Online information seeking by patients with bipolar disorder:results from an international multisite survey

Background: Information seeking is an important coping mechanism for dealing with chronic illness. Despite a growing number of mental health websites, there is little understanding of how patients with bipolar disorder use the Internet to seek information. Methods: A 39 question, paper-based, anonymous survey, translated into 12 languages, was completed by 1222 patients in 17 countries as a convenience sample between March 2014 and January 2016. All patients had a diagnosis of bipolar disorder from a psychiatrist. Data were analyzed using descriptive statistics and generalized estimating equations to account for correlated data. Results: 976 (81 % of 1212 valid responses) of the patients used the Internet, and of these 750 (77 %) looked for information on bipolar disorder. When looking online for information, 89 % used a computer rather than a smartphone, and 79 % started with a general search engine. The primary reasons for searching were drug side effects (51 %), to learn anonymously (43 %), and for help coping (39 %). About 1/3 rated their search skills as expert, and 2/3 as basic or intermediate. 59 % preferred a website on mental illness and 33 % preferred Wikipedia. Only 20 % read or participated in online support groups. Most patients (62 %) searched a couple times a year. Online information seeking helped about 2/3 to cope (41 % of the entire sample). About 2/3 did not discuss Internet findings with their doctor. Conclusion: Online information seeking helps many patients to cope although alternative information sources remain important. Most patients do not discuss Internet findings with their doctor, and concern remains about the quality of online information especially related to prescription drugs. Patients may not rate search skills accurately, and may not understand limitations of online privacy. More patient education about online information searching is needed and physicians should recommend a few high quality websites.

Differential activation in temporal, cingulate and prefrontal cortices during response inhibition in bipolar disorder

Background: Increased impulsivity and aberrant response inhibition have been observed in bipolar disorder (BD). This study examined the functional abnormalities and underlying neural processes during response inhibition in BD, and its relationship to impulsivity. Methods: We assessed impulsivity using the Barratt Impulsiveness Scale (BIS) and, using functional magnetic resonance imaging (fMRI), measured neural activity in response to an Affective Go-NoGo Task, consisting of emotional facial stimuli (fear, happy, anger faces) and non-emotional control stimuli (neutral female and male faces) in euthymic BD (n=23) and healthy individuals (HI; n=25). Results: BD patients were significantly more impulsive, yet did not differ from HI on accuracy or reaction time on the emotional go/no-go task. Comparing neural patterns of activation when processing emotional Go versus emotional NoGo trials yielded increased activation in BD within temporal and cingulate cortices and within prefrontal-cortical regions in HI. Furthermore, higher BIS scores for BD were associated with slower reaction times, and indicative of compensatory cognitive strategies to counter increased impulsivity. Conclusions: These findings illustrate cognition-emotion interference in BD and the observed differences in neural activation indicate potentially altered emotion modulation. Increased activation in brain regions previously shown in emotion regulation and response inhibition tasks could represent a disease-specific marker for BD

Towards person-centered neuroimaging markers for resilience and vulnerability in Bipolar Disorder

Improved clinical care for Bipolar Disorder (BD) relies on the identification of diagnostic markers that can reliably detect disease-related signals in clinically heterogeneous populations. At the very least, diagnostic markers should be able to differentiate patients with BD from healthy individuals and from individuals at familial risk for BD who either remain well or develop other psychopathology, most commonly Major Depressive Disorder (MDD). These issues are particularly pertinent to the development of translational applications of neuroimaging as they represent challenges for which clinical observation alone is insufficient. We therefore applied pattern classification to task-based functional magnetic resonance imaging (fMRI) data of the n-back working memory task, to test their predictive value in differentiating patients with BD (n=30) from healthy individuals (n=30) and from patients' relatives who were either diagnosed with MDD (n=30) or were free of any personal lifetime history of psychopathology (n=30). Diagnostic stability in these groups was confirmed with 4-year prospective follow-up. Task-based activation patterns from the fMRI data were analyzed with Gaussian Process Classifiers (GPC), a machine learning approach to detecting multivariate patterns in neuroimaging datasets. Consistent significant classification results were only obtained using data from the 3-back versus 0-back contrast. Using contrast, patients with BD were correctly classified compared to unrelated healthy individuals with an accuracy of 83.5%, sensitivity of 84.6% and specificity of 92.3%. Classification accuracy, sensitivity and specificity when comparing patients with BD to their relatives with MDD, were respectively 73.1%, 53.9% and 94.5%. Classification accuracy, sensitivity and specificity when comparing patients with BD to their healthy relatives were respectively 81.8%, 72.7% and 90.9%. We show that significant individual classification can be achieved using whole brain pattern analysis of task-based working memory fMRI data. The high accuracy and specificity achieved by all three classifiers suggest that multivariate pattern recognition analyses can aid clinicians in the clinical care of BD in situations of true clinical uncertainty regarding the diagnosis and prognosis.

Influence of birth cohort on age of onset cluster analysis in bipolar I disorder

PURPOSE: Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database. METHODS: The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared. RESULTS: There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups. CONCLUSION: These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

Quantitative assessment of the pharmacotherapy of biopolar disorder and schizophrenia

The work present in this thesis was aimed at assessing the efficacy of lithium in the acute treatment of mania and for the prophylaxis of bipolar disorder, and investigating the value of plasma haloperidol concentration for predicting response to treatment in schizophrenia. The pharmacogenetics of psychotropic drugs is critically appraised to provide insights into interindividual variability in response to pharmacotherapy, In clinical trials of acute mania, a number of measures have been used to assess the severity of illness and its response to treatment. Rating instruments need to be validated in order for a clinical study to provide reliable and meaningful estimates of treatment effects, Eight symptom-rating scales were identified and critically assessed, The Mania Rating Scale (MRS) was the most commonly used for assessing treatment response, The advantage of the MRS is that there is a relatively extensive database of studies based on it and this will no doubt ensure that it remains a gold standard for the foreseeable future. Other useful rating scales are available for measuring mania but further cross-validation and validation against clinically meaningful global changes are required. A total of 658 patients from 12 trials were included in an evaluation of the efficacy of lithium in the treatment of acute mania. Treatment periods ranged from 3 to 4 weeks. Efficacy was estimated using (i) the differences in the reduction in mania severity scores, and (ii) the ratio and difference in improvement response rates. The response rate ratio for lithium against placebo was 1.95 (95% CI 1.17 to 3.23). The mean number needed to treat was 5 (95% CI 3 to 20). Patients were twice as likely to obtain remission with lithium than with chlorpromazine (rate ratio = 1.96, 95% CI 1.02 to 3.77). The mean number needed to treat (NNT) was 4 (95% CI 3 to 9). Neither carbamazepine nor valproate was more effective than lithium. The response rate ratios were 1.01 (95% CI 0.54 to 1.88) for lithium compared to carbarnazepine and 1.22 (95% CI 0.91 to 1.64) for lithium against valproate. Haloperidol was no better than lithium on the basis of improvement based on assessment of global severity. The differences in effects between lithium and risperidone were -2.79 (95% CI -4.22 to -1.36) in favour of risperidone with respect to symptom severity improvement and -0.76 (95% CI -1.11 to -0,41) on the basis of reduction in global severity of disease. Symptom and global severity was at least as well controlIed with lithium as with verapamil. Lithium caused more side-effects than placebo and verapamil, but no more than carbamazepine or valproate. A total of 554 patients from 13 trials were included in the statistical analysis of lithium's efficacy in the prophylaxis of bipolar disorder. The mean follow-up period was 5-34 months. The relapse risk ratio for lithium versus placebo was 0.47 (95% CI 0.26 to 0.86) and the NNT was 3 (95% CI 2 to 7). The relapse risk ratio for lithium versus imipramine was 0.62 (95% CI 0.46 to 0.84) and the NNT was 4 (951% Cl 3 to 7), The combination of lithium and imipramine was no more effective than lithium alone. The risk of relapse was greater with lithium alone than with the lithium-divalproate combination. A risk difference of 0.60 (95% CI 0.21 to 0.99) and an NNT of 2 (95% CI 1 to 5) were obtained. Lithium was as effective as carbamazepine. Based on individual data concerning plasma haloperidol concentration and percent improvement in psychotic symptoms, our results suggest an acceptable concentration range of 11.20-30.30 ng/mL A minimum of 2 weeks should be allowed before evaluating therapeutic response. Monitoring of drug plasma levels seems not to be necessary unless behavioural toxicity or noncompliance is suspected. Pharmacokinetics and pharmacodynamics, which are mainly determined by genetic factors, contribute to interindividual and interethnic variations in clinical response to drugs. These variations are primarily due to differences in drug metabolism. Variability in pharmacokinetics of a number of drugs is associated with oxidation polymorphism. Debrisoquine/sparteine hydroxylase (CYP2D6) and the S-mephenytoin hydroxylase (CYP2C19) are polymorphic P450 enzymes with particular importance in psychopharmacotherapy. The enzymes are responsible for the metabolism of many commonly used antipsychotic and antidepressant drugs. The incidence of poor metabolisers of debrisoquine and S-mephenytoin varies widely among populations. Ethnic variations in polymorphic isoenzymes may, at least in part, explain ethnic differences in response to pharmacotherapy of antipsychotics and antidepressant drugs.

Abnormal amygdala-prefrontal effective connectivity to happy faces differentiates bipolar from major depression

Background - Bipolar disorder is frequently misdiagnosed as major depressive disorder, delaying appropriate treatment and worsening outcome for many bipolar individuals. Emotion dysregulation is a core feature of bipolar disorder. Measures of dysfunction in neural systems supporting emotion regulation might therefore help discriminate bipolar from major depressive disorder. Methods - Thirty-one depressed individuals—15 bipolar depressed (BD) and 16 major depressed (MDD), DSM-IV diagnostic criteria, ages 18–55 years, matched for age, age of illness onset, illness duration, and depression severity—and 16 age- and gender-matched healthy control subjects performed two event-related paradigms: labeling the emotional intensity of happy and sad faces, respectively. We employed dynamic causal modeling to examine significant among-group alterations in effective connectivity (EC) between right- and left-sided neural regions supporting emotion regulation: amygdala and orbitomedial prefrontal cortex (OMPFC). Results - During classification of happy faces, we found profound and asymmetrical differences in EC between the OMPFC and amygdala. Left-sided differences involved top-down connections and discriminated between depressed and control subjects. Furthermore, greater medication load was associated with an amelioration of this abnormal top-down EC. Conversely, on the right side the abnormality was in bottom-up EC that was specific to bipolar disorder. These effects replicated when we considered only female subjects. Conclusions - Abnormal, left-sided, top-down OMPFC–amygdala and right-sided, bottom-up, amygdala–OMPFC EC during happy labeling distinguish BD and MDD, suggesting different pathophysiological mechanisms associated with the two types of depression.

Elevated amygdala activity to sad facial expressions:a state marker of bipolar but not unipolar depression

Background - Difficulties in emotion processing and poor social function are common to bipolar disorder (BD) and major depressive disorder (MDD) depression, resulting in many BD depressed individuals being misdiagnosed with MDD. The amygdala is a key region implicated in processing emotionally salient stimuli, including emotional facial expressions. It is unclear, however, whether abnormal amygdala activity during positive and negative emotion processing represents a persistent marker of BD regardless of illness phase or a state marker of depression common or specific to BD and MDD depression. Methods - Sixty adults were recruited: 15 depressed with BD type 1 (BDd), 15 depressed with recurrent MDD, 15 with BD in remission (BDr), diagnosed with DSM-IV and Structured Clinical Interview for DSM-IV Research Version criteria; and 15 healthy control subjects (HC). Groups were age- and gender ratio-matched; patient groups were matched for age of illness onset and illness duration; depressed groups were matched for depression severity. The BDd were taking more psychotropic medication than other patient groups. All individuals participated in three separate 3T neuroimaging event-related experiments, where they viewed mild and intense emotional and neutral faces of fear, happiness, or sadness from a standardized series. Results - The BDd—relative to HC, BDr, and MDD—showed elevated left amygdala activity to mild and neutral facial expressions in the sad (p < .009) but not other emotion experiments that was not associated with medication. There were no other significant between-group differences in amygdala activity. Conclusions - Abnormally elevated left amygdala activity to mild sad and neutral faces might be a depression-specific marker in BD but not MDD, suggesting different pathophysiologic processes for BD versus MDD depression.

Right orbitofrontal corticolimbic and left corticocortical white matter connectivity differentiate bipolar and unipolar depression

Objectives - The absence of pathophysiologically relevant diagnostic markers of bipolar disorder (BD) leads to its frequent misdiagnosis as unipolar depression (UD). We aimed to determine whether whole brain white matter connectivity differentiated BD from UD depression. Methods - We employed a three-way analysis of covariance, covarying for age, to examine whole brain fractional anisotropy (FA), and corresponding longitudinal and radial diffusivity, in currently depressed adults: 15 with BD-type I (mean age 36.3 years, SD 12.0 years), 16 with recurrent UD (mean age 32.3 years, SD 10.0 years), and 24 healthy control adults (HC) (mean age 29.5 years, SD 9.43 years). Depressed groups did not differ in depression severity, age of illness onset, and illness duration. Results - There was a main effect of group in left superior and inferior longitudinal fasciculi (SLF and ILF) (all F = 9.8; p = .05, corrected). Whole brain post hoc analyses (all t = 4.2; p = .05, corrected) revealed decreased FA in left SLF in BD, versus UD adults in inferior temporal cortex and, versus HC, in primary sensory cortex (associated with increased radial and decreased longitudinal diffusivity, respectively); and decreased FA in left ILF in UD adults versus HC. A main effect of group in right uncinate fasciculus (in orbitofrontal cortex) just failed to meet significance in all participants but was present in women. Post hoc analyses revealed decreased right uncinate fasciculus FA in all and in women, BD versus HC. Conclusions - White matter FA in left occipitotemporal and primary sensory regions supporting visuospatial and sensory processing differentiates BD from UD depression. Abnormally reduced FA in right fronto-temporal regions supporting mood regulation, might underlie predisposition to depression in BD. These measures might help differentiate pathophysiologic processes of BD versus UD depression.

State-dependent microstructural white matter changes in bipolar I depression

Abnormalities in fronto-limbic-striatal white matter (WM) have been reported in bipolar disorder (BD), but results have been inconsistent across studies. Furthermore, there have been no detailed investigations as to whether acute mood states contribute to microstructural changes in WM tracts. In order to compare fiber density and structural integrity within WM tracts between BD depression and remission, whole-brain fractional anisotropy (FA) and mean diffusivity (MD) were assessed in 37 bipolar I disorder (BD-I) patients (16 depressed and 21 remitted), and 26 healthy individuals with diffusion tensor imaging. Significantly decreased FA and increased MD in bilateral prefronto-limbic-striatal white matter and right inferior fronto-occipital, superior and inferior longitudinal fasciculi were shown in all BD-I patients versus controls, as well as in depressed BD-I patients compared to both controls and remitted BD-I patients. Depressed BD-I patients also exhibited increased FA in the ventromedial prefrontal cortex. Remitted BD-I patients did not differ from controls in FA or MD. These findings suggest that BD-I depression may be associated with acute microstructural WM changes.

Gabapentin treatment for bipolar disorders

OBJECTIVE: To review the effectiveness data on the use of gabapentin in bipolar disorders. DATA SOURCES: Clinical literature was accessed through MEDLINE (January 1985–November 2000). Key search terms included gabapentin, mood stabilizer, and bipolar disorder. DATA SYNTHESIS: Bipolar disorder is a complex condition that can be difficult to treat effectively. Mood stabilizers are increasingly being used to manage bipolar disorder. Studies that used gabapentin in bipolar disorders are evaluated. CONCLUSIONS: From the data presented, gabapentin cannot be recommended for treatment of bipolar disorder. Further studies are required to determine whether gabapentin has any role in the management of bipolar disorder.

Managing bipolar depression:a therapeutic challenge?

Most people with bipolar disorder first seek treatment for depressive rather than manic symptoms. However, effective management of bipolar depression remains a challenge. In this review, Celia Feetam highlights how bipolar depression differs from unipolar depression both in its characteristics and in the approach to its treatment. © 2011 John Wiley & Sons, Ltd.

Facial affect processing inbipolar disorder:a magnetoencephalography study

Background: Identifying biological markers to aid diagnosis of bipolar disorder (BD) is critically important. To be considered a possible biological marker, neural patterns in BD should be discriminant from those in healthy individuals (HI). We examined patterns of neuromagnetic responses revealed by magnetoencephalography (MEG) during implicit emotion-processing using emotional (happy, fearful, sad) and neutral facial expressions, in sixteen BD and sixteen age- and gender-matched healthy individuals. Methods: Neuromagnetic data were recorded using a 306-channel whole-head MEG ELEKTA Neuromag System, and preprocessed using Signal Space Separation as implemented in MaxFilter (ELEKTA). Custom Matlab programs removed EOG and ECG signals from filtered MEG data, and computed means of epoched data (0-250ms, 250-500ms, 500-750ms). A generalized linear model with three factors (individual, emotion intensity and time) compared BD and HI. A principal component analysis of normalized mean channel data in selected brain regions identified principal components that explained 95% of data variation. These components were used in a quadratic support vector machine (SVM) pattern classifier. SVM classifier performance was assessed using the leave-one-out approach. Results: BD and HI showed significantly different patterns of activation for 0-250ms within both left occipital and temporal regions, specifically for neutral facial expressions. PCA analysis revealed significant differences between BD and HI for mild fearful, happy, and sad facial expressions within 250-500ms. SVM quadratic classifier showed greatest accuracy (84%) and sensitivity (92%) for neutral faces, in left occipital regions within 500-750ms. Conclusions: MEG responses may be used in the search for disease specific neural markers.

Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development

Mood stabilising drugs such as lithium (LiCl) and valproic acid (VPA) are the first line agents for treating conditions such as Bipolar disorder and Epilepsy. However, these drugs have potential developmental effects that are not fully understood. This study explores the use of a simple human neurosphere-based in vitro model to characterise the pharmacological and toxicological effects of LiCl and VPA using gene expression changes linked to phenotypic alterations in cells. Treatment with VPA and LiCl resulted in the differential expression of 331 and 164 genes respectively. In the subset of VPA targeted genes, 114 were downregulated whilst 217 genes were upregulated. In the subset of LiCl targeted genes, 73 were downregulated and 91 were upregulated. Gene ontology (GO) term enrichment analysis was used to highlight the most relevant GO terms associated with a given gene list following toxin exposure. In addition, in order to phenotypically anchor the gene expression data, changes in the heterogeneity of cell subtype populations and cell cycle phase were monitored using flow cytometry. Whilst LiCl exposure did not significantly alter the proportion of cells expressing markers for stem cells/undifferentiated cells (Oct4, SSEA4), neurons (Neurofilament M), astrocytes (GFAP) or cell cycle phase, the drug caused a 1.4-fold increase in total cell number. In contrast, exposure to VPA resulted in significant upregulation of Oct4, SSEA, Neurofilament M and GFAP with significant decreases in both G2/M phase cells and cell number. This neurosphere model might provide the basis of a human-based cellular approach for the regulatory exploration of developmental impact of potential toxic chemicals.

QT interval prolongation related to psychoactive drug treatment:a comparison of monotherapy versus polytherapy

Background - Several antipsychotic agents are known to prolong the QT interval in a dose dependent manner. Corrected QT interval (QTc) exceeding a threshold value of 450 ms may be associated with an increased risk of life threatening arrhythmias. Antipsychotic agents are often given in combination with other psychotropic drugs, such as antidepressants, that may also contribute to QT prolongation. This observational study compares the effects observed on QT interval between antipsychotic monotherapy and psychoactive polytherapy, which included an additional antidepressant or lithium treatment. Method - We examined two groups of hospitalized women with Schizophrenia, Bipolar Disorder and Schizoaffective Disorder in a naturalistic setting. Group 1 was composed of nineteen hospitalized women treated with antipsychotic monotherapy (either haloperidol, olanzapine, risperidone or clozapine) and Group 2 was composed of nineteen hospitalized women treated with an antipsychotic (either haloperidol, olanzapine, risperidone or quetiapine) with an additional antidepressant (citalopram, escitalopram, sertraline, paroxetine, fluvoxamine, mirtazapine, venlafaxine or clomipramine) or lithium. An Electrocardiogram (ECG) was carried out before the beginning of the treatment for both groups and at a second time after four days of therapy at full dosage, when blood was also drawn for determination of serum levels of the antipsychotic. Statistical analysis included repeated measures ANOVA, Fisher Exact Test and Indipendent T Test. Results - Mean QTc intervals significantly increased in Group 2 (24 ± 21 ms) however this was not the case in Group 1 (-1 ± 30 ms) (Repeated measures ANOVA p < 0,01). Furthermore we found a significant difference in the number of patients who exceeded the threshold of borderline QTc interval value (450 ms) between the two groups, with seven patients in Group 2 (38%) compared to one patient in Group 1 (7%) (Fisher Exact Text, p < 0,05). Conclusions - No significant prolongation of the QT interval was found following monotherapy with an antipsychotic agent, while combination of these drugs with antidepressants caused a significant QT prolongation. Careful monitoring of the QT interval is suggested in patients taking a combined treatment of antipsychotic and antidepressant agents.

The use of topiramate in mood stabilization

OBJECTIVE: To review data on the effectiveness of topiramate as a mood stabilizer. DATA SOURCES: Clinical literature accessed through MEDLINE (1985-September 2001) and the manufacturer. Key search terms included topiramate, mania, mood stabilizer, and bipolar disorder. DATA SYNTHESIS: The traditional standard therapy for bipolar disorder has been lithium. Other mood stabilizers are increasingly being used to manage this complex disorder. Studies that used topiramate in bipolar disorders were evaluated. CONCLUSIONS: The present data from open trials suggest that topiramate may possibly possess antimanic properties. Controlled, double-blind studies are required to confirm this efficacy