Antimanic Efficacy Research Articles

British contributions to the therapeutic use of John Cade's lithium.

Coinciding with the 75th anniversary of John Cade's seminal publication that first reported lithium's antimanic efficacy, we briefly recount the salient findings of the historic paper and draw attention to the important psychiatric research in Britain that reinforced its findings and the critical British opinions that likely impeded its clinical use.

Vitamin D3 and zinc supplements augment the antimanic efficacy of lithium and olanzapine treatments in an animal model of mania

ABSTRACT Objective: Bipolar disorder (BD) is a challenging psychiatric disorder and a complex disease. The associated reduction in serum vitamin D3 (VitD3) levels in BD patients and the contribution of zinc (Zn) to the treatment, along with the severe side effects of lithium (Li) treatment, were encouraging to assess the efficacy of different correlated combinations of therapeutic/nutraceutical treatments such as olanzapine (Oln), VitD3, and Zn against Li. Methods: Mania was induced in C57BL/6 mice by administering methylphenidate (MPH) for 14 consecutive days. On the 8th day of MPH injection, different treatment regimens were administered, Li, Oln, VitD3/Zn, VitD3/Zn/Oln, VitD3 + Zn + Oln + Li50mg/kg (C50), and VitD3 + Zn + Oln + Li100mg/kg (C100). Both VitD3 (850 IU/kg) and Zn (180 mg/kg) were supplied with food for 2 weeks before starting the induction of mania, which continued until the end of MPH administration. Behavioral, brain oxidative stress, thyroid hormones, VitD3, Zn, GsK-3β, and Bcl2 levels, as well as brain histopathological alterations, were assessed. Results: Manic mice exhibited alterations in all tested parameters, and the histopathological examination of the cortex and hippocampus confirmed these results. The VitD3/Zn/Oln, C50, and C100 treatment regimens reversed most of the behavioral and pathophysiological alterations; however, the C50 treatment regimen was the most efficient. Conclusions: This study emphasizes the importance of combining different antimanic medications like Li and Oln with nutraceutical supplements to increase their antimanic efficacy, reduce their adverse effects, and, ideally, improve the BD patient's quality of life.

Antimanic Efficacy, Tolerability, and Acceptability of Clonazepam: A Systematic Review and Meta-Analysis.

(1) Background: The use of benzodiazepines for the treatment of acute mania remains prevalent. This systematic review and meta-analysis provides an updated assessment of Clonazepam's antimanic efficacy, tolerability, and acceptability. (2) Methods: A systematic search of multiple databases and clinical trial registries was conducted, aiming to identify any controlled studies of Clonazepam vs. placebo or any other pharmacotherapy for the treatment of acute mania. Pairwise meta-analytic evaluations were performed. (3) Results: Six studies were included with a total number of 192 participants, all of which were randomized controlled trials. Clonazepam may be superior to a placebo in the acute phase of treatment and no different to Lithium and Haloperidol in terms of efficacy, both acutely and in the medium to long term. Clonazepam may be an acceptable and well-tolerated treatment for acute mania, especially when used as an augmentation strategy. Comparisons were underpowered, with minimal sample sizes and only one study per comparison in many cases, thus limiting the generalizability of our findings and hindering firm clinical conclusions. (4) Conclusions: Given the prevalence of benzodiazepine use in current practice, more and larger studies are urgently needed.

A systematic review and network meta-analysis of antimanic drugs for the treatment of acute mania used in Japan.

This review aimed to clarify whether antimanic agents used in Japan are superior to placebo for the treatment of acute mania, based on reports of randomized controlled trials (RCTs) conducted in Japan and other East Asian countries. A literature search was conducted using the MEDLINE, PubMed, and Ichushi databases from their dates of inception to July 31, 2021, for studies written in English or Japanese with a primary diagnosis of bipolar I disorder, comparing any of the following active drugs to treat acute mania in adults: aripiprazole, carbamazepine, chlorpromazine, haloperidol, lithium, olanzapine, sultopride, timiperone, and zotepine. A random-effects network meta-analysis was performed within a frequentist framework. The quality of each included study was evaluated using the revised Cochrane risk-of-bias tool for randomized trials. The outcomes adopted were the response rate for efficacy and dropout rate for tolerability during 3 weeks from baseline. Eleven RCTs, totaling 1148 participants, were reviewed. The pooled odds ratio (OR) (±95% confidence interval [CI]) was calculated. Timiperone (OR = 4.53, CI 1.09-18.80), sultopride (OR = 3.76, CI 1.08-13.05), and aripiprazole (OR = 1.99, CI 1.22-3.24) were significantly more effective than placebo. Olanzapine (OR = 0.51, CI 0.29-0.90) was significantly superior in acceptability to placebo. The results showed no significant differences from placebo for carbamazepine, chlorpromazine, haloperidol, lithium, and olanzapine. These results suggest that noninferiority trials alone cannot always confirm the antimanic drug efficacy and that direct placebo-controlled trials are necessary to verify the antimanic efficacy of the drugs.

Dopamine Receptor Partial Agonists: Do They Differ in Their Clinical Efficacy?

Dopamine receptor partial agonists (DRPAs; aripiprazole, brexpiprazole, and cariprazine) constitute a novel class of antipsychotics. Although they share a similar mechanism of action, DRPAs differ in their pharmacodynamics, pharmacokinetics, drug interactions, or safety and tolerability. The antipsychotic efficacy of all three drugs was established in several placebo-controlled randomized trials (RCTs) in schizophrenia, both acute phase and relapse prevention. In addition, each of the DRPA agents has been tested in other psychiatric disorders, including bipolar disorder or major depression. However, a few studies have examined their comparative clinical efficacy. There are no head-to-head comparisons between aripiprazole, brexpiprazole, or cariprazine. In two acute schizophrenia RCTs of cariprazine and brexpiprazole, aripiprazole was used as an indirect comparator to control for study sensitivity. To assess potential differences in the efficacy of DRPAs, we reviewed data from controlled trials, systematic reviews, and meta-analyses. Our results showed that the acute antipsychotic effects of DRPAs, as measured by the number needed to treat, are comparable. The three agents were superior to placebo in acute treatment, and cariprazine was found to be effective in the reduction of primary negative symptoms of schizophrenia. In the therapy of bipolar disorder, aripiprazole and cariprazine showed antimanic efficacy, cariprazine was also effective in the management of bipolar depression, and aripiprazole was effective for relapse prevention. The addon administration of aripiprazole or brexpiprazole reduced symptoms of major depression. Aripiprazole can control acute agitation associated with psychosis or bipolar disorder; brexpiprazole showed the potential to manage agitation in dementia patients. Aripiprazole has also established evidence of efficacy in children and adolescents and other conditions: OCD, tic disorders, and autism spectrum disorder. Our review of published data suggests that in terms of clinical efficacy, DRPAs are a heterogeneous group, with each drug possessing its own therapeutic benefits.

Efficacy of Carbamazepine and Its Derivatives in the Treatment of Bipolar Disorder.

Background and Objectives: This review is dedicated to the use of carbamazepine and its derivatives oxcarbazepine and eslicarbazepine in bipolar disorder and their relative strengths in treating and preventing new depressive or manic episodes. This paper will discuss the evidence of their efficacy relative to the polarity of relapse from controlled acute and maintenance/relapse prevention studies in bipolar patients. Materials and Methods: A Medline search was conducted for controlled acute and maintenance studies with carbamazepine, oxcarbazepine, and eslicarbazepine in bipolar disorder. In addition, abstracts reporting on controlled studies with these medications from key conferences were taken into consideration. Results: Information was extracted from 84 articles on the acute and prophylactic efficacy of the medications under consideration. They all appear to have stronger efficacy in treating acute mania than depression, which also translates to better protection against manic than depressive relapses for carbamazepine. Still, there is a paucity of controlled acute studies on bipolar depression for all and, with the exception of carbamazepine, a lack of long-term monotherapy maintenance data. For eslicarbazepine, the efficacy in bipolar disorder remains largely unknown. Especially with carbamazepine, tolerability issues and drug–drug interactions need to be kept in mind. Conclusions: Two of the medications discussed in this review, carbamazepine and oxcarbazepine, match Class A criteria according to the criteria proposed by Ketter and Calabrese, meaning acute antimanic efficacy, prevention of manic relapses, and not causing or worsening depression.

Effects of tamoxifen and glutamate and glutamine levels in brain regions in repeated sleep deprivation-induced mania model in mice.

Protein kinase C inhibitor tamoxifen reduces symptoms of acute mania in bipolar patients and mania-like behaviors in animals. Memory impairment and altered levels of glutamate and glutamate/glutamine ratio have been reported in mania. Tamoxifen suppresses glutamate release which plays an important role in memory. The present study evaluated whether tamoxifen's activity participates in its antimanic efficacy in repeated sleep deprivation mania model. Mice were divided into control and 24-h sleep-deprived groups and were treated with vehicle or 1mg/kg tamoxifen twice daily for 8days. Sleep deprivation was repeated three times at intervals of 2days. Square crossing and rearing were recorded as measures of locomotor activity. Memory and risk taking behavior were evaluated using novel object recognition and staircase tests, respectively. Glutamate and glutamine levels were measured in the frontal cortex and hippocampus. Behavioral tests were conducted 24h after the second or immediately after the third sleep deprivations. Sleep deprivation increased locomotor activity and risk taking. Glutamate and glutamine levels and glutamate/glutamine ratio in the frontal cortex and hippocampus were unaffected. Locomotor hyperactivity was prevented by tamoxifen treatment. No change in the recognition index suggested lack of memory impairment in the model. These findings confirm the relevance of repeated sleep deprivation as a mania model and tamoxifen as an antimanic agent. However, future research is needed to further address lack of memory impairment in the model and lack of glutamatergic influence on the model and antimanic effect of tamoxifen.

Lithium treatment in the era of personalized medicine

In 1949, an Australian psychiatrist, John Cade, reported on the antimanic efficacy of lithium carbonate, which is regarded as an introduction of lithium into contemporary psychiatry. Since the 1960s, lithium has been a precursor of mood stabilizers and has become first-choice drug for the prevention of affective episodes in mood disorders. For nearly four decades, lithium has also been used for the augmentation of antidepressant drugs in treatment-resistant depression. The knowledge of clinical and biological factors connected with the capability of long-term lithium treatment to prevent manic and depressive recurrences makes an important element of the personalized medicine of mood disorders. Excellent prophylactic lithium responders can be characterized by distinct mood episodes, with full remissions between them, the absence of other psychiatric morbidity, and the family history of bipolar illness. In recent years, many other clinical and biological factors connected with such a response have been identified, helping to select the best candidates for lithium prophylaxis. The antisuicidal effect of lithium during its long-term administration has been demonstrated and should also be taken into account as the element of personalized medicine for the pharmacological prophylaxis of patients with mood disorders. Several studies pertaining to personalized medicine were also dedicated to lithium treatment of acute mood episodes. Lithium still has a value in the treatment of mania and bipolar depression. However, it seems that the more important indication would be the augmentation of antidepressant drugs in treatment-resistant depression. The factors connected with the efficacy of lithium in these conditions are reviewed.

Tamoxifen for bipolar disorder: Systematic review and meta-analysis

Tamoxifen is an oral medication that has been proposed as a potential treatment for bipolar disorder. Tamoxifen acts to inhibit the intracellular action of protein kinase C, which is also an action of well-established treatments such as lithium and valproate. Here we aimed to identify randomised controlled trials (RCTs) of tamoxifen in the treatment of bipolar disorder and synthesise their results using meta-analysis. RCTs were identified by searching of electronic databases and from discussion with experts in the field. Data were extracted, and meta-analyses performed in R. Five placebo-controlled RCTs of tamoxifen in the treatment of acute mania were identified. There were no trials in the treatment of episodes of bipolar depression, or for relapse prevention. The studies of mania treatment were of between three and six weeks duration. Tamoxifen was studied either as monotherapy (two trials) or as augmentation of lithium or valproate (three trials). Change in mania scale scores favoured tamoxifen over placebo: SMD -2.14 (95% CI -3.39 to -0.89; 4 trials), as did endpoint mania scale scores SMD 1.23 (95% CI 0.60-1.87; 5 trials). Response rates were also higher: RR 4.35 (1.99-9.50; 4 trials). Acceptability was similar to placebo: RR 1.03 (0.94-1.13; 5 trials). Tamoxifen appears to be a promising potential treatment for episodes of mania. Future studies could investigate its effects as an adjunct to dopamine antagonists for improved anti-manic efficacy, and establish its longer term effects on mood, particularly depression and relapse.

A Review of the Pharmacological and Clinical Profile of Newer Atypical Antipsychotics as Treatments for Bipolar Disorder: Considerations for Use in Older Patients.

Bipolar disorder prevalence rates vary in the older adult population (defined as age ≥ 65years), ranging from 1% in community dwellers to as high as 8-10% in hospital inpatients. Although older agents, including lithium and valproic acid, offer significant antimanic efficacy, as supported by a recent randomized controlled trial (RCT), there is growing interest in using atypical antipsychotics to treat bipolar disorder in older adults. Newer atypical antipsychotics are of interest based on their tolerability and efficacy in the general adult bipolar population. The aim of this review was to systematically examine efficacy and tolerability of newer atypical antipsychotics for older adult bipolar disorder (OABD). We conducted a systematic search utilizing the MEDLINE, EMBASE, PsycINFO and Cochrane Library electronic databases, with the aim of identifying all RCTs comparing newer atypical antipsychotics approved by the US FDA since 2002 (including brexpiprazole, cariprazine, lurasidone, iloperidone, asenapine, paliperidone, and aripiprazole) with placebo or another comparator, in the treatment of any phase of bipolar disorder (including mania, depression or mixed episodes while used as an acute or maintenance treatment) in older adults (> 65years). We found no RCT data on any of the examined agents. Hence, we changed our search criteria to include studies with a lower age cut-off (≥ 55years), as well as the inclusion of posthoc studies. Two posthoc studies on lurasidone suggest its reasonable safety and efficacy profile in the acute and maintenance treatment of OABD; however, there are no pharmacoeconomic data on the use of lurasidone in the treatment of OABD. Research data from open-label studies on oral asenapine and aripiprazole as add-on therapy suggest that these two agents are adequately tolerated and improved symptoms of depression and mania in OABD; hence, there is an urgent need to conduct RCTs on these two agents. Lastly, we found no studies for the treatment of OABD with brexpiprazole, cariprazine, iloperidone, or paliperidone.

Efficacy and Effectiveness of Lithium in the Long-Term Treatment of Bipolar Disorders: An Update 2018.

For more than 40 years, lithium has been the gold standard in the long-term treatment of bipolar disorders. In the course of the last 15 years, other drugs have been approved in this indication and are widely used in clinical practice at the expense of lithium. New research from the last few years, however, indicates that lithium is still the first-line treatment in this indication. Against this background and lithium's proven acute antimanic efficacy, we should perhaps be using lithium more regularly (in combination with an atypical antipsychotic, if necessary) right from the start for the acute treatment of a manic episode and, once remission has been achieved and euthymia maintained during continuation treatment, to regularly taper off the atypical antipsychotic, if possible, and continue with lithium as monotherapy for prophylactic treatment. This might lead to lithium being used more consistently with the scientific evidence in the long-term treatment of bipolar disorders. It remains uncertain, however, to predict who will respond to and tolerate lithium prophylactically, and more research is needed to deliver the best possible individualized care to our patients.

A Preclinical Study of Casein Glycomacropeptide as a Dietary Intervention for Acute Mania.

BackgroundCasein glycomacropeptide is a peptide that lacks phenylalanine, tyrosine, and tryptophan. This profile may enable it to deplete phenylalanine, tyrosine, and tryptophan, and subsequently the synthesis of dopamine and serotonin in the brain. Dopamine- and serotonin-depleting amino acid mixtures have shown promise as acute antimanic treatments. In this study, we explore the depleting effects on amino acids, dopamine and serotonin as well as its actions on manic-like and other behavior in rats.MethodsCasein glycomacropeptide and a selection of amino acid mixtures were administered orally at 2, 4, or 8 h or for 1 week chronically. Amino acid and monoamine levels were measured in plasma and brain and behavior was assessed in the amphetamine-hyperlocomotion, forced swim, prepulse inhibition, and elevated plus maze tests.ResultsCasein glycomacropeptide induced a time-dependent reduction in tyrosine, tryptophan, and phenylalanine in brain and plasma which was augmented by supplementing with leucine. Casein glycomacropeptide +leucine reduced dopamine in the frontal cortex and serotonin in the hippocampus, frontal cortex, and striatum after 2 and 4 h. Casein glycomacropeptide+leucine also had antimanic activity in the amphetamine-induced hyperlocomotion test at 2 h after a single acute treatment and after 1 week of chronic treatment.ConclusionsCasein glycomacropeptide-based treatments and a branched-chain amino acid mixture affected total tissue levels of dopamine in the frontal cortex and striatum and serotonin in the frontal cortex, striatum, and hippocampus of rats in a time-dependent fashion and displayed antimanic efficacy in a behavioral assay of mania.

A multi-centre, randomised, double-blind, placebo-controlled clinical trial of methylphenidate in the initial treatment of acute mania (MEMAP study)

Based on many clinical and preclinical findings the ‘vigilance regulation model of mania’ postulates that an unstable regulation of wakefulness is a pathogenetic factor in both mania and Attention Deficit Hyperactivity Disorder (ADHD) and induces hyperactivity and sensation seeking as an autoregulatory attempt to stabilize wakefulness. Accordingly, stimulant medications with their vigilance stabilizing properties could have rapid antimanic effects similar to their beneficial effects in ADHD. The MEMAP study – a multi-center, double-blind, placebo-controlled and randomized clinical trial (RCT) – assessed the antimanic efficacy and safety of a 2.5-day treatment with methylphenidate (20–40mg/day). Of 157 screened patients with acute mania, 42 were randomly assigned to receive 20–40mg per day of methylphenidate in one or two applications, or placebo. The primary outcome was the change in Young Mania Rating Scale (YMRS) sum scores from baseline to day 2.5 in the methylphenidate group compared to the placebo group. A group sequential design was chosen to justify early RCT termination based on efficacy or futility at an interim analysis after inclusion of 40 patients. In the interim analysis, the change from baseline in the YMRS total score at day 2.5 was not significantly different between both groups (F(1,37)=0.23; p=0.64). Thus, futility was declared for methylphenidate and the RCT was stopped. In summary, although methylphenidate was well tolerated and safe in the full analysis set, it failed to show efficacy in the treatment of acute mania. Trial registration: clinicaltrials.gov (URL: http://www.clinicaltrials.gov; registration number: NCT01541605).

Antimanic Efficacy of a Novel Kv3 Potassium Channel Modulator.

Kv3.1 and Kv3.2 voltage-gated potassium channels are expressed on parvalbumin-positive GABAergic interneurons in corticolimbic brain regions and contribute to high-frequency neural firing. The channels are also expressed on GABAergic neurons of the basal ganglia, substantia nigra, and ventral tegmental area (VTA) where they regulate firing patterns critical for movement control, reward, and motivation. Modulation of Kv3.1 and Kv3.2 channels may therefore have potential in the treatment of disorders in which these systems have been implicated, such as bipolar disorder. Following the recent development of a potassium channel modulator, AUT1-an imidazolidinedione compound that specifically increases currents mediated by Kv3.1 and Kv3.2 channels in recombinant systems-we report that the compound is able to reverse 'manic-like' behavior in two mouse models: amphetamine-induced hyperactivity and ClockΔ19 mutants. AUT1 completely prevented amphetamine-induced hyperactivity in a dose-dependent manner, similar to the atypical antipsychotic, clozapine. Similar efficacy was observed in Kv3.2 knockout mice. In contrast, AUT1 was unable to prevent amphetamine-induced hyperactivity in mice lacking Kv3.1 channels. Notably, Kv3.1-null mice displayed baseline hyperlocomotion, reduced anxiety-like behavior, and antidepressant-like behavior. In ClockΔ19 mice, AUT1 reversed hyperactivity. Furthermore, AUT1 application modulated firing frequency and action potential properties of ClockΔ19 VTA dopamine neurons potentially through network effects. Kv3.1 protein levels in the VTA of ClockΔ19 and WT mice were unaltered by acute AUT1 treatment. Taken together, these results suggest that the modulation of Kv3.1 channels may provide a novel approach to the treatment of bipolar mania.

Endoxifen, a New Treatment Option for Mania: A Double-Blind, Active-Controlled Trial Demonstrates the Antimanic Efficacy of Endoxifen.

The protein kinase C (PKC) signaling system plays a role in mood disorders and PKC inhibitors such as endoxifen may be an innovative medicine for bipolar disorder (BP) patients. In this study we show for the first time the antimanic properties of endoxifen in patients with bipolar I disorder (BPD I) with current manic or mixed episode. In a double‐blind, active‐controlled study, 84 subjects with BPD I were randomly assigned to receive endoxifen (4 mg/day or 8 mg/day) or divalproex in a 2:1 ratio. Patients orally administered 4 mg/day or 8 mg/day endoxifen showed significant improvement in mania assessed by the Young Mania Rating Scale as early as 4 days. The effect remained significant throughout the 21‐day period. At study end point, response rates were 44.44% and 64.29% at 4 mg/day and 8 mg/day of endoxifen treatment, respectively. Thus, endoxifen has been shown as a promising novel antimanic or mood stabilizing agent.

Antimanic Treatment With Tamoxifen Affects Brain Chemistry: A Double-Blind, Placebo-Controlled Proton Magnetic Resonance Spectroscopy Study

BackgroundThe antimanic efficacy of a protein kinase C inhibitor, tamoxifen, has been tested in several clinical trials, all reporting positive results. However, mechanisms underlying the observed clinical effects require further confirmation through studies of biological markers. MethodsWe investigated the effect of tamoxifen versus placebo on brain metabolites via a proton magnetic resonance spectroscopy study. Scanning was performed in 48 adult manic patients with bipolar disorder type I (mean Young Mania Rating Scale score of 37.8 ± 5.8) at baseline and after 3 weeks of double-blind treatment. We hypothesized that alleviation of manic symptoms would improve the levels of markers associated with brain energy metabolism (creatine plus phosphocreatine [total creatine (tCr)]) and neuronal viability (N-acetylaspartate). ResultsThe Young Mania Rating Scale scores decreased from 38.6 ± 4.5 to 20.0 ± 11.1 in the tamoxifen group and increased from 37.0 ± 6.8 to 43.1 ± 7.8 in the placebo group (p < .001). Proton magnetic resonance spectroscopy measurements revealed a 5.5% ± 13.8% increase in tCr levels in dorsomedial prefrontal cortex in the tamoxifen group and a 5.3% ± 13.1% decrease in tCr in the placebo group (p = .027). A significant correlation between the Young Mania Rating Scale score change and tCr percent change was observed in the whole group (Spearman rho = .341, p = .029). Levels of both tCr and N-acetylaspartate in the responder group were increased by 9.4% ± 15.2% and 6.1% ± 11.7%, respectively, whereas levels in the nonresponder group were decreased by 2.1% ± 13.2% and 6.5%± 10.5%, respectively (p < .05). ConclusionsTamoxifen effectively treated mania while increasing brain tCr levels, consistent with involvement of both excessive protein kinase C activation and impaired brain energy metabolism in the development of bipolar manic states.

PMH41 - Cost-Effectiveness of Asenapine Versus Atypical Antipsychotics Used in Turkey in the Treatment of Bipolar I Disorder

Asenapine is a new atypical antipsychotic approved in Turkey for the treatment of bipolar I disorder (BD-I) and schizophrenia. Asenapine has demonstrated comparable antimanic efficacy over olanzapine in a head-to-head study. However, unlike olanzapine, asenapine is associated with a favorable metabolic profile as well as with a minimal weight gain. Post-hoc analyses of a clinical study vs. olanzapine illustrated higher incidence of developing metabolic syndrome (MetS) with olanzapine than with asenapine after 52 weeks of treatment. The aim of this study is to assess the cost-effectiveness of asenapine in the treatment of BD-I compared with the most widely used atypical antipsychotics with a focus on the long-term consequences of MetS which increases the risk of diabetes and cardiovascular diseases (CVD). Perspective of National Pharmaceutical Reimbursement Authority was applied and life expectancy horizon was adopted. Risks of metabolic syndrome after 52 weeks of treatment were derived from randomized clinical studies of asenapine and indirect comparison of other atypical antipsychotics vs olanzapine. Risks of developing diabetes and CVD were based on published risk models. Treatment costs associated with metabolic consequences as well as cost of atypical antipsychotics were derived from local sources. Number of diabetes and CVD avoided is used as effectiveness measure in the model. Asenapine dominates (more effective and less expensive) all atypical antipsychotics in the treatment of BD-I. Compared to olanzapine, quetiapine, aripiprazole, risperidone and paliperidone (all genericized), asenapine was associated with incremental total costs of 2418 TL, 1786 TL, 804 TL and 877 TL; and associated with incremental total number of diabetes & CVD avoided of 0.054, 0.038, 0.010 and 0.037 respectively. The lower incidence of developing MetS associated with asenapine compared to olanzapine and other atypicals is associated with lower treatment costs and lower incidence of diabetes and CVD in Turkey.

Physical health of patients with bipolar disorder

Bipolar disorder is a chronic, typically early onsetting group of mental disorders with a lifelong risk of relapse. It is characterized by recurrent periods of depression and pathologically elevated mood consisting of increased energy and activity during which patients may experience sleep loss, over-confidence, impaired concentration, extreme talkativeness, and engage in irresponsible risk-taking behavior. As a result, it is often problematic to undertake usual activities and maintain interpersonal relationships (World Health Organization [WHO], 2001). An estimated 2.4% of the world’s population suffer from some form of bipolar disorder, with a lifetime prevalence of 0.6% for bipolar I disorder and 0.4% for bipolar II disorder, while 1.4% of the total population has a lifetime prevalence of subsyndromal bipolar disorder (Merikangas et al., 2011). Bipolar disorders are categorized into bipolar I and bipolar II depending on a patient history of major depressive and hypomanic episodes only (bipolar II), or depressive and manic episodes in addition to hypomanic and mixed episodes (bipolar I). Subsyndromal symptoms may be diagnosed as bipolar disorder not otherwise specified. Patients with bipolar disorder encounter many difficulties in leading a normal lifestyle, even with the support of family, friends and carers, and therefore tend to have a low quality of life (QoL), which is powerfully influenced by two factors: the nature of mental illness itself and treatment-related comorbidities. Features of social disability that may trouble patients with bipolar disorder include problems in developing and sustaining friendships and difficulties in maintaining intimate relationships with a partner. Furthermore, the inability to manage money, housework, and coping with an emergency (Kai and Crosland, 2001) impedes a normal lifestyle. Possibly as a consequence of poor QoL, “self

Antidepressant Action of Atypical Antipsychotics

Article AbstractZiprasidone has many pharmacodynamic properties that suggest it may have antidepressant action. Ziprasidone has established antimanic efficacy, and therefore, there is reason to hope that ziprasidone may be useful in the treatment of depression, especially when there is a risk of a switch into mania. A recent randomized controlled trial (RCT), however, found that ziprasidone monotherapy was no better than placebo in patients with major depressive disorder. Earlier RCTs had found ziprasidone to be ineffective in bipolar depression. These findings do not encourage the use of ziprasidone monotherapy to treat depression. Assuming that these findings are valid, a second take-home message is that clinicians should not rely too much on pharmacodynamic properties to guide expectations of clinical efficacy. Last, but not least, a note is presented on how evidence-based medicine principles should be applied in the interpretation of the results of the ziprasidone RCT in major depressive disorder with regard to a clinical case in point.

Cariprazine (RGH-188), a D3-preferring dopamine D3/D2 receptor partial agonist antipsychotic candidate demonstrates anti-abuse potential in rats

Cariprazine (RGH-188) is a D₃-preferring dopamine D₃/D₂ receptor partial agonist antipsychotic candidate for the treatment of schizophrenia and bipolar mania. Substance abuse is a frequent comorbidity of both disorders and is associated with serious health issues. Based on preclinical efficacy, dopamine D₂ and D₃ receptor partial agonists and antagonists are assumed to have relapse-preventing potential in human cocaine addiction. We investigated the anti-abuse potential of cariprazine in cocaine self-administration paradigms. Aripiprazole and bifeprunox were used as comparators because of their pharmacological similarity to cariprazine. The effects of compounds on cocaine's rewarding effect were investigated in a continuous self-administration regimen. The relapse-preventing potential of drugs was studied in rats with a history of cocaine self-administration after a period of complete abstinence in a relapse to cocaine-seeking paradigm. Cariprazine, as well as aripiprazole and bifeprunox, were able to reduce the rewarding effect of cocaine (minimum effective doses were 0.17, 1, and 0.1 mg/kg, respectively) and attenuated relapse to cocaine seeking with half maximal effective dose [ED₅₀] values of 0.2, 4.2, and 0.17 mg/kg, respectively. These results may predict a relapse-preventing action for cariprazine in humans in addition to its already established antipsychotic and antimanic efficacy.