Association of Occupational Dysfunction and Hospital Admissions With Different Polygenic Profiles in Bipolar Disorder.

OBJECTIVE: Many but not all persons with bipolar disorder require hospital care because of severe mood episodes. Likewise, some but not all patients experience long-term occupational dysfunction that extends beyond acute mood episodes. It is not known whether these dissimilar outcomes of bipolar disorder are driven by different polygenic profiles. Here, polygenic scores (PGSs) for major psychiatric disorders and educational attainment were assessed for associations with occupational functioning and psychiatric hospital admissions in bipolar disorder. METHODS: A total of 4,782 patients with bipolar disorder and 2,963 control subjects were genotyped and linked to Swedish national registers. Longitudinal measures from at least 10 years of registry data were used to derive percentage of years without employment, percentage of years with long-term sick leave, and mean number of psychiatric hospital admissions per year. Ordinal regression was used to test associations between outcomes and PGSs for bipolar disorder, schizophrenia, major depressive disorder, attention deficit hyperactivity disorder (ADHD), and educational attainment. Replication analyses of hospital admissions were conducted with data from the Bipolar Disorder Research Network cohort (N=4,219). RESULTS: Long-term sick leave and unemployment in bipolar disorder were significantly associated with PGSs for schizophrenia, ADHD, major depressive disorder, and educational attainment, but not with the PGS for bipolar disorder. By contrast, the number of hospital admissions per year was associated with higher PGSs for bipolar disorder and schizophrenia, but not with the other PGSs. CONCLUSIONS: Bipolar disorder severity (indexed by hospital admissions) was associated with a different polygenic profile than long-term occupational dysfunction. These findings have clinical implications, suggesting that mitigating occupational dysfunction requires interventions other than those deployed to prevent mood episodes.

Association of premorbid intelligence with level of functioning and illness severity in bipolar disorder.

BACKGROUND: Bipolar disorder is a severe psychiatric syndrome defined by periodic mood shifts. Patients with bipolar disorder show cognitive impairments relative to healthy controls. The risk of developing schizophrenia, and partially also bipolar disorder, has previously been shown to increase with lower premorbid intelligence. It is not known if premorbid intelligence is associated with level of functioning and illness severity of people having developed bipolar disorder. METHODS: We used multiple linear and ordinal regression to analyze how premorbid intelligence, as measured at conscription, associate with functional outcome and illness severity in Swedish male bipolar disorder patients (n = 788). RESULTS: We found that lower premorbid intelligence is associated with lower percentage of time in work, after adjusting for age and bipolar subtype, and correcting for multiple comparisons. We also found a strong negative association with the total number of inpatient episodes and psychiatric comorbidity, but not with interepisodic remission, treatment with psychotherapy or lithium or the presence of any complicating socioeconomical factors. Adjusting for confounding genetic factors using polygenic risk scores for bipolar disorder and schizophrenia had no effect on the associations. LIMITATIONS: This study lacks females and controls and may thus have lower generalizability. CONCLUSION: In conclusion, premorbid intelligence is associated with both level of functioning and illness severity as well as comorbidity in bipolar disorder patients. Further research is needed to develop targeted interventions for this subgroup of bipolar disorder patients.

Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia.

Postsynaptic density is reduced in schizophrenia, and risk variants increasing complement component 4A (C4A) gene expression are linked to excessive synapse elimination. In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in patients with first-episode psychosis (FEP) who develop schizophrenia (FEP-SCZ: median 0.41 fmol/ul [CI = 0.34-0.45], FEP-non-SCZ: median 0.29 fmol/ul [CI = 0.22-0.35], healthy controls: median 0.28 [CI = 0.24-0.33]). We show that the CSF elevation of C4A in FEP-SCZ exceeds what can be expected from genetic risk variance in the C4 locus, and in patient-derived cellular models we identify a mechanism dependent on the disease-associated cytokines interleukin (IL)-1beta and IL-6 to selectively increase neuronal C4A mRNA expression. In patient-derived CSF, we confirm that IL-1beta correlates with C4A controlled for genetically predicted C4A RNA expression (r = 0.39; CI: 0.01-0.68). These results suggest a role of C4A in early schizophrenia pathophysiology.

Cerebrospinal fluid proteomic study of two bipolar disorder cohorts.

The pathophysiology of bipolar disorder remains to be elucidated and there are no diagnostic or prognostic biomarkers for the condition. In this explorative proteomic study, we analyzed 201 proteins in cerebrospinal fluid (CSF) from mood stable bipolar disorder patients and control subjects sampled from two independent cohorts, amounting to a total of 204 patients and 144 controls. We used three Olink Multiplex panels, whereof one specifically targets immune biomarkers, to assess a broad set of CSF protein concentrations. After quality control and removal of proteins with a low detection rate, 105 proteins remained for analyses in relation to case-control status and clinical variables. Only case-control differences that replicated across cohorts were considered. Results adjusted for potential confounders showed that CSF concentrations of growth hormone were lower in bipolar disorder compared with controls in both cohorts. The effect size was larger when the analysis was restricted to bipolar disorder type 1 and controls. We found no indications of immune activation or other aberrations. Growth hormone exerts many effects in the central nervous system and our findings suggest that growth hormone might be implicated in the pathophysiology of bipolar disorder.

A serum proteomic study of two case-control cohorts identifies novel biomarkers for bipolar disorder.

We set out to identify novel protein associations with potential as clinically viable biomarkers for bipolar disorder. To this end, we used proximity extension assay to analyze 201 unique proteins in blood serum from two independent cohorts comprising patients with bipolar disorder and healthy controls (total n = 493). We identified 32 proteins significantly associated with bipolar disorder in both case-control cohorts after adjusting for relevant covariates. Twenty-two findings are novel to bipolar disorder, but 10 proteins have previously been associated with bipolar disorder: chitinase-3-like protein 1, C-C motif chemokine 3 (CCL3), CCL4, CCL20, CCL25, interleukin 10, growth/differentiation factor-15, matrilysin (MMP-7), pro-adrenomedullin, and TNF-R1. Next, we estimated the variance in serum protein concentrations explained by psychiatric drugs and found that some case-control associations may have been driven by psychiatric drugs. The highest variance explained was observed between lithium use and MMP-7, and in post-hoc analyses and found that the serum concentration of MMP-7 was positively associated with serum lithium concentration, duration of lithium therapy, and inversely associated with estimated glomerular filtration rate in an interaction with lithium. This is noteworthy given that MMP-7 has been suggested as a mediator of renal tubulointerstitial fibrosis, which is characteristic of lithium-induced nephropathy. Finally, we used machine learning to evaluate the classification performance of the studied biomarkers but the average performance in unseen data was fair to moderate (area under the receiver operating curve = 0.72). Taken together, our serum biomarker findings provide novel insight to the etiopathology of bipolar disorder, and we present a suggestive biomarker for lithium-induced nephropathy.

Serum concentration of zinc is elevated in clinically stable bipolar disorder patients.

BACKGROUND: Bipolar disorder (BD) is a chronic psychiatric disorder characterized by recurrent mood episodes interspersed with euthymic periods. A growing number of studies have indicated that zinc plays an important role in coordinating immune responses, as well as being involved in synaptic transmission. In the current study, we set out to measure serum levels of zinc in a meticulously phenotyped cohort of 121 euthymic BD subjects and 30 matched controls. METHODS: Serum levels of zinc were measured by photometry. To assess the interplay between zinc levels and immune activation in BD, we measured serum levels of high-sensitive C-reactive protein (hsCRP) levels by immunoturbidimetric assay, and serum levels of monocyte chemoattractant protein-1 (MCP-1), chitinase 3-like protein 1 (YKL-40), and soluble cluster of differentiation 14 (sCD14) by electrochemiluminescence enzyme-linked immunosorbent assays. The baseline clinical diagnostic instrument for BD was the Affective Disorder Evaluation, and executive functioning was assessed by using the Delis-Kaplan Executive Function System. RESULTS: Controlling for potential confounding factors, BD patients displayed increased serum levels of zinc unrelated to hsCRP, MCP-1, YKL-40, and sCD14 levels. Serum levels of zinc did not associate with executive functioning or measurements of disease severity. DISCUSSION: This study suggests that the zinc homeostasis is disturbed in BD and that this dyshomeostasis is not related to ongoing mood symptoms or immune activation. Of note, serum levels were increased and hence do not support continuous zinc supplementation in BD.

Cerebrospinal fluid proteomics targeted for central nervous system processes in bipolar disorder.

The etiopathology of bipolar disorder is largely unknown. We collected cerebrospinal fluid (CSF) samples from two independent case-control cohorts (total n = 351) to identify proteins associated with bipolar disorder. A panel of 92 proteins targeted towards central nervous system processes identified two proteins that replicated across the cohorts: the CSF concentrations of testican-1 were lower, and the CSF concentrations of C-type lectin domain family 1 member B (CLEC1B) were higher, in cases than controls. In a restricted subgroup analysis, we compared only bipolar type 1 with controls and identified two additional proteins that replicated in both cohorts: draxin and tumor necrosis factor receptor superfamily member 21 (TNFRSF21), both lower in cases than controls. This analysis additionally revealed several proteins significantly associated with bipolar type 1 in one cohort, falling just short of replicated statistical significance in the other (tenascin-R, disintegrin and metalloproteinase domain-containing protein 23, cell adhesion molecule 3, RGM domain family member B, plexin-B1, and brorin). Next, we conducted genome-wide association analyses of the case-control-associated proteins. In these analyses, we found associations with the voltage-gated calcium channel subunit CACNG4, and the lipid-droplet-associated gene PLIN5 with CSF concentrations of TNFRSF21 and CLEC1B, respectively. The reported proteins are involved in neuronal cell-cell and cell-matrix interactions, particularly in the developing brain, and in pathways of importance for lithium's mechanism of action. In summary, we report four novel CSF protein associations with bipolar disorder that replicated in two independent case-control cohorts, shedding new light on the central nervous system processes implicated in bipolar disorder.

Long-term trajectory of cognitive performance in people with bipolar disorder and controls: 6-year longitudinal study.

BACKGROUND: Cross-sectional studies have found impaired cognitive functioning in patients with bipolar disorder, but long-term longitudinal studies are scarce. AIMS: The aims of this study were to examine the 6-year longitudinal course of cognitive functioning in patients with bipolar disorder and healthy controls. Subsets of patients were examined to investigate possible differences in cognitive trajectories. METHOD: Patients with bipolar I disorder (n = 44) or bipolar II disorder (n = 28) and healthy controls (n = 59) were tested with a comprehensive cognitive test battery at baseline and retested after 6 years. We conducted repeated measures ANCOVAs with group as a between-subject factor and tested the significance of group and time interaction. RESULTS: By and large, the change in cognitive functioning between baseline and follow-up did not differ significantly between participants with bipolar disorder and healthy controls. Comparing subsets of patients, for example those with bipolar I and II disorder and those with and without manic episodes during follow-up, did not reveal subgroups more vulnerable to cognitive decline. CONCLUSIONS: Cognitive performance remained stable in patients with bipolar disorder over a 6-year period and evolved similarly to healthy controls. These findings argue against the notion of a general progressive decline in cognitive functioning in bipolar disorder.

Five-year outcomes of ADHD diagnosed in adulthood.

There is a dearth of long-term follow-up studies of adults diagnosed with ADHD. Here, the aim was to evaluate long-term outcomes in a group of ADHD patients diagnosed in adulthood and receiving routine psychiatric health care. Adults diagnosed with any type of ADHD (n = 52) and healthy controls (n = 73) were assessed at baseline and at a 5-year follow-up, using Global Assessment of Functioning (GAF), Clinical Global Impression (CGI), Brown ADD Scale (BADDS) and Adult ADHD Self-Report Scale (ASRS). A multivariate regression method was used to identify factors predicting 5-year outcomes, including baseline ratings, medication intensity, comorbidity, intelligence quotient (IQ), age, and sex. After 5 years, ADHD patients reported fewer and/or less severe symptoms compared to baseline, but remained at clinically significant symptom levels and with functional deficits. Baseline self-reports of ADHD symptoms predicted their own 5-year outcome and low baseline functioning level predicted improved global functioning at follow-up. Factors previously reported to predict short-term outcomes (i.e., medication, comorbidity, IQ, age, and sex) did not anticipate long-term outcomes in present study.

DAS-II Cognitive Profiles Are Not Diagnostically Meaningful For Autism: A ROC Analysis.

Intelligence assessment is an integral part of a comprehensive autism evaluation. Many past studies have described a cognitive profile of autistic individuals characterized by higher nonverbal than verbal IQ scores. The diagnostic utility of this profile, however, remains unknown. We leveraged receiver operating characteristic methods to determine the sensitivity, specificity, and area under the curve (AUC) of three different IQ profiles in a large sample of children who have an autism spectrum disorder diagnosis (N = 1,228, Simons Simplex Collection) who completed the Differential Ability Scales-Second Edition (DAS-II), School Age compared to the normative sample provided by the DAS-II publisher (N = 2,200). The frequently discussed nonverbal > verbal IQ profile performed near chance at distinguishing ASD from normative individuals (AUC: 0.54, 95% CI [0.52-0.56]), and performed significantly worse for females than males (AUC: females: 0.46 [0.41-0.52]; males: 0.55 [0.53-0.58]). All cognitive profiles showed AUC < 0.56. We conclude that while significant differences between verbal and nonverbal IQ scores exist at the group level, these differences are small in an absolute sense and not meaningful at an individual level. We do not recommend using cognitive profiles to aid in autism diagnostic decision-making. LAY SUMMARY: Some researchers and clinicians have reported an "autistic cognitive profile" of higher nonverbal intelligence than verbal intelligence. In an analysis of over 1,000 autistic children, we found that the group's average nonverbal intelligence is usually higher than their verbal intelligence. However, this pattern should not be used by clinicians to make an individual diagnosis of autism because our results show it is not helpful nor accurate.

Executive functioning but not IQ or illness severity predicts occupational status in bipolar disorder.

BACKGROUND: Bipolar disorder is associated with significant functional deficits including occupational functioning. Despite the high rates of unemployment and sick leave in the patient population, only a limited number of studies have examined factors associated with occupational functioning in bipolar disorder. The aim of the study was to investigate the relative importance of demographic, clinical, and neuropsychological factors on occupational dysfunction in bipolar disorder. METHODS: A sample of 120 partially or fully remitted bipolar disorder I and II patients were included in the study. Patients were stratified into an active and an inactive group based on the number of hours per week working or studying. Active (n = 86) and inactive (n = 34) patients were compared with respect to demographic factors, clinical characteristics, medication, measures of psychosocial functioning, and cognitive functioning (i.e., IQ and executive functions). No other cognitive domains were examined. RESULTS: Univariate analyses revealed better overall cognitive function in active patients in terms of IQ and executive functioning. However, only executive functioning accounted for a significant amount of the variance in occupational status when other significant predictors were taken into account. CONCLUSIONS: Executive functioning was a more powerful predictor of occupational status in bipolar disorder patients than IQ and other clinical factors, including illness severity.

Psychoeducation for bipolar disorder and risk of recurrence and hospitalization - a within-individual analysis using registry data.

BACKGROUND: The efficacy of psychoeducation for bipolar disorder has been demonstrated in clinical trials, but it is not known if the results translate into effectiveness in routine clinical practice. The aim was to determine the effectiveness of psychoeducation for bipolar disorder in a routine clinical setting. METHOD: We identified 2819 patients with at least three registrations in the Swedish Quality Assurance Register for Bipolar Disorder. Among those, 402 had not been exposed to psychoeducation at the first visit, but received psychoeducation during any of the following registrations. Using within-individual analyses, the risk of recurrence after having received psychoeducation was compared with the risk prior to psychoeducation. RESULTS: In adjusted within-individuals comparisons, periods after psychoeducation was associated with decreased risks of any recurrence [odds ratio (OR) 0.57, 95% CI 0.42-0.78], (hypo-)manic or mixed episodes (OR 0.54, 95% CI 0.39-0.76), depressive episodes (OR 0.63, 95% CI 0.47-0.86), and inpatient care (OR 0.54, 95% CI 0.33-0.86) relative to periods prior to psychoeducation. There was no association with rates of involuntary sectioning or suicide attempts. CONCLUSIONS: The results suggest that psychoeducation for bipolar disorder reduces the risk of mood episodes and inpatient care also when implemented in routine clinical practice.

Neuropsychological profiles of adult bipolar disorder patients with and without comorbid attention-deficit hyperactivity disorder.

BACKGROUND: Comorbid attention-deficit/hyperactivity disorder (ADHD) is common in bipolar disorder and associated with worse outcomes. Cognitive testing might be a tool to identify this group. Here we compare the neuropsychological profiles of bipolar disorder patients with (BD + cADHD) and without (BD - cADHD) childhood attention-deficit hyperactivity disorder. METHODS: Adult patients with BD - cADHD (n = 66), BD + cADHD (n = 32), and healthy controls (n = 112) were tested using a comprehensive battery of neuropsychological tests. Patients underwent rigorous diagnostic assessments for bipolar disorder and ADHD, as well as a parental interview to establish childhood ADHD. RESULTS: The neuropsychological profiles of the groups were similar, except that the BD + cADHD group performed significantly worse on working memory. Working memory did not differ between those in the BD + cADHD group who only had a history of childhood ADHD and those that still met criteria for ADHD in adulthood. CONCLUSIONS: Cognitive testing had limited power to differentiate between bipolar disorder adults with and without childhood ADHD. The BD + cADHD subgroup cannot explain the significant cognitive heterogeneity seen in bipolar disorder patients.

Classification of cognitive performance in bipolar disorder.

OBJECTIVE: To understand the etiology of cognitive impairment associated with bipolar disorder, we need to clarify potential heterogeneity in cognitive functioning. To this end, we used multivariate techniques to study if the correlation structure of cognitive abilities differs between persons with bipolar disorder and controls. METHOD: Clinically stable patients with bipolar disorder (type I: n = 64; type II: n = 44) and healthy controls (n = 86) were assessed with a wide range of cognitive tests measuring executive function, speed, memory, and verbal skills. Data were analysed with multivariate techniques. RESULTS: A distinct subgroup (∼30%) could be identified that performed significantly poorer on tests concerning memory function. This cognitive phenotype subgroup did not differ from the majority of bipolar disorder patients with respect to other demographic or clinical characteristics. CONCLUSIONS: Whereas the majority of patients performed similar to controls, a subgroup of patients with bipolar disorder differed substantially from healthy controls in the correlation pattern of low-level cognitive abilities. This suggests that cognitive impairment is not a general trait in bipolar disorder but characteristic of a cognitive subgroup. This has important clinical implications for cognitive rehabilitation and remediation.

Personality traits in bipolar disorder and influence on outcome.

BACKGROUND: The aim was to investigate the personality profile of bipolar disorder I and II, and healthy controls, and to study whether personality influences the course of bipolar disorder. METHODS: One hundred ten patients with bipolar disorder I, 85 patients with bipolar disorder II, and 86 healthy individuals had their personality profile assessed using the Swedish universities Scales of Personality (SSP), an instrument developed to explore personality-related vulnerabilities and correlates of psychiatric disorders. Patients were followed prospectively for 2 years. To assess the impact of Neuroticism, Aggressiveness, and Disinhibition on illness course, we performed logistic regressions with the outcome variables mood episodes (depressive, hypo/manic, mixed), suicide attempts, violence, and the number of sick leave days. RESULTS: Bipolar disorder I and II demonstrated higher global measures of Neuroticism, Aggressiveness, and Disinhibition as compared with healthy controls. A third of the patients scored ≥1 SD above the population-based normative mean on the global neuroticism measure. The two subtypes of bipolar disorder were, however, undistinguishable on all of the personality traits. In the unadjusted model, higher neuroticism at baseline predicted future depressive episodes and suicide attempts/violent behavior, but this association disappeared when adjusting for baseline depressive symptoms as assessed with MADRS. CONCLUSIONS: A significant minority of the patients scored ≥1 SD above the population mean on the global measures of Neuroticism, Aggressiveness and Disinhibition; scores this high are usually evident clinically. Yet, the personality profile does not seem to have prognostic value over a 2-year period.

Cognitive functioning in clinically stable patients with bipolar disorder I and II.

OBJECTIVES: Bipolar disorder is accompanied by cognitive impairments, which persists during euthymic phases. The purpose of the present study was to identify those neuropsychological tests that most reliably tell euthymic bipolar patients and controls apart, and to clarify the extent to which these cognitive impairments are clinically significant as judged from neuropsychological norms. METHODS: Patients with bipolar disorder (type I: n = 64; type II: n = 44) and controls (n = 86) were examined with a comprehensive neuropsychological test battery yielding 47 measures of executive functioning, speed, memory, and verbal skills. Multivariate analysis was used to build a model of cognitive performance with the ability to expose underlying trends in data and to reveal cognitive differences between patients and controls. RESULTS: Patients with bipolar disorder and controls were partially separated by one predictive component of cognitive performance. Additionally, the relative relevance of each cognitive measure for such separation was decided. Cognitive tests measuring set shifting, inhibition, fluency, and searching (e.g., Trail Making Test, Color-Word) had strongest discriminating ability and most reliably detected cognitive impairments in the patient group. CONCLUSIONS: Both bipolar disorder type I and type II were associated with cognitive impairment that for a sizeable minority is significant in a clinical neuropsychological sense. We demonstrate a combination of neuropsychological tests that reliably detect cognitive impairment in bipolar disorder.