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.

Familial and disease specific abnormalities in the neural correlates of the Stroop Task in Bipolar Disorder

Patients with Bipolar Disorder (BD) perform poorly on tasks of selective attention and inhibitory control. Although similar behavioural deficits have been noted in their relatives, it is yet unclear whether they reflect dysfunction in the same neural circuits. We used functional magnetic resonance imaging and the Stroop Colour Word Task to compare task related neural activity between 39 euthymic BD patients, 39 of their first-degree relatives (25 with no Axis I disorders and 14 with Major Depressive Disorder) and 48 healthy controls. Compared to controls, all individuals with familial predisposition to BD, irrespective of diagnosis, showed similar reductions in neural responsiveness in regions involved in selective attention within the posterior and inferior parietal lobules. In contrast, hypoactivation within fronto-striatal regions, implicated in inhibitory control, was observed only in BD patients and MDD relatives. Although striatal deficits were comparable between BD patients and their MDD relatives, right ventrolateral prefrontal dysfunction was uniquely associated with BD. Our findings suggest that while reduced parietal engagement relates to genetic risk, fronto-striatal dysfunction reflects processes underpinning disease expression for mood disorders. © 2011 Elsevier Inc.

Dissociable brain structural changes associated with predisposition, resilience, and disease expression in bipolar disorder

Genetic factors are important in the etiology of bipolar disorder (BD). However, first-degree relatives of BD patients are at risk for a number of psychiatric conditions, most commonly major depressive disorder (MDD), although the majority remain well. The purpose of the present study was to identify potential brain structural correlates for risk and resilience to mood disorders in patients with BD, type I (BD-I) and their relatives. Structural magnetic resonance imaging scans were acquired from 30 patients with BD-I, 50 of their firstdegree relatives (28 had no Axis I disorder, while 14 had MDD) and 52 controls. We used voxel-based morphometry, implemented in SPM5 to identify group differences in regional gray matter volume. From the identified clusters, potential differences were further examined based on diagnostic status (BD-I patients, MDD relatives, healthy relatives, controls). Whole-brain voxel-based analysis identified group differences in the left hemisphere in the insula, cerebellum, and substantia nigra. Increased left insula volume was associated with genetic preposition to BD-I independent of clinical phenotype. In contrast, increased left substantia nigra volume was observed in those with the clinical phenotype of BD-I. Changes uniquely associated with the absence of a clinical diagnosis in BD relatives were observed in the left cerebellum. Our data suggest that in BD, genetic and phenotype-related influences on brain structure are dissociable; if replicated, these findings may help with early identification of high-risk individuals who are more likely to transition to syndromal states. Copyright © 2009 Society for Neuroscience.

The impact of the Val158Met catechol-O-methyltransferase genotype on neural correlates of sad facial affect processing in patients with bipolar disorder and their relatives

Background - The Met allele of the catechol-O-methyltransferase (COMT) valine-to-methionine (Val158Met) polymorphism is known to affect dopamine-dependent affective regulation within amygdala-prefrontal cortical (PFC) networks. It is also thought to increase the risk of a number of disorders characterized by affective morbidity including bipolar disorder (BD), major depressive disorder (MDD) and anxiety disorders. The disease risk conferred is small, suggesting that this polymorphism represents a modifier locus. Therefore our aim was to investigate how the COMT Val158Met may contribute to phenotypic variation in clinical diagnosis using sad facial affect processing as a probe for its neural action. Method - We employed functional magnetic resonance imaging to measure activation in the amygdala, ventromedial PFC (vmPFC) and ventrolateral PFC (vlPFC) during sad facial affect processing in family members with BD (n=40), MDD and anxiety disorders (n=22) or no psychiatric diagnosis (n=25) and 50 healthy controls. Results - Irrespective of clinical phenotype, the Val158 allele was associated with greater amygdala activation and the Met allele with greater signal change in the vmPFC and vlPFC. Signal changes in the amygdala and vmPFC were not associated with disease expression. However, in the right vlPFC the Met158 allele was associated with greater activation in all family members with affective morbidity compared with relatives without a psychiatric diagnosis and healthy controls. Conclusions - Our results suggest that the COMT Val158Met polymorphism has a pleiotropic effect within the neural networks subserving emotional processing. Furthermore the Met158 allele further reduces cortical efficiency in the vlPFC in individuals with affective morbidity. © 2010 Cambridge University Press.

Pituitary volume in patients with bipolar disorder and their first-degree relatives

Background: Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been reported in bipolar disorder (BD), but previous magnetic resonance imaging (MRI) studies of pituitary gland volume in BD have yielded inconsistent findings. In addition, the contribution of genetic factors to the pituitary changes in BD remains largely unknown. Method: We used MRI to investigate the pituitary volume in 29 remitted patients with BD, 49 of their first-degree relatives (of whom 15 had a diagnosis of Major Depressive Disorder), and 52 age- and gender-matched healthy controls. Results: BD patients had a significantly larger pituitary volume compared with their relatives and healthy controls. Pituitary volume did not differ between controls and healthy relatives or relatives diagnosed with major depression. Limitations: Direct measures of HPA function (i.e., hormonal levels) were not available. Conclusions: These findings suggest that enlarged pituitary volume is associated with disease expression but not genetic susceptibility to BD. © 2009 Elsevier B.V. All rights reserved.

Psychiatric adverse effects of zonisamide in patients with epilepsy and mental disorder comorbidities

Over the last few years, zonisamide has been proposed as a potentially useful medication for patients with focal seizures, with or without secondary generalization. Since psychiatric adverse effects, including mania, psychosis, and suicidal ideation, have been associated with its use, it was suggested that the presence of antecedent psychiatric disorders is an important factor associated with the discontinuation of zonisamide therapy in patients with epilepsy. We, therefore, set out to assess the tolerability profile of zonisamide in a retrospective chart review of 23 patients with epilepsy and comorbid mental disorders, recruited from two specialist pediatric (n=11) and adult (n=12) neuropsychiatry clinics. All patients had a clinical diagnosis of treatment-refractory epilepsy after extensive neurophysiological and neuroimaging investigations. The vast majority of patients (n=22/23, 95.7%) had tried previous antiepileptic medications, and most adult patients (n=9/11, 81.8%) were on concomitant medication for epilepsy. In the majority of cases, the psychiatric adverse effects of zonisamide were not severe. Four patients (17.4%) discontinued zonisamide because of lack of efficacy, whereas only one patient (4.3%) discontinued it because of the severity of psychiatric adverse effects (major depressive disorder). The low discontinuation rate of zonisamide in a selected population of patients with epilepsy and neuropsychiatric comorbidity suggests that this medication is safe and reasonably well-tolerated for use in patients with treatment-refractory epilepsy. Given the limitations of the present study, including the relatively small sample size, further research is warranted to confirm this finding. © 2013 Elsevier Inc.

Recognition accuracy and response bias to happy and sad facial expressions in patients with major depression

Impaired facial expression recognition has been associated with features of major depression, which could underlie some of the difficulties in social interactions in these patients. Patients with major depressive disorder and age- and gender-matched healthy volunteers judged the emotion of 100 facial stimuli displaying different intensities of sadness and happiness and neutral expressions presented for short (100 ms) and long (2,000 ms) durations. Compared with healthy volunteers, depressed patients demonstrated subtle impairments in discrimination accuracy and a predominant bias away from the identification as happy of mildly happy expressions. The authors suggest that, in depressed patients, the inability to accurately identify subtle changes in facial expression displayed by others in social situations may underlie the impaired interpersonal functioning.

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.

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.

Dissociable patterns of neural activity during response inhibition in depressed adolescents with and without suicidal behavior

Objectives - Impaired attentional control and behavioral control are implicated in adult suicidal behavior. Little is known about the functional integrity of neural circuitry supporting these processes in suicidal behavior in adolescence. Method - Functional magnetic resonance imaging was used in 15 adolescent suicide attempters with a history of major depressive disorder (ATTs), 15 adolescents with a history of depressive disorder but no suicide attempt (NATs), and 14 healthy controls (HCs) during the performance of a well-validated go-no-go response inhibition and motor control task that measures attentional and behavioral control and has been shown to activate prefrontal, anterior cingulate, and parietal cortical circuitries. Questionnaires assessed symptoms and standardized interviews characterized suicide attempts. Results - A 3 group by 2 condition (go-no-go response inhibition versus go motor control blocks) block-design whole-brain analysis (p < .05, corrected) showed that NATs showed greater activity than ATTs in the right anterior cingulate gyrus (p = .008), and that NATs, but not ATTs, showed significantly greater activity than HCs in the left insula (p = .004) to go-no-go response inhibition blocks. Conclusions - Although ATTs did not show differential patterns of neural activity from HCs during the go-no-go response inhibition blocks, ATTs and NATs showed differential activation of the right anterior cingulate gyrus during response inhibition. These findings indicate that suicide attempts during adolescence are not associated with abnormal activity in response inhibition neural circuitry. The differential patterns of activity in response inhibition neural circuitry in ATTs and NATs, however, suggest different neural mechanisms for suicide attempt versus major depressive disorder in general in adolescence that should be a focus of further study.

Discovering biomarkers for antidepressant response:protocol from the Canadian biomarker integration network in depression (CAN-BIND) and clinical characteristics of the first patient cohort

Background: Major Depressive Disorder (MDD) is among the most prevalent and disabling medical conditions worldwide. Identification of clinical and biological markers ("biomarkers") of treatment response could personalize clinical decisions and lead to better outcomes. This paper describes the aims, design, and methods of a discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). The CAN-BIND research program investigates and identifies biomarkers that help to predict outcomes in patients with MDD treated with antidepressant medication. The primary objective of this initial study (known as CAN-BIND-1) is to identify individual and integrated neuroimaging, electrophysiological, molecular, and clinical predictors of response to sequential antidepressant monotherapy and adjunctive therapy in MDD. Methods: CAN-BIND-1 is a multisite initiative involving 6 academic health centres working collaboratively with other universities and research centres. In the 16-week protocol, patients with MDD are treated with a first-line antidepressant (escitalopram 10-20 mg/d) that, if clinically warranted after eight weeks, is augmented with an evidence-based, add-on medication (aripiprazole 2-10 mg/d). Comprehensive datasets are obtained using clinical rating scales; behavioural, dimensional, and functioning/quality of life measures; neurocognitive testing; genomic, genetic, and proteomic profiling from blood samples; combined structural and functional magnetic resonance imaging; and electroencephalography. De-identified data from all sites are aggregated within a secure neuroinformatics platform for data integration, management, storage, and analyses. Statistical analyses will include multivariate and machine-learning techniques to identify predictors, moderators, and mediators of treatment response. Discussion: From June 2013 to February 2015, a cohort of 134 participants (85 outpatients with MDD and 49 healthy participants) has been evaluated at baseline. The clinical characteristics of this cohort are similar to other studies of MDD. Recruitment at all sites is ongoing to a target sample of 290 participants. CAN-BIND will identify biomarkers of treatment response in MDD through extensive clinical, molecular, and imaging assessments, in order to improve treatment practice and clinical outcomes. It will also create an innovative, robust platform and database for future research. Trial registration: ClinicalTrials.gov identifier NCT01655706. Registered July 27, 2012.

Medical conditions and depressive, anxiety, and somatic symptoms in older adults with and without generalized anxiety disorder

OBJECTIVE: The objective of this study was to examine medical illness and anxiety, depressive, and somatic symptoms in older medical patients with generalized anxiety disorder (GAD). METHOD: A case-control study was designed and conducted in the University of California, San Diego (UCSD) Geriatrics Clinics. A total of fifty-four older medical patients with GAD and 54 matched controls participated. MEASUREMENTS: The measurements used for this study include: Brief Symptom Inventory-18, Mini International Neuropsychiatric Interview, and the Anxiety Disorders Interview Schedule. RESULTS: Older medical patients with GAD reported higher levels of somatic symptoms, anxiety, and depression than other older adults, as well as higher rates of diabetes and gastrointestinal conditions. In a multivariate model that included somatic symptoms, medical conditions, and depressive and anxiety symptoms, anxiety symptoms were the only significant predictors of GAD. CONCLUSION: These results suggest first, that older medical patients with GAD do not primarily express distress as somatic symptoms; second, that anxiety symptoms in geriatric patients should not be discounted as a byproduct of medical illness or depression; and third, that older adults with diabetes and gastrointestinal conditions may benefit from screening for anxiety.

The impact of general intellectual ability and white matter volume on the functional outcome of patients with bipolar disorder and their relatives

Background: There is substantial evidence that cognitive deficits and brain structural abnormalities are present in patients with Bipolar Disorder (BD) and in their first-degree relatives. Previous studies have demonstrated associations between cognition and functional outcome in BD patients but have not examined the role of brain morphological changes. Similarly, the functional impact of either cognition or brain morphology in relatives remains unknown. Therefore we focused on delineating the relationship between psychosocial functioning, cognition and brain structure, in relation to disease expression and genetic risk for BD. Methods: Clinical, cognitive and brain structural measures were obtained from 41 euthymic BD patients and 50 of their unaffected first-degree relatives. Psychosocial function was evaluated using the General Assessment of Functioning (GAF) scale. We examined the relationship between level of functioning and general intellectual ability (IQ), memory, attention, executive functioning, symptomatology, illness course and total gray matter, white matter and cerebrospinal fluid volumes. Limitations: Cross-sectional design. Results: Multiple regression analyses revealed that IQ, total white matter volume and a predominantly depressive illness course were independently associated with functional outcome in BD patients, but not in their relatives, and accounted for a substantial proportion (53%) of the variance in patients' GAF scores. There were no significant domain-specific associations between cognition and outcome after consideration of IQ. Conclusions: Our results emphasise the role of IQ and white matter integrity in relation to outcome in BD and carry significant implications for treatment interventions. © 2010 Elsevier B.V.

Efficacy and safety of second-generation antipsychotic long-acting injections (SGA LAIs) in maintenance treatment of bipolar disorder:protocol for a systematic review and meta-analysis

INTRODUCTION: Bipolar disorder requires long-term treatment but non-adherence is a common problem. Antipsychotic long-acting injections (LAIs) have been suggested to improve adherence but none are licensed in the UK for bipolar. However, the use of second-generation antipsychotics (SGA) LAIs in bipolar is not uncommon albeit there is a lack of systematic review in this area. This study aims to systematically review safety and efficacy of SGA LAIs in the maintenance treatment of bipolar disorder. METHODS AND ANALYSIS: The protocol is based on Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) and will include only randomised controlled trials comparing SGA LAIs in bipolar. PubMed, EMBASE, CINAHL, Cochrane Library (CENTRAL), PsychINFO, LiLACS, http://www.clinicaltrials.gov will be searched, with no language restriction, from 2000 to January 2016 as first SGA LAIs came to the market after 2000. Manufacturers of SGA LAIs will also be contacted. Primary efficacy outcome is relapse rate or delayed time to relapse or reduction in hospitalisation and primary safety outcomes are drop-out rates, all-cause discontinuation and discontinuation due to adverse events. Qualitative reporting of evidence will be based on 21 items listed on standards for reporting qualitative research (SRQR) focusing on study quality (assessed using the Jadad score, allocation concealment and data analysis), risk of bias and effect size. Publication bias will be assessed using funnel plots. If sufficient data are available meta-analysis will be performed with primary effect size as relative risk presented with 95% CI. Sensitivity analysis, conditional on number of studies and sample size, will be carried out on manic versus depressive symptoms and monotherapy versus adjunctive therapy.

Definitions and factors associated with subthreshold depressive conditions:a systematic review

BACKGROUND: Subthreshold depressive disorders (minor and subthrehold depression) have been defined in a wide range of forms, varying on the number of symptoms and duration required. Disability associated with these conditions has also been reported. Our aim was to review the different definitions and to determine factors associated with these conditions in order to clarify the nosological implications of these disorders. METHODS: A Medline search was conducted of the published literature between January 2001 and September 2011. Bibliographies of the retrieved papers were also analysed. RESULTS: There is a wide heterogeneity in the definition and diagnostic criteria of minor and subthreshold depression. Minor depression was defined according to DSM-IV criteria. Regarding subthreshold depression, also called subclinical depression or subsyndromal symptomatic depression, between 2 and 5 depressive symptoms were required for the diagnosis, and a minimum duration of 2 weeks. Significant impairment associated with subthreshold depressive conditions, as well as comorbidity with other mental disorders, has been described. CONCLUSIONS: Depression as a disorder is better explained as a spectrum rather than as a collection of discrete categories. Minor and subthreshold depression are common conditions and patients falling below the diagnostic threshold experience significant difficulties in functioning and a negative impact on their quality of life. Current diagnostic systems need to reexamine the thresholds for depressive disorders and distinguish them from ordinary feelings of sadness.