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Question: Are antipsychotic dose equivalents between acute mania and schizophrenia the same?, Study Selection and Analysis: Six databases were systematically searched (from inception to 17 September 2022) to identify blinded randomised controlled trials (RCTs) that used a flexible-dose oral antipsychotic drug for patients with acute mania. The mean and SD of the effective dose and the pre-post changes in manic symptoms were extracted. A network meta-analysis (NMA) under a frequentist framework was performed to examine the comparative efficacy between the antipsychotics. A classic mean dose method (sample size weighted) was used to calculate each antipsychotic dose equivalent to 1 mg/day olanzapine for acute mania. The antipsychotic dose equivalents of acute mania were compared with published data for schizophrenia., Findings: We included 42 RCTs which enrolled 11 396 participants with acute mania. The NMA showed that risperidone was superior to olanzapine (reported standardised mean difference: -022, 95% CI -0.41 to -0.02), while brexpiprazole was inferior to olanzapine (standardised mean difference: 0.36, 95% CI 0.08 to 0.64). The dose equivalents to olanzapine (with SD) were 0.68 (0.23) for haloperidol, 0.32 (0.07) for risperidone, 0.60 (0.11) for paliperidone, 8.00 (1.41) for ziprasidone, 41.46 (5.98) for quetiapine, 1.65 (0.32) for aripiprazole, 1.23 (0.20) for asenapine, 0.53 (0.14) for cariprazine and 0.22 (0.03) for brexpiprazole. Compared with the olanzapine dose equivalents for schizophrenia, those of acute mania were higher for quetiapine (p<0.001, 28.5%) and aripiprazole (p<0.001, 17.0%), but lower for haloperidol (p<0.001, -8.1%) and risperidone (p<0.001, -15.8%)., Conclusions: Antipsychotic drugs have been considered first-line treatment for acute mania, warranting specific dose equivalence for scientific and clinical purposes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. Published by BMJ.)

A systematic review and random-effects model network meta-analysis was conducted to compare the efficacy, acceptability, tolerability, and safety of pharmacological interventions for adults with acute bipolar mania. We searched PubMed, the Cochrane Library, and Embase databases for eligible studies published before March 14, 2021. Randomized controlled trials (RCTs) of oral medication monotherapy lasting ≥10 days in adults with mania were included, and studies that allowed the use of antipsychotics as a rescue medication during a trial were excluded. The primary outcomes were response to treatment (efficacy) and all-cause discontinuation (acceptability). The secondary outcomes were the improvement of mania symptoms and discontinuation due to inefficacy. Of the 79 eligible RCTs, 72 double-blind RCTs of 23 drugs and a placebo were included in the meta-analysis (mean study duration = 3.96 ± 2.39 weeks, n = 16442, mean age = 39.55 years, with 50.93% males). Compared with the placebo, aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone outperformed response to treatment (N = 56, n = 14503); aripiprazole, olanzapine, quetiapine, and risperidone had lower all-cause discontinuation; however, topiramate had higher all-cause discontinuation (N = 70, n = 16324). Compared with the placebo, aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone outperformed the improvement of mania symptoms (N = 61, n = 15466), and aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, valproate, and ziprasidone had lower discontinuation due to inefficacy (N = 50, n = 14284). In conclusions, these antipsychotics, carbamazepine, lithium, tamoxifen, and valproate were effective for acute mania. However, only aripiprazole, olanzapine, quetiapine, and risperidone had better acceptability than the placebo., (© 2021. The Author(s).)

In this paper we present the case of a female teenager patient who was diagnosed with bipolar affective disorder and during psychotropic treatment with risperidone, the prolactin levels ranged between 55 ng/mL and 85 ng/mL at monthly repeated dosing. During this period, the patient presented somatic alterations in her state of health. The patient benefited from brain imaging, which revealed that in sella turcica is distinguished a well-defined and relatively homogeneous formation, measuring approximately 11/8 mm, suggestive of a pituitary adenoma. After changing the antipsychotic treatment, the pituitary formation resolved to a subsequent imaging re-evaluation.

Background: Comorbidity of bipolar disorder and obsessive-compulsive disorder is common in adolescence. Obsessive-compulsive disorder symptoms may be episodic and secondary to alterations in mood, and display specific features. Management of pediatric bipolar disorder-obsessive-compulsive disorder is challenging, as pharmacotherapy of obsessive-compulsive disorder may induce or exacerbate manic episodes and there is limited evidence of treatment efficacy. Electroconvulsive therapy is sparsely used in children and adolescents, but is documented to be a safe and efficacious intervention in adults with bipolar disorder. In view of the severity of symptoms in juvenile mania, studies on treatment strategies are warranted. We report a case of an adolescent with bipolar disorder-obsessive-compulsive disorder who was successfully treated with electroconvulsive therapy during an episode of severe mania., Case Presentation: A 16-year-old girl of Middle East origin first presented to us with depressed mood, irritability, and increased obsessive-compulsive disorder symptoms, which were initially interpreted in the context of acute stress secondary to migration. She had been diagnosed with bipolar disorder and obsessive-compulsive disorder in her previous home country, but had difficulties in accounting for earlier psychiatric history. During hospitalization her mood switched to a manic state with mixed and psychotic features, at times showing aggression toward others. Interruption in her lithium treatment for a short period and possibly the introduction of an atypical antipsychotic could in part have been triggering factors. After 8 weeks of in-patient care and psychotropic drug trials, electroconvulsive therapy was initiated and administered every second or third day for 4 weeks, with marked positive response. No apparent side effects were reported., Conclusions: This case demonstrates the need for a detailed medical history, taking special note of periodicity and character of obsessive-compulsive disorder symptoms, in adolescents with mood disorders. When treating culturally diverse patients, extra consideration should be taken. Special concerns in the pharmacological treatment to avoid the patient's condition from worsening must be addressed, including giving priority to mood stabilization before obsessive-compulsive disorder symptoms. There are potential benefits in considering electroconvulsive therapy in young patients with severe mania where first-line treatment options have failed.

Available antipsychotics show different efficacy on manic symptoms of bipolar patients, but few studies have investigated the speed of action of the various compounds. For this reason, purpose of the present paper was to compare antipsychotic mono-therapies in terms of speed of action in a sample of manic bipolar patients. In total, 155 bipolar patients, treated with antipsychotic mono-therapy and followed-up in Inpatient Psychiatry Clinic of University of Milan, were included in this single-blind comparative study. Clinical response was defined as a reduction of Young Mania Rating Scale (YMRS) scores ⩾50%, while remission as a YMRS score <10. After 4 days patients who had been treated with asenapine, were more likely to have achieved a clinical response than those in treatment with haloperidol ( p = 0.001). After 7 days, a more frequent clinical response was achieved by patients treated with asenapine than those who had been treated with haloperidol ( p < 0.001) or olanzapine ( p = 0.047). Asenapine appears to be faster in determining treatment response in manic patients compared with haloperidol and less markedly with olanzapine.

A patient with bipolar I disorder has been treated with lithium and haloperidol for the last 20 years and received an ACE inhibitor for his hypertension since 9 years ago. Despite regular clinic follow-ups and blood monitoring, he recently developed tremors and delirium. On hospital admission, serum level of lithium was far above toxic level. Mental state examination revealed an anxious and disorientated man with irrelevant speech. Immediate discontinuation of lithium resulted in slow reduction of serum lithium levels and gradual resolution of tremor but his delirium persisted for 2 weeks. His condition took a turn for the worse when he developed acute renal failure and arm abscess. We discussed about lithium toxicity and the vulnerability factors which have induced delirium and renal failure in this patient., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background Context: Acute fixed cervical kyphosis may be a rare presentation of conversion disorder, psychogenic dystonia, and potentially as a side effect from typical antipsychotic drugs. Haldol has been associated with acute dystonic reactions. In some cases, rigid deformities ensue. We are reporting a case of a fixed cervical kyphosis after the use of Haldol., Purpose: To present a case of a potential acute dystonic reaction temporally associated with Haldol ingestion leading to fixed cervical kyphosis., Study Design: This is a case report., Methods: A patient diagnosed with bipolar disorder presented to the emergency room several times with severe neck pain and stiffness. The neck appeared fixed in flexion with extensive osteophyte formation over a 3-month period., Results: The patient's condition was resolved by a posterior-anterior-posterior surgical approach. It corrected the patient's cervical curvature from 88° to 5°., Conclusions: Acute dystonic reactions have the potential to apply enough pressure on bone to cause rapid osteophyte formation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Manic episodes of bipolar disorder and psychotic exacerbations of schizophrenia, for which the antipsychotic drugs are most commonly prescribed, are frequently seen in the postpartum period. Despite the existence of single use of antipsychotics, data on safety of combined antipsychotics on the breastfed infants are limited. This report presents the clinical outcome of 2 infants exposed to combined antipsychotic during the lactation period.

Aim: Oxidative stress is defined as exposure to excessive oxidants and/or decrease in antioxidant capacity. Several studies have shown the effects of free radicals and antioxidant defense systems in bipolar disorder. We aimed to investigate the role of thioredoxin (TRX), which is a novel oxidative stress marker in patients with bipolar disorder., Methods: Sixty-eight hospitalized bipolar patients who were in manic episode were included in the study. As a control group, 30 healthy people were elected. Two groups were formed. The first group consisted of patients who were undergoing electroconvulsive treatment + antipsychotic treatment (haloperidol+quetiapine) and members of the other group were taking only antipsychotic treatment. Plasma thioredoxin levels were measured before and after treatment., Results: Pretreatment plasma TRX levels of patients were significantly lower than the controls (P < 0.05). Comparing pre- and post-treatment plasma TRX levels of all patients, post-treatment plasma TRX levels were significantly lower than the pre-treatment plasma TRX levels (P < 0.05). When we compared TRX levels between the electroconvulsive treatment + antipsychotic treatment group and the antipsychotic treatment group (P > 0.05) and within groups (P > 0.05) we did not find any statistically significant difference., Conclusion: Oxidative balance is impaired in bipolar disorder manic episode in favor of the oxidants. Decreased plasma TRX levels in the manic episode probably mean that antioxidant capacity is decreased in the bipolar disorder patients in the manic episode. Further studies in euthymic and depressive states are also needed to gain more insight into the role of TRX in bipolar disorder., (© 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.)

We investigated serum total oxidative and anti-oxidative status in manic patients. Group1 was formed as ECT+antipsychotic, group2 was antipsychotic and healthy volunteers as group3. The anti-oxidative status was significantly lower in group1 than group3. No significant change was found between pre and post-treatment oxidative and anti-oxidative status, whereas significantly increased oxidative stress index has been found in group2. Total anti-oxidative status in manic states seems to be inadequate which remains to be maintained after the treatment., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Capgras delusion (CD) has multiple etiologies including neurodegenerative disorders and can be associated with violent behavior. CD is a common complication of Alzheimer dementia (AD); however, CD with violent behavior is uncommon in AD. We report escalating violent behavior by a patient with advanced AD and CD who presented to the emergency department (ED) and required admission to an academic medical center., Methods: Case analysis with PubMed literature review., Results: A 75-year-old male with a 13-year history of progressive AD, asymptomatic bipolar disorder, chronic kidney disease, hypertension, hyperlipidemia, and benign prostatic hypertrophy presented to the ED with recurrent/escalating violence toward his wife, whom he considered an impostor. His psychotropic regimen included potentially inappropriate medications (PIMs) for geriatric/AD patients-topiramate/amitriptyline/chlordiazepoxide/olanzapine-that are associated with delirium, cognitive decline, dementia, and mortality. Renal dosing for topiramate, reduction in PIMs/anticholinergic burden, and substituting haloperidol for olanzapine resolved his violent behavior and CD., Conclusions: CD in AD is a risk factor for violent behavior. As the geriatric population in the United States grows, CD in patients with AD may present more frequently in the ED, requiring proper treatment. Pharmacovigilance is necessary to minimize PIMs in geriatric/AD patients. Clinicians and other caregivers require further education to appropriately address CD in AD.

Background: Nesfatin 1 is a newly identified peptide structured satiety hormone that is claimed to be responsible for the provision of appetite and metabolic regulation in hypothalamus. The change in appetite and energy is a well-known clinical feature of affective disorders and within treatment. We aimed to investigate serum nesfatin 1 level in patients with bipolar disorder who were in manic episode and the influences of treatment modalities on nesfatin 1 level., Methods: Sixty eight patients were elected and were divided into two groups as: antipsychotic treatment (haloperidol 10-30 mg/daily+quetiapine 100-900 mg/daily) arm and ECT+antipsychotic treatment arm. And 30 healthy controls were included in the study., Results: There was no significant difference according to mean age between patients and controls. Initial nesfatin 1 levels in patients and in both subgroups of patients were statistically lower than in healthy control group. The initial level of nesfatin 1 between ECT+antipsychotic and pure antipsychotic patient groups was not statistically significant. We found a trend of increment in nesfatin 1 level after treatment in both patient groups., Conclusions: This study is the first that revealed significantly lower nesfatin 1 level in manic episode than healthy controls. ECT+antipsychotic and antipsychotic treatments have no significant effects on nesfatin 1 level after manic episode treatment. These findings should be interpreted cautiously because of small sample size and being drug free only for one week., (© 2013 Elsevier B.V. All rights reserved.)

Background: there is a lack of scientific data regarding speed of action of antimanic treatments, a relevant issue in clinical practice., Objective: to assess differences in the speed of onset of antimanic efficacy between haloperidol (as most studied first-generation antipsychotic) and second-generation antipsychotics., Experimental Procedures: meta-analysis of double-blind randomized clinical trials in acute mania, comparing treatment with haloperidol and with second-generation antipsychotics. Search was conducted in MEDLINE and CENTRAL databases (last search: September 2011). Differences in mania scale score reduction at week 1 were assessed., Results: 8 randomized clinical trials fulfilled inclusion criteria and 1 of them was excluded due to low methodological quality. 2037 Manic patients had been treated with antipsychotics in the 7 trials. Haloperidol was found to be significantly more efficacious in the reduction of the mania scale score at week 1. The effect size was small, the Standardized Mean Difference (SMD) being 0.17, with a 95% Confidence Interval ranging from 0.01 to 0.32. Haloperidol was significantly more efficacious than olanzapine (SMD: 0.40 [0.21, 0.59]) and ziprasidone (0.39 [0.18, 0.61]). A non-significant trend towards superiority of haloperidol was found over aripiprazole (SMD: 0.13 [-0.02, 0.19]). There were no significant differences between haloperidol and quetiapine (0.17 [-0.11, 0.44]), and haloperidol and risperidone (SMD: -0.10 [0.30, 0.09])., Conclusions: haloperidol shows a faster onset of antimanic action than second-generation antipsychotics. This difference may be related to D2 affinity. Haloperidol may be considered a treatment option in severely ill manic patients who require urgent relief of symptoms., (Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.)

As much as the ideal treatment goal for severe mental illnesses such as bipolar disorder and schizophrenia is to prevent or delay the recurrence or relapse of acute episodes, when the patient presents with an acute episode, the goal should be to manage behavioural symptoms, and return to prior levels of symptomatic control. In a serious mental illness, the management of the acutely agitated state may require rapid tranquillisation (RT) to control violent and/or disturbed behaviour when all other methods of de-escalation have failed. Current clinical practice guidelines for emergency interventions in the case of acutely disturbed behaviours favour calming the patient by reducing agitation with mild sedation, but not sleep, to allow continued interaction with the patient, to ensure an accurate diagnosis, and to enable patients to be actively engaged in treatment decisions. Pharmacotherapy is an essential element in RT and the available agents used may be unique and separate from the patient's regular course of treatment, primarily because agents used in RT may not be suitable for long-term treatment due to an unfavourable efficacy and safety profile. Therefore, the choice of pharmacotherapy is essential to achieve an effective RT and a smooth transition to standard care and routine daily life for the patient. Of the available agents for RT, aripiprazole demonstrated a favourable efficacy and safety profile both over the short-term - including in its intramuscular form (IM) - and in the long-term treatment of bipolar I disorder and schizophrenia. The objective of this article is to assess the available clinical data on IM aripiprazole as a treatment option for the rapid control of agitation and disturbed behaviours in these conditions and to provide a consensus statement based on the expertise of UK healthcare practitioners in acute treatment units.

Background: Treatment of acute mania with second-generation antipsychotics has been claimed to involve a lower risk of switch to depression than haloperidol. However, clinical guidelines clearly state that this is not a proven fact., Methods: Meta-analysis of double-blind randomized controlled trials in acute mania, comparing rates of switch to depression with atypical antipsychotics and with haloperidol. Search was conducted in MEDLINE and CENTRAL databases (last search: September 2011)., Results: 8 randomized clinical trials fulfilled inclusion criteria. 2 of them were excluded because of low methodological quality or lack of data. 5 second-generation antipsychotics (aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone) were compared to haloperidol. In the mixed effects model the Risk Ratio for depressive switch was 0.71 (0.52, 0.96) favouring atypical antipsychotics. In the random effects model the difference did not reach statistical significance. In the heterogeneity analysis, exclusion of an outlying aripiprazole trial yielded a Risk Ratio of 0.58 (0.42, 0.82) with a non-significant heterogeneity test. Although no atypical antipsychotic was individually significantly superior to haloperidol, a trend could be seen favouring olanzapine (RR=0.56 [0.29, 1.08]), quetiapine (RR=0.36 [0.10, 1.33]), and ziprasidone (RR=0.51 [0.22, 1.18])., Limitations: All trials were industry supported, with some variability in dosage of haloperidol. Switch to depression was not the primary outcome of the trials. Heterogeneity could be explained as a lack of class-effect for atypicals., Conclusions: Treating acute mania with atypicals is associated to 42% less risk of switch to depression than with haloperidol. Nevertheless, caution should be taken when considering this a class effect, as only olanzapine, quetiapine, and ziprasidone may show a better profile., (Copyright © 2012 Elsevier B.V. All rights reserved.)

There are few studies of female stalkers in literature addressing different study populations. There appears to be a high incidence of mental disease among female stalkers, having an important role in inducing the harassment. We present a woman affected by a bipolar disorder who had a long affair with her victim, broken off in 2007. Stalking began in January 2009 and continued for 6 months, during which time she was not taking drugs and was in a decompensated clinical phase. In July 2009, she was denounced for harassment; the authorities demanded a psychiatric examination. The woman then resumed taking the medication regularly. In December 2009, although she was in complete remission, she began stalking once more. This case shows that even when there seems to be an evident relation between psychopathology and crime, it is always necessary to evaluate to what extent the mental disorder is responsible for the criminal behavior., (© 2012 American Academy of Forensic Sciences.)

Objective: The current study evaluated the efficacy and safety of risperidone and haloperidol as an adjunctive agent in combination with divalproate in patients with an episode of acute mania., Methods: This 6-week randomized, single-blind study was conducted in psychiatric wards of a mental hospital. A total of 41 patients were randomly assigned to the risperidone (risperidone plus divalproate) or haloperidol groups (haloperidol plus divalproate). Efficacy was assessed by changes in symptom rating scales [Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression (CGI) scores]. Safety and tolerability were assessed by monitoring the Extrapyramidal Symptom Rating Scale (ESRS) and Hamilton Rating Scale for depression., Results: Mean doses at baseline, and at weeks 4 and 6 were 3.77, 4.95 and 5.00 mg/day of risperidone and 5.89, 9.95 and 8.58 mg/day of haloperidol, respectively. Risperidone was shown to have significant anti-manic effects which was observed as early as week 1, following start of treatment. The BPRS scores were in favor of risperidone at week 2. Patients receiving risperidone exhibited significant greater global improvement on the CGI, as early as week 2 and over the entire treatment period, than haloperidol after 4 weeks of treatment. The ESRS at endpoint were significantly higher in the haloperidol patients., Conclusions: Risperidone plus divalproate was more efficacious than haloperidol plus divalproate for treatment of acute mania, and was well tolerated due to its evidence showing rapid anti-manic action, effective and sustained control of manic and psychotic symptoms and a favorable safety and tolerability profile in acute mania.

Background: No current data were available regarding the efficacy and safety of olanzapine in Japanese patients with bipolar I disorder with a current manic/mixed episode., Methods: Patients received blindly olanzapine (5-20 mg/day; N=105), haloperidol (2.5-10 mg/day; N=20), or placebo (N=99) for 3 weeks. For the following 3 weeks, the olanzapine and haloperidol groups continued their treatment, while the placebo group switched blindly to olanzapine. The primary efficacy measure was the mean change in Young Mania Rating Scale (YMRS) total score; secondary efficacy measures included bipolar disorder remission rate and switch-to depression. Safety measures included treatment-emergent adverse events (TEAEs), weight and extrapyramidal symptoms (EPSs)., Results: YMRS total score significantly decreased in the olanzapine group compared with the placebo group (-5.62 [95% CI: -8.87, -2.37], p<0.001) after 3 weeks. Compared with haloperidol, olanzapine was not markedly different in improving overall bipolar symptomatology, and fewer olanzapine-treated patients switched to symptomatic depression (2.4% vs 16.7%, p=0.014). Overall incidences of TEAEs were not significantly different among the groups, and EPSs in olanzapine group were less severe than in the haloperidol group., Limitations: The small haloperidol sample size limited the conclusions that can be drawn from the statistical comparisons between the active treatments., Conclusions: This was the first study to evaluate an atypical antipsychotic in Japanese patients with manic bipolar I disorder. Consistent with previous non-Japanese studies, olanzapine was generally well-tolerated and superior to placebo in improving the severity of manic symptoms. Compared to haloperidol, fewer olanzapine-treated patients switched to symptomatic depression, and EPSs were less severe., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Clinical trials today are conducted in multiple countries to enhance patient recruitment and improve efficiency of trials. However, the demographic and cultural diversity may contribute to variations in study outcomes. Here we conducted post-hoc analyses for a placebo-controlled study with ziprasidone and haloperidol for the treatment of acute mania to address the demographic, dosing, and outcome disparities in India, Russia and the USA. We compared the baseline characteristics, outcomes and discontinuations in patients and explored the relationship between the outcome measures across these countries. We found substantial differences in baseline characteristics of subjects, administered dosage and disease severity in India compared to the USA and Russia. Conversely, US subjects had a higher placebo response compared to subjects in Russia and India. These results are probably due to demographic differences in patient populations and psychiatric clinical practice across countries. While we offer initial ideas to address the disparities identified in this analysis, it is clear that further research to improve our understanding of geographical differences is essential to ensure globally applicable results for clinical trials in psychiatry.

Context: The hippocampus is strongly implicated in schizophrenia and, to a lesser degree, bipolar disorder. Proteomic investigations of the different regions of the hippocampus may help us to clarify the basis and the disease specificity of the changes., Objective: To determine whether schizophrenia and bipolar disorder are associated with distinct patterns of differential protein expression in specific regions of the hippocampus., Design, Setting, and Patients: A postmortem comparative proteomic study, including validation of differential expression, was performed. Midhippocampus samples from well-matched groups of 20 subjects with schizophrenia, 20 subjects with bipolar disorder, and 20 control cases from the Stanley Medical Research Institute Array Collection were analyzed., Main Outcome Measures: We used laser-assisted microdissection to enrich for tissue from the hippocampal regions and 2-dimensional difference gel electrophoresis to compare protein profiles. Levels of differentially expressed proteins were confirmed by enzyme-linked immunosorbent assay and Western blotting. Hippocampi from haloperidol-treated mice were used to help discriminate drug-associated from disease-associated protein changes., Results: Across all hippocampal regions, 108 protein spots in schizophrenia and 165 protein spots in bipolar disorder were differentially expressed compared with controls. Sixty-one proteins were differentially expressed in both disorders. One hundred fifty-two of these proteins were identified by mass spectrometry, and they implicated a range of different processes including cytoskeletal and metabolic functions. In both disorders, cornu ammonis regions 2 and 3 were affected to a significantly greater degree than other hippocampal regions. Additionally, numerous proteins showed expression changes in more than 1 region and more than 1 disorder. Validation work confirmed changes in septin 11 and in the expression of proteins involved in clathrin-mediated endocytosis in both schizophrenia and bipolar disorder., Conclusions: Overall, similar protein changes were observed in schizophrenia and bipolar disorder and for the first time indicate that the most prominent proteomic changes occur within the hippocampus in cornu ammonis regions 2 and 3. The cytoskeletal protein septin 11 and the cellular trafficking process of clathrin-mediated endocytosis are implicated by our study.

The objective of this article is to assess the clinical characteristics of akathisia in patients with schizophrenia, schizoaffective disorder, or bipolar I disorder receiving aripiprazole, haloperidol, olanzapine, or placebo. We conducted post hoc analyses of pooled safety data from trials in patients with schizophrenia, schizoaffective disorder, and bipolar I disorder. Outcome measures included the incidence of akathisia, time to onset, duration, severity, and discontinuation due to akathisia, concomitant use of benzodiazepines and/or anticholinergics, Barnes Akathisia Rating Scale (BARS) scores, and the correlation between antipsychotic efficacy and akathisia. The results for schizophrenia and schizoaffective disorder were as follows: akathisia in 9% of aripiprazole- and 6% of placebo-treated patients; 12.5% of aripiprazole- versus 24% of haloperidol-treated patients; 11% of aripiprazole- versus 6% of olanzapine-treated patients. Bipolar I disorder: akathisia in 18% of aripiprazole- and 5% of placebo-treated patients. The clinical characteristics of akathisia were similar between each data set, regardless of disease. Akathisia was generally mild-to-moderate in severity. Discontinuation due to akathisia was low in both the schizophrenia trials (aripiprazole 0.3%; placebo 0%; aripiprazole 0.9%; haloperidol 2.3%; aripiprazole 1.2%; olanzapine 0.2%) and the bipolar trials (aripiprazole 2.3%; placebo 0%). Treatment-emergent akathisia was not associated with a poorer clinical response. In conclusion, akathisia with aripiprazole occurred early in treatment, was mild-to-moderate in severity, led to few study discontinuations, and did not compromise therapeutic efficacy.

This study was carried out to compare the efficacy of intravenous sodium valproate with intramuscular haloperidol in patients with acute mania. A total of 30 patients meeting DSM-IV criteria for acute manic episodes were enrolled. They were randomly assigned to 2 groups of 15 patients each. Both groups were treated twice daily with haloperidol (10 mg, intramuscular) and sodium valproate (500 mg, intravenous). The patients were assessed on days 1, 5, 9, and 13. Improvement in symptoms was assessed by reduction in the Young Mania Rating Scale (YMRS). Outcome criterions for analysis were latency of response and remission; additional drugs were required for sedation. At the end of the 2-week study period, overall response rate in both the groups was similar (P > .1). In comparison to haloperidol group, patients treated with sodium valproate showed faster response, and on day 5, significant reduction in YMRS score was observed in the group treated with sodium valproate (P < .05). Total amount of lorazepam was less in patients treated with sodium valproate. Extrapyramidal symptom episodes were observed in 60% of patients treated with haloperidol. Sodium valproate in the treatment of acute mania is as efficacious as haloperidol but provides a faster response. It is safer compared to haloperidol.

Bipolar disorder has a significant prevalence in the overall population, and carries considerable functional impairment for sufferers as well as a very negative impact on their relatives and caregivers. These facts were widely accepted by attendees to this year's biannual conference of the International Society for Bipolar Disorder, as was the concept that, although less apparent due to the lack of overt mania, type II bipolar disorder is not a mild form of the disease, but an even worse condition with severe depressive episodes that carry a high risk for suicide. And suicide is, in fact, among the most fearful threats of bipolar disorder. Sao Paulo, and this year's ISBD meeting, offered an opportunity for discussing treatments for patients suffering from manic, depressive and mixed states associated with bipolar disorder, and this report will review and summarize findings directly related to pharmacotherapy for the disease., (Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.)

Aims: Atypical antipsychotics are increasingly used in the management of acute mania. This study was conducted to investigate the efficacy and tolerability of zotepine compared to haloperidol in combination with a mood stabilizer (lithium or valproate) for treatment of acute mania., Methods: This was a multi-center, randomized, rater-blinded, parallel-group, flexible-dose study. Forty-five hospitalized patients with moderate-to-severe manic, bipolar disorder (DSM-IV) were randomly assigned to a zotepine or a haloperidol 4-week treatment group., Results: There was no significant between-group difference in the Young Mania Rating Scale total scores between the zotepine and haloperidol groups (-23.7 + or - 12.1 vs -22.3 + or - 11.0, respectively). The adverse events in both groups were mild to moderate. The haloperidol group reported a higher incidence of treatment-related adverse events, especially parkinsonism and akathisia, compared to the zotepine group. Serum uric acid decreased more in the zotepine group than in the haloperidol group., Conclusion: In combination with a mood stabilizer, zotepine appears to be as effective as haloperidol in treating moderate-to-severe mania in the acute phase, but has the advantages of lowering hyperuricemia and fewer extrapyramidal side-effects. Double-blinded studies with larger sample sizes are warranted to confirm these findings.

This 12-week, double-blind, two-part study in 438 adults with bipolar-associated acute mania began with a 3-week period comparing ziprasidone (80-160 mg/day) and placebo with haloperidol (8-30 mg/day) as active reference. Changes from baseline Mania Rating Scale (MRS) scores for ziprasidone and haloperidol were superior to placebo from day 2 (P = 0.001) to week 3 (P < 0.001); change from baseline at week 3 was greater for haloperidol than ziprasidone (P or=50% decrease from baseline MRS score) was 36.9, 54.7 and 20.5% for ziprasidone, haloperidol and placebo, respectively (P

Objective: To compare antipsychotic and mood stabilizer (MS) efficacy and tolerability in youth and adults with bipolar mania., Methods: Medline/PubMed search for studies including: (i) youth (< 18 years) or adults (> or = 18 years); (ii) bipolar I disorder; (iii) double-blind, randomized, placebo-controlled trial (DB-RPCT); (iv) < or = 12 weeks of treatment; and (v) calculable effect sizes (ES) and/or numbers needed to treat/harm (NNT/NNH) +/- 95% confidence intervals (CI). Non-overlapping 95% CIs determined significant group differences., Results: We identified nine DB-RPCTs in youth (n = 1,609), 5 evaluating second-generation antipsychotics (SGAs) (n = 1,140) and 4 evaluating MSs (n = 469). We also identified 23 DB-RPCTs in adults (n = 6,501), 14 including SGAs (n = 3,297), 5 using haloperidol as an active comparator (n = 580), and 11 including MSs (n = 2,581). Young Mania Rating Scale scores improved significantly more with SGAs than MSs in youth (ES = 0.65, CI: 0.53-0.78 versus 0.24, CI: 0.06-0.41) and adults (ES = 0.48, CI: 0.41-0.55 versus 0.24, CI: 0.17-0.31). After excluding topiramate studies, SGAs had larger ES than MSs only in youth (ES = 0.65, CI: 0.53-0.78 versus 0.20, CI: 0.02-0.39), but not adults (ES = 0.48, CI: 0.41-0.55 versus 0.46, CI: 0.37-0.55). However, in adults SGAs had significantly larger ES regarding Clinical Global Impressions scores than MSs, even without topiramate (ES = 0.75, CI: 0.68-0.82 versus 0.24, CI: 0.07-0.41). Rates of response, remission, and discontinuation due to any reason compared to placebo were similar between medication and age groups, except for more favorable NNTs for remission with SGAs than MSs in adults after excluding topiramate. SGAs caused more weight gain than MSs in youth (ES = 0.53, CI: 0.41-0.66 versus 0.10, CI: -0.12-0.33), but not in adults (ES = 0.13, CI: 0.05-0.22 versus 0.00, CI: -0.08-0.08). However, results were heterogeneous and not significant in either age group after excluding topiramate. Nevertheless, SGA-related weight gain was significantly greater in youth than adults. In youth, SGA-related somnolence was greater than with MSs (NNH = 4.7, CI: 3.9-6.0 versus 9.5, CI: 6.3-23.5), and more likely than in adults (NNH = 7.1, CI: 6.1-8.8). Conversely, youth experienced less akathisia with SGAs than adults (NNH = 20.4, CI: 14.1-36.5 versus 10.2, CI: 8.1-13.7), likely due to lower doses/slower titration., Conclusions: In treating mania, potentially greater short-term efficacy compared to placebo with SGAs versus MS needs to be balanced against increased adverse events, especially in youth.

Malignant neuroleptic syndrome (MNS) is a serious and potentially fatal side-effect of neuroleptic treatment. Beside antipsychotic drugs, other psychotropic drugs such as antidepressants and lithium carbonate can cause this life threatening side-effect. Underlying mechanism of this side-effect is still unknown and debated. So far some risk factors have been identified, with clinical observations and recent pharmacogenetic research suggesting (with inconsistent findings) correlation between genetic mechanisms and predisposition to MNS. Polymorphisms of CYP2D6 enzyme through which most psychotropic drugs are metabolized and TaqIA DRD2 which is target for antipsychotic drugs could be the link between pharmacogenetic factors and potential for development of MNS. In this paper we present two case reports with clinical presentation of three consecutive MNS. One patient developed MNS while he was taking combination of drugs: first time haloperidol, promazine and fluphenazine, second time fluphenazine and perazine and third time clozapine, promazine and valproic acid consecutively. The other patient developed MNS while taking following combination of drugs: first time haloperidol and lithium carbonate, second time risperidone and third time clozapine consecutively. Pharmacogenetic analysis for CYP2D6 and TaqI A DRD2 polymorphisms for both patients was done. Genotypisation of CYP2D6*1*3*4*5*6 in both patients showed no evidence of poor metabolizer phenotype. On the other hand, first patient was heterozygous for CYP2D6*4 (genotype *1/*4). CYP2D6 polymorphisms could have clinical significance because may lead to toxicity and unwanted side-effects in standard usual antipsychotic dose ranges. Analysis Taql A DRD2 polymorphism for first patient showed that he is heterozygous for A1 allele (genotype A1A2) which is commonly associated with predisposition to MNS. According to our literature three consecutive MNS are rarely described, and incidence of MNS generally is too low to perform clinical research. Many patophysiological mechanisms may probably underlie this complex and potentially fatal syndrome, still unknown etiology. But, genetic mechanisms could be significant. Further pharmacogenetic research, findings and analysis in patients who develop single or repeated MNS are strongly recommended. In long term, pharmacogenetic analysis, implemented in daily clinical practice, could help in prevention of this extremely serious side-effect.

Background: While the factor structure of clinical symptoms in schizophrenia has been examined and provided crucial information about the illness, there is much less information available in bipolar disorder. This study examined the structure of symptoms of bipolar disorder at an unmedicated baseline assessment and after double-blind treatment with ziprasidone, haloperidol, or placebo. We hypothesized, consistent with recent studies of schizophrenia, that the factor structure after treatment would be similar to the structure of untreated symptoms at study baseline., Methods: Hospitalized patients with manic (n = 363) or mixed (n = 71) bipolar episodes were rated with the Hamilton Depression Rating Scale (HAM-D) and the Mania Rating Scale [(MRS); derived from the Schedule for Affective Disorders and Schizophrenia - Change Bipolar Scale]. After 21 days of double-blind treatment, all patients were again rated with the MRS and HAM-D., Results: Exploratory orthogonal factor analysis (varimax rotation) including both HAM-D total scores and the MRS items found different five-factor solutions for mixed and manic patients at the unmedicated baseline assessment. Confirmatory modeling indicated that these models, with some modifications, fit the data well. At the endpoint, however, a single-factor solution was found for mixed and manic groups., Implications: Symptomatology in bipolar disorder is multifactorial in an acute and unmedicated state, with slightly different factor structures for mixed and manic episodes. Following treatment, a single severity dimension is detected. These results suggest that symptom dimensions in mania may be different from those seen in schizophrenia, where different elements of symptoms have been proven to have different functional correlates and treatment response.

Background: Antiphospholipid syndrome (APS) is a prothrombotic condition characterized by recurrent vascular thrombosis and/or pregnancy morbidity in the presence of circulating antiphospholipid antibodies. Central nervous system (CNS) involvement is a prominent feature of APS, and many neurological manifestations have been described in published reports. There are limited data on psychiatric syndromes occurring in association with APS, and there have been no previous reports of mania associated with APS., Method: The authors present the case of a 31-year-old man who experienced an acute manic episode in association with APS. They review the literature on psychiatric manifestations of APS, discuss potential mechanisms of CNS pathogenesis, and consider diagnostic and treatment implications of the co-occurrence of APS and psychiatric symptoms.

Background: This study aimed to compare the treatment responses between smokers and non-smokers in bipolar mania clinical trials., Methods: Post-hoc analysis was conducted on data collected from three double-blind, randomised controlled trials in bipolar mania that had similar inclusion criteria. Patients were randomised to olanzapine (N=70) or placebo (N=69) for 3 weeks in Trial 1, olanzapine (N=234) or haloperidol (N=216) for 12 weeks in Trial 2, and olanzapine (N=125) or divalproex (N=126) for 47 weeks in Trial 3. This study analysed the Young Mania Rating Scale (YMRS) total scores and Clinical Global Impressions scale for bipolar disorder (CGI-BP) mania severity scores between smokers and non-smokers for each trial and for the pooled data from all three trials, using a mixed-effects model repeated measures approach., Results: For the pooled data, non-smokers showed superior treatment outcomes on both the YMRS (P=0.002) and CGI-BP (P<0.001), as well as longer time to discontinuation for any cause utilising Kaplan-Meier survival curves. For the individual trials, non-smokers showed greater improvement than smokers on both CGI-BP and YMRS in both treatment arms of Trial 2 (CGI-BP: haloperidol P=0.011, olanzapine P=0.042; YMRS: haloperidol P=0.010, olanzapine P=0.019), and in the olanzapine arm of Trial 3 (CGI-BP: P=0.002; YMRS: P=0.006). No significant difference in outcomes was found between smokers and non-smokers in Trial 1., Limitations: Post-hoc design, categorical definition of smoking status, unavailable antipsychotic drug levels, confounding effects of trial medications and substance abuse., Conclusions: Smoking appears to be associated with worse treatment outcomes in mania.

Background: Medication nonadherence is a significant problem among patients with bipolar disorder., Objective: To compare adherence and persistence among patients with bipolar disorder initiated on antipsychotics in a state Medicaid system over a 12 month follow-up period., Methods: Claims data for patients with bipolar disorder from a de-identified Medicaid database were examined. Patients were classified into 4 monotherapy treatment groups (risperidone, olanzapine, quetiapine, or typical antipsychotic) based on the first prescription filled between January 1, 1999, and December 31, 2001. Adherence and persistence were analyzed over a 12 month follow-up period. Adherence was measured using the Medication Possession Ratio (MPR). Persistence was defined as the total number of days from the initiation of treatment to therapy modification (ie, discontinuation, switching, or combination with another antipsychotic). Adjustment for confounding variables was undertaken using ordinary least-squares and Cox proportional hazard regression modeling., Results: The mean MPRs were 0.68 for risperidone (n = 231), 0.68 for olanzapine (n = 283), 0.71 for quetiapine (n = 106), and 0.46 for typical antipsychotics (n = 205). Patients initiated on typical antipsychotics were 23.6% less adherent than patients initiated on risperidone (p < 0.001). Mean persistence (days) was 194.8 for risperidone, 200.9 for olanzapine, 219.8 for quetiapine, and 179.2 for typical antipsychotics. Extended Cox regression modeling indicated no significant differences between antipsychotics in hazards of therapy modification within 250 days of initiation. However, patients initiated on typical antipsychotics were 5.2 times more likely to modify therapy compared with those initiated on risperidone after 250 days of antipsychotic therapy (p < 0.001)., Conclusions: Adherence and persistence were similar between atypical antipsychotic groups. The typical antipsychotic group, however, demonstrated lower adherence and a greater likelihood of patients modifying therapy compared with the risperidone cohort.

Purpose: The efficacy and tolerability of quetiapine in the treatment of acute mania were reviewed., Summary: Five randomized, placebo-controlled trials involving quetiapine as monotherapy or adjunct therapy in combination with either divalproex or lithium in the treatment of bipolar mania in either adolescents or adults were identified and reviewed. The primary outcome measure used in the trials was a change in Young Mania Rating Scale total scores. Monotherapy trials evaluated quetiapine, lithium, haloperidol, and placebo. Quetiapine was superior to placebo in both trials. Quetiapine and lithium showed comparable efficacy in one study, though lithium serum concentrations may have been suboptimal. Haloperidol was superior to quetiapine in efficacy at day 21 but similar at day 84. In the two trials evaluating quetiapine or placebo as adjunct therapy to lithium or divalproex, quetiapine was significantly more efficacious than placebo in one trial. In adolescents, quetiapine was more effective than placebo as an adjunct to divalproex. The most common adverse effects clearly attributable to quetiapine in these trials were somnolence and dry mouth. Quetiapine did not induce extrapyramidal effects, but weight gain was notable with the drug., Conclusion: While quetiapine treatment demonstrated efficacy in the majority of the studies, the robustness of its efficacy is questionable. The use of quetiapine as first-line therapy for acute mania is not recommended based on the available results and cost considerations. However, it may be a useful second-line agent, particularly when sensitivity to extrapyramidal symptoms limits treatment options.

Data from a published double-blind randomized trial comparing olanzapine versus haloperidol in acute mania were used to address the response and tolerability of Latin American patients. Primary efficacy end point was the remission rate (Young Mania Rating Scale score

The effects of haloperidol and olanzapine on polysomnographic measures made in bipolar patients during manic episodes were compared. Twelve DSM-IV mania patients were randomly assigned to receive either haloperidol (mean +/- SD final dosage: 5.8 +/- 3.8 mg) or olanzapine (mean +/- SD final dosage: 13.6 +/- 6.9 mg) in a 6-week, double-blind, randomized, controlled clinical trial. One-night polysomnographic evaluation was performed before and after the haloperidol or olanzapine treatment. Psychopathology and illness severity were rated respectively with the Young Mania Rating Scale (YMRS) and the Clinical Global Impressions - Bipolar version (CGI-BP). There was a significant improvement in the YMRS and CGI-BP scores at the end of the study for both groups. Mixed ANOVA used to compare the polysomnographic measures of both drugs demonstrated significant improvement in sleep measures with olanzapine. In the olanzapine group, statistically significant time-drug interaction effects on sleep continuity measures were observed: sleep efficiency (mean +/- SEM pre-treatment value: 6.7 +/- 20.3%; after-treatment: 85.7 +/- 10.9%), total wake time (pre-treatment: 140.0 +/- 92.5 min; after-treatment: 55.2 +/- 44.2 min), and wake time after sleep onset (pre-treatment: 109.7 +/- 70.8 min; after-treatment: 32.2 +/- 20.7 min). Conversely, improvement of polysomnographic measures was not observed for the haloperidol group (P > 0.05). These results suggest that olanzapine is more effective than haloperidol in terms of sleep-promoting effects, although olanzapine is comparatively as effective as haloperidol in treating mania. Polysomnography records should provide useful information on how manic states can be affected by psychopharmacological agents.

Objectives: To evaluate extrapyramidal symptoms (EPS), including akathisia, with quetiapine in patients with bipolar mania., Methods: Data were analyzed from four similarly designed, randomized, double-blind, 3- to 12-week studies. Two studies evaluated quetiapine monotherapy (up to 800 mg/day) (n = 209) versus placebo (n = 198), with lithium or haloperidol monotherapy as respective active controls. Two studies evaluated quetiapine (up to 800 mg/day) in combination with a mood stabilizer (lithium or divalproex, QTP + Li/DVP) (n = 196) compared to placebo and mood stabilizer (PBO + Li/DVP) (n = 203). Extrapyramidal symptoms were evaluated using the Simpson-Angus Scale (SAS), the Barnes Akathisia Rating Scale (BARS), adverse event reports and anticholinergic drug usage., Results: The incidence of EPS-related adverse events, including akathisia, was no different with quetiapine monotherapy (12.9%) than with placebo (13.1%). Similarly, EPS-related adverse events with QTP + Li/DVP (21.4%) were no different than with PBO + Li/DVP (19.2%). Adverse events related to EPS occurred in 59.6% of patients treated with haloperidol (n = 99) monotherapy, whereas 26.5% of patients treated with lithium (n = 98) monotherapy experienced adverse events related to EPS. The incidence of akathisia was low and similar with quetiapine monotherapy (3.3%) and placebo (6.1%), and with QTP + Li/DVP (3.6%) and PBO + Li/DVP (4.9%). Lithium was associated with a significantly higher incidence (p < 0.05) of tremor (18.4%) than quetiapine (5.6%); cerebellar tremor, which is a known adverse effect of lithium, may have contributed to the elevated rate of tremor in patients receiving lithium therapy. Haloperidol induced a significantly higher incidence (p < 0.001) of akathisia (33.3% versus 5.9%), tremor (30.3% versus 7.8%), and extrapyramidal syndrome (35.4% versus 5.9%) than quetiapine. No significant differences were observed between quetiapine and placebo on SAS and BARS scores. Anticholinergic use was low and similar with quetiapine or placebo., Conclusions: In bipolar mania, the incidence of EPS, including akathisia, with quetiapine therapy is similar to that with placebo.

Purpose: Intracerebroventricular (ICV) administration of ouabain, a potent sodium pump inhibitor, has been used to model mania. Antipsychotic agents have demonstrated efficacy in the management of acute mania. This study was undertaken to determine the prophylactic efficacy of olanzapine and haloperidol in the ouabain mania model., Methods: Male Sprague-Dawley rats (4-8/group) were treated with two haloperidol decanoate intramuscular shots one week apart (21 mg/kg) or twice daily olanzapine intraperitoneal injections at low dose (1 mg/kg/day) or high dose (6 mg/kg/day) for 7 days prior to ICV administration of ouabain. Open field locomotion was quantified at baseline and after ouabain administration., Results: Ouabain caused a significant increase in open field locomotion (253.7+/-SEM 55.12 vs control 53.1+/-12.13 squares traversed in 30 min in the olanzapine experiments, P<0.05; and 236.5+/-41.42 vs 129.3+/-38.23, P<0.05 in the haloperidol experiments). Olanzapine alone at low dose (102.2+/-37.7) or high dose (151.2+/-49.2) did not alter open field activity. Low dose olanzapine (176.6+/-73.27) but not high dose (307.5+/-167.32) caused a modest reduction of the ouabain effect. Haloperidol alone significantly reduced motoric activity compared to control (55.6+/-18.0, P<0.05), and prevented ouabain-induced hyperactivity (60.3+/-33.1, P<0.05)., Conclusion: Haloperidol, but not olanzapine, demonstrated efficacy in this mania model, but methodological details may have reduced the effect of olanzapine.

Background: The main objectives in treating mania are to control dangerous behaviour, reduce suicide, produce appropriate acute sedation and shorten the episode of mood disturbance. Among different drugs, haloperidol has for many years been used in treating psychotic patients, but it has a troublesome side effect profile., Objectives: To assess the effects of haloperidol for the treatment of mania in comparison with placebo or other active drugs, either as monotherapy or add-on treatment., Search Strategy: We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (11 October 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2005), MEDLINE (1966-2003), EMBASE (1980-2003), CINAHL (1982-2003), PsycINFO (1872-2003) and reference lists. We also contacted experts, triallists and pharmaceutical companies in the field., Selection Criteria: Randomised trials comparing haloperidol with placebo or other active treatment in the treatment of acute manic or mixed episodes in patients with bipolar disorder or schizoaffective disorder., Data Collection and Analysis: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We collected adverse effects information from the trials., Main Results: Fifteen trials involving 2022 people were included. Compared to placebo, haloperidol was more effective at reducing manic symptoms, both as monotherapy (Weighted Mean Difference (WMD) -5.85, 95% Confidence Interval (CI) -7.69 to -4.00) and as adjunctive treatment to lithium or valproate (WMD -5.20, 95% CI -9.26 to -1.14). There was a statistically significant difference, with haloperidol being less effective than aripiprazole (Relative Risk (RR) 1.45, 95% CI 1.22 to 1.73). No significant differences between haloperidol and risperidone, olanzapine, carbamazepine or valproate were found. Compared with placebo, a statistically significant difference in favour of haloperidol in failure to complete treatment (RR 0.74, 95% Cl 0.57 to 0.96) was reported. Haloperidol was associated with less weight gain than olanzapine (RR: 0.28, 95% CI 0.12 to 0.67), but with a higher incidence of tremor (RR: 3.01, 95% CI 1.55 to 5.84) and other movement disorders., Authors' Conclusions: There is some evidence that haloperidol is an effective treatment for acute mania. From the limited data available, there was no difference in overall efficacy of treatment between haloperidol and olanzapine or risperidone. Some evidence suggests that haloperidol could be less effective than aripiprazole. Referring to tolerability, when considering the poor evidence comparing drugs, clinicians and patients should consider different side effect profiles as an important issue to inform their choice.

Objectives: The objective of this study was to describe clinical and work functional outcomes associated with 6-month open-label olanzapine treatment for bipolar I disorder., Methods: The study consisted of 249 patients entering a 6-month open label phase after 12 weeks of acute double-blind haloperidol or olanzapine treatment. Baseline for analysis was defined as the beginning of open-label treatment. The clinical outcomes were symptomatic remission defined by a Y-MRS total score < or = 12 and a HAM-D total score < or = 8 at the end of 6 months of treatment. The work functional outcomes included work functional scores, the proportion of patients who reported to 'work' as employee, volunteers, students, or house workers and the proportion of patients who specifically reported to 'work for pay'., Results: A total of 240 patients reported work functional outcomes post open-label baseline. Among them, 15.4% patients moved into a 'work group' from a 'no-work group' at baseline, while 7.1% did the opposite (p = 0.0065) and 13.3% reported an improvement to 'work for pay' status from a 'not working for pay' status at baseline, while there was 4.2% of worsening in employment status (p = 0.0007). Overall, improvement in the work functional score was found at all post-baseline time points, beginning at month two (p = 0.003)., Limitations: Results of this study need to be confirmed by double-blind randomized controlled studies. There was a lack of detailed information on work functioning from the questionnaire., Conclusions: Open-label olanzapine treatment for 6 months was associated with improvements in work functional outcomes in patients with bipolar disorder.

Antipsychotic drugs, potent dopamine receptor antagonists, are commonly used in the treatment of psychotic and affective illness. The discovery of antagonistic interactions between A2A adenosine receptors (ARs) and D2 dopamine receptors (DRs) in the central nervous system suggests that the adenosine system may be involved in the pathogenesis of psychiatric and neurological disorders. In the present study, we demonstrated for the first time that human platelets co-express A2A ARs and D2 DRs assembled into an heteromeric complexes. We also investigated the effects of chronic treatment with either typical or atypical antipsychotics on A2A AR binding parameters and receptors responsiveness in human platelets from patients affected by bipolar disorder. Chronic administration of typical antipsychotics induced a significant upregulation of A2A AR binding sites. Since no effects on A2A AR were obtained following "in vitro" platelet treatment with a typical antipsychotic (haloperidol), we could exclude a direct effect of the drug on A2A AR at the peripheral level. Moreover, typical antipsychotics induced a significant increase in the agonist potency to mediate A2A AR-G protein coupling. On the contrary, chronic treatment with atypical antipsychotics did not induce any significant alterations in A2A AR equilibrium binding parameters and receptor responsiveness suggesting that typical but not atypical antipsychotic drugs induced a selective modification of A2A AR binding parameters in human platelets. These results are in accordance with the literature data describing the selective A2A AR upregulation induced by typical antipsychotics in human striatum suggesting platelets as a peripheral model of the interactions between adenosine and dopamine system occurring in the central nervous system.

Background: Risperidone, an atypical antipsychotic, is used to treat mania both alone and in combination with other medicines., Objectives: To review the efficacy and tolerability of risperidone as treatment for mania., Search Strategy: The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR-Studies December 2004), The Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, MEDLINE, CINAHL and PsycINFO were searched in December 2004. Reference lists and English language textbooks were searched; researchers in the field and Janssen-Cilag were contacted., Selection Criteria: Randomised controlled trials comparing risperidone with placebo or other drugs in acute manic or mixed episodes., Data Collection and Analysis: Two reviewers independently extracted data from trial reports. Janssen-Cilag was asked to provide missing information., Quality Assessment: As in other trials of treatment for mania, the high proportion of imputed efficacy data resulting from rates of failure to complete treatment of between 12% and 62% may have biased the results., Main Results: Six trials (1343 participants) of risperidone as monotherapy or as adjunctive treatment to lithium, or an anticonvulsant, were identified. Permitted doses were consistent with those recommended by the manufacturers of Haldol (haloperidol) and Risperdal (risperidone) for treatment of mania and trials involving haloperidol allowed antiparkinsonian treatment. Risperidone monotherapy was more effective than placebo in reducing manic symptoms, using the Young Mania Rating Scale (YMRS) (weighted mean difference (WMD) -5.75, 95% confidence interval (CI) -7.46 to -4.04, P<0.00001; 2 trials) and in leading to response, remission and sustained remission. Effect sizes for monotherapy and adjunctive treatment comparisons were similar. Low levels of baseline depression precluded reliable assessment of efficacy for treatment of depressive symptoms. Risperidone as monotherapy and as adjunctive treatment was more acceptable than placebo, with lower incidence of failure to complete treatment (RR 0.66, 95% CI 0.52 to 0.82, P = 0.0003; 5 trials). Overall risperidone caused more weight gain, extrapyramidal disorder, sedation and increase in prolactin level than placebo. There was no evidence of a difference in efficacy between risperidone and haloperidol either as monotherapy or as adjunctive treatment. The acceptability of risperidone and haloperidol in incidence of failure to complete treatment was comparable. Overall risperidone caused more weight gain than haloperidol but less extrapyramidal disorder and comparable sedation., Authors' Conclusions: Risperidone, as monotherapy and adjunctive treatment, is effective in reducing manic symptoms. The main adverse effects are weight gain, extrapyramidal effects and sedation. Risperidone is comparable in efficacy to haloperidol. Higher quality trials are required to provide more reliable and precise estimates of its costs and benefits.

Tardive dyskinesia (TD), which is frequently seen in patients treated with dopamine receptor blocking agents, is difficult to manage. We report on a young Chinese man with bipolar disorder who developed TD after haloperidol treatment, involving the trunk, limbs, and orofacial area. TD persisted despite switching to atypical antipsychotic agents and treatment with valproate, benzodiazepines, and tetrabenazine. Resolution only occurred years later when he developed quadriplegia arising from infective myelitis of the cervical cord (C4-5). He had concomitant vertebral osteomyelitis, which was successfully treated with intravenous antibiotics. With intensive rehabilitation, he recovered the use of his limbs, but had no recurrence of TD. We attribute the resolution of orofacial dyskinesias with a cervical lesion to the interconnections between the orofacial area and cervical spine via the trigeminal nucleus (which has fibers descending as far caudally as C6), as well as to resetting of cortical maps., (Copyright (c) 2005 Movement Disorder Society.)

Background: Previous research on pharmacotherapy with conventional antipsychotics has suggested that patients with affective disorders have higher rates of treatment-emergent extrapyramidal symptoms (EPS) than patients with schizophrenia. It is not known whether this differential vulnerability holds true for treatment with atypical antipsychotics such as olanzapine. The present analysis retrospectively examined olanzapine clinical trial data for incidence of treatment-emergent EPS in patients with either schizophrenia or bipolar disorder., Method: Study participants were 4417 patients meeting DSM-III or DSM-IV criteria for either schizophrenia or bipolar mania participating in olanzapine clinical trials through July 31, 2001. Data were pooled across haloperidol-controlled trials and separately across placebo-controlled trials. Measures of EPS included rates of treatment-emergent EPS adverse event by type (i.e., dystonic, parkinsonian, or residual), Simpson-Angus Scale score mean change, rates of treatment-emergent parkinsonism, and rates of anticholinergic use., Results: Consistent with prior research, haloperidol-treated patients with bipolar disorder appeared to be more vulnerable to the development of EPS than those with schizophrenia. However, olanzapine-treated patients with bipolar disorder were no more likely to develop EPS than those with schizophrenia., Conclusion: Results support previous research regarding conventional antipsychotics and suggest that olanzapine therapy does not increase the risk of EPS for patients with bipolar disorder.

Methods: Patients (n=302) with bipolar I disorder (manic episode) were randomised to 12 weeks' double-blind treatment with quetiapine (flexibly dosed up to 800 mg/day), placebo, or haloperidol (up to 8 mg/day). The primary efficacy outcome variable was change from baseline to Day 21 in Young Mania Rating Scale (YMRS) score., Results: YMRS score improved with quetiapine at Day 21 (-12.29 versus -8.32 for placebo; P<0.01). The difference in favor of quetiapine increased by Day 84 (-17.52 versus -9.48; P<0.001). Haloperidol also showed an advantage over placebo at Days 21 and 84 (P<0.001). There was no significant difference in efficacy measures between quetiapine and haloperidol groups at any assessment except Day 21. The only common adverse event with quetiapine was somnolence (12.7%). Extrapyramidal symptoms (EPS), including akathisia, occurred at 59.6% with haloperidol, 12.7% with quetiapine, 15.8% with placebo. Most quetiapine responders (84%) received a dose of 400-800 mg/day., Conclusions: Quetiapine was effective and well tolerated. The efficacy and tolerability profile of haloperidol (including its propensity for EPS) supported study validity.

Background: Despite several treatmentoptions, adherenceto therapy is poor in patients with bipolar disorder., Aims: A double-blind, controlled comparison of aripiprazole and haloperidol in patients with bipolar I disorder experiencing acute manic or mixed episodes., Method: Patients (n=347) were randomised to receive aripiprazole or haloperidol in this 12-week, multicentre study. The primary outcome measure was the number of patients in response (greater, similar 50% improvement from baseline in Young Mania Rating Scale score) and receiving therapy at week 12., Results: At week 12, significantly more patients taking aripiprazole (49.7%) were in response and receiving therapy compared with those taking haloperidol (28.4%; P < 0.001). Continuation rates differed markedly between treatments (week 12: aripiprazole, 50.9%; haloperidol, 29.1%). Extrapyramidal adverse events were more frequent with haloperidol than aripiprazole (62.7% v. 24.0%)., Conclusions: Aripiprazole showed superior levels of response and tolerability to haloperidol in the treatment of an acute manic episode for up to 12 weeks.