work when combining with haloperidol. Aripiprazole is reported to alleviate antidepressant-induced excessive sweating by adjusting thermoregulatory function in the hypothalamus.3 Mrs C's blood glucose level was not significantly different to her previous data. Besides, the sweating alleviated without adjusting diabetic medication. We consider diabetes to be less likely to induce hyperhidrosis. To summarize, hyperhidrosis associated with zotepine and haloperidol use in this case was possibly related to dopamine depletion, which was modified by aripiprazole. Clinicians should be prudent when prescribing zotepine in patients with concurrent haloperidol use.

Reduced expression of haloperidol conditioned catalepsy in rats by the dopamine D3 receptor antagonists nafadotride and NGB 2904

Haloperidol, a dopamine (DA) D2 receptor-preferring antagonist, produces catalepsy whereby animals maintain awkward posture for a period of time. Sub-threshold doses of haloperidol fail to produce catalepsy initially, however, when the drug is given repeatedly in the same test environment, gradual day-to-day increases in catalepsy are observed. More importantly, if sensitized rats are injected with saline instead of haloperidol they continue to be cataleptic in the test environment suggesting that environment-drug associations may play a role. DA D3 receptors have been implicated in a number of conditioned behaviors. We were interested if DA D3 receptors contribute to catalepsy sensitization and conditioning in rats. We tested this hypothesis using the DA D3 receptor-selective antagonist NGB 2904 (0.5, 1.8mg/kg) and the DA D3 receptor-preferring antagonist nafadotride (0.1, 0.5mg/kg). For 10 consecutive conditioning days rats were treated with one of the D3 receptor antagonists alone or in combination with haloperidol (0.25mg/kg) and tested for catalepsy, quantified by the time a rat remained with its forepaws on a horizontal bar. On test day (day 11), rats were injected with saline or the D3 receptor antagonist and tested for conditioned catalepsy in the previously drug-paired environment. Rats treated with NGB 2904 or nafadotride alone did not develop catalepsy. Rats treated with haloperidol or haloperidol plus NGB 2904 or nafadotride developed catalepsy sensitization with repeated conditioning. When injected with saline they continued to exhibit catalepsy in the test environment — now conditioned. On the other hand, NGB 2904 (1.8mg/kg) or nafadotride (0.5mg/kg) given on the test day (after sensitization to haloperidol) significantly attenuated the expression of conditioned catalepsy. Our data suggest that the D3 receptor antagonist NGB 2904 (1.8mg/kg) and nafadotride (0.5mg/kg) significantly attenuate conditioned catalepsy in rats when given in test but not when given during sensitization. Results implicate DA D3 receptors in regulating the expression of conditioned catalepsy.

No negative symptoms in healthy volunteers after single doses of amisulpride, aripiprazole, and haloperidol

Noncompliance and poor outcome in patients with schizophrenia are closely related to the negative symptoms secondary to antipsychotics. No controlled study has evaluated whether amisulpride and aripiprazole induce negative symptoms. The aim of this study was to assess the effects of single doses of amisulpride, aripiprazole, haloperidol, and risperidone in healthy volunteers. Seventy-eight young volunteers took part in this double-blind, randomized, placebo-controlled, parallel study of four antipsychotics: 400 mg amisulpride, 10 mg aripiprazole, 3 mg haloperidol, and 2 mg risperidone. Assessments of negative symptoms were done 4 h after administration using both subjective rating scales (Neuroleptic Induced Deficit Syndrome Scale and Subjective Deficit Syndrome Scale) and an objective rating scale (Scale for the Assessment of Negative Symptoms). Risperidone only produced significant increases on the avolition score of the Neuroleptic Induced Deficit Syndrome Scale and blunted affect and alogia scores of the Scale for the Assessment of Negative Symptoms compared with placebo. The effect on blunted affect persisted after controlling for mental sedation. Amisulpride, aripiprazole, and haloperidol did not induce negative symptoms. Aripiprazole and risperidone induced mild extrapyramidal symptoms. The most common adverse events were somnolence and cognitive slowing. These data indicate that a single risperidone dose induces negative symptoms in normal volunteers, whereas amisulpride, aripiprazole, and haloperidol do not. These characteristics of antipsychotics should be considered when choosing optimal drugs for patients with psychosis.

The blood concentration and organ distribution of haloperidol at therapeutic and toxic doses in severe fatty liver disease

The aim of this study was to investigate the difference between the pharmacokinetics of haloperidol in normal rats and in rats with fatty liver disease. A therapeutic dosage (0.1 mg/kg) and a toxic dose (15 mg/kg) of haloperidol were administrated to normal 9-week-old male rats or those with severe fatty liver disease, and the blood concentration of haloperidol was determined 15 min, 1, 2, and 3 h following haloperidol administration. The concentration of haloperidol in the organs was determined 1, 2, and 3 h after the haloperidol administration. Additionally, the volume of the portal vein blood flow was measured 3 h after haloperidol administration. When given at the therapeutic dosage, the concentrations of haloperidol in both the blood and organs of the rats with fatty liver disease were significantly higher than those in the normal rats. However, when given at the toxic level, the blood and organ haloperidol concentrations 1 h after administration tended to be lower in the rats with fatty liver disease than those in the normal rats; these lower haloperidol levels returned to be the levels in the normal rats 3 h after the administration of haloperidol. The volume of the portal vein blood flow significantly increased following the toxic haloperidol dose as compared with the volume pre-administration and following the therapeutic haloperidol dose in the normal rats. However, the volume did not change after the toxic or the therapeutic dose of haloperidol compared with pre-administration in rats with severe fatty liver disease, although it was significantly higher than in the normal rats. The pathway for haloperidol metabolism might have been saturated before the administration of haloperidol in rats with fatty liver disease; thus, it is possible that the blood concentration of haloperidol tends to be much higher in individuals with severe fatty liver disease than in those with normal livers in an inverse proportion to the dosage of haloperidol.