Neuroleptic Agents Research Articles

Recovery of Cyanine-Dye Nucleotide Triphosphates

Despite the clinical efficacy of the most thoroughly studied conventional neuroleptic agent haloperidol, and the atypical antipsychotic risperidone is well established, little information is available on their molecular effects. Recent advances in high-density DNA microarray techniques allow the possibility to analyze thousands of genes simultaneously for their differential gene expression patterns in various biological processes, and to determine mechanisms of drug action. The aim of this series of experiments was to gain experience in antipsychotic gene-expression profiling and characterize (in the parlance of genomics) the “antipsychotic transcriptome.” In this prospective animal study, broad-scale gene expression profiles were characterized for brains of rats treated with antipsychotics and compared with those of sham controls. We used DNA microarrays containing 8000 sequences to measure the expression patterns of multiple genes in rat fronto-temporo-parietal cortex after intraperitoneal treatment with haloperidol or risperidone. A number of transcripts were differentially expressed between control and treated samples, of which only 36 and 89 were found to significantly differ in expression as a result of exposure to haloperidol or risperidone, respectively (P < 0.05). Acutely, 13 genes were more highly expressed and 15 transcripts were found to be significantly less abundant, whereas chronically nine genes were up-regulated and none of them was repressed in haloperidol-treated cortices. Risperidone acutely induced 43 and repressed 46 genes, and chronically over-expressed 6 and down-regulated 11 transcripts. Selected genes were assayed by real-time PCR, then normalized to β-actin. These assays confirmed the significance of the array results for all transcripts tested. Despite their differing receptor affinity and selectivity, our findings indicate that haloperidol and risperidone interfere with cell survival, neural plasticity, signal transduction, ionic homeostasis and metabolism in a similar manner.

Differential Inhibition of T-Type Calcium Channels by Neuroleptics

T-type calcium channels play critical roles in cellular excitability and have been implicated in the pathogenesis of a variety of neurological disorders including epilepsy. Although there have been reports that certain neuroleptics that primarily target D2 dopamine receptors and are used to treat psychoses may also interact with T-type Ca channels, there has been no systematic examination of this phenomenon. In the present paper we provide a detailed analysis of the effects of several widely used neuroleptic agents on a family of exogenously expressed neuronal T-type Ca channels (alpha1G, alpha1H, and alpha1I subtypes). Among the neuroleptics tested, the diphenylbutylpiperidines pimozide and penfluridol were the most potent T-type channel blockers with Kd values (approximately 30-50 nm and approximately 70-100 nm, respectively), in the range of their antagonism of the D2 dopamine receptor. In contrast, the butyrophenone haloperidol was approximately 12- to 20-fold less potent at blocking the various T-type Ca channels. The diphenyldiperazine flunarizine was also less potent compared with the diphenylbutylpiperadines and preferentially blocked alpha1G and alpha1I T-type channels compared with alpha1H. The various neuroleptics did not significantly affect T-type channel activation or kinetic properties, although they shifted steady-state inactivation profiles to more negative values, indicating that these agents preferentially bind to channel inactivated states. Overall, our findings indicate that T-type Ca channels are potently blocked by a subset of neuroleptic agents and suggest that the action of these drugs on T-type Ca channels may significantly contribute to their therapeutic efficacy.

筋肉注射で使用される持効性ハロペリドール使用中に発生した悪性症候群の１例

Neuroleptic malignant syndrome (NMS) occurs suddenly in patients treated with neuroleptic agents and involves high mortality. We report a case of NMS due to intramuscular injection of haloperidol decanoate. A 29-year-old man with paranoia schizophrenia since the age of 19 years was treated with neuroleptics. From 4 months ago, he was treated with haloperidol decanoate (50mg i.m. monthly), increased to 100mg/month. On the day before admission, he took an overdose of neuroleptics (include chlorpromazine hydrochloride 4.2g). He was transfered to our hospital due to drug intoxication. After admission, he developed NMS. After onset, haloperidol decanoate and all other neuroleptics were stopped. He was treated with dantrolene, bromocriptine, muscle relaxants, and intensive care including assisted ventilation, but his clinical condition and laboratory data did not improved for 25 days. In this case, we studied drug concentration in muscles undergoing haloperidol decanoate injection to determine the possible muscle resection for decreasing the blood concentration of the drug, but the patient recovered without muscle resection.

Family-based association study of the serotonin-2A receptor gene (5-HT2A) and bipolar disorder.

The serotonin 2A receptor gene (5-HT2A) is of great interest for research in neuropsychiatric disorders based on the observation that various neuroleptic agents and antidepressants bind with relatively high affinity at 5-HT2A receptors, and the fact that the receptor density in platelets tends to increase in depression. To test for the presence of association between 5-HT2A and bipolar disorder (BP), we studied a large number of triad families having probands affected with DSM-IV bipolar I (BPI), bipolar II (BPII) or schizoaffective disorder, bipolar type. Two polymorphisms of 5-HT2A, 102T/C, and His452Tyr were analyzed in the 274 bipolar triad families. Both the transmission disequilibrium test (TDT) and haplotype TDT were performed on the genotype data. We also calculated the maternal transmission and paternal transmission for each allele and compared the mean ages of onset across probands grouped by genotype at each of the two markers. No significant transmission disequilibrium between the alleles of 5-HT2A and BP was found. Separate studies of the sub-phenotypes also failed to demonstrate significant association. However, we found a trend towards transmission disequilibrium with the haplotype 102C.His452 (p = 0.0504). This trend may become more significant with a larger sample size. At present, results of this study suggest that the 5-HT2A is unlikely to play a major role in the genetic susceptibility to BP. Future studies will be directed towards increasing sample size, focusing on subtypes of BP or biochemical measures as phenotypes, and investigating other polymorphisms of 5-HT2A to provide more information at the DNA level.

Metabolic studies on haloperidol and its tetrahydropyridinyl dehydration product (HPTP) in C57BL/6 mouse brain preparations.

The neuroleptic agent haloperidol (HP) and its tetrahydropyridinyl dehydration product HPTP are biotransformed by humans, baboons and rodents to the HP pyridinium (HPP(+)) and reduced HP pyridinium (RHPP(+)) species, potential neurotoxic metabolites that have been detected in the brain. HPP(+), however, does not pass the mouse blood-brain barrier since it is not detected in the brain following systemic administration. We report here that C57BL/6 mouse brain preparations catalyze the oxidation of HP and HPTP to HPP(+). The initial rate of HPP(+) formation from HPTP by whole brain homogenates was estimated to be approximately 20 times faster than that observed with HP as substrate. HPTP also was converted to HPP(+) by mouse brain microsomal preparations and brain slices. These results suggest that the presence of HPP(+) in the C57BL/6 mouse brain following systemic administration of HPTP may be due primarily to its in situ metabolism to HPP(+). Attempts to identify the catalyst responsible for these biotransformations, however, have not been successful.

Neuroleptic Malignant Syndrome: Review, Diagnostic Critique

Neuroleptic malignant syndrome (NMS) can be defined as an idiosyncratic and potentially fatal reaction to neuroleptic agents that consists of fever, mental status changes, muscle rigidity, autonomic dysfunction, respiratory distress and rhabdomyolysis. The pathogenesis of NMS is still not fully understood. The diagnosis presents a challenge and the diagnostic criteria need further refinement. The presentation and course of NMS are quite variable and can range from a progressive, fulminating, downhill course to a relatively benign and self-limiting course. Despite great improvements in the management of the syndrome, prevention and early diagnosis are the most important aspects of treatment.

Inhibition of human alpha1E subunit-mediated ca2+ channels by the antipsychotic agent chlorpromazine.

Chlorpromazine is a neuroleptic antipsychotic agent with a long history of clinical use. Its primary mode of action is thought to be through modulation of monoaminergic inter-neuronal communication; however, its side-effect profile indicates substantial activities in other systems. Recent work has begun to uncover actions of this compound on ion channels. In this light we have investigated the actions of chlorpromazine on the recombinant alpha1E subunit-encoded voltage-sensitive Ca2+ channel (VSCC) that is believed to encode drug-resistant R-type currents found in neurones and other cells. Chlorpromazine produced a dose-dependent antagonism of these channels that was reversed on drug removal. The mean IC50 was close to 10 microM. At this concentration, the level of antagonism observed was dependent on the membrane potential, with greater inhibition being observed at more negative test potentials. Furthermore, chlorpromazine induced substantial changes in the steady-state inactivation properties of alpha1Ebeta3-mediated currents, although it was not seen to elicit a corresponding change in inactivation kinetics. These results are discussed with regard to the possible clinical mechanisms of chlorpromazine actions.

Augmentation strategies in the treatment of schizophrenia.

Use of augmenting agents in schizophrenia is a common practice in response to resistant symptoms or comorbid illness. Increasingly, clinicians are combining more than one antipsychotic agent, despite a lack of evidence from controlled studies to support this approach. A rationale can be made for adding higher-potency agents to clozapine in an attempt to optimize D2 dopamine receptor blockade, but this strategy requires further study before it should be adopted in clinical practice. Older reports have explored the use of antidepressants, mood stabilizers, and anxiolytics as augmenting agents. These agents appear to improve comorbid affective or anxiety symptoms, but earlier evidence of improvement in psychotic or negative symptoms has not been replicated consistently. Glutamatergic agents acting at the glycine coagonist site of the N-methyl-d-aspartate receptor, including glycine, d-cycloserine, and d-serine, have demonstrated impressive therapeutic effects for negative symptoms when added to conventional neuroleptic agents, but do not appear to enhance clozapine efficacy. Given the high rates of symptom persistence and disability associated with schizophrenia, the need for augmentation strategies is great, but no approach has clearly emerged as effective for a substantial portion of patients. Although certain approaches may prove helpful for individual patients, augmentation should not be used unless monotherapy has been optimized, and should not be continued long-term unless benefits are clear.

Economic Outcomes of Risperidone in Comparison to Typical Neuroleptic Agents for Treatment-Resistant Psychosis: A Community-Based Study

Objective: To compare the costs of treatment for psychosis with risperidone and typical neuroleptics in severely ill outpatients treated in a community mental health setting. Methods: This was an open, retrospective, controlled cohort comparison of actual costs of psychiatric treatment in a group of 17 patients treated with risperidone for psychotic disorders and 15 typical neuroleptic-treated controls matched for severity of illness. Assignment to the two groups was nonrandomized, and outcome data were gathered for the duration of the study for each subject, with dropouts included. Results: Risperidone use did not lead to increased treatment expenses compared with typical neuroleptic use in a mean of approximately nine months follow-up. The median overall cost per patient per year was $2,703 in the risperidone group, compared with $2,551 in the typical neuroleptic group (p = 0.64). Increased drug costs (mean expenses per patient per year: $1,631 for risperidone vs. $357 for typical neuroleptics; p = 0.005) were offset by reduced expenses due to decreased hospitalization rates (mean expenses per patient per year: $1,379 for risperidone vs. $3,920 for typical neuroleptics; p = 0.04). Use of other outpatient services did not significantly differ between the two groups. Conclusions: Use of risperidone led to lower hospitalization rates in this severely ill sample and did not lead to greater overall expense than typical neuroleptic use.

A sensitive LC assay for the simultaneous determination of centbutindole and its metabolite in rat serum using fluorescence detection.

Centbutindole (+/-) 2-gamma-[(p-fluorobenzoyl)propyl]-1, 2, 3, 4, 6, 7, 12, 12a-octahydro-pyrazino (2', 1': 6, 1) pyrido [3, 4-b] indole (I), is a new neuroleptic agent developed by Central Drug Research Institute, India. In the present study, a high performance liquid chromatography (HPLC) assay method for the simultaneous assay for I and its metabolite (II) in rat serum was developed and validated. The present method requires only 1 ml of serum with detection levels similar to that reported earlier using 4 ml serum. This assay has been found to be more suited for pre-clinical as well as phase IV studies. Linearity was observed between 1.25 and 40 ng/ml for I and 0.625 and 20 ng/ml for II in rat serum. Recoveries were consistent for both the analytes over the concentration ranges studied. Variation in intra-and inter-batch accuracy and precision were within acceptable limits of +/-20% at lowest limit of quantitation, whereas at higher concentrations it was +/-15%. The assay method was employed for the study of the pharmacokinetics and metabolism of I in rats. The parent compound and its metabolites were quantitated in serum and could be monitored up to 24 h post dose.

Diabetes mellitus inducida por olanzapina: Caso clínico

Atypical antipsychotics are widely used in psychotic disorders, refractory to conventional neuroleptic agents. They induce minimal extra pyramidal side effects, probably due to their greater affinity for certain dopaminergic receptors. However, this polyreceptor affinity may be responsible for the development of other side effects. We report a 48 years old male drinker and addicted to cocaine, that after two months of Olanzapine use, developed a severe diabetes mellitus with fasting blood glucose values reaching 514 mg/dl. When he was admitted to the hospital, physical examination was normal and his body mass index was 28 kg/m2. Olanzapine was discontinued and blood glucose values gradually returned to normal. After two months of follow up, the patient is on dietary treatment and with a fasting glucose of 132 mg/dl.

Use of Propofol and Other Nonbenzodiazepine Sedatives in the Intensive Care Unit

Sedatives continue to be used on a routine basis in critically ill patients. Although many agents are available and some approach an ideal, none are perfect. Patients require continuous reassessment of their pain and need for sedation. Pathophysiologic abnormalities that cause agitation, confusion, or delirium must be identified and treated before unilateral administration of potent sedative agents that may mask potentially lethal insufficiencies. The routine use of standardized and validated sedation scales and monitors is needed. It is hoped that reliable objective monitors of patients' level of consciousness and comfort will be forthcoming. Each sedative agent discussed in this article seems to have a place in the ICU pharmacologic armamentarium to ensure the safe and comfortable delivery of care. Etomidate is an attractive agent for short-term use to provide the rapid onset and offset of sedation in critically ill patients who are at risk for hemodynamic instability but seem to need sedation or anesthesia to perform a procedure or manipulate the airway. Ketamine administered through intramuscular injection or intravenous infusion provides quick, intense analgesia and anesthesia and allows patients to tolerate limited but painful procedures. The risk/benefit ratio associated with the use of this neuroleptic agent must be weighed carefully. Ketamine is contraindicated in patients who lack normal intracranial compliance or who have significant myocardial ischemia. Barbiturates are reserved mainly to induce coma in patients at risk for severe CNS ischemia, which frequently is associated with refractory intracranial hypertension, or in patients with status epilepticus. When administered in high doses, these drugs have prolonged sedative and depressant effects. Judicious hemodynamic monitoring is required when barbiturate coma is induced. Haloperidol is indicated in the treatment of delirium. Patients should be monitored for extrapyramidal side effects and, when they require higher doses, for potential electrocardiographic prolongation of the QT interval. Dexmedetomidine may evolve into an agent with qualities comparable with midazolam and propofol, and it may even become a drug of choice in select patients. Further study is required, however. Propofol has many of the qualities of an ideal sedative agent. Benzodiazepines and narcotics often are used in concert with propofol to provide reliable amnesia and to relieve pain, respectively. Propofol frequently causes hypotension when administered as a bolus or infusion, particularly in patients with limited cardiac reserve or hypovolemia. More data must be obtained to identify potential deleterious effects of hypertriglyceridemia, and further evaluation of the potential benefits in certain patient populations, such as neurosurgical patients, is needed.

Psychopharmacology in supportive care of cancer: a review for the clinician. IV. Other psychotropic agents.

Besides benzodiazepine, antidepressant and neuroleptic agents, all of which have established roles in supportive care, other psychotropic drugs deserve consideration in selected conditions affecting patients with advanced cancer. This article briefly reviews relevant aspects of miscellaneous psychotropics available for secondline treatment, including nonbenzodiazepine sedative, hypnotic and anxiolytic drugs, anaesthetic agents, stimulants, and analgesic adjuvants acting on the central nervous system. The proper use of such subsidiary psychotropic agents requires that both their specificities and the particular characteristics of palliative care patients are taken into account.

Testosterone-mediated modulation of HERG blockade by proarrhythmic agents

Diverse drugs from many therapeutic classes exert cardiotoxic side effects by inducing torsades de pointes (TdP), a life threatening cardiac arrhythmia, which often results from drug interaction with HERG (human ether-a-go-go related gene) encoded K + channels, that generate an I Kr component of the delayed rectifier cardiac K + current. Men are known to be at a lower risk for drug-induced TdP than women suggesting a role of sex steroid hormones, androgens and estrogens, in modulation of drug sensitivity of cardiac K + channels, particularly those encoded by HERG. Here by using neuroleptic agents haloperidol, pimozide, and fluspirilene, all of which can induce TdP, and a steroid hormone-sensitive system Xenopus oocytes for HERG channels expression we show that testosterone is able to reduce HERG-blocking potency of neuroleptics. Haloperidol, pimozide, and fluspirilene inhibited HERG current with ic 50 of 1.36, 1.74, and 2.34 μM, and maximal block of 73%, 76% and 65%, respectively. The action of these neuroleptics was voltage-dependent, most consistent with an open-channel blocking mechanism. Pretreatment of HERG-expressing oocytes with 1 μM testosterone increased the ic 50 values to 2.73, 2.08, and 5.04 μM, reduced the maximal block to 65%, 59%, and 64%, and strongly diminished voltage-dependence of the blockade. Testosterone treatment per se produced about a 35% reduction of HERG current compared with untreated oocytes. Our data suggest that androgens may protect against the arrhythmogenic actions of some cardiotoxic drugs.

Efficacy and safety of clozapine and olanzapine: an open-label study comparing two groups of Parkinson's disease patients with dopaminergic-induced psychosis.

Clozapine, an atypical neuroleptic agent, improves dopaminergic-induced psychosis in parkinsonian patients without increasing motor disability. However, because of the risk of agranulocytosis periodic hematological controls are mandatory. Olanzapine, another atypical neuroleptic, does not require such monitoring, which may represent a practical advantage. Therefore, for 12weeks we compared the tolerability and efficacy of clozapine and olanzapine in two groups of nine consecutive parkinsonian psychotic patients treated with these compounds. All the patients on clozapine (mean starting dose: 13.1+/-7.9mg/d) completed the study despite reporting a number of adverse events, including somnolence, falls, orthostatic hypotension, and syncope. In contrast, early withdrawal occurred in three of the nine patients receiving olanzapine, due to severe gait deterioration and drowsiness (mean starting dose: 3.9+/-1.3mg/d). Psychotic symptoms improved in both groups, as reflected by a reduction of 71.7% in clozapine and a 61.7% reduction in olanzapine, in five selected items from the Neuropsychiatric Inventory. On conclusion of the study, parkinsonism had improved in the clozapine group with a 19.7% decrease in the raw scores and a 7.9% decrease in the weighted scores according to the Cornell University Rating Scale for parkinsonism (mean dose: 16.9+/- 10.3mg/d). Conversely, the six patients receiving olanzapine who finished the study experienced aggravated parkinsonian symptoms, with a 25.5% worsening in the raw scores and a 24.6% worsening in the weighted scores (mean dose: 4.7+/-2.3mg/d). We postulate that the early drop-outs in the olanzapine-treated parkinsonian group may be attributable to a non-specific effect of the drug as a result of starting at too high a dose, and that the worsening of parkinsonism following prolonged treatment may have been caused by the drug's blocking effect on striatal D2 receptors.

Rhodium catalyzed hydroformylation of 1,1-bis( p-fluorophenyl)allyl or propargyl alcohol: a key step in the synthesis of Fluspirilen and Penfluridol

Fluspirilen ( 1) and Penfluridol ( 2), two neuroleptic agents, belong to a wide class of pharmaceuticals that contain in their molecules a 4,4-bis( p-fluorophenyl)butyl group bound to a nitrogen atom of a pyrrolidine, piperidine or piperazine moiety. A key intermediate for the synthesis of compounds 1 and 2, 4,4-bis( p-fluorophenyl)butylbromide ( 15), has been prepared starting from commercially available 4,4′-difluorobenzophenone ( 7) following a preparative route involving the rhodium catalyzed hydroformylation in toluene or in the biphasic system toluene/water or cyclohexane/water of 1,1-bis( p-fluorophenyl)-2-propenol ( 8) and/or 1,1-bis( p-fluorophenyl)-2-propynol ( 12). Fluspirilen and Penfluridol were obtained in 70–80% yield by reaction of bromide 15 with 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one ( 16) and 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol ( 17), respectively. The overall yields of the two pharmaceuticals 1 and 2, based on starting ketone 7, were about 35–40%.

Effects of two atypical neuroleptics, olanzapine and risperidone, on the function of the urinary bladder and the external urethral sphincter in anesthetized rats

BackgroundA previous report showed that the atypical neuroleptic clozapine resulted in marked changes in urodynamic parameters and greatly inhibited the activity of the external urethral sphincter in anesthetized rats. Such findings may help explain the high incidence of urinary disturbances reported during clozapine therapy. In an effort to extend our observations to other atypical neuroleptic agents, the present study investigated the effects of two newer atypical antipsychotics, olanzapine and risperidone, on the bladder and external urethral sphincter during cystometry in anesthetized rats.ResultsAt a dose of 0.1 mg/kg (i.v.), olanzapine decreased the micturition volume and increased the residual volume. In addition, olanzapine decreased the expulsion time and the amplitude of the high frequency oscillations observed during the expulsion phase. Larger doses (1 mg/kg) had a greater effect. Olanzapine also reduced the activity recorded from the external urethral sphincter, and the bursting observed during the expulsion phase was abolished by 1.0 mg/kg. Risperidone had similar effects although the maximal effects were smaller than those observed with olanzapine. The amplitude of bladder contractions elicited by electrical stimulation of the pelvic nerve was reduced by olanzapine but not risperidone suggesting a possible anti-muscarinic peripheral effect of olanzapine.ConclusionsOlanzapine and risperidone significantly altered several voiding parameters and decreased the activity of the external urethral sphincter in the anesthetized rat. We propose that these effects are due to the central action of these drugs and not to peripheral effects. These findings may explain some of the clinical reports of urinary incontinence with risperidone and may predict similar occurrences with olanzapine therapy.

Neuroleptic and anticholinergic drug use in Chinese patients with schizophrenia resident in a state psychiatric hospital in Singapore

Objective: The objective of this study was to survey the prescribing pattern in Chinese patients with chronic schizophrenia in a state mental hospital in Singapore, and to compare our findings with those of surveys of Chinese patients in other countries. Method: We surveyed the use of neuroleptic and anticholinergic agents among Chinese patients with chronic schizophrenia (n = 534) in a state mental hospital in Singapore. Results: Fifty-nine per cent of the patients received two or more neuroleptics (median daily dose of 400 mg chlorpromazine equivalents, range 50–2875 mg). There were no differences in gender distribution between those prescribed multiple neuroleptics as against an older group of those receiving none or only one neuroleptic medication. Sixty-six per cent of the patients were receiving depot neuroleptics, with more than half of these subjects also receiving additional oral neuroleptics. Patients who were prescribed multiple neuroleptics received significantly higher total doses than those receiving just one neuroleptic. Only 1% of patients were prescribed an atypical neuroleptic. Sixty-five per cent of patients were prescribed an anticholinergic agent. Those prescribed anticholinergic agents were younger, in receipt of higher doses of neuroleptic medications and had lower Simpson-Angus scores for extrapyramidal side-effects. Conclusions: The pervasive use of multiple typical neuroleptics, marked under-utilisation of atypical neuroleptics, and the lack of anticholinergic medication in patients who might benefit from such treatment are issues of substantial concern, warranting action in both psychiatry practice and mental health policy.

Neuroleptic and anticholinergic drug use in Chinese patients with schizophrenia resident in a state psychiatric hospital in Singapore.

The objective of this study was to survey the prescribing pattern in Chinese patients with chronic schizophrenia in a state mental hospital in Singapore, and to compare our findings with those of surveys of Chinese patients in other countries. We surveyed the use of neuroleptic and anticholinergic agents among Chinese patients with chronic schizophrenia (n = 534) in a state mental hospital in Singapore. Fifty-nine per cent of the patients received two or more neuroleptics (median daily dose of 400 mg chlorpromazine equivalents, range 50-2875 mg). There were no differences in gender distribution between those prescribed multiple neuroleptics as against an older group of those receiving none or only one neuroleptic medication. Sixty-six per cent of the patients were receiving depot neuroleptics, with more than half of these subjects also receiving additional oral neuroleptics. Patients who were prescribed multiple neuroleptics received significantly higher total doses than those receiving just one neuroleptic. Only 1% of patients were prescribed an atypical neuroleptic. Sixty-five per cent of patients were prescribed an anticholinergic agent. Those prescribed anticholinergic agents were younger, in receipt of higher doses of neuroleptic medications and had lower Simpson-Angus scores for extrapyramidal side-effects. The pervasive use of multiple typical neuroleptics, marked underutilisation of atypical neuroleptics, and the lack of anticholinergic medication in patients who might benefit from such treatment are issues of substantial concern, warranting action in both psychiatry practice and mental health policy.

Valproate for acute mania reduced neuroleptic administration and improved symptoms on mania and global function scales

Müller-Oerlinghausen B, Retzow A, Henn FA, et al, for the European Valproate Mania Study Group. Valproate as an adjunct to neuroleptic medication for the treatment of acute episodes of mania:...