Bipolar Probands Research Articles

Pragmatic issues and prescribing patterns in bipolar disorder: A mental health professional's survey.

There is substantial treatment gap between the suggested guidelines and pragmatic clinical practice for psychotropic usage in bipolar disorder (BD) due to the lack of naturalistic studies and not taking into account the transcultural differences and diverse background. We intend to study this treatment gap and elucidate the preference of psychotropics and prescription patterns, critical clinical issues faced and related pragmatics in BD by conducting the mental health professionals survey. After focused discussions, Canadian Network for Mood and Anxiety Treatments guidelines being the primary anchor, a 46-item online survey questionnaire was prepared. With 25.4% response rate, 127 psychiatrists were evaluated using Survey Monkey® electronic platform on the demographics, predominant polarity; usage of antipsychotics, antidepressants, and electroconvulsive therapy, psychotropic's preference (monotherapy vs. polytherapy) in the acute and maintenance phase of BD. Majority of the participants were males (70.9%) and placed in government institute or medical colleges. Majority agreed that child and adolescent and old age bipolar probands are not routinely seen but subthreshold BD cases are frequent; did not prefer mood stabilizer in pregnancy (61.4%) and antidepressants, preferred polytherapy in acute but monotherapy in maintenance phase (after 3rd episode), seldom preferred ECT as an option (more in suicidality), agreed to a subset of BD being refractory and neuroprogressive. This study elucidates the importance of treatment preferences, prescribing patterns and pragmatic issues faced by the clinicians. These patterns if studied longitudinally in a systematic manner would help in modifying the potential treatment strategies and reduce treatment gap.

Risk of cardiometabolic diseases among siblings of patients with bipolar disorder

BackgroundCardiometabolic diseases are suggested to be associated with bipolar disorder. However, the risk of metabolic disorders in unaffected siblings of patients with bipolar disorder remains unclear. MethodsFrom the Taiwan National Health Insurance Research Database, 7,225 unaffected siblings of bipolar probands and 28,900 age-/sex-/income-/residence-matched control individuals were included and followed until the end of 2011. Individuals who developed metabolic disorders during the follow-up period were identified. ResultsThe unaffected siblings of bipolar probands had a higher prevalence of dyslipidemia (5.4% vs. 4.5%, p = 0.001), younger age at diagnosis of type 2 diabetes mellitus (34.81 vs. 37.22, p = 0.024), and higher prevalence of any stroke (1.5% vs. 1.1%, p = 0.007) than the controls. Moreover, only male siblings of bipolar probands had an increased risk of dyslipidemia (odds ratio [OR]: 1.28, 95% confidence interval [CI]: 1.10–1.48) and higher rates of any stroke (OR: 1.38, 95% CI: 1.02–1.85) and ischemic stroke (OR: 2.43, 95% CI: 1.60–3.70) during the follow-up compared with the controls. DiscussionUnaffected siblings of bipolar patients, particularly brothers, had a higher prevalence of dyslipidemia and ischemic stroke compared with the controls. The result suggests the familial association between cardiometabolic diseases and bipolar disorder. Further research may be necessary to identify this shared etiology between the disorders.

Longitudinal sleep phenotypes among offspring of bipolar parents and community controls

BackgroundSleep disturbances are a prominent feature of bipolar disorder (BP). However, it remains unclear how sleep phenotypes may evolve among at-risk youth, and their relevance to BP onset. MethodsPittsburgh Bipolar Offspring Study (BIOS) offspring (ages 10–18) and their parents completed assessments approximately every two years pertaining to current psychopathology and offspring sleep habits. A latent transition analysis (LTA) identified latent sleep groups within offspring based on their ratings of six sleep domains using the School Sleep Habits Survey. Demographic and clinical characteristics were compared between sleep groups. Logistic regression tested links between sleep group and BP onset at the subsequent assessment. ResultsThe LTA model identified latent groups of good, poor, and variable sleepers. We observed an overall trend of good sleep becoming variable, and then poor, as youth age. Offspring in the poor sleep group were more likely to have psychopathology. Adjusting for age and depression, poor sleepers had nearly twice the odds of developing BP relative to good (OR=1.99, CI=0.45–8.91) or variable (OR=2.03, CI=0.72–5.72) sleepers. LimitationsLimitations include the use of proximal sleep phenotypes to predict BP onset, and a self-report measure of sleep ConclusionsWe found three non-overlapping sleep phenotype groups in a large sample of offspring of bipolar probands and offspring of demographically-matched community control parents. Clinicians should consider that youth will likely experience variable and/or poor sleep as they age, and that at-risk youth with poor sleep may be at increased risk of developing MDD and BP at their next assessment.

Thought Disorder in Schizophrenia and Bipolar Disorder Probands, Their Relatives, and Nonpsychiatric Controls.

Thought disorder (TD) has long been associated with schizophrenia (SZ) and is now widely recognized as a symptom of mania and other psychotic disorders as well. Previous studies have suggested that the TD found in the clinically unaffected relatives of SZ, schizoaffective and bipolar probands is qualitatively similar to that found in the probands themselves. Here, we examine which quantitative measures of TD optimize the distinction between patients with diagnoses of SZ and bipolar disorder with psychotic features (BP) from nonpsychiatric controls (NC) and from each other. In addition, we investigate whether these same TD measures also distinguish their respective clinically unaffected relatives (RelSZ, RelBP) from controls as well as from each other. We find that deviant verbalizations are significantly associated with SZ and are co-familial in clinically unaffected RelSZ, but are dissociated from, and are not co-familial for, BP disorder. In contrast, combinatory thinking was nonspecifically associated with psychosis, but did not aggregate in either group of relatives. These results provide further support for the usefulness of TD for identifying potential non-penetrant carriers of SZ-risk genes, in turn enhancing the power of genetic analyses. These findings also suggest that further refinement of the TD phenotype may be needed in order to be suitable for use in genetic studies of bipolar disorder.

10. Brain Structure Biomarkers at the Psychosis/Nonpsychosis Interphase: Findings From the Bipolar–Schizophrenia Network for Intermediate Phenotypes

Background: The study presents whole brain and regional gray matter density (GMD) characteristics contrasted along the psychosis/nonpsychosis interface in (1) schizophrenia—schizoaffective—psychotic bipolar—nonpsychotic bipolar probands, and (2) their first-degree relatives organized by lifetime psychosis expression, from the B–SNIP consortium sample. Methods: A total of 1652 3Tesla T1-weighted MPRAGE or IR-SPGR scans were analyzed using Voxel-Based Morphometry (SPM8/VBM8/DARTEL) with subsequent subject-level regional GMD characterization. Results: Among probands, individuals with schizophrenia (mean d = 0.66) and schizoaffective disorder (mean d = 0.73) showed overlapping and diffusely distributed GMD reductions spanning cortical and subcortical regions, with the largest effects in the frontotemporal, cingulate, and insular cortices, compared to healthy controls. Probands with psychotic bipolar disorder contrasted with controls showed modest GMD reductions (mean d = 0.54), primarily localized to anterior limbic regions. The data for nonpsychotic bipolar probands will be also reported; we predict normal/near-normal GMD characteristics, relative to controls. Among relatives organized by lifetime psychosis manifestations, relatives with DSM-IV Axis I psychotic disorders and Axis II psychosis spectrum personality disorders (schizoid, paranoid, and schizotypal) showed GMD reductions intermediate in magnitude between the psychosis probands and healthy controls, primarily localized to bilateral frontal regions. In contrast, relatives without lifetime Axis I/II psychotic disorders showed GMD not different from healthy controls. No effect of concurrent medications (antipsychotics, mood stabilizers, antidepressants) on GMD outcomes was detected in probands; the majority of relatives were unmedicated. Conclusion: Our findings indicate divergent GMD characteristics for psychotic versus nonpsychotic phenotypes among probands with severe mental illness and their biological relatives and suggest that GMD alterations may serve as a biomarker unique to psychosis.

CLINICAL AND GENETIC PREDICTION OF ONSET AND COURSE OF ILLNESS IN SUBJECTS AT RISK FOR BIPOLAR DISORDER

As part of a five-site collaborative study, we are following 300 adolescents/young adults at high risk for bipolar disorder and related conditions (because they are close relatives of a bipolar proband), along with 150 age-matched controls. A new follow-up protocol is beginning over the next several months. The risk for major mood disorder is ~35% for high risk offspring and ~7% for controls. An additional reference sample, available for studies of course of illness is the BiGS sample, including > 600 families with multiple cases of bipolar disorder and >4000 unrelated bipolar cases. Using these three samples (high risk, familial BP, case BP) we describe the development of a clinical subtyping scheme and its potential use in predicting risk and course of illness. We have now obtained complete, newly imputed, genotype data from the PGC on all of our cases and ethnically matched controls, as well as the high risk sample. These data are being used to develop polygenic risk scores for use in prediction of illness (as part of the research, not for clinical purposes currently). We are also using the genotype data in conjunction with our published work on bipolar pathways (Nurnberger et al, JAMA Psychiatry, 2014) in order to derive pathway-specific polygenic risk scores. These will be applied to BPI cases in general and to the specific subtypes we have described (Monahan et al, Psychological Medicine, 2015): 1) pure BPI, 2) BPI plus internalizing disorder, 3) BPI plus externalizing disorder, and 4) BPI plus externalizing and internalizing disorder.

Brain Structure Biomarkers in the Psychosis Biotypes: Findings From the Bipolar-Schizophrenia Network for Intermediate Phenotypes

BackgroundThe current definitions of psychotic illness lack biological validity, motivating alternative biomarker-driven disease entities. Building on experimental constructs—Biotypes—that were previously developed from cognitive and neurophysiologic measures, we contrast brain anatomy characteristics across Biotypes alongside conventional diagnoses, examining gray matter density (GMD) as an independent validator for the Biotypes. MethodsWhole brain GMD measures were examined in probands, their relatives, and healthy subjects organized by Biotype and then by DSM-IV-TR diagnosis (n = 1409) using voxel-based morphometry with subsequent subject-level regional characterization and distribution analyses. ResultsProbands grouped by Biotype versus healthy controls showed a stepwise pattern of GMD reductions as follows: Biotype1, extensive and diffusely distributed GMD loss, with the largest effects in frontal, anterior/middle cingulate cortex, and temporal regions; Biotype2, intermediate and more localized reductions, with the largest effects in insula and frontotemporal regions; and Biotype3, small reductions localized to anterior limbic regions. Relatives showed regionally distinct GMD reductions versus healthy controls, with primarily anterior (frontotemporal) effects in Biotype1; posterior (temporo-parieto-cerebellar) in Biotype2; and normal GMD in Biotype3. Schizophrenia and schizoaffective probands versus healthy controls showed overlapping GMD reductions, with the largest effects in frontotemporal and parietal regions; psychotic bipolar probands had small reductions, primarily in frontal regions. GMD changes in relatives followed regional patterns observed in probands, albeit less extensive. Biotypes showed stronger between-group separation based on GMD than the conventional diagnoses and were the strongest predictor of GMD change. ConclusionsGMD biomarkers depicted unique brain structure characteristics within Biotypes, consistent with their cognitive and sensorimotor profiles, and provided stronger discrimination for biologically driven biotypes than symptom-based diagnoses.

Impaired Context Processing is Attributable to Global Neuropsychological Impairment in Schizophrenia and Psychotic Bipolar Disorder.

Context processing may reflect a specific cognitive impairment in schizophrenia. Whether impaired context processing is observed across psychotic disorders or among relatives of affected individuals, and whether it is a deficit that is independent from the generalized neuropsychological deficits seen in psychotic disorders, are less established. Schizophrenia, schizoaffective, and psychotic bipolar probands (n = 660), their first-degree relatives (n = 741), and healthy individuals (n = 308) studied by the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium performed an expectancy task requiring use of contextual information to overcome a pre-potent response. Sensitivity for target detection and false alarm rates on trials requiring inhibition or goal maintenance were measured. Proband groups and relatives with psychosis spectrum personality traits demonstrated reduced target sensitivity and elevated false alarm rates. False alarm rate was higher under inhibition vs goal maintenance conditions although this difference was attenuated in schizophrenia and schizoaffective proband groups. After accounting for global neuropsychological impairment, as reflected by the composite score from the Brief Assessment of Cognition in Schizophrenia neuropsychological battery, deficits in schizophrenia and bipolar proband groups were no longer significant. Performance measures were moderately familial. Reduced target detection, but not a specific deficit in context processing, is observed across psychotic disorders. Impairments in both goal maintenance and response inhibition appear to contribute comparably to deficits in schizophrenia and schizoaffective disorder, whereas greater difficulty with response inhibition underlies deficits in bipolar disorder. Yet, these deficits are not independent from the generalized neurocognitive impairment observed in schizophrenia and psychotic bipolar disorder.

Virginia Woolf, neuroprogression, and bipolar disorder.

Family history and traumatic experiences are factors linked to bipolar disorder. It is known that the lifetime risk of bipolar disorder in relatives of a bipolar proband are 5-10% for first degree relatives and 40-70% for monozygotic co-twins. It is also known that patients with early childhood trauma present earlier onset of bipolar disorder, increased number of manic episodes, and more suicide attempts. We have recently reported that childhood trauma partly mediates the effect of family history on bipolar disorder diagnosis. In light of these findings from the scientific literature, we reviewed the work of British writer Virginia Woolf, who allegedly suffered from bipolar disorder. Her disorder was strongly related to her family background. Moreover, Virginia Woolf was sexually molested by her half siblings for nine years. Her bipolar disorder symptoms presented a pernicious course, associated with hospitalizations, suicidal behavioral, and functional impairment. The concept of neuroprogression has been used to explain the clinical deterioration that takes places in a subgroup of bipolar disorder patients. The examination of Virgina Woolf’s biography and art can provide clinicians with important insights about the course of bipolar disorder.

Relevance of brain plasticity to neuroprogression and staging of bipolar disorders – opposing effects of illness burden and lithium treatment

IntroductionBrain changes in bipolar disorders (BD) may represent inherited risk factors or consequences of the illness (brain plasticity). Neuroanatomical changes, which predispose for BD could aid in early diagnosis, whereas the neuronal sequellae of BD could yield biological outcome measures for prevention and treatment.MethodsTo separate neuroanatomical changes into those that increase the risk of BD versus those that result from it, we acquired MRI/clinical data from participants at different stages of BD, including: (1) affected and unaffected offspring of bipolar parents (n = 86); (2) participants with substantial illness burden who had had at least 2 years of current Li treatment (n = 37) or were Li naive (n = 19). We also recruited 99 healthy controls matched to the above-mentioned cohorts by age and sex.ResultsRelative to controls, both the affected and unaffected offpring of bipolar probands showed increased right inferior frontal gyrus (rIFG) volume, but comparable hippocampal volumes and prefrontal N-acetyl aspartate (NAA) levels. Larger rIFG volume was associated with an increased risk of conversion to psychiatric disorders within 4 years following the MRI scanning (hazard ratio = 4.5). In contrast, Li naive patients with substantial illness burden had smaller rIFG, hippocampal volumes and prefrontal NAA levels than controls, who were comparable in these indices to the the Li treated subjects with substantial illness burden.ConclusionsBrain structural changes in BD may not be static, but may instead result from an interplay between illness burden and compensatory processes. This illness related brain plasticity may be modulated by lithium treatment.Disclosure of interestThe authors have not supplied his declaration of competing interest.

Enhanced neurocognitive functioning and positive temperament in twins discordant for bipolar disorder.

Based on evidence linking creativity and bipolar disorder, a model has been proposed whereby factors influencing liability to bipolar disorder confer certain traits with positive effects on reproductive fitness. The authors tested this model by examining key traits known to be associated with evolutionary fitness, namely, temperament and neurocognition, in individuals carrying liability for bipolar disorder. Schizophrenia probands and their co-twins were included as psychiatric controls. Twin pairs discordant for bipolar disorder and schizophrenia and control pairs were identified through the Swedish Twin Registry. The authors administered a neuropsychological test battery and temperament questionnaires to samples of bipolar probands, bipolar co-twins, schizophrenia probands, schizophrenia co-twins, and controls. Multivariate mixed-model analyses of variance were conducted to compare groups on temperament and neurocognitive scores. Bipolar co-twins showed elevated scores on a "positivity" temperament scale compared with controls and bipolar probands, while bipolar probands scored higher on a "negativity" scale compared with their co-twins and controls, who did not differ. Additionally, bipolar co-twins showed superior performance compared with controls on tests of verbal learning and fluency, while bipolar probands showed performance decrements across all neurocognitive domains. In contrast, schizophrenia co-twins showed attenuated impairments in positivity and overall neurocognitive functioning relative to their ill proband counterparts. These findings suggest that supra-normal levels of sociability and verbal functioning may be associated with liability for bipolar disorder. These effects were specific to liability for bipolar disorder and did not apply to schizophrenia. Such benefits may provide a partial explanation for the persistence of bipolar illness in the population.

Hippocampal Volume Is Reduced in Schizophrenia and Schizoaffective Disorder But Not in Psychotic Bipolar I Disorder Demonstrated by Both Manual Tracing and Automated Parcellation (FreeSurfer)

This study examined hippocampal volume as a putative biomarker for psychotic illness in the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) psychosis sample, contrasting manual tracing and semiautomated (FreeSurfer) region-of-interest outcomes. The study sample (n = 596) included probands with schizophrenia (SZ, n = 71), schizoaffective disorder (SAD, n = 70), and psychotic bipolar I disorder (BDP, n = 86); their first-degree relatives (SZ-Rel, n = 74; SAD-Rel, n = 62; BDP-Rel, n = 88); and healthy controls (HC, n = 145). Hippocampal volumes were derived from 3Tesla T1-weighted MPRAGE images using manual tracing/3DSlicer3.6.3 and semiautomated parcellation/FreeSurfer5.1,64bit. Volumetric outcomes from both methodologies were contrasted in HC and probands and relatives across the 3 diagnoses, using mixed-effect regression models (SAS9.3 Proc MIXED); Pearson correlations between manual tracing and FreeSurfer outcomes were computed. SZ (P = .0007-.02) and SAD (P = .003-.14) had lower hippocampal volumes compared with HC, whereas BDP showed normal volumes bilaterally (P = .18-.55). All relative groups had hippocampal volumes not different from controls (P = .12-.97) and higher than those observed in probands (P = .003-.09), except for FreeSurfer measures in bipolar probands vs relatives (P = .64-.99). Outcomes from manual tracing and FreeSurfer showed direct, moderate to strong, correlations (r = .51-.73, P < .05). These findings from a large psychosis sample support decreased hippocampal volume as a putative biomarker for schizophrenia and schizoaffective disorder, but not for psychotic bipolar I disorder, and may reflect a cumulative effect of divergent primary disease processes and/or lifetime medication use. Manual tracing and semiautomated parcellation regional volumetric approaches may provide useful outcomes for defining measurable biomarkers underlying severe mental illness.

Porous Diagnostic Boundaries: A New Emphasis for the Bulletin

Porous Diagnostic Boundaries: A New Emphasis for the Bulletin

Resting State Electroencephalogram Oscillatory Abnormalities in Schizophrenia and Psychotic Bipolar Patients and Their Relatives from the Bipolar and Schizophrenia Network on Intermediate Phenotypes Study

Abnormal resting state electroencephalogram (EEG) oscillations are reported in schizophrenia (SZ) and bipolar disorder, illnesses with overlapping symptoms and genetic risk. However, less evidence exists on whether similar EEG spectral abnormalities are present in individuals with both disorders or whether these abnormalities are present in first-degree relatives, possibly representing genetic predisposition for these disorders. Investigators examined 64-channel resting state EEGs of 225 SZ probands and 201 first-degree relatives (SZR), 234 psychotic bipolar (PBP) probands and 231 first-degree relatives (PBPR), and 200 healthy control subjects. Eight independent resting state EEG spectral components and associated spatial weights were derived using group independent component analysis. Analysis of covariance was conducted on spatial weights to evaluate group differences. Relative risk estimates and familiality were evaluated on abnormal spectral profiles in probands and relatives. Both SZ and PBP probands exhibited increased delta, theta, and slow and fast alpha activity. Post-hoc pair-wise comparison revealed increased frontocentral slow beta activity in SZ and PBP probands as well as SZR and PBPR. Augmented frontal delta activity was exhibited by SZ probands and SZR, whereas PBP probands and PBPR showed augmented fast alpha activity. Both SZ and PBP probands demonstrated aberrant low-frequency activity. Slow beta activity was abnormal in SZ and PBP probands as well as SZR and PBPR perhaps indicating a common endophenotype for both disorders. Delta and fast alpha activity were unique endophenotypes for SZ and PBP probands, respectively. The EEG spectral activity exhibited moderate relative risk and heritability estimates, serving as intermediate phenotypes in future genetic studies for examining biological mechanisms underlying the pathogenesis of the two disorders.

Gray Matter Volume as an Intermediate Phenotype for Psychosis: Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP)

The study examined gray matter volume across psychosis diagnoses organized by dimensional and DSM-IV categories from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) sample. In total, 351 probands with psychosis (146 with schizophrenia, 90 with schizoaffective disorder, and 115 with psychotic bipolar I disorder), 369 of their first-degree relatives (134 were relatives of individuals with schizophrenia, 106 of individuals with schizoaffective disorder, and 129 of individuals with psychotic bipolar I disorder), and 200 healthy comparison subjects were assessed. Gray matter volumes from 3-T T1-weighted images were analyzed using the VBM8 toolbox for SPM8, and outcomes were determined at a false discovery rate-corrected threshold of p<0.005. Across the psychosis dimension, probands (N=351) and relatives with psychosis spectrum disorders (N=34) showed substantial overlapping gray matter reductions throughout the neocortex, whereas relatives without psychosis spectrum (N=332) had normal gray matter volumes relative to comparison subjects. Across DSM-IV diagnoses, schizophrenia and schizoaffective probands showed overlapping gray matter reductions in numerous cortical and subcortical regions, whereas psychotic bipolar probands showed limited gray matter reductions localized to the frontotemporal cortex relative to comparison subjects. All relative groups had gray matter volumes that did not differ from comparison subjects. Across the dimensional psychosis categories, these findings indicate extensive neocortical gray matter reductions in psychosis probands and relatives with psychosis spectrum disorders, possibly reflecting lifetime psychosis burden, but normal gray matter in nonpsychotic relatives. Traditional DSM-IV psychosis grouping revealed partially divergent gray matter phenotypes for probands with schizophrenia or schizoaffective disorder (extensive neocortical or subcortical gray matter reductions) relative to those with psychotic bipolar disorder (smaller reductions were limited to frontotemporal regions). The dimensional conceptualization of psychosis appears useful in defining more homogenous disease categories that may help identify underlying psychosis biomarkers and develop a biologically driven diagnostic system and targeted treatments.

Neuropsychological Impairments in Schizophrenia and Psychotic Bipolar Disorder: Findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) Study

Familial neuropsychological deficits are well established in schizophrenia but remain less well characterized in other psychotic disorders. This study from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium 1) compares cognitive impairment in schizophrenia and bipolar disorder with psychosis, 2) tests a continuum model of cognitive dysfunction in psychotic disorders, 3) reports familiality of cognitive impairments across psychotic disorders, and 4) evaluates cognitive impairment among nonpsychotic relatives with and without cluster A personality traits. Participants included probands with schizophrenia (N=293), psychotic bipolar disorder (N=227), schizoaffective disorder (manic, N=110; depressed, N=55), their first-degree relatives (N=316, N=259, N=133, and N=64, respectively), and healthy comparison subjects (N=295). All participants completed the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery. Cognitive impairments among psychotic probands, compared to healthy comparison subjects, were progressively greater from bipolar disorder (z=-0.77) to schizoaffective disorder (manic z=-1.08; depressed z=-1.25) to schizophrenia (z=-1.42). Profiles across subtests of the BACS were similar across disorders. Familiality of deficits was significant and comparable in schizophrenia and bipolar disorder. Of particular interest were similar levels of neuropsychological deficits in relatives with elevated cluster A personality traits across proband diagnoses. Nonpsychotic relatives of schizophrenia probands without these personality traits exhibited significant cognitive impairments, while relatives of bipolar probands did not. Robust cognitive deficits are present and familial in schizophrenia and psychotic bipolar disorder. Severity of cognitive impairments across psychotic disorders was consistent with a continuum model, in which more prominent affective features and less enduring psychosis were associated with less cognitive impairment. Cognitive dysfunction in first-degree relatives is more closely related to psychosis-spectrum personality disorder traits in psychotic bipolar disorder than in schizophrenia.

Elevated Antisaccade Error Rate as an Intermediate Phenotype for Psychosis Across Diagnostic Categories

Elevated antisaccade error rate, reflecting problems with inhibitory behavioral control, is a promising intermediate phenotype for schizophrenia. Here, we consider whether it marks liability across psychotic disorders via common or different neurophysiological mechanisms and whether it represents a neurocognitive risk indicator apart from the generalized cognitive deficit. Schizophrenia (n = 267), schizoaffective (n = 150), and psychotic bipolar (n = 202) probands, their first-degree relatives (ns = 304, 193, 242, respectively), and healthy controls (n = 244), participating in the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium, performed antisaccade and prosaccade tasks and completed a neuropsychological battery. Antisaccade error rate was elevated in proband groups with greatest deficit observed in schizophrenia and was unrelated to symptoms and antipsychotic treatment. Increased error rate was also observed among relatives, even those without history of psychosis or psychosis spectrum personality traits. Relatives' deficits were similar across proband diagnoses. Error rate was familial and remained elevated in proband and relative groups after accounting for generalized cognitive impairment. Speed of attentional shifting, indexed by prosaccade latency, was similarly influenced in all groups by manipulations that freed vs increasingly engaged attention systems and was inversely associated with antisaccade error rate in all but schizophrenia probands. These findings indicate that elevated antisaccade error rate represents an intermediate phenotype for psychosis across diagnostic categories, and that it tracks risk beyond that attributable to the generalized cognitive deficit. The greater severity of antisaccade impairment in schizophrenia and its independence from attention shifting processes suggest more severe and specific prefrontal inhibitory control deficits in this disorder.

Discrimination within Recognition Memory in Schizophrenia.

Episodic memory is one of the most affected cognitive domains in schizophrenia. First-degree biological relatives of individuals with schizophrenia also have been found to exhibit a similar, but milder, episodic memory deficit. Unlike most studies that focus on the percent of previously presented items recognized, the current investigation sought to further elucidate the nature of memory dysfunction associated with schizophrenia by examining the discrimination of old and new material during recognition (measured by d') to consider false recognition of new items. Using the Recurring Figures Test and the California Verbal Learning Test (CVLT), we studied a sample of schizophrenia probands and the first-degree biological relatives of patients with schizophrenia, as well as probands with bipolar disorder and first-degree biological relatives to assess the specificity of recognition memory dysfunction to schizophrenia. The schizophrenia sample had poorer recognition discrimination in both nonverbal and verbal modalities; no such deficits were identified in first-degree biological relatives or bipolar disorder probands. Discrimination in schizophrenia and bipolar probands failed to benefit from the geometric structure in the designs in the manner that controls did on the nonverbal test. Females performed better than males in recognition of geometric designs. Episodic memory dysfunction in schizophrenia is present for a variety of stimulus domains and reflects poor use of item content to increase discrimination of old and new items.

Is Aberrant Functional Connectivity A Psychosis Endophenotype? A Resting State Functional Magnetic Resonance Imaging Study

Schizophrenia and bipolar disorder share overlapping symptoms and risk genes. Shared aberrant functional connectivity is hypothesized in both disorders and in relatives. We investigated resting state functional magnetic resonance imaging in 70 schizophrenia and 64 psychotic bipolar probands, their respective first-degree relatives (n = 70 and 52), and 118 healthy subjects. We used independent component analysis to identify components representing various resting state networks and assessed spatial aspects of functional connectivity within all networks. We first investigated group differences using five-level, one-way analysis of covariance (ANCOVA), followed by post hoc t tests within regions displaying ANCOVA group differences and correlation of such functional connectivity measures with symptom ratings to examine clinical relationships. Seven networks revealed abnormalities (five-level one-way ANCOVA, family-wise error correction p < .05): A) fronto-occipital, B) midbrain/cerebellum, C) frontal/thalamic/basal ganglia, D) meso/paralimbic, E) posterior default mode network, F) fronto-temporal/paralimbic and G) sensorimotor networks. Abnormalities in networks B and F were unique to schizophrenia probands. Furthermore, abnormalities in networks D and E were common to both patient groups. Finally, networks A, C, and G showed abnormalities shared by probands and their relative groups. Negative correlation with Positive and Negative Syndrome Scale negative and positive scores were found in regions within network C and F respectively, and positive correlation with Positive and Negative Syndrome Scale negative scores was found in regions in network D among schizophrenia probands only. Schizophrenia, psychotic bipolar probands, and their relatives share both unique and overlapping within-network brain connectivity abnormalities, revealing potential psychosis endophenotypes.

Examining the Comorbidity Between Attention Deficit Hyperactivity Disorder and Bipolar I Disorder: A Meta-Analysis of Family Genetic Studies

The existence of comorbidity between attention deficit hyperactivity disorder (ADHD) and bipolar I disorder has been documented in clinical and epidemiological studies, in studies of children and adults, and in diagnosed ADHD and bipolar I patient samples. Yet questions remain about the validity of diagnosing bipolar I disorder in ADHD youth. The authors aim to clarify these issues by reviewing family genetic studies of ADHD and bipolar I disorder. The authors applied random-effects meta-analysis to family genetic studies of ADHD and bipolar I disorder. Twenty bipolar proband studies provided 37 estimates of the prevalence of ADHD in 4,301 relatives of bipolar probands and 1,937 relatives of comparison probands. Seven ADHD proband studies provided 12 estimates of the prevalence of bipolar I disorder in 1,877 relatives of ADHD probands and 1,601 relatives of comparison probands. These studies found a significantly higher prevalence of ADHD among relatives of bipolar probands and a significantly higher prevalence of bipolar I disorder among relatives of ADHD probands. These results could not be accounted for by publication biases, unusual results from any one observation, sample characteristics, or study design features. The authors found no evidence of heterogeneity in the ADHD or bipolar family studies. The results suggest that ADHD plus bipolar comorbidity cannot be accounted for by misdiagnoses, but additional research is needed to rule out artifactual sources of comorbidity. More research is also needed to determine whether comorbidity of ADHD and bipolar I disorder constitutes a familial subtype distinct from its constituent disorders, which if confirmed would have implications for diagnostic nosology and genetic studies.