Manic Symptoms In Bipolar Disorder Research Articles

Acoustic features from speech as markers of depressive and manic symptoms in bipolar disorder: A prospective study.

Voice features could be a sensitive marker of affective state in bipolar disorder (BD). Smartphone apps offer an excellent opportunity to collect voice data in the natural setting and become a useful tool in phase prediction in BD. We investigate the relations between the symptoms of BD, evaluated by psychiatrists, and patients' voice characteristics. A smartphone app extracted acoustic parameters from the daily phone calls of n = 51 patients. We show how the prosodic, spectral, and voice quality features correlate with clinically assessed affective states and explore their usefulness in predicting the BD phase. A smartphone app (BDmon) was developed to collect the voice signal and extract its physical features. BD patients used the application on average for 208 days. Psychiatrists assessed the severity of BD symptoms using the Hamilton depression rating scale -17 and the Young Mania rating scale. We analyze the relations between acoustic features of speech and patients' mental states using linear generalized mixed-effect models. The prosodic, spectral, and voice quality parameters, are valid markers in assessing the severity of manic and depressive symptoms. The accuracy of the predictive generalized mixed-effect model is 70.9%-71.4%. Significant differences in the effect sizes and directions are observed between female and male subgroups. The greater the severity of mania in males, the louder (β = 1.6) and higher the tone of voice (β = 0.71), more clearly (β = 1.35), and more sharply they speak (β = 0.95), and their conversations are longer (β = 1.64). For females, the observations are either exactly the opposite-the greater the severity of mania, the quieter (β = -0.27) and lower the tone of voice (β = -0.21) and less clearly (β = -0.25) they speak - or no correlations are found (length of speech). On the other hand, the greater the severity of bipolar depression in males, the quieter (β = -1.07) and less clearly they speak (β = -1.00). In females, no distinct correlations between the severity of depressive symptoms and the change in voice parameters are found. Speech analysis provides physiological markers of affective symptoms in BD and acoustic features extracted from speech are effective in predicting BD phases. This could personalize monitoring and care for BD patients, helping to decide whether a specialist should be consulted.

Inhibition of MMP8 effectively alleviates manic-like behavior and reduces neuroinflammation by modulating astrocytic CEBPD

There is an intrinsic relationship between psychiatric disorders and neuroinflammation, including bipolar disorder. Ouabain, an inhibitor of Na+/K+-ATPase, has been implicated in the mouse model with manic-like behavior. However, the molecular mechanisms linking neuroinflammation and manic-like behavior require further investigation. CCAAT/Enhancer-Binding Protein Delta (CEBPD) is an inflammatory transcription factor that contributes to neurological disease progression. In this study, we demonstrated that the expression of CEBPD in astrocytes was increased in ouabain-treated mice. Furthermore, we observed an increase in the expression and transcript levels of CEBPD in human primary astrocytes following ouabain treatment. Transcriptome analysis revealed high MMP8 expression in human primary astrocytes following CEBPD overexpression and ouabain treatment. We confirmed that MMP8 is a CEBPD-regulated gene that mediates ouabain-induced neuroinflammation. In our animal model, treatment of ouabain-injected mice with M8I (an inhibitor of MMP8) resulted in the inhibition of manic-like behavior compared to ouabain-injected mice that were not treated with M8I. Additionally, the reduction in the activation of astrocytes and microglia was observed, particularly in the hippocampal CA1 region. Excessive reactive oxygen species formation was observed in ouabain-injected mice, and treating these mice with M8I resulted in the reduction of oxidative stress, as indicated by nitrotyrosine staining. These findings suggest that MMP8 inhibitors may serve as therapeutic agents in mitigating manic symptoms in bipolar disorder.

Correlation between emotion dysregulation and mood symptoms of bipolar disorder: A systematic review and meta-analysis.

Emotion dysregulation (ED) is a transdiagnostic construct characterized by difficulties regulating intense emotions. People with bipolar disorder (BD) are more likely to show ED and use maladaptive emotion regulation strategies than adaptive ones. However, little is known about whether ED in BD is a trait or it is rather an epiphenomenon of mood symptoms. We conducted a systematic review and meta-analysis of the evidence across major literature databases reporting correlations between measures of emotion regulation (overall ED and different emotion regulation strategies) and measures of depressive and (hypo)manic symptoms in BD from inception until April 12th, 2022. Fourteen studies involving 1371 individuals with BD were included in the qualitative synthesis, of which 11 reported quantitative information and were included in the meta-analysis. ED and maladaptive strategies were significantly higher during periods with more severe mood symptoms, especially depressive ones, while adaptive strategies were lower. ED significantly correlates with BD symptomatology, and it mainly occurs during mood alterations. ED may be a target for specific psychotherapeutic and pharmacological treatments, according to precision psychiatry. However, further studies are needed, including patients with mood episodes and longitudinal design, to provide more robust evidence and explore the causal direction of the associations.

Smartphone-based interventions in bipolar disorder: Systematic review and meta-analyses of efficacy. A position paper from the International Society for Bipolar Disorders (ISBD) Big Data Task Force.

The clinical effects of smartphone-based interventions for bipolar disorder (BD) have yet to be established. To examine the efficacy of smartphone-based interventions in BD and how the included studies reported user-engagement indicators. We conducted a systematic search on January 24, 2022, in PubMed, Scopus, Embase, APA PsycINFO, and Web of Science. We used random-effects meta-analysis to calculate the standardized difference (Hedges' g) in pre-post change scores between smartphone intervention and control conditions. The study was pre-registered with PROSPERO (CRD42021226668). The literature search identified 6034 studies. Thirteen articles fulfilled the selection criteria. We included seven RCTs and performed meta-analyses comparing the pre-post change in depressive and (hypo)manic symptom severity, functioning, quality of life, and perceived stress between smartphone interventions and control conditions. There was significant heterogeneity among studies and no meta-analysis reached statistical significance. Results were also inconclusive regarding affective relapses and psychiatric readmissions. All studies reported positive user-engagement indicators. We did not find evidence to support that smartphone interventions may reduce the severity of depressive or manic symptoms in BD. The high heterogeneity of studies supports the need for expert consensus to establish ideally how studies should be designed and the use of more sensitive outcomes, such as affective relapses and psychiatric hospitalizations, as well as the quantification of mood instability. The ISBD Big Data Task Force provides preliminary recommendations to reduce the heterogeneity and achieve more valid evidence in the field.

Linkage of Young Mania Rating Scale to Clinical Global Impression Scale to Enhance Utility in Clinical Practice and Research Trials.

The Young Mania Rating Scale (YMRS) is the gold standard to assess manic symptoms of bipolar disorder, yet the clinical meaning of scores is unknown. To clinically understand and interpret YMRS scores, we examined linkages between the total and change scores of YMRS with the Clinical Global Impression (CGI) ratings. Individual participant data (N=2,988) from eight randomized, double-blind, placebo-controlled trials were included. Data were collected at baseline and subsequent visits. Spearman's correlation coefficients ρ were computed, and equipercentile linking was implemented. A YMRS score of 6 points corresponded approximately to 'borderline mentally ill,' 12 points to 'mildly ill,' 20 points to 'moderately ill,' 30 points to 'markedly ill,' 40 points to 'severely ill,' and 52 points to 'among the most extremely ill' patients on the CGI-S. A reduction of CGI-S by one point as well as 'minimally improved' on the CGI-I corresponded approximately to an absolute decrease of 4 to 8 YMRS points or a 21% to 29% reduction of YMRS baseline score whereas a reduction of CGI-S by two points and 'much improved' on the CGI-I corresponded to an absolute decrease of 10 to 15 points or a 42% to 53% reduction of YMRS baseline score. The current study findings offer clinicians meaningful cutoff values to interpret YMRS scores. Moreover, these values contribute to the definition of treatment targets, response, remission, and entry criteria in mania trials.

Effect of nighttime bedroom light exposure on mood episode relapses in bipolar disorder.

A previous cross-sectional study reported that nighttime light is associated with increased occurrence of manic symptoms in bipolar disorder; however, the longitudinal association between nighttime light and subsequent mood episode relapses remains unclear. We determined whether bedroom nighttime light was associated with mood episode relapses in patients with bipolar disorder. This prospective cohort study included 172 outpatients with bipolar disorder who participated in an Association between the Pathology of Bipolar Disorder and Light Exposure in Daily Life (APPLE) cohort study. A portable photometer was used to measure illuminance in the bedroom from bedtime to rising time during 7 consecutive nights for baseline assessment. Then, the participants were assessed at a 2-year follow-up for mood episode relapses. Of the 172 participants, 157 (91%) completed the 2-year follow-up, and 39 (22%) experienced manic or hypomanic episodes (with or without mixed features), during that time. In the Cox proportional-hazards model, the hazard ratio (HR) for manic/hypomanic episode relapses was significantly higher when the average nighttime illuminance was ≥3lux (n=71) than when it was <3lux (n=101; HR, 2.54; 95% confidence interval (CI), 1.33-4.84). In the multivariable model adjusted for a propensity score in relation to nighttime light, the relationship remained significant (HR, 2.17; 95% CI, 1.04-4.52). The association between nighttime light and depressive episode relapses was not significantly different. Keeping the bedroom dark at night may prevent hypomanic and manic episodes.

Integrated pathophysiology of schizophrenia, major depression, and bipolar disorder as monoamine axon disorder

Recent studies provide evidence that similar to early-stage Parkinson's disease, depression is a neurodegenerative disease characterized by the degeneration of monoamine axons. The major difference between the two disorders is that the symptoms of depression become evident without loss of monoamine neurons, while the motor symptoms of Parkinson's disease appear after loss of the cell body. Given that the axonal degeneration of monoamine neurons underlies the pathophysiology of neurological (Parkinson's disease) and neuropsychiatric (depression) diseases, axonal impairment of monoamine neurons is thought to also occur in schizophrenia and bipolar disorder and play a significant role in the pathophysiology of these mental illnesses. The positive symptoms of schizophrenia and manic symptoms of bipolar disorder are known to occur in hyper-monoaminergic states, opposite to depressive symptoms, negative/cognitive symptoms of schizophrenia, and motor disorders of Parkinson's disease, all occurring in hypo-monoaminergic states. Since monoamine axons have the capacity to spontaneously regenerate or sprout in response to damage in the adult brain and sometimes show hyperinnervation due to excessive regeneration/sprouting beyond normal levels, it is possible that schizophrenia and bipolar disorder are disorders that include excessive regeneration/sprouting of monoamine axons leading to hyper-monoaminergic states. Together, based on accumulating data from animal and human studies, the pathophysiology of schizophrenia, major depression, and bipolar disorder is summarized as follows: The degeneration of monoamine axons is associated with the negative and cognitive symptoms of schizophrenia, major and bipolar depression, while hyper-regeneration/sprouting of monoamine axons underlies the positive symptoms of schizophrenia and bipolar mania. The integrated understanding of schizophrenia, major depression, and bipolar disorder as monoamine axon disorder will open the door to the development of new diagnosis and treatment methods for major mental illnesses as well as early-stage Parkinson's disease.

Alcohol use moderates the relationship between symptoms of mental illness and aggression.

Diagnosis of mental illness (MI) inconsistently predicts aggressive behavior although co-occurrence of substance use appears to increase the frequency of aggression in MI populations. We propose that alcohol use should moderate the relationship between mental disorders marked by deficits in self-control and aggression and victimization. In the present study, alcohol use, physical aggression perpetration, physical aggression victimization, injury and psychiatric symptoms were assessed in a sample of 297 substance use disorder patients (102 women; Mage = 38.9, SD = 20.2) recruited from a residential treatment facility. Negative binomial regression analyses examined the relationship of physical aggression, victimization, and injury over the previous 12 months to symptoms of bipolar mania, psychosis, posttraumatic stress disorder, antisocial personality disorder (ASPD), and daily volume of alcohol consumed. Consistent with past research relating MI to aggression, rates of victimization were higher than rates of perpetration. Results demonstrated that alcohol use moderated the relationship of manic symptoms of bipolar disorder to perpetration of aggression and causing injury to others. Three way-interactions between gender, alcohol use, and both psychotic and ASPD symptoms were related to victimization. The combination of heavy alcohol use and increased psychotic or ASPD symptoms was related to greater victimization for women but not for men. Women with more psychotic symptoms who were heavy drinkers were also more likely to report causing injury to another person. Results were generally consistent with the multiple-thresholds model of alcohol-related aggression; however, the moderating effects of alcohol use were dependent on gender and type MI. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Alcohol and lithium have opposing effects on the period and phase of the behavioral free-running activity rhythm

Bipolar patients have a high prevalence of comorbid alcohol use and abuse disorders, while chronic alcohol drinking may increase the presence and severity of certain symptoms of bipolar disorder. As such, there may be many individuals that are prescribed lithium to alleviate the manic symptoms of bipolar disorder, but also drink alcohol concurrently. In addition, both alcoholics and individuals with bipolar disorder often exhibit disruptions to their sleep-wake cycles and other circadian rhythms. Interestingly, both ethanol and lithium are known to alter both the period and the phase of free-running rhythms in mammals. While lithium is known to lengthen the period, ethanol seems to shorten the period and attenuate the responses to acute light pulses. Therefore, the present study aimed to determine whether ethanol and lithium have opposing effects on the circadian pacemaker when administered together. C57BL/6J mice were provided drinking solutions containing lithium, alcohol, or both, and their free-running rhythms along with their response to photic phase shifts were investigated. Mice treated with lithium displayed period lengthening, which was almost completely negated when ethanol was added. Moreover, ethanol significantly attenuated light-induced phase delays while the addition of lithium partially restored this response. These results indicate that alcohol and lithium have opposing effects on behavioral circadian rhythms. Individuals with bipolar disorder who are prescribed lithium and who drink alcohol might be inadvertently altering their sleep and circadian cycles, which may exacerbate their symptoms.

Development of gummi drugs of aripiprazole as hospital formulations.

About half of patients with schizophrenia have poor adherence to taking medication, so many have recurrence, therefore, providing formulations that enable patients to continue their medication without interruption is important. We aimed to develop a gummi drug that contains aripiprazole (which can reduce schizophrenia and manic symptoms in bipolar disorder). We were able to develop gummi drugs (OD-G, PW-G and OS-G) using three commercially available aripiprazole products (Abilify® orally disintegrating tablets, powder formulation, and oral solutions, respectively) as hospital formulations. Furthermore, we developed improved OD-G (iOD-G), which contained high aripiprazole content. Pharmaceutical characteristics of iOD-G were demonstrated to be suitable for hospital formulations, and iOD-G could be stored for ≤1 month. No significant differences in the dissolution and pharmacokinetics of divided portions of iOD-G were observed when compared with commercially available aripiprazole products. This study confirmed that new dosage forms of aripiprazole in gummi drugs can be developed as hospital formulations, which will contribute to improve medication adherence of patients.

Tamoxifen use for the management of mania: a review of current preclinical evidence

Preliminary data on the efficacy of tamoxifen in reducing manic symptoms of bipolar disorder (BD) suggest that this agent may be a potential treatment for the management of this psychiatric disorder. However, the antimanic properties of tamoxifen have not been fully elucidated, hampering the development and/or use of mood-stabilising drugs that may share its same therapeutic mechanisms of action. Notably, we may gain a greater understanding of the neurobiological and therapeutic properties of tamoxifen by using suitable animal models of mania. Here, we review the preclinical studies that have evaluated the effects of tamoxifen to provide an overview of the current progress in our understanding of its antimanic actions, highlighting the critical role of protein kinase C (PKC) as a therapeutic target for the treatment of BD. To date, this field has struggled to make significant progress, and the organisation of an explicit battery of tests is a valuable tool for assessing a number of prominent facets of BD, which may provide a greater understanding of the entire scope of this disease.

Cognitive manic symptoms in bipolar disorder associated with polymorphisms in the DAOA and COMT genes.

IntroductionBipolar disorder is characterized by severe mood symptoms including major depressive and manic episodes. During manic episodes, many patients show cognitive dysfunction. Dopamine and glutamate are important for cognitive processing, thus the COMT and DAOA genes that modulate the expression of these neurotransmitters are of interest for studies of cognitive function.MethodologyFocusing on the most severe episode of mania, a factor was found with the combined symptoms of talkativeness, distractibility, and thought disorder, considered a cognitive manic symptoms (CMS) factor. 488 patients were genotyped, out of which 373 (76%) had talkativeness, 269 (55%) distractibility, and 372 (76%) thought disorder. 215 (44%) patients were positive for all three symptoms, thus showing CMS (Table 1). As population controls, 1,044 anonymous blood donors (ABD) were used. Case-case and case-control design models were used to investigate genetic associations between cognitive manic symptoms in bipolar 1 disorder and SNPs in the COMT and DAOA genes.10.1371/journal.pone.0067450.t001Table 1Clinical characteristics of the Bipolar 1 patient sample.Bipolar disorder type 1 [n]488Men [n (%)]209 (43)Talkativeness [n (%)]373 (76)Distracibility [n (%)]269 (55)Thought disorder [n (%)]372 (76)Cognitive manic symptoms* [n (%)]215 (44)Men [n (%)]81 (39)Non-Cognitive manic symptoms [n (%)]248 (51)Men [n (%)]117 (56)Unknown [n (%)]25 (5)Men [n (%)]11 (44)Anonymous blood donors (ABD)1044Men [n (%)]616 (59)*having all three symptoms: talkativeness, distractibility, and tought disorder.ResultsThe finding of this study was that cognitive manic symptoms in patients with bipolar 1 disorder was associated with genetic variants in the DAOA and COMT genes. Nominal association for DAOA SNPs and COMT SNPs to cognitive symptoms factor in bipolar 1 disorder was found in both allelic (Table 2) and haplotypic (Table 3) analyses. Genotypic association analyses also supported our findings. However, only one association, when CMS patients were compared to ABD controls, survived correction for multiple testing by max (T) permutation. Data also suggested interaction between SNPs rs2391191 in DAOA and rs5993883 in COMT in the case-control model.10.1371/journal.pone.0067450.t002Table 2Allelic association in bipolar 1 patients with cognitive manic symptoms (CMS) patients compared to non-CMS and to ABD controls in the DAOA and COMT genes.BP1 CMSBP1 non-CMSABDBP1 CMS vs. non-CMSb BP1 CMS vs. ABD controlsb GeneSNPa aa/ab/bbaa/ab/bbaa/ab/bbpEMP1c EMP2d OR [95% CI] e pEMP1c EMP2d OR [95% CI] e DAOA rs3916967 (C/T)32/88/8950/118/77177/494/3610.0180.0180.210.72 [0.55–0.93]0.0290.0260.280.78 [0.66–1.0] DAOA rs2391191 (A/C)28/75/7939/111/70179/487/3570.0550.0390.500.75 [0.57–1.0]0.0200.0190.210.75 [0.63–1.0] DAOA rs1935062 (C/A)26/67/8935/102/86146/460/4050.120.120.780.80 [0.58–1.0]0.0690.0660.520.80 [0.65–1.0] COMT rs5993883 (T/G)33/120/5371/112/57269/510/2230.0250.0300.270.73 [0.56–0.95]0.0017* 1.0E−4 * 0.021* 0.68 [0.91–1.4] COMT rs165599 (G/A)29/94/8725/93/12687/443/5010.0930.0940.691.27 [1.0–1.8]0.0140.0170.161.34 [1.1–1.7]aSNP (minor allele(a)/major allele(b)).bgender and rs1718119 as covariate.cpoint-wise p-value from 10,000 pemutations with no covarite (EMP1).dcorrected empirical p-value by max (T) permutation.eodds ratio (OR), the proportion of minor versus major allele affected (cognitive manic symptoms factor)/proportion of minor versus major allele unaffected (non-cognitive manic symptoms factor or ABD controls).*significant after correction for multiple testing by max (T) permutation.10.1371/journal.pone.0067450.t003Table 3Haplotype association of haplotype group 1 in bipolar 1 patients with cognitive manic symptoms (CMS) compared with non-CMS patients or ABD controls in the DAOA gene.CMS vs non-CMSb CMS vs ABDb DAOA rs3916967rs2391191rs1935062Fa pOR [95% CI]c Fa pOR [95% CI]c Haplotype 1CAC0.320.250.83 [0.66–1.1]0.330.140.83 [0.71–1.1]Haplotype 2TGC0.0320.340.64 [0.32–1.1]0.0370.190.58 [0.37–1.1]Haplotype 3CAA0.0740.0770.58 [0.39–0.89]0.0750.100.65 [0.47–1.0]Haplotype 4TGA0.570.0291.38 [1.17–1.8]0.560.00571.41 [1.1–1.6]afrequency (F) in sample.bgender and rs1718119 as covariates.codds ratios (OR) for each haplotype.ConclusionIdentifying genes associated with cognitive functioning has clinical implications for assessment of prognosis and progression. Our finding are consistent with other studies showing genetic associations between the COMT and DAOA genes and impaired cognition both in psychiatric disorders and in the general population.

Prevalence of mixed mania using 3 definitions

ObjectivesMixed episodes are a combination of depressive and manic symptoms in bipolar disorder (BD). We want to identify the proportion of patients who have depressive symptoms during an acute episode and also the validity of current methods for its diagnosis. Material and methodCross-sectional multicentre study of patients with type I BD who are admitted to specialized units. 368 patients in 76 centres were included. The patients should have a well established diagnosis of BD and need hospitalisation. The severity of the disorder and clinical status were evaluated upon admission and discharge using CGI-BP-M clinical impression scales, the Hamilton depression scale (HAMD-17) and the Young mania rating scale (YMRS). Upon admission, the necessary criteria for diagnosing a mixed type episode were recorded according to DSM-IV-TR, ICD-10 and McElroy criteria. Clinical judgment of the current type of episode was also recorded. ResultsPrevalence estimations for mixed episodes were: 12.9% according to DSM-IV-TR (n=45), 9% according to ICD-10 (n=31), 16.7% according to McElroy criteria (n=58), and 23.2% according to clinical judgment (n=81). Statistically significant differences were found between the estimated prevalence rates (Cochrane's Q-test, p<0.0001), with the maximum concordance level found between the McElroy and ICD-10 (Kappa=0.66, 95% CI, 0.54–0.77). The DSM-IV-TR criteria only present moderate concordance with ICD-10 (Kappa=0.65, 95% CI, 0.52 to 0.78) and McElroy criteria (Kappa=0.62, 95% CI, 0.50 to 0.74). ConclusionsThe definition of mixed episodes for BD must be revised to improve consensus and, consequently, therapeutic management. Current diagnostic systems, based on DSM-IV and IDC-10, only capture a limited proportion of patients suffering from mixed episodes, giving rise to important limitations concerning the therapeutic management of BP patients.

MicroRNA-134 plasma levels before and after treatment for bipolar mania

Studies have previously documented that microRNAs (miRNAs), with their key roles in regulating both synaptic plasticity and brain development, are candidate genetic contributors to the etiopathology of bipolar disorder (BD). Moreover, miRNA identified as targets for the actions of chronic lithium and VPA are known to play diverse and intriguing roles in brain function. In particular, the brain specific miR-134 has recently been identified as a potential regulator of dendritic spine volume and synapse formation. Recently, circulating miRNAs have been reported as promising biomarkers for various pathologic conditions. We assessed the hypothesis that miRNA-134 may be present and detectable in circulating blood, and that miRNA-134 may serve as a biomarker of mania episodes in BD. In the present study, we recruited 21 bipolar I, manic (DSM-IV) patients and controls matched by sex and age for quantification of miR-134 level in plasma using real-time RT-PCR method. We found that: Plasma miR-134 levels in drug-free, 2-week medicated, and 4-week medicated bipolar mania patients were significantly decreased when compared with controls, and the level was increased on following medication. Decreased circulating miR-134 level both in drug-free and medicated patients did presented negative correlation with the clinical scales. Overall, these results suggest that the decreased plasma miR-134 levels may be directly associated with the pathophysiology and severity of manic symptoms in BD. Plasma miRNA-134 in BD may be considered as a potential peripheral marker that can respond to acute manic episodes and associate with effective mood stabilizers treatment.

The Expert Consensus Guideline Series

Poor adherence to medication treatment can have devastating consequences for patients with mental illness. The goal of this project was to develop recommendations for addressing adherence problems to improve patient outcomes. The editors identified important topics and questions concerning medication adherence problems in serious mental illness that are not fully addressed in the literature. A survey was developed containing 39 questions (521 options) asking about defining nonadherence, extent of adherence problems in schizophrenia and bipolar disorder, risk factors for nonadherence, assessment methods, and interventions for specific types of adherence problems. The survey was completed by 41 (85%) of the 48 experts to whom it was sent. Results of the literature review and survey were used to develop recommendations for assessing and improving adherence in patients with serious mental illness. ASSESSING ADHERENCE: The experts endorsed percentage of medication not taken as the preferred method of defining adherence, with 80% or more of medication taken endorsed as an appropriate cut-off for adherence in bipolar disorder and schizophrenia. Although self- and physician report are the most common methods used to assess adherence in clinical settings, they are often inaccurate and may underestimate nonadherence. The experts recommend that, if possible, clinicians also use more objective measures (e.g., pill counts, pharmacy records, and, when appropriate, serum levels such as are used for lithium). Use of a validated self-report scale may help improve accuracy. The majority of the experts believed the average patient with schizophrenia or bipolar disorder in their practices takes only 51%-70% of prescribed medication. FACTORS ASSOCIATED WITH NONADHERENCE: The experts endorsed poor insight and lack of illness awareness, distress associated with specific side effects or a general fear of side effects, inadequate efficacy with persistent symptoms, and believing medications are no longer needed as the most important factors leading to adherence problems in schizophrenia and bipolar disorder. The experts considered weight gain a side effect that is very likely to lead to adherence problems in patients with schizophrenia and bipolar disorder; sedation was considered a more important contributor to adherence problems in bipolar disorder than schizophrenia. The experts rated persistent positive or negative symptoms in schizophrenia and persistent grandiosity and manic symptoms in bipolar disorder as the most important symptomatic contributors to adherence problems in these illnesses. It is important to identify the specific factors that may be contributing to a patient's adherence problems in order to customize interventions to target those problems. Multiple problems may be involved, requiring a combination of interventions. Adherence problems are complex and multidetermined. The experts recommended customized interventions focused on the underlying causes.

Omega-3 fatty acids for bipolar disorder

Bipolar disorder is a complex psychiatric disorder and is amongst the top thirty causes of worldwide disability. Mood stabilisers are the primary pharmacological intervention, both in the treatment of acute episodes and in prophylaxis. There is, however, mounting evidence that dietary supplementation with omega-3 fatty acids may be beneficial in psychiatric conditions, particularly those involving disturbances of mood. To review the efficacy of omega-3 fatty acids as either a monotherapy or an adjunctive treatment for bipolar disorder. Electronic searches of the following databases were performed: CCDANCTR-Studies and CCDANCTR-References were searched on 12/2/2008, Supplementary searches were carried out on Biological Abstracts, CINAHL, The Cochrane Library, CCDAN Register, EMBASE, MEDLINE, and PsycINFO. The search strategy also included cited reference searching, personal contact with all authors of studies initially included and contact with the omega-3 producing pharmaceutical companies. All relevant randomised controlled trials were included in the review. Studies involving males and females of all ages with a diagnosis of bipolar disorder qualified for inclusion. Studies using any type or dose of omega-3 fatty acid treatment as monotherapy or in addition to standard pharmacotherapy were eligible. The primary outcome was symptom severity; and secondary outcomes were adverse effects, dropout and satisfaction with treatment. Two review authors independently inspected the citations identified from the search. Potentially relevant abstracts were identified and full papers ordered and reassessed for inclusion and methodological quality. All relevant data were extracted. The weighted mean difference (WMD) was used for continuous outcome data, with 95% confidence intervals (CI). Five studies met inclusion criteria for the review, however, methodological quality was highly variable. Only one study, involving 75 participants, provided data for analysis, and showed a benefit of active treatment over control for depression symptom levels (WMD -3.93, 95% CI -7.00 to -0.86)and Clinical Global Impression scores (WMD -0.75, 95% CI -1.33 to -0.17) but not for mania (WMD -2.81, 95% CI -7.68 to 1.90). No serious adverse effects were reported in the five studies. The pattern of dropout was highly variable between studies. Results from one study showed positive effects of omega-3 as an adjunctive treatment for depressive but not manic symptoms in bipolar disorder. These findings must be regarded with caution owing to the limited data available. There is an acute need for well-designed and executed randomised controlled trials in this field.

Atypical antipsychotics: newer options for mania and maintenance therapy

Vieta E, Goikolea JM. Atypical antipsychotics: newer options for mania and maintenance therapy. Bipolar Disord 2005: 7 (Suppl. 4): 21-33. (c) Blackwell Munksgaard, 2005Atypical antipsychotics have been used to treat patients with schizophrenia for many years, but now there is increasing evidence of their utility in the treatment of bipolar disorder. In the past few years several atypical agents have received regulatory approval for use in bipolar mania. Through a review of randomized controlled trials for five commonly used atypical drugs, olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole, this article evaluates their efficacy in the acute and maintenance phases of bipolar disorder. The evidence shows that atypical antipsychotics are effective in the treatment of manic symptoms, either alone or in combination with traditional mood stabilizers such as lithium and divalproex. Although emerging data indicate that atypical antipsychotics will be a promising addition to those therapies that are currently available for managing patients during the maintenance phase of bipolar illness, their potential in the long-term management of bipolar disorder remains to be fully explored. Atypical antipsychotics appear to have broadly similar efficacy against manic symptoms of bipolar disorder, but there are important differences in their tolerability profiles, which are likely to be of particular relevance during long-term treatment. A brief assessment of tolerability issues surrounding the use of atypical agents in bipolar disorder and other aspects of treatment that have impact on the clinical effectiveness of the therapy are considered.

Translating knowledge of genetics and pharmacology into improving everyday practice

Bipolar disorder is associated with significant morbidity and mortality; however, many aspects of this disorder remain poorly understood. It is likely that rapid advances in molecular genetics and neuroimaging will play a major role in advancing our understanding of bipolar disorder in future. Molecular genetics studies have already identified some candidate genes; for example, the BDNF, G72 and XBP1 genes, and chromosomal 'hot spots', which may confer a predisposition to development of bipolar disorder. Such advances may facilitate earlier, easier and more accurate diagnosis and provide novel targets for the treatment of this condition. Brain imaging studies using positron emission tomography and single photon emission computed tomography have shown that reduction in brain 5-hydroxytryptamine type 2 (5-HT(2)) receptors may be associated with prevention of or relief from depressive symptoms. Similarly, other imaging studies suggest that increased dopamine levels in the synapse mediate the symptoms of bipolar mania and that reduction in dopamine transmission through reduction in dopamine synthesis or blockade of dopamine D(2) receptors may be associated with antimanic effects. The ability of atypical antipsychotics to block both 5-HT(2) and D(2) receptors and downregulate 5-HT(2) receptors may explain how these drugs treat both the depressive and manic symptoms of bipolar disorder. Although molecular genetics and imaging techniques are not yet used as clinical tools for bipolar disorder, they provide valuable data to improve the understanding of the pathophysiology of bipolar disorder and should lead to new treatments and potentially episode prevention.

Aripiprazole: A Novel Atypical Antipsychotic Drug With a Uniquely Robust Pharmacology

ABSTRACTAripiprazole (Abilify®) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia. Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G‐protein coupled receptors (GPCRs) [especially dopamine (D2) and 5‐HT1A] and antagonistic action at others (especially 5‐HT2A). Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia. In short‐term studies rapid onset of action (within one week) has been demonstrated. Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder. At recommended doses, aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and Schizoaffective disorder. There is only limited information available on the use of aripiprazole in children and adolescents, and pilot data suggest that a revised dosing strategy, based on weight, is indicated in this population. In the long‐term studies, the use of aripiprazole was associated with continued efficacy, good compliance and increased time‐to‐relapse.Aripiprazole represents the first functionally selective atypical antipsychotic drug.

Impact of Depressive Symptoms Compared With Manic Symptoms in Bipolar Disorder

In the present study, we assessed the functional impact of depressive versus manic symptoms in bipolar disorder. A survey comprising the Sheehan Disability Scale (SDS), the Social Adjustment Scale Self-Report (SAS-SR), the Mood Disorder Questionnaire (MDQ), and other questions was mailed to a representative subset of 4810 individuals (with or without bipolar disorder) from a U.S. population-based epidemiologic study conducted in 2001. Of the 3191 evaluable surveys returned, 593 respondents screened positive for bipolar disorder on the MDQ and/or reported a physician diagnosis of bipolar disorder. In the 4 weeks prior to the survey, subjects reported a mean of 12.4 days of depressive symptoms and 7.0 days of manic symptoms (p < .0001). The majority of days with depressive (79.8%) and manic (77.1%) symptoms were disruptive. Both total and mean scores on each domain of the SDS (work, social life, family life) reflect significantly greater impairment because of depressive versus manic symptoms during the 4 weeks prior to the survey (p < .0001). Among the 118 employed subjects who missed at least 1 day of work in the past month, more workdays were missed because of depressive versus manic symptoms (0.78 vs. 0.15, p < .004). For each domain of the SAS-SR, functional impairment was attributed significantly more often to depressive symptoms than manic symptoms (p < .0001). Similar results were observed for the 12 months preceding the survey. Self-reported depressive symptoms are more frequent than manic symptoms and cause greater disruption of occupational, family, and social functioning. These findings underscore the need to improve the recognition and management of bipolar depression.