Vitamin D, Folate and the Intracranial Volume in Schizophrenia and Bipolar Disorder and Healthy Controls.

Vitamin D and folate deficiency are considered risk factors for schizophrenia and bipolar disorders, but it is unknown how vitamin D and folate influence the growing brain, cranium or the clinical phenotype. Serum vitamin D and folate levels are in part genetically regulated. We investigated whether adult vitamin D and folate levels are associated with the intracranial volume (ICV) under the hypothesis that developmental vitamin D or folate levels influence neurodevelopment and that current levels are associated with ICV. Ninety patients with severe mental disorders and 91 healthy controls underwent 3 T magnetic resonance imaging and serum sampling. Multiple linear regression was used to assess the contribution of serum vitamin D, folate and patient-control status on ICV. We show that vitamin D levels were within lower range for patients and controls (48.8 ± 22.1 nmol/l and 53.4 ± 20.0 nmol/l, respectively). A significant positive association was found between vitamin D and ICV (p = 0.003, r = 0.22), folate was trend-significantly associated with ICV. Folate and vitamin D were significantly associated (p = 0.0001, r = 0.28). There were nonsignificant patient-control differences and no interaction effects. The results suggest that Vitamin D is associated with ICV as detected in the adult. Further studies are warranted for replication and to investigate possible mechanisms and genetic associations.

Vitamin D Deficiency Associated With Cognitive Functioning in Psychotic Disorders.

BACKGROUND: Cognitive dysfunctions are core features of psychotic disorders with substantial impact on daily functioning. Vitamin D deficiency has been found to be related to cognitive dysfunctions, but the associations between vitamin D deficiency and cognition in persons with a psychotic disorder are largely unknown. METHODS: This cross-sectional study included 225 patients with a DSM-IV psychotic disorder consecutively recruited from 2003 to 2014 and 159 randomly selected healthy controls, assessed by a cognitive test battery, a clinical protocol (including Structured Clinical Interview for DSM-IV Axis I Disorders and Positive and Negative Syndrome Scale), and a physical examination including vitamin D measurements. Multiple regression models were performed to evaluate the effect of vitamin D deficiency (defined serum 25-hydroxyvitamin D [25(OH)D] < 25 nmol/L) on key cognitive domains: processing speed, verbal learning, verbal memory, and executive functioning. RESULTS: Vitamin D deficiency was significantly associated with decreased processing speed (ie, Digit Symbol Coding) (t = -2.6, P = .01; total model: adjusted R² = 0.40, F6, 374 = 43.8, P < .001) and decreased fluency (ie, verbal fluency) (t = -2.1, P = .04; total model: adjusted R² = 0.35, F6, 373 = 34.2, P < .001) when the results were controlled for age, ethnicity, IQ, patient versus control status, and substance or alcohol abuse. Additional analyses indicated that negative symptoms diluted the association between vitamin D deficiency and processing speed (t = -1.72, P = .09) and verbal fluency (t = -1.35, P = .18) in patients. CONCLUSION: The associations between vitamin D deficiency and processing speed and verbal fluency are good arguments for planning large-scale randomized controlled studies in target populations so conclusions can be made about the potential beneficial effect of vitamin D on cognition in psychotic disorders.

Task modulations and clinical manifestations in the brain functional connectome in 1615 fMRI datasets.

OBJECTIVE: An abundance of experimental studies have motivated a range of models concerning the cognitive underpinnings of severe mental disorders, yet the conception that cognitive and brain dysfunction is confined to specific cognitive domains and contexts has limited ecological validity. Schizophrenia and bipolar spectrum disorders have been conceptualized as disorders of brain connectivity; yet little is known about the pervasiveness across cognitive tasks. METHODS: To address this outstanding issue of context specificity, we estimated functional network connectivity from fMRI data obtained during five cognitive tasks (0-back, 2-back, go/no-go, recognition of positive faces, negative faces) in 90 patients with schizophrenia spectrum, 97 patients with bipolar spectrum disorder, and 136 healthy controls, including 1615 fMRI datasets in total. We tested for main effects of task and group, and their interactions, and used machine learning to classify task labels and predict cognitive domain scores from brain connectivity. RESULTS: Connectivity profiles were positively correlated across tasks, supporting the existence of a core functional connectivity backbone common to all tasks. However, 76.2% of all network links also showed significant task-related alterations, robust on the single subject level as evidenced by high machine-learning performance when classifying task labels. Independent of such task-specific modulations, 9.5% of all network links showed significant group effects, particularly including sensory (sensorimotor, visual, auditory) and cognitive (frontoparietal, default-mode, dorsal attention) networks. A lack of group by task interactions revealed that the pathophysiological sensitivity remained across tasks. Such pervasiveness across tasks was further supported by significant predictions of cognitive domain scores from the connectivity backbone obtained across tasks. CONCLUSIONS: The high accuracies obtained when classifying cognitive tasks support that brain connectivity indices provide sensitive and specific measures of cognitive states. Importantly, we provide evidence that brain network dysfunction in severe mental disorders is not confined to specific cognitive tasks and show that the connectivity backbone common to all tasks is predictive of cognitive domain traits. Such pervasiveness across tasks may support a generalization of pathophysiological models from different domains, thereby reducing their complexity and increasing their ecological validity. Future research incorporating a wider range of cognitive tasks, involving other sensory modalities (auditory, somatosensory, motor) and requirements (learning, perceptual inference, decision making, etc.), is needed to assess if under certain circumstances, context dependent aberrations may evolve. Our results provide further evidence from a large sample that fMRI based functional network connectivity can be used to reveal both, state and trait effects in the connectome.

Low vitamin D is associated with negative and depressive symptoms in psychotic disorders.

BACKGROUND: There are indications that low S-25(OH)D is associated with increased disease severity in psychotic disorder. Our first aim was to investigate the relations between low S-25(OH)D and positive, negative and depressive symptoms. Our second aim was to explore if associations between S-25(OH)D and symptoms were influenced by levels of inflammatory markers. METHODS: Participants (N=358) with a medical history of one or more psychotic episodes were recruited. Current symptomatology was assessed by The Structured Interview for the Positive and Negative Syndrome Scaleanalyzed by a five-factor model. The Calgary Depression Scale for Schizophrenia was used to assess depression and suicidal ideation. Blood samples were analyzed for S-25(OH)D, CRP, sTNF-R1, IL-Ra and OPG. We performed bivariate correlations and multiple regression models to evaluate the effect of S-25(OH)D on the outcomes. RESULTS: Low S-25(OH)D was significantly associated with negative symptoms (adjusted R2=0.113, F(6,357)=8.58, p<0.001) and with depression (adjusted R2=0.045, F(4,357)=5.233, p<0.001) when adjusting for possible confounding factors (i.e. gender, education, diagnose, hospitalization status, ethnicity, season and thyroid status). CRP was correlated with both S-25(OH)D (rho=-0.13, p=0.02) and negative symptoms (rho=0.14, p=0.01), but did not act as a mediator. The correlations between S-25(OH)D and the inflammatory markers sTNF-R1, IL-Ra and OPG were not significant. CONCLUSION: There is a strong association between low S-25(OH)D and higher negative and depressive symptoms in psychotic disorders. Randomized controlled trials should be performed to investigate the effect of vitamin D supplementation as adjuvant treatment strategy in patients with prominent negative or depressive symptoms.

A history of childhood trauma is associated with slower improvement rates: Findings from a one-year follow-up study of patients with a first-episode psychosis.

BACKGROUND: The aim of this study was to investigate whether childhood trauma was associated with more severe clinical features in patients with first-episode psychosis, both at the initial assessment and after one year. METHODS: Ninety-six patients with a first-episode of a DSM-IV diagnosis of psychosis, in addition to 264 healthy controls from the same catchment area, were recruited to the TOP NORMENT study. A history of childhood trauma was obtained using the Childhood Trauma Questionnaire (CTQ). Function and symptom severity were measured using the Global Assessment of Functioning (GAF) Scale divided into function (GAF-F) and symptoms (GAF-S), the Positive and Negative Syndrome Scale (PANSS) and the Young Mania Rating Scale (YMRS). All clinical assessments were completed at two time points: At an initial assessment within the first year of initiating treatment for psychosis and after one year. RESULTS: Childhood trauma was associated with significantly reduced global functioning and more severe clinical symptoms at both baseline and follow-up, whereas emotional neglect was associated with a significantly reduced improvement rate for global functioning (GAF-F) over the follow-up period. CONCLUSION: Our data indicate that patients with first-episode psychosis who report a history of childhood trauma constitute a subgroup characterized by more severe clinical features over the first year of treatment, as well as slower improvement rates.

Interleukin 1 receptor antagonist and soluble tumor necrosis factor receptor 1 are associated with general severity and psychotic symptoms in schizophrenia and bipolar disorder.

BACKGROUND: Previous studies suggest elevated inflammation in schizophrenia and bipolar disorder, with increased activity of the Interleukin 1 (IL-1), interleukin 6 (IL-6), tumor necrosis factor (TNF)-alpha, von Willebrand factor (vWf) and osteoprotegerin (OPG). It is unclear how immune activation is involved in the psychopathology. We investigated if elevated inflammation was associated with disease severity (trait) or current symptom level (state), comparing psychotic with general characteristics. METHODS: Plasma levels of sTNF receptor 1 (sTNF-R1), IL-1 receptor antagonist (IL-1Ra), IL-6, vWf and OPG were measured with ELISA techniques in 322 patients with schizophrenia spectrum and bipolar disorder. Current symptom level (state) was measured with Global Assessment of Functioning (GAF) and Positive and Negative Syndrome Scale (PANSS). Disease severity (trait) was measured with premorbid adjustment scale (PAS), age at onset, number of psychotic episodes and number and length of hospitalizations. RESULTS: After controlling for confounders, IL-1Ra and TNF-R1 were independently associated with GAF, and significantly correlated with PANSS negative and positive, respectively. In addition, Il-1Ra was associated with PAS, and sTNF-R1 with number of hospitalizations and psychotic episodes. VWf was significantly correlated with psychotic episodes, OPG with hospitalizations and IL-6 with history of psychosis. Linear regression analysis showed that GAF remained associated with sTNF-R1 and IL-1Ra with PANSS, after controlling for the other clinical measures. CONCLUSIONS: This supports that inflammatory markers, particularly IL-1Ra and sTNF-R1 are associated with both general disease severity and psychotic features. This supports a role of immune activation in the core pathological mechanisms of severe mental disorders.

Cannabis use and premorbid functioning as predictors of poorer neurocognition in schizophrenia spectrum disorder.

BACKGROUND: Evidence of associations between neurocognitive function and cannabis use in schizophrenia is inconclusive. However, direct measures of cannabis intake and premorbid function are rarely explored in this context. We investigated the relation between cannabis use, determined by its presence in urine, and neurocognitive functioning in schizophrenia controlling for the potential bias of premorbid functioning. METHODS: Naturalistic study of 364 patients with schizophrenia spectrum disorder from catchment areas in Oslo, Norway. Hierarchical multiple regression analyses were used to assess the relationship between cannabis in urine and measures of neurocognitive functioning, with adjustment for confounders, including premorbid functioning. RESULTS: Cannabis was detected in the urine of 21 patients, who had significant dysfunction in several neurocognitive domains independent of a current diagnosis of cannabis abuse. However, level of premorbid functioning explained the associations for all measures. CONCLUSION: Differences in premorbid functioning may explain apparent differences in neurocognitive function between schizophrenia spectrum patients using cannabis or not. The findings suggest that illness-related traits present early in life can affect both later cannabis use and neurocognition, probably by complex mechanisms.

Perceived discrimination is associated with severity of positive and depression/anxiety symptoms in immigrants with psychosis: a cross-sectional study.

BACKGROUND: Immigration status is a significant risk factor for psychotic disorders, and a number of studies have reported more severe positive and affective symptoms among immigrant and ethnic minority groups. We investigated if perceived discrimination was associated with the severity of these symptoms among immigrants in Norway with psychotic disorders. METHODS: Cross-sectional analyses of 90 immigrant patients (66% first-generation, 68% from Asia/Africa) in treatment for psychotic disorders were assessed for DSM-IV diagnoses with the Structured Clinical Interview for DSM Disorders (SCID-I, sections A-E) and for present symptom severity by The Structured Positive and Negative Syndrome Scale (SCI-PANSS). Perceived discrimination was assessed by a self-report questionnaire developed for the Immigrant Youth in Cultural Transition Study. RESULTS: Perceived discrimination correlated with positive psychotic (r=0.264, p<0.05) and depression/anxiety symptoms (r=0.282, p<0.01), but not negative, cognitive, or excitement symptoms. Perceived discrimination also functioned as a partial mediator for symptom severity in African immigrants. Multiple linear regression analyses controlling for possible confounders revealed that perceived discrimination explained approximately 10% of the variance in positive and depression/anxiety symptoms in the statistical model. CONCLUSIONS: Among immigrants with psychotic disorders, visible minority status was associated with perceived discrimination and with more severe positive and depression/anxiety symptoms. These results suggest that context-specific stressful environmental factors influence specific symptom patterns and severity. This has important implications for preventive strategies and treatment of this vulnerable patient group.

Sex-specific cortisol levels in bipolar disorder and schizophrenia during mental challenge--relationship to clinical characteristics and medication.

OBJECTIVE: Our objective was to examine the cortisol release during a mental challenge in severe mental disorders versus healthy controls (HC), analyzing effects of sex, clinical characteristics and medication, and comparing Bipolar Disorder (BD) to Schizophrenia (SCZ). METHODS: Patients with BD and SCZ (n=151) were recruited from a catchment area. HC (n=98) were randomly selected from the same area. Salivary samples were collected before and after a mental challenge and cortisol levels determined. RESULTS: During the challenge there was an interaction between group and sex (P = 0.015) with male patients having a blunted cortisol release compared to male HC (P = 0.037). Cortisol change did not differ significantly between BD and SCZ. In all patients, the cortisol change correlated with number of psychotic episodes (r = -0.23, P = 0.025), and in females patients, with number of depressive episodes (r = -0.33, P = 0.015). Patients using antidepressants had a greater cortisol release during challenge than those not using antidepressants (P = 0.043). CONCLUSIONS: Male patients with severe mental disorders seem to have a uniform abnormal cortisol release during mental challenges which associates with clinical course, and with beneficial effects of antidepressants.

Excessive cannabis use is associated with earlier age at onset in bipolar disorder.

The aim of the study was to investigate which factors are associated with age at onset in bipolar disorder with a specific focus on excessive alcohol and cannabis use, and the sequence of the onsets of excessive substance use and bipolar disorder. We investigated a naturalistic sample of 151 patients with bipolar I and II disorder receiving psychiatric treatment. Whether the presence of excessive substance use prior to bipolar disorder onset or the type of substance used (alcohol or cannabis) was associated with differences in age at onset was investigated using hierarchical and multiple linear regression analyses, adjusting for potential confounders. Patients with excessive alcohol use had a significantly later onset compared with patients with excessive cannabis use. Excessive general substance use prior to bipolar disorder onset was associated with a later onset. However, excessive cannabis use was associated with an earlier onset whether it preceded or followed bipolar disorder onset, also after adjusting for possible confounders. Excessive use of alcohol or other substances was not independently associated with age at onset in multivariate analyses. Alcohol use was associated with a later onset compared with cannabis use, suggesting different relationships to the onset of bipolar disorder. Lifetime use of cannabis predicted an earlier onset, independent of the sequence of onsets. This indicates that an early onset may increase the risk of cannabis use and that cannabis use may trigger bipolar disorder in vulnerable individuals.

Excessive substance use in bipolar disorder is associated with impaired functioning rather than clinical characteristics, a descriptive study.

BACKGROUND: There is a strong association between bipolar disorder (BD) and substance use disorder (SUD). The clinical and functional correlates of SUD in BD are still unclear and little is known about the role of excessive substance use that does not meet SUD criteria. Thus, the aims of the current study were to investigate lifetime rates of illicit substance use in BD relative to the normal population and if there are differences in clinical and functional features between BD patients with and without excessive substance use. METHODS: 125 consecutively recruited BD in- and outpatients from the Oslo University Hospitals and 327 persons randomly drawn from the population in Oslo, Norway participated. Clinical and functional variables were assessed. Excessive substance use was defined as DSM-IV SUD and/or excessive use according to predefined criteria. RESULTS: The rate of lifetime illicit substance use was significantly higher among patients compared to the reference population (OR = 3.03, CI = 1.9-4.8, p < .001). Patients with excessive substance use (45% of total) had poorer educational level, occupational status, GAF-scores and medication compliance, with a trend towards higher suicidality rates, compared to patients without. There were no significant group differences in current symptom levels or disease course between groups. CONCLUSION: The percentage of patients with BD that had tried illicit substances was significantly higher than in the normal population. BD patients with excessive substance use clearly had impaired functioning, but not a worse course of illness compared to patients without excessive substance use. An assessment of substance use beyond SUD criteria in BD is clinically relevant.