Manic Bipolar Disorder Patients Research Articles

Assessment of Serum High Density Lipoprotein, Low Density Lipoprotein, and Very Low Density Lipoprotein in Bipolar Disorder Subjects

Background: Bipolar disorder (BD) is a psychiatric condition and is defined as mood swings that alternate between mania, hypomania, and depression. Studies have been conducted globally to assess lipid profile (High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), and Very Low Density Lipoprotein (VLDL)) for BD with varying results. No such studies have been conducted in Pakistan. Therefore, current study was designed to assess lipid profile (HDL, LDL, VLDL) in clinically diagnosed bipolar BD. Materials and Methods: One hundred and twelve blood samples were collected of diagnosed BD patients visiting Sheikh Zayd Hospital (SZH) and Punjab Institute of Mental Health (PIMH) Lahore. HDL, LDL and VLDL were estimated using standard biochemical methods. Results: Results obtained were statistically analyzed using SPSS. A total of 112 BD patients, 48 (58.5%) were manic, 26 (31.7%) were depressive, 8 (9.8%) were euthymic. The mean HDL (41.26±12.57 mg/dl), LDL level (115.15±38.26 mg/dl) in bipolar group (manic, depressive and euthymic) as compared to control group were statistically significant with p-value 0.026. The mean VLDL level (33.17±18.43 mg/dl) level in bipolar and control groups was statistically insignificant with p-value 0.609. Conclusions: The present study suggests that HDL level is decreased in manic BD patients. The raised value of LDL-C is found in depressive and euthymic patients. VLDL level was same in BD and control groups. Keywords: Bipolar Disorder, Lipid Profile, High Density Lipoprotein, Low Density Lipoprotein, Very Low Density Lipoprotein

Tryptophan Catabolites in Bipolar Disorder: A Meta-Analysis.

ObjectiveTryptophan catabolites (TRYCATs) are implicated in the pathophysiology of mood disorders by mediating immune-inflammation and neurodegenerative processes. We performed a meta-analysis of TRYCAT levels in bipolar disorder (BD) patients compared to healthy controls.MethodsA systematic literature search in seven electronic databases (PubMed, Embase, Web of Science, Cochrane, Emcare, PsycINFO, Academic Search Premier) was conducted on TRYCAT levels in cerebrospinal fluid or peripheral blood according to the PRISMA statement. A minimum of three studies per TRYCAT was required for inclusion. Standardized mean differences (SMD) were computed using random effect models. Subgroup analyses were performed for BD patients in a different mood state (depressed, manic). The methodological quality of the studies was rated using the modified Newcastle-Ottawa Quality assessment Scale.ResultsTwenty-one eligible studies were identified. Peripheral levels of tryptophan (SMD = -0.44; p < 0.001), kynurenine (SMD = - 0.3; p = 0.001) and kynurenic acid (SMD = -.45; p = < 0.001) were lower in BD patients versus healthy controls. In the only three eligible studies investigating TRP in cerebrospinal fluid, tryptophan was not significantly different between BD and healthy controls. The methodological quality of the studies was moderate. Subgroup analyses revealed no significant difference in TRP and KYN values between manic and depressed BD patients, but these results were based on a limited number of studies.ConclusionThe TRYCAT pathway appears to be downregulated in BD patients. There is a need for more and high-quality studies of peripheral and central TRYCAT levels, preferably using longitudinal designs.

Chronic nicotine, but not suramin or resveratrol, partially remediates the mania-like profile of dopamine transporter knockdown mice

Bipolar disorder (BD) is a severe mental illness affecting 2% of the global population. Current pharmacotherapies provide incomplete symptom remediation, highlighting the need for novel therapeutics. BD is characterized by fluctuations between mania and depression, likely driven by shifts between hyperdopaminergia and hypercholinergia, respectively. Hyperdopaminergia may result from insufficient activity of the dopamine transporter (DAT), the primary mediator of synaptic dopamine clearance. The DAT knockdown (DAT KD) mouse recreates this mechanism and exhibits a highly reproducible hyperexploratory profile in the cross-species translatable Behavioral Pattern Monitor (BPM) that is: (a) consistent with that observed in BD mania patients; and (b) partially normalized by chronic lithium and valproate treatment. The DAT KD/BPM model of mania therefore exhibits high levels of face-, construct-, and predictive-validity for the pre-clinical assessment of putative anti-mania drugs. Three different drug regimens – chronic nicotine (nicotinic acetylcholine receptor (nAChR) agonist; 40 mg/kg/d, 26 d), subchronic suramin (anti-purinergic; 20 mg/kg, 1 × /wk, 4 wks), and subchronic resveratrol (striatal DAT upregulator; 20 mg/kg/d, 4 d) – were administered to separate cohorts of male and female DAT KD- and wildtype (WT) littermate mice, and exploration was assessed in the BPM. Throughout, DAT KD mice exhibited robust hyperexploratory profiles relative to WTs. Nicotine partially normalized this behavior. Resveratrol modestly upregulated DAT expression but did not normalize DAT KD behavior. These results support the mania-like profile of DAT KD mice, which may be partially remediated by nAChR agonists via restoration of disrupted catecholaminergic/cholinergic equilibrium. Delineating the precise mechanism of action of nicotine could identify more selective therapeutic targets.

Convergent neural substrates of inattention in bipolar disorder patients and dopamine transporter-deficient mice using the 5-choice CPT.

Bipolar disorder (BD) is a debilitating psychiatric illness affecting 2%-5% of the population. Although mania is the cardinal feature of BD, inattention and related cognitive dysfunction are observed across all stages. Since cognitive dysfunction confers poor functional outcome in patients, understanding the relevant neural mechanisms remains key to developing novel-targeted therapeutics. The 5-choice continuous performance test (5C-CPT) is a mouse and fMRI-compatible human attentional task, requiring responding to target stimuli while inhibiting responding to nontarget stimuli, as in clinical CPTs. This task was used to delineate systems-level neural deficits in BD contributing to inattentive performance in human subjects with BD as well as mouse models with either parietal cortex (PC) lesions or reduced dopamine transporter (DAT) expression. Mania BD participants exhibited severe 5C-CPT impairment. Euthymic BD patients exhibited modestly impaired 5C-CPT. High impulsivity BD subjects exhibited reduced PC activation during target and nontarget responding compared with healthy participants. In mice, bilateral PC lesions impaired both target and nontarget responding. In the DAT knockdown mouse model of BD mania, knockdown mice exhibited severely impaired 5C-CPT performance versus wildtype littermates. These data support the role of the PC in inattention in BD-specifically regarding identifying the appropriate response to target vs nontarget stimuli. Moreover, the findings indicate that severely reduced DAT function/hyperdopaminergia recreates the attentional deficits observed in BD mania patients. Determining the contribution of DAT in the PC to attention may provide a future target for treatment development.

Depression and Mania Induce Pro-inflammatory Activation of Macrophages Following Application of Serum from Individuals with Bipolar Disorder.

ObjectiveEvidence has suggested that immune imbalance is involved with bipolar disorder (BD); however, its precise mechanism is poorly understood. This study investigated whether biochemical changes in the serum from BD patients could modulate the phenotype of cultured macrophages.MethodsEighteen subjects with BD and five healthy individuals were included in this study. The human monocyte cell line U-937 was activated with phorbol 12-myristate 13-acetate (PMA) and polarization was induced with RPMI-1640 media supplemented with 10% serum from each patient for 24 hours. Gene expression of selected M1 and M2 markers was assessed by quantitative PCR.ResultsMacrophages exposed to serum of manic and depressive BD patients displayed an increase of interleukin-1β (6.40±3.47 and 9.04±5.84 vs. 0.23±0.11; p<0.05) and tumor necrosis factor-α (2.23±0.91 and 2.03±0.45 vs. 0.62±0.24; p=0.002 and p=0.004, respectively) compared to euthymic group (there was no difference between euthymic and controls). In parallel, U-937 macrophages treated with serum of patients in acute episode displayed a down-regulation of CXCL9 (0.29±0.20 vs. 1.86±1.61; p=0.006) and CXCL10 expression (0.36±0.15 and 0.86±0.24 vs. 1.83±0.88; p<0.000 and p=0.04) compared to the euthymia group.ConclusionOur results are consistent with previous studies showing that changes in peripheral blood markers could modulate M1/M2 polarization in BD. The evidence of macrophages as source of inflammatory cytokines might be helpful to unravel how the mononuclear phagocyte system is involved in the etiology of BD.

Dopamine transporter knockdown mice in the behavioral pattern monitor: A robust, reproducible model for mania-relevant behaviors

Efforts to replicate results from both basic and clinical models have highlighted problems with reproducibility in science. In psychiatry, reproducibility issues are compounded because the complex behavioral syndromes make many disorders challenging to model. We develop translatable tasks that quantitatively measure psychiatry-relevant behaviors across species. The behavioral pattern monitor (BPM) was designed to analyze exploratory behaviors, which are altered in patients with bipolar disorder (BD), especially during mania episodes. We have repeatedly assessed the behavioral effects of reduced dopamine transporter (DAT) expression in the BPM using a DAT knockdown (KD) mouse line (~10% normal expression). DAT KD mice exhibit a profile in the BPM consistent with acutely manic BD patients in the human version of the task—hyperactivity, increased exploratory behavior, and reduced spatial d (Perry et al., 2009). We collected data from multiple DAT KD BPM experiments in our laboratory to assess the reproducibility of behavioral outcomes across experiments. The four outcomes analyzed were: 1) transitions (amount of locomotor activity); 2) rearings (exploratory activity); 3) holepokes (exploratory activity); and 4) spatial d (geometrical pattern of locomotor activity). By comparing DAT KD mice to wildtype (WT) littermates in every experiment, we calculated effect sizes for each of the four outcomes and then calculated a mean effect size using a random effects model. DAT KD mice exhibited robust, reproducible changes in each of the four outcomes, including increased transitions, rearings, and holepokes, and reduced spatial d, vs. WT littermates. Our results demonstrate that the DAT KD mouse line in the BPM is a consistent, reproducible model of mania-relevant behaviors. More work must be done to assess reproducibility of behavioral outcomes across experiments in order to advance the field of psychiatry and develop more effective therapeutics for patients.

The COMT Val158Met Polymorphism and Exploratory Behavior in Bipolar Mania

Background: The catechol-O-methyltransferase (COMT) Val158Met gene influences cognition and behavior in psychiatric illnesses; its low-activity allele, methionine (Met), may be associated with behavior reflecting catecholamine overactivity. Heightened motor activity and increased positive valence are central features of bipolar disorder (BD) and have been quantified in the human Behavioral Pattern Monitor (hBPM), an exploration paradigm based upon the rodent open field. We examined whether hBPM behavior was related to the COMT gene in a small sample of manic BD patients. Methods: Twenty-six acutely hospitalized manic BD patients were genotyped for the COMT Val158Met polymorphism and tested in the hBPM, an unfamiliar room containing novel objects. Movements around the hBPM and object interactions were video-recorded for 15 min and rated. Results: Met homozygote BD patients demonstrated significantly more interactions with multiple objects and more time spent with objects in the hBPM. Valine (Val) homozygote patients exhibited the least object exploration, while heterozygote patients demonstrated intermediate levels. Conclusion: This preliminary study suggests that arousal and positive valence are influenced in a linear fashion by COMT, presumably due to increased catecholamine in frontal regions, but these findings require replication in a larger sample. The hBPM can enable cross-species and transdiagnostic studies to inform neurobiology of psychiatric disorders.

Cortical inhibition in symptomatic and remitted mania compared to healthy subjects: A cross-sectional study.

Transcranial magnetic stimulation (TMS)-derived cortical reactivity studies provide a unique opportunity to non-invasively study gamma amino butyric acid (GABA)-mediated inhibitory neurotransmission in bipolar disorder (BD). Earlier studies were conducted in smaller samples and on patients who were on medications that can potentially confound the results. We aimed to study short-interval (SICI) and long-interval intracortical inhibition (LICI) in medication-naïve/free symptomatic (manic) BD patients (n=39), first episode mania (FEM) patients who had recently (≤6months) remitted with treatment (remitted FEM; n=28) and healthy subjects (HSs; n=45). Resting motor threshold (RMT), stimulation intensity to elicit a 1-mV motor evoked potential (MEP) (SI1mV ), SICI and LICI were measured in three groups using single- and paired-pulse TMS. Motor thresholds were higher in the manic BD and HS groups compared to the remitted FEM group (P<.001). SICI was lower (P=.026) but LICI was higher (P=.044) in the manic BD and remitted FEM groups compared to the HS group. Lower motor thresholds in remitted FEM perhaps reflect the effect of treatment, and could be studied as potential prognostic neuromarkers. Inverse findings for SICI (reduced) and LICI (increased) in BD indicate a possible differential involvement of the GABAA and GABAB subreceptor systems. These could be trait markers as they are impaired in both mania and euthymia.

Serum of bipolar patients induces pro-inflammatory activation of macrophages

IntroductionEvidence has suggested that immune imbalance is involved with bipolar disorder (BD); however, its precise mechanism is poorly understood.ObjectiveThis study investigated whether biochemical changes in the serum from BD patients could modulate the phenotype of macrophages.MethodsEighteen subjects with BD and healthy individuals (n = 5) were included in this study. The human monocyte cell line U-937 was activated with PMA (phorbol 12-myristate 13-acetate) and polarization was induced with RPMI-1640 media supplemented with 10% serum from each patient for 24 h. Gene expression of selected M1 and M2 markers was assessed by qPCR.ResultsMacrophages exposed to serum of manic and depressive BD patients displayed an increase of IL-1β (6.40 ± 3.47 and 9.04 ± 5.84 versus 0.23 ± 0.11; P &lt; 0.05) and TNF-α (2.23 ± 0.91 and 2.03 ± 0.45 versus 0.62 ± 0.24; P = 0.002 and P = 0.004, respectively) compared to remitted group. In parallel, U-937 macrophages treated with serum of patients in acute episode displayed a down-regulation of CXCL9 (0.29 ± 0.20 versus 1.86 ± 1.61; P = 0.006) and CXCL10 expression (0.36 ± 0.15 and 0.86 ± 0.24 versus 1.83 ± 0.88; P &lt; 0.000 and P = 0.04) compared to remitters.ConclusionsOur results are consistent with previous studies showing that changes in peripheral blood markers could modulate M1/M2 polarization in BD. The evidence of macrophages as source of inflammatory cytokines might be helpful to unravel how the mononuclear phagocyte system can be involved in the etiology of BD.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Serum S100B in manic bipolar disorder patients: Systematic review and meta-analysis

BackgroundBipolar disorder (BD) is a neuropsychiatric disorder characterized by recurrent episodes of mania/hypomania, affecting more than 1% of the world population. S100B is a calcium-binding protein, mostly produced and secreted by astrocytes in the CNS that participate in several cellular responses. Previous studies have shown that patients with bipolar disorder had higher peripheral S100B levels than healthy individuals, suggesting a potential role for S100B BD. MethodsIn this study, a systematic and quantitative meta-analysis of studies S100B serum was performed according to the guidelines PRISMA-statement to confirm the increase of serum S100B in patients with manic bipolar disorder. ResultsWe included in the meta-analysis two studies that reported the mean and standard deviation of serum S100B 52 patients manic BP and 52 control studies. Our results showed higher levels of S100B peripheral TB patients compared with healthy controls. In this meta-analysis, we found evidence that serum S100B are increased in patients with bipolar disorder. ConclusionIn conclusion, several studies have observed morphological abnormalities in the brains of bipolar disorder patients, changes in the peripheral S100B levels in mood disorders were described, and this protein could be a putative marker for damage to the brain. Thus, in this meta-analysis we have found evidence, based on two studies of 52 patients and 52 healthy controls, that the serum concentrations of S100B are increased in bipolar disorder patients.

Altered serum levels of TNF-α, IL-6 and IL-18 in manic, depressive, mixed state of bipolar disorder patients

Bipolar disorder (BD) is associated with alterations of cytokines in the immune system. The aim of this study was to assess the serum levels of TNF-α, IL-6 and IL-18 in manic, depressive, mixed state patients of BD. The correlations between the serum cytokines levels with the demographic characteristics and the psychiatric symptoms were also assessed. We measured serum TNF-α, IL-6 and IL-18 levels using an enzyme-linked immunosorbent assay (ELISA) from 59 BD patients (37 in manic state, 12 in depressive state, 10 in mixed state) and 80 healthy control subjects. The psychotic symptoms of BD were assessed using the Hamilton Depression Scale (HAMD) and the Young Mania Rating Scale (YMRS). The results showed that serum TNF-α and IL-6 levels in manic, depressive and mixed state BD patients were significantly higher than that in controls, while serum IL-18 level was only significantly higher in depressive patients. Serum IL-6 level was significantly positively correlated with YMRS scores in manic episode as well as in mixed episode. When gender and age were added as potentially confounding covariate terms, the differences between controls and each mood state patients were still significant. Our findings provided additional evidence that elevated TNF-α, IL-6 and IL-18 pathway activities may be involved in the psychopathology of BD. Due to the lack of controlling important confounding factors, such as BMI, smoking status and alcohol use, further studies are required to confirm the roles of TNF-α, IL-6 and IL-18.

Diagnosis and characterization of mania: Quantifying increased energy and activity in the human behavioral pattern monitor

Increased energy or activity is now an essential feature of the mania of Bipolar Disorder (BD) according to DSM-5. This study examined whether objective measures of increased energy can differentiate manic BD individuals and provide greater diagnostic accuracy compared to rating scales, extending the work of previous studies with smaller samples. We also tested the relationship between objective measures of energy and rating scales. 50 hospitalized manic BD patients were compared to healthy subjects (HCS, n=39) in the human Behavioral Pattern Monitor (hBPM) which quantifies motor activity and goal-directed behavior in an environment containing novel stimuli. Archival hBPM data from 17 schizophrenia patients were used in sensitivity and specificity analyses.Manic BD patients exhibited higher motor activity than HCS and higher novel object interactions. hBPM activity measures were not correlated with observer-rated symptoms, and hBPM activity was more sensitive in accurately classifying hospitalized BD subjects than observer ratings. Although the findings can only be generalized to inpatient populations, they suggest that increased energy, particularly specific and goal-directed exploration, is a distinguishing feature of BD mania and is best quantified by objective measures of motor activity. A better understanding is needed of the biological underpinnings of this cardinal feature.

Locomotor Profiling from Rodents to the Clinic and Back Again.

The quantification of unconditioned motoric activity is one of the oldest and most commonly utilized tools in behavioral studies. Although typically measured in reference to psychiatric disorders, e.g., amphetamine-induced hyperactivity used as a model of schizophrenia, bipolar disorder (BD), and Tourette's syndrome, the motoric behavior of psychiatric patients had not been quantified similarly to rodents until recently. The rodent behavioral pattern monitor (BPM) was reverse-translated for use in humans, providing the quantification of not only motoric activity but also the locomotor exploratory profile of various psychiatric populations. This measurement includes the quantification of specific exploration and locomotor patterns. As an example, patients with BD, schizophrenia, and those with history of methamphetamine dependence exhibited unique locomotor profiles. It was subsequently determined that reducing dopamine transporter function selectively recreated the locomotor profile of BD mania patients and not any other patient population. Hence, multivariate locomotor profiling offers a first-step approach toward understanding the neural mechanism(s) underlying abnormal behavior in patients with psychiatric disorders. Advances in wearable technology will undoubtedly enable similar multivariate assessments of exploratory and locomotor behavior in "real-world" contexts. Furthermore, trans-diagnostic studies of locomotor activity profiles will inform about essential brain-based functions that cut across diagnostic nosologies.

Treatment implications of predominant polarity and the polarity index: a comprehensive review.

Background:Bipolar disorder (BD) is a serious and recurring condition that affects approximately 2.4% of the global population. About half of BD sufferers have an illness course characterized by either a manic or a depressive predominance. This predominant polarity in BD may be differentially associated with several clinical correlates. The concept of a polarity index (PI) has been recently proposed as an index of the antimanic versus antidepressive efficacy of various maintenance treatments for BD. Notwithstanding its potential clinical utility, predominant polarity was not included in the DSM-5 as a BD course specifier.Methods:Here we searched computerized databases for original clinical studies on the role of predominant polarity for selection of and response to pharmacological treatments for BD. Furthermore, we systematically searched the Pubmed database for maintenance randomized controlled trials (RCTs) for BD to determine the PI of the various pharmacological agents for BD.Results:We found support from naturalistic studies that bipolar patients with a predominantly depressive polarity are more likely to be treated with an antidepressive stabilization package, while BD patients with a manic-predominant polarity are more frequently treated with an antimanic stabilization package. Furthermore, predominantly manic BD patients received therapeutic regimens with a higher mean PI. The calculated PI varied from 0.4 (for lamotrigine) to 12.1 (for aripiprazole).Conclusions:This review supports the clinical relevance of predominant polarity as a course specifier for BD. Future studies should investigate the role of baseline, predominant polarity as an outcome predictor of BD maintenance RCTs.

Effectiveness of Short-Term Olanzapine in Patients With Bipolar I Disorder, With or Without Comorbidity With Substance Use Disorder

Prognosis of comorbid bipolar disorder (BD) and drug abuse is poor. We assessed the efficacy of olanzapine in manic or mixed BD patients, with (SUD) or without (N-SUD) comorbidity with substance use disorder (SUD) and its effect on drug abuse, days of abuse, and craving. Eighty patients with BD-I (40 SUD) were hospitalized for a manic or mixed episode and received add-on olanzapine. Assessments were conducted at admission, discharge, and 4 and 8 weeks after discharge. Primary outcome was the proportion of responders and remitters in each group. We used a logistic regression model to adjust for possible confounders. We assessed craving and drug-abuse days with a visual analog scale and the Timeline Follow-Back. SUD and N-SUD were similar on response and remission, adjusted for sex, age, years ill, age at first episode, first episode depressive, number of hospitalizations, and duration of hospitalization (odds ratio, 1.09; 95% confidence interval, 1.02-2.29). Mood rating scores dropped significantly from baseline to end point in both groups. Timeline follow-back decreased in SUD from 22.5 to 7.3 at 8 weeks postdischarge, whereas craving dropped from 8.3 to 5.1 (P < 0.03). The effectiveness of short-term olanzapine in BD-I mania or mixed mania did not differ according to SUD comorbidity. Treatment was followed by less substance use/abuse and craving in comorbid bipolar-SUD patients.

Theory of mind performance using a story comprehension task in bipolar mania compared to schizophrenia and healthy controls

IntroductionTheory of mind (ToM) refers to the ability to understand the mental state of self and others. There is limited research into this topic in bipolar disorder (BD), with no previous study examining ToM in a BD group within a psychotic manic phase.MethodsTwenty-eight psychotic manic BD patients were compared with 30 schizophrenia (SCZ) patients and 29 healthy controls (HC). Participants performed a ToM story comprehension task that compared ToM stories and non-ToM stories (which we relabelled non-ToM “semantic” stories). Performance was examined by answering comprehension questions.ResultsBoth patient groups were equally impaired on their scores for ToM stories (scores BD = 10/24, SCZ = 9/24, HC = 14/24, p < .001). Interestingly, both patient groups showed reduced performance on non-ToM semantic stories (scores BD = 12/24, SCZ = 9/24, HC = 15/24, p < .001); SCZ showed a larger deficit. Reduced ToM performance was correlated with delusion severity in the BD group only.ConclusionsToM performance was impaired in BD patients experiencing psychotic symptoms. Patient performance was also impaired on the control condition (i.e., non-ToM semantic stories) supporting an additional deficit in semantic processing.

S.06.01 Multi-omics profiling approaches to biomarker discovery in bipolar disorder

Major depressive disorder (MDD) and bipolar disorder (BD) are debilitating mental diseases. Currently the diagnosis of these disorders is only based on subjective clinical assessments and the identification of molecular biomarkers could contribute to improved understanding of the underlying pathophysiological pathways. In turn, this could lead to more accurate empirical diagnoses and improved treatment strategies. Recently we carried out central (post mortem) and peripheral (blood) molecular profiling on MDD and BD patients. Shotgun proteomic analysis of dorsolateral prefrontal cortex samples from MDD patients (+/− psychosis) revealed alterations associated with energy metabolism and synaptic function. Interestingly, the psychosis proteomics changes showed a marked overlap with brain proteome profiles of schizophrenia patients. Separate analysis of post mortem pituitary and hippocampal proteome profiles of BD patients showed disruption of hormones, core histones and mitochondrial pathways. Proteome analysis by multiplexed immunoassay analysis of plasma from 25 BD mania patients showed hormonal dysregulation and disturbances in energy and lipid metabolism. Mass spectrometry analysis of plasma from 17 BD mania patients identified changes in inflammatory and coagulation proteins. We then followed up 13 patients after they experienced a manic episode and this revealed marked suppression of plasma pro-inflammatory markers. Ultimately, further molecular and functional investigations could lead to increased understanding of these disorders and help to distinguish different subtypes these broad psychiatric classifications. In turn, this could lead to novel approaches for drug target identification and discovery strategies.

S.06.04 Staging and biomarkers in bipolar disorders

Major depressive disorder (MDD) and bipolar disorder (BD) are debilitating mental diseases. Currently the diagnosis of these disorders is only based on subjective clinical assessments and the identification of molecular biomarkers could contribute to improved understanding of the underlying pathophysiological pathways. In turn, this could lead to more accurate empirical diagnoses and improved treatment strategies. Recently we carried out central (post mortem) and peripheral (blood) molecular profiling on MDD and BD patients. Shotgun proteomic analysis of dorsolateral prefrontal cortex samples from MDD patients (+/− psychosis) revealed alterations associated with energy metabolism and synaptic function. Interestingly, the psychosis proteomics changes showed a marked overlap with brain proteome profiles of schizophrenia patients. Separate analysis of post mortem pituitary and hippocampal proteome profiles of BD patients showed disruption of hormones, core histones and mitochondrial pathways. Proteome analysis by multiplexed immunoassay analysis of plasma from 25 BD mania patients showed hormonal dysregulation and disturbances in energy and lipid metabolism. Mass spectrometry analysis of plasma from 17 BD mania patients identified changes in inflammatory and coagulation proteins. We then followed up 13 patients after they experienced a manic episode and this revealed marked suppression of plasma pro-inflammatory markers. Ultimately, further molecular and functional investigations could lead to increased understanding of these disorders and help to distinguish different subtypes these broad psychiatric classifications. In turn, this could lead to novel approaches for drug target identification and discovery strategies.

A 40-week double-blind aripiprazole versus lithium follow-up of a 12-week acute phase study (total 52weeks) in bipolar I disorder

This study followed manic or mixed bipolar I subjects for an additional 40 weeks after initial randomization to 12 weeks of lithium versus aripiprazole monotherapy. This is the only long-term, double-blind study comparing lithium and aripiprazole. Patients continued receiving either aripiprazole 15 or 30 mg/day, or lithium 900, 1200 or 1500 mg/day in a double-blind fashion for 40 weeks after completing a 12-week double-blind study (52 weeks total treatment). Efficacy endpoints included adjusted mean change from baseline to Week 52 in Young Mania Rating Scale (YMRS) total score and Montgomery-Åsberg Depression Rating Scale (MADRS) total scores (observed cases). Remission was defined as YMRS total score≤12. Safety and tolerability were also assessed. Of the 66 patients who entered the extension phase, only 20 patients (30.3%) completed the entire phase (aripiprazole n=7; lithium n=13). The significant improvement that occurred over the first 12 weeks was maintained over the 40 weeks of blinded continuation (from Week 12 through Week 52). The most common treatment-emergent adverse events in the extension phase for aripiprazole were akathisia, headache, somnolence, anxiety and nasopharyngitis (all 8%), and for lithium were insomnia (15.8%), headache (13.2%), diarrhea (13.2%) and vomiting (10.5%). Mean weight change was +2.71 kg for lithium and +5.66 kg for aripiprazole (p=0.46). This trial was not powered to statistically compare active treatments, and long-term completion rates were low in both groups. Aripiprazole monotherapy appears to be equivalently useful to lithium for the extended treatment of mixed or manic bipolar disorder patients.

Repeated Assessment of Exploration and Novelty Seeking in the Human Behavioral Pattern Monitor in Bipolar Disorder Patients and Healthy Individuals

BackgroundExploration and novelty seeking are cross-species adaptive behaviors that are dysregulated in bipolar disorder (BD) and are critical features of the illness. While these behaviors have been extensively quantified in animals, multivariate human paradigms of exploration are lacking. The human Behavioral Pattern Monitor (hBPM), a human version of the animal open field, identified a signature pattern of hyper-exploration in manic BD patients, but whether exploratory behavior changes with treatment is unknown. The objective of this study was to assess the sensitivity of the hBPM to changes in manic symptoms, a necessary step towards elucidating the neurobiology underlying BD.Methodology and Principal FindingsTwelve acutely hospitalized manic BD subjects and 21 healthy volunteers were tested in the hBPM over three sessions; all subjects were retested one week after their first session and two weeks after their second session. Motor activity, spatial and entropic (degree of unpredictability) patterns of exploration, and interactions with novel objects were quantified. Manic BD patients demonstrated greater motor activity, extensive and more unpredictable patterns of exploration, and more object interactions than healthy volunteers during all three sessions. Exploration and novelty-seeking slightly decreased in manic BD subjects over the three sessions as their symptoms responded to treatment, but never to the level of healthy volunteers. Among healthy volunteers, exploration did not significantly decrease over time, and hBPM measures were highly correlated between sessions.Conclusions/SignificanceManic BD patients showed a modest reduction in symptoms yet still demonstrated hyper-exploration and novelty seeking in the hBPM, suggesting that these illness features may be enduring characteristics of BD. Furthermore, behavior in the hBPM is not subject to marked habituation effects. The hBPM can be reliably used in a repeated-measures design to characterize exploration and novelty seeking and, in parallel with animal studies, can contribute to developing treatments that target neuropsychiatric disease.