von Willebrand's disease and psychotic disorders: co-segregation and genetic associations

Objectives:  To evaluate co-segregation and genetic associations between von Willebrand's disease (vWD) and psychotic disorders.
Methods:  The study was initiated following ascertainment of a nuclear family in which four members were diagnosed with vWD and psychotic/mood disorders. As co-segregation was uncertain in the extended pedigree, we also investigated population-based linkage and association using polymorphisms of vWF , the gene conferring susceptibility to vWD. Three common vWF polymorphisms were investigated among 194 patients with psychotic disorders (bipolar I disorder, BD I; schizoaffective disorder, SZA and schizophrenia, SZ) and their parents. The cases were also compared with unrelated population-based controls (n = 183).
Results:  The transmission disequilibrium test and related analyses suggested nominally significant transmission distortion of one allele and related haplotypes to the probands from their parents. The most significant results were obtained among patients with BD I, and similar trends were also evident in the SZ sample. Comparisons between the cases and population-based controls did not reveal associations, though marginally significant case–control differences were obtained in the BD I sample.
Conclusions:  These studies are consistent with association and linkage between vWF and BD I. However, given the relatively small sample, stochastic variation is an alternative explanation.     

Evaluating clinicians' representations of schizoaffective disorder

BackgroundSchizoaffective disorder (SAD) has routinely exhibited poor diagnostic accuracy and reliability. In addition to phenomenological problems with the definition of SAD, the way in which clinicians represent the symptoms of the disorder could contribute to its poor diagnostic outcomes.PurposeThe present study sought to examine clinicians' representations of SAD compared to schizophrenia (SCZ), bipolar disorder with psychotic features (BiPD-PSY), and major depressive disorder with psychotic features (MDD-PSY).MethodParticipants (N = 113) were clinicians recruited via email as part of a larger study. They were randomly assigned to either select symptoms from a predetermined criteria list or freely list features of the disorders based on their own mental representations.ResultsParticipants' conceptualizations of SAD were not entirely congruent with DSM-5 criteria; they conceptualized it as less psychotic than SCZ and less affective than the two mood disorder tasks. SAD was conceptualized as significantly more depressive than manic.ConclusionsThis study's findings support the notion that clinicians' conceptualizations of SAD are not entirely congruent with its DSM-5 criteria, which could contribute to diagnostic difficulties.     

Folie a deux in bipolar affective disorder: a case report

Background:  The syndrome of folie a deux is uncommon and often described in the context of schizophrenia. We report a case of induced delusional disorder associated with bipolar affective disorder (BAD).
Case report:  We present a case of monozygotic twins in their late 60s with an unusually close relation with one another and relative isolation from other people. Both twins have been diagnosed as suffering from BAD and relapsed into mania with psychotic symptoms. During their hospital stay they exhibited features consistent with folie a deux. Separation caused disappearance of the phenomenon whilst the affective disorder persisted.
Conclusion:  This case highlights the unusual and rare phenomenon of folie a deux occurring in the context of BAD. It also suggests current difficulty in defining folie a deux as an entity according to current diagnostic criteria.     

Clinical characteristics of unipolar disorder and bipolar disorder according to the lifetime presence of recurrent panic attacks

Objectives:  The frequent comorbidity of panic and affective disorders has been described in previous studies. However, it is not clear how panic disorder comorbidity in unipolar disorder and bipolar disorder is related to illness course.
Methods:  We compared lifetime clinical characteristics of illness and items of symptomatology in samples of individuals with bipolar I disorder (n = 290) and unipolar disorder (n = 335) according to the lifetime presence of recurrent panic attacks.
Results:  We found significant differences in clinical course of illness characteristics that were shared across the unipolar and bipolar samples according to the lifetime presence of panic attacks. We also found a number of differences according to the presence of panic attacks that may be specific to the diagnostic group.
Conclusions:  Distinguishing patients who have mood disorder diagnoses, especially bipolar I disorder, according to the lifetime presence of panic attacks may not only be of use in clinical practice, but may also be informative for aetiological research, such as molecular genetic studies.     

Polarity at illness onset in bipolar I disorder and clinical course of illness

Objectives:  Studies have suggested that episode polarity at illness onset in bipolar disorder may be predictive of some aspects of lifetime clinical characteristics. We here examine this possibility in a large, well-characterized sample of patients with bipolar I disorder.
Methods:  We assessed polarity at onset in patients with bipolar I disorder (N = 553) recruited as part of our ongoing studies of affective disorders. Lifetime clinical characteristics of illness were compared in patients who had a depressive episode at first illness onset (n = 343) and patients who had a manic episode at first illness onset (n = 210).
Results:  Several lifetime clinical features differed between patients according to the polarity of their onset episode of illness. A logistic regression analysis showed that the lifetime clinical features significantly associated with a depressive episode at illness onset in our sample were: an earlier age at illness onset; a predominantly depressive polarity during the lifetime; more frequent and more severe depressive episodes; and less prominent lifetime psychotic features.
Conclusions:  Knowledge of pole of onset may help the clinician in providing prognostic information and management advice to an individual with bipolar disorder.     

Effects of childhood trauma on working memory in affective and non-affective psychotic disorders

Childhood trauma is a significant risk factor for the development of psychotic disorders, and may influence executive brain functions. We thus set out to investigate the long-term effects of childhood trauma exposure on brain function of adult chronic patients diagnosed with schizophrenia, schizoaffective disorder and (psychotic) bipolar-I disorder while performing a standard 2/0-back working memory task. Participants were 50 cases diagnosed with schizophrenia/schizoaffective disorder (SCZ), 42 cases with bipolar-I disorder (BD), and 47 healthy controls (HC). Among this sample, 56 clinical cases (SCZ?=?32; BD?=?24) and 17 HC reported significant levels of childhood trauma, while 36 clinical cases (SCZ?=?18; BD?=?18) and 30 HC did not. Effects of childhood trauma on working memory-related brain activation were examined in combined samples of clinical cases (independently of diagnosis) relative to HCs, as well as within each diagnostic category. Case–control analyses revealed increased activation of the left inferior parietal lobule as a main effect of trauma exposure. In addition, trauma exposure interacted with a diagnosis of SCZ or BD to reveal trauma-related increased activation in the cuneus in clinical cases and decreased activation in this region in controls. Disorder-specific functional alterations were also evident in the SCZ sample, but not BD. Childhood trauma exposure elicits aberrant function of parietal regions involved in working memory performance regardless of clinical status, as well as task-relevant visual regions that participates to attentional processes. Childhood trauma may therefore contribute to alterations in attention in SCZ and BD while performing an n-back working memory task.     

The Maudsley bipolar disorder project. A survey of psychotropic prescribing patterns in bipolar I disorder

Objectives:  The outcome of Bipolar 1 Disorder (BD1) is greatly dependent on the adequacy and appropriateness of its treatment. As the treatment choices in BD1 disorder are increasing the aim of this study was to examine the current use of the pharmacological agents in BD1 patients and its association with clinical characteristics.
Methods:  Case note review of the pharmacotherapy of a sample of BD1 patients from a specified South London sector of a National Health Service Trust.
Results:  Half of the patients were on mood-stabilizers (usually lithium) and their use was associated with female gender and multiple admissions. Antipsychotics were more commonly used in patients with psychotic features and multiple manic episodes. Antidepressants were rarely prescribed alone and were not associated with increased number of manic episodes. Combination treatments were mostly used in patients in acute episodes and with multiple hospitalizations.
Conclusions:  In ordinary care, the treatment of BD1 is often driven by symptoms and falls short of the existing practice guidelines.     

White matter abnormalities in bipolar disorder and schizophrenia detected using diffusion tensor magnetic resonance imaging

Objectives:  Strong qualitative and quantitative evidence exists of white matter abnormalities in both schizophrenia and bipolar disorder (BD). Diffusion tensor imaging (DTI) studies suggest altered connectivity in both disorders. We aim to address the diagnostic specificity of white matter abnormalities in these disorders.
Methods:  DTI was used to assess white matter integrity in clinically stable patients with familial BD (n = 42) and familial schizophrenia (n = 28), and in controls (n = 38). Differences in fractional anisotropy (FA) were measured using voxel-based morphometry and automated region of interest analysis.
Results:  Reduced FA was found in the anterior limb of the internal capsule (ALIC), anterior thalamic radiation (ATR), and in the region of the uncinate fasciculus in patients with BD and those with schizophrenia compared with controls. A direct comparison between patient groups found no significant differences in these regions. None of the findings were associated with psychotropic medication.
Conclusions:  Reduced integrity of the ALIC, uncinate fasciculus, and ATR regions is common to both schizophrenia and BD. These results imply an overlap in white matter pathology, possibly relating to risk factors common to both disorders.     

Decreased self-reported arousal in schizophrenia during aversive picture viewing compared to bipolar disorder and healthy controls

Both schizophrenia (SCZ) and bipolar disorder (BD) are associated with disturbances in emotion processing. Previous studies suggest that patients with SCZ assess unpleasant pictures as less arousing than healthy controls (HC), while patients with BD assess neutral pictures as more arousing than HC. No previous studies have investigated whether there is a difference in emotional response across all three groups. Our aim was to explore whether there was a difference in the evaluation of valence and in arousal between SCZ, BD and HC for aversive and neutral pictures. We showed 72 pictures (neutral, non-socially aversive and socially aversive) from the International Affective Picture System (IAPS) to 347 subjects. There was a clear interaction effect between the diagnostic group and increasing picture aversiveness for both valence and arousal. There were no significant differences in valence ratings between the different groups or in arousal ratings on any type of stimuli between BD patients and HC. However, SCZ patients reported significantly lower arousal for aversive stimuli, particularly with a social content, when compared to BD patients and HC. This was more pronounced in females. The presence of lifetime psychotic symptoms did not influence emotional responses.     

Laterality of pain in migraine with comorbid unipolar depressive and bipolar II disorders

Objectives:  The purpose of the present study has been to examine differences in the laterality of pain in patients with migraine and comorbid unipolar depressive (UP) and bipolar II (BP II) disorders.
Methods:  Semi-structured interviews of 102 patients with major affective disorders were conducted, using DSM-IV criteria for affective disorders combined with Akiskal's criteria for affective temperaments and International Headache Society criteria for migraine. The group of patients reported on in the present study encompass 47 subjects with UP (n=24) or BP II (n=23) disorders. Fifteen of the bipolar II patients fulfilled DSM-IV criteria while eight were diagnosed according to the broader criteria of Akiskal.
Results:  Sixteen of the 38 patients with migraine headaches had bilateral pain or pain equally often on the left or right side while 22 had pain predominantly located on one side. Among the UP patients the pain was most often on the right side (8/10) while among the BP II patients the pain was most often on the left (9/12, p = 0.01). Apart from the presence of hypomanic symptoms in the BP II group there were no clinical or demographic characteristics that distinguished these two sub-groups of affective disorders.
Conclusions:  These results indicate that there may be a differential affection of the cerebral hemispheres in patients with migraine and comorbid unipolar depressive disorder versus patients with migraine and comorbid bipolar II disorder.     

Association study of 5'-UTR polymorphisms of the human dopamine transporter gene with manic depression

Objectives:  To determine the degree of association of five single nucleotide polymorphisms at the 5'-untranslated region (5'-UTR) of the human dopamine transporter gene (hSLC6A3; hDAT1) in bipolar affective disorder.
Methods:  In a case–control design study, the polymorphisms were genotyped for allelic and genotypic distribution between 105 index cases (50 males) with bipolar affective disorder according to DSM IV and 199 unaffected control subjects (120 males).
Results:  At the 5'-UTR locus of hSLC6A3, no significant allelic or genotypic differences were observed between index cases and controls. However, distinct 5-locus genotypes accumulated in subjects with bipolar affective disorder compared to control subjects (p = 0.029, odds ratio 1.84, 95% confidence interval 1.12–3.02).
Conclusions:  In conclusion, our data do not provide evidence for a major role of the 5'-UTR of the dopamine transporter gene in bipolar affective disorder. A minor contribution of distinct genotypes may be possible and warrants replication in extended samples.     

Structural connectivity associated with familial risk for mental illness: A meta‐analysis of diffusion tensor imaging studies in relatives of patients with severe mental disorders

Schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) are heritable conditions with overlapping genetic liability. Transdiagnostic and disorder‐specific brain changes associated with familial risk for developing these disorders remain poorly understood. We carried out a meta‐analysis of diffusion tensor imaging (DTI) studies to investigate white matter microstructure abnormalities in relatives that might correspond to shared and discrete biomarkers of familial risk for psychotic or mood disorders. A systematic search of PubMed and Embase was performed to identify DTI studies in relatives of SCZ, BD, and MDD patients. Seed‐based d Mapping software was used to investigate global differences in fractional anisotropy (FA) between overall and disorder‐specific relatives and healthy controls (HC). Our search identified 25 studies that met full inclusion criteria. A total of 1,144 relatives and 1,238 HC were included in the meta‐analysis. The overall relatives exhibited decreased FA in the genu and splenium of corpus callosum (CC) compared with HC. This finding was found highly replicable in jack‐knife analysis and subgroup analyses. In disorder‐specific analysis, compared to HC, relatives of SCZ patients exhibited the same changes while those of BD showed reduced FA in the left inferior longitudinal fasciculus (ILF). The present study showed decreased FA in the genu and splenium of CC in relatives of SCZ, BD, and MDD patients, which might represent a shared familial vulnerability marker of severe mental illness. The white matter abnormalities in the left ILF might represent a specific familial risk for bipolar disorder.     

Increased oxidative stress in the anterior cingulate cortex of subjects with bipolar disorder and schizophrenia

Background:  Recent studies indicate the presence of mitochondrial dysfunction in brains of subjects with bipolar disorder (BD). Because the mitochondrial electron transport chain is a major source for production of reactive oxygen species that cause oxidative stress, we sought to determine in the present study if BD is associated with oxidative stress.
Methods:  Postmortem anterior cingulate brain sections from subjects with BD, major depressive disorder (MDD), or schizophrenia, and from nonpsychiatric, non-neurologic comparison controls were generously provided by the Stanley Foundation Neuropathology Consortium. Oxidative stress was determined by analyzing 4-hydroxynonenal (4-HNE), a major product of lipid peroxidation. The level of 4-HNE was determined by measuring 4-HNE protein adducts using immunohistochemistry.
Results:  We found that 4-HNE levels were significantly increased by 59% in BD subjects and by 47% in schizophrenia subjects, but not in MDD subjects, when compared with controls. Levels of 4-HNE were negatively correlated with pH in all 60 subjects. When pH was used as covariate, 4-HNE levels were still significantly increased in BD subjects when compared with controls. Further, 4-HNE levels were significantly correlated with pH values only in BD subjects, but not in MDD, schizophrenia, or control subjects.
Conclusions:  Oxidative damage in the brain may contribute in part to the pathological process in BD and schizophrenia. This finding also suggests antioxidative stress as a probable alternative approach to the pharmacological treatment of these psychiatric disorders.     

Longitudinal outcome in patients with bipolar disorder assessed by life-charting is influenced by DSM-IV personality disorder symptoms

Objectives:  Few studies have examined the question of how personality features impact outcome in bipolar disorder (BD), though results from extant work and studies in major depressive disorder suggest that personality features are important in predicting outcome. The primary purpose of this paper was to examine the impact of DSM-IV personality disorder symptoms on long-term clinical outcome in BD.
Methods:  The study used a 'life-charting' approach in which 87 BD patients were followed regularly and treated according to published guidelines. Outcome was determined by examining symptoms over the most recent year of follow-up and personality symptoms were assessed with the Structured Clinical Interview for DSM-IV (SCID-II) instrument at entry into the life-charting study.
Results:  Patients with better outcomes had fewer personality disorder symptoms in seven out of 10 disorder categories and Cluster A personality disorder symptoms best distinguished euthymic and symptomatic patients.
Conclusions:  These results raise important questions about the mechanisms linking personality pathology and outcome in BD, and argue that conceptual models concerning personality pathology and BD need to be further developed. Treatment implications of our results, such as need for psychosocial interventions and treatment algorithms, are also described.     

Eyeblink conditioning anomalies in bipolar disorder suggest cerebellar dysfunction

Objectives:  Accumulating research implicates the cerebellum in non-motor psychological processes and psychiatric diseases, including bipolar disorder (BD). Despite recent evidence that cerebellar lesions have been documented to trigger bipolar-like symptoms, few studies have directly examined the functional integrity of the cerebellum in those afflicted with BD.
Methods:  Using a single-cue delay eyeblink conditioning procedure, the functional integrity of the cerebellum was examined in 28 individuals with BD (9 manic, 8 mixed, and 11 euthymic) and 28 age-matched healthy controls.
Results:  Analysis of the bipolar group as a whole indicated a conditioned response acquisition and timing deficit compared to controls. However, when the bipolar group was categorized according to mood state (mixed, manic, euthymic), individuals tested during mixed episodes were strikingly impaired, performing significantly worse than all other groups on both the acquisition and timing of conditioned responses.
Conclusions:  These findings extend prior research implicating cerebellar functional abnormalities in BD and suggest that cerebellar dysfunction may be associated with mood state and course of illness.     

Associations between major psychiatric disorder polygenic risk scores and blood-based markers in UK biobank

Major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD) have both shared and discrete genetic risk factors, and are associated with peripheral abnormalities. The relationships between such genetic architectures and blood-based markers are, however, unclear.We investigated relationships between polygenic risk scores (PRS) for these disorders and peripheral markers in the UK Biobank cohort. We calculated polygenic risk scores for n = 367,329 (MDD PRS), n = 366,465 (SCZ PRS), and n = 366,383 (BD PRS) UK Biobank cohort subjects. We then examined associations between disorder PRS and 58 inflammatory/immune, hematological, bone, cardiovascular, hormone, liver, renal and diabetes-associated blood markers using two generalized linear regression models: ‘minimally adjusted’ controlling for variables such as age and sex, and ‘fully adjusted’ including additional lifestyle covariates: BMI, alcohol and smoking status, and medication intake.There were 38/58 MDD PRS, 32/58 SCZ PRS, and 20/58 BD PRS-blood marker associations detected for our minimally adjusted model. Of these, 13/38 (MDD PRS), 14/32 (SCZ PRS), and 10/20 (BD PRS) associations remained significant after controlling for lifestyle factors. Many were disorder-specific, with 8/13 unique MDD PRS associations identified. Several disorder-specific associations for MDD and SCZ were immune-related, with mostly positive and negative associations identified for MDD and SCZ PRS respectively.This study suggests that MDD, SCZ and BD have both shared and distinct peripheral markers associated with disorder-specific genetic risk. The results also implicate inflammatory dysfunction in MDD and SCZ, albeit with differences in patterns between the two conditions, and enrich our understanding of potential underlying pathophysiological mechanisms in major psychiatric disorders.     

Bipolar-panic disorder comorbidity within bipolar disorder families: a study of siblings

Objectives:  Although anxiety disorders often co-occur with bipolar disorder in clinical settings, relatively few studies of bipolar disorder have looked specifically at panic comorbidity. This report examines lifetime panic comorbidity within a sample of families with a history of bipolar disorder.
Methods:  One hundred and nine probands with bipolar disorder and their 226 siblings were interviewed as part of a family-genetic study. Logistic regression was used to model bipolar disorder as a predictor of comorbid panic in those with affective disorder, with age at interview and gender included as covariates.
Results:  The percentage with panic attacks was low in those without affective disorder (3%) compared with those with unipolar depression (22%) or bipolar disorder (32%). Panic disorder was found only in those with affective disorder (6% for unipolar, 16% for bipolar). When bipolar disorder and unipolar disorder were compared, controlling for age and sex, having bipolar disorder was associated with panic disorder (OR = 3.0, 95% CI = 1.1, 7.8) and any panic symptoms (OR = 2.0, CI = 1.0,3.8) and more weakly with the combination of panic disorder and recurrent attacks (OR = 1.8, CI = 0.9, 3.5).
Conclusions:  The absence of panic disorder and the low prevalence of any panic symptoms in those without bipolar or unipolar disorder suggest that panic is associated primarily with affective disorder within families with a history of bipolar disorder. Furthermore, panic disorder and symptoms are more common in bipolar disorder than in unipolar disorder in these families.     

Review of functional magnetic resonance imaging studies comparing bipolar disorder and schizophrenia

Whalley HC, Papmeyer M, Sprooten E, Lawrie SM, Sussmann JE, McIntosh AM. Review of functional magnetic resonance imaging studies comparing bipolar disorder and schizophrenia.
Bipolar Disord 2012: 14: 411–431. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: Although bipolar disorder (BD) and schizophrenia (SCZ) have a number of clinical features and certain susceptibility genes in common, they are considered separate disorders, and it is unclear which aspects of pathophysiology are specific to each condition. Here, we examine the functional magnetic resonance imaging (fMRI) literature to determine the evidence for diagnosis‐specific patterns of brain activation in the two patient groups. Method: A systematic search was performed to identify fMRI studies directly comparing BD and SCZ to examine evidence for diagnosis‐specific activation patterns. Studies were categorized into (i) those investigating emotion, reward, or memory, (ii) those describing executive function or language tasks, and (iii) those looking at the resting state or default mode networks. Studies reporting estimates of sensitivity and specificity of classification are also summarized, followed by studies reporting associations with symptom severity measures. Results: In total, 21 studies were identified including patients (n = 729) and healthy subjects (n = 465). Relative over‐activation in the medial temporal lobe and associated structures was found in BD versus SCZ in tasks involving emotion or memory. Evidence of differences between the disorders in prefrontal regions was less consistent. Accuracy values for assignment of diagnosis were generally lower in BD than in SCZ. Few studies reported significant symptom associations; however, these generally implicated limbic regions in association with manic symptoms. Conclusions: Although there are a limited number of studies and a cautious approach is warranted, activation differences were found in the medial temporal lobe and associated limbic regions, suggesting the presence of differences in the neurobiological substrates of SCZ and BD. Future studies examining symptom dimensions, risk‐associated genes, and the effects of medication will aid clarification of the mechanisms behind these differences.