M. Aas

Abnormal cortisol awakening response predicts worse cognitive function in patients with first-episode psychosis

BACKGROUNDnCognitive impairment, particularly in memory and executive function, is a core feature of psychosis. Moreover, psychosis is characterized by a more prominent history of stress exposure, and by dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. In turn, stress exposure and abnormal levels of the main HPA axis hormone cortisol are associated with cognitive impairments in a variety of clinical and experimental samples; however, this association has never been examined in first-episode psychosis (FEP).nnnMETHODnIn this study, 30 FEP patients and 26 controls completed assessment of the HPA axis (cortisol awakening response and cortisol levels during the day), perceived stress, recent life events, history of childhood trauma, and cognitive function. The neuropsychological battery comprised general cognitive function, verbal and non-verbal memory, executive function, perception, visuospatial abilities, processing speed, and general knowledge.nnnRESULTSnPatients performed significantly worse on all cognitive domains compared to controls. In patients only, a more blunted cortisol awakening response (that is, more abnormal) was associated with a more severe deficit in verbal memory and processing speed. In controls only, higher levels of perceived stress and more recent life events were associated with a worse performance in executive function and perception and visuospatial abilities.nnnCONCLUSIONSnThese data support a role for the HPA axis, as measured by cortisol awakening response, in modulating cognitive function in patients with psychosis; however, this association does not seem to be related to the increased exposure to psychosocial stressors described in these patients.

A Systematic Review of Cognitive Function in First-Episode Psychosis, Including a Discussion on Childhood Trauma, Stress, and Inflammation

Objective: To carry out a systematic review of the literature addressing cognitive functions in first-episode psychosis (FEP), divided into domains. Although this is not a full “cognitive-genetics-in-schizophrenia review,” we will also include putative ideas of mechanism(s) behind these impairments, focusing on how early stress, and genetic vulnerability may moderate cognitive function in psychosis. Method: Relevant studies were identified via computer literature searches for research published up to and including January 2013, only case-control studies were included for the neurocognitive meta-analysis. Results: Patients with FEP present global cognitive impairment compared to healthy controls. The largest effect size was observed for verbal memory (Cohen’s d effect sizeu2009=u20092.10), followed by executive function (effect sizeu2009=u20091.86), and general IQ (effect sizeu2009=u20091.71). However, effect sizes varied between studies. Conclusion: Cognitive impairment across domains, up to severe level based on Cohen’s effect size, is present already in FEP studies. However, differences in levels of impairment are observed between studies, as well as within domains, indicating that further consolidation of cognitive impairment over the course of illness may be present. Cognitive abnormalities may be linked to a neurodevelopmental model including increased sensitivity to the negative effect of stress, as well as genetic vulnerability. More research on this field is needed.

Indications of a dose–response relationship between cannabis use and age at onset in bipolar disorder

Cannabis use seems to play a causal role in the development of psychotic disorders. Recent evidence suggests that it may also precipitate onset in bipolar disorder. We here investigate if there is a dose-response relationship between cannabis use and age at onset in bipolar disorder, and whether there are interactions between cannabis use and illness characteristics (presenting polarity and presence of psychosis). Consecutively recruited patients with a DSM-IV, SCID verified diagnosis of bipolar I, II or NOS disorder (n=324) participated. Two-way ANCOVAS were used to investigate the effect of levels of cannabis use (<10 times during one month lifetime, >10 times during one month lifetime or a cannabis use disorder) on age at onset, including interaction effects with illness characteristics, while controlling for possible confounders. There was a significant association indicating a dose-response relationship between cannabis use and age at onset, which remained statistically significant after controlling for possible confounders (gender, bipolar subtype, family history of severe mental illness and alcohol or other substance use disorders). There were no interaction effects between cannabis use and presenting polarity or presence of psychosis. Doses of cannabis used may affect the age at onset of bipolar disorder.

Anomalous self-experience and childhood trauma in first-episode schizophrenia

BACKGROUNDnAnomalous self-experiences (ASEs) are viewed as core features of schizophrenia. Childhood trauma (CT) has been postulated as a risk factor for developing schizophrenia.nnnAIMnThe aim of this study is to investigate the relationships between CT, depression and ASEs in schizophrenia.nnnMETHODnASEs were assessed in 55 patients in the early treated phases of schizophrenia using the Examination of Anomalous Self-Experience (EASE) instrument. Data on CT were collected using the Childhood Trauma Questionnaire, short form (CTQ-SF). This consists of 5 subscales: physical abuse, sexual abuse, emotional abuse, emotional neglect, and physical neglect. Assessment of depression was based on the Calgary Depression Scale for Schizophrenia (CDSS).nnnRESULTSnWe found significant associations between EASE total score and CTQ total score and between EASE total score and emotional neglect subscore in women, but not men. We also found significant associations between CDSS total score and CTQ total score and between CDSS total score and emotional abuse, emotional neglect, and physical neglect subscores in women, but not men. In men we did not find any significant associations between EASE total score, CDSS total score and any CTQ scores.nnnCONCLUSIONnCT was significantly associated with higher levels of ASEs in women in the early treated phases of schizophrenia, but not in men. This again associated with an increase in depressive symptoms.

Inflammatory evidence for the psychosis continuum model

BACKGROUNDnInflammation and immune activation have been implicated in the pathophysiology of severe mental disorders. Previous studies of inflammatory markers, however, have been limited with somewhat inconsistent results.nnnAIMSnWe aimed to determine the effect sizes of inflammatory marker alterations across diagnostic groups of the psychosis continuum and investigate association to antipsychotic medications.nnnMETHODSnPlasma levels of soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin 1 receptor antagonist (IL-1Ra), osteoprotegerin (OPG), and von Willebrand factor (vWf) were measured in patients (n=992) with schizophrenia spectrum (SCZ, n=584), schizoaffective disorder (SA, n=93), affective spectrum disorders (AFF, n=315), and healthy controls (HC, n=638).nnnRESULTSnLevels of sTNF-R1 (p=1.8×10(-8), d=0.23) and IL-1Ra (p=0.002, d=0.16) were increased in patients compared to HC. The SCZ group had higher levels of sTNF-R1 (p=8.5×10(-8), d=0.27) and IL-1Ra (p=5.9×10(-5), d=0.25) compared to HC, and for sTNF-R1 this was also seen in the SA group (p=0.01, d=0.3) and in the AFF group (p=0.002, d=0.12). Further, IL-1Ra (p=0.004, d=0.25) and vWf (p=0.02, d=0.21) were increased in the SCZ compared to the AFF group. There was no significant association between inflammatory markers and use of antipsychotic medication.nnnCONCLUSIONnWe demonstrate a small increase in sTNF-R1 and IL-1Ra in patients with severe mental disorders supporting a role of inflammatory mechanisms in disease pathophysiology. The increase was more pronounced in SCZ compared to AFF supporting a continuum psychosis model related to immune factors.

Affective lability mediates the association between childhood trauma and suicide attempts, mixed episodes and co-morbid anxiety disorders in bipolar disorders

BACKGROUNDnMany studies have shown associations between a history of childhood trauma and more severe or complex clinical features of bipolar disorders (BD), including suicide attempts and earlier illness onset. However, the psychopathological mechanisms underlying these associations are still unknown. Here, we investigated whether affective lability mediates the relationship between childhood trauma and the severe clinical features of BD.nnnMETHODnA total of 342 participants with BD were recruited from France and Norway. Diagnosis and clinical characteristics were assessed using the Diagnostic Interview for Genetic Studies (DIGS) or the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I). Affective lability was measured using the short form of the Affective Lability Scale (ALS-SF). A history of childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Mediation analyses were performed using the SPSS process macro.nnnRESULTSnUsing the mediation model and covariation for the lifetime number of major mood episodes, affective lability was found to statistically mediate the relationship between childhood trauma experiences and several clinical variables, including suicide attempts, mixed episodes and anxiety disorders. No significant mediation effects were found for rapid cycling or age at onset.nnnCONCLUSIONSnOur data suggest that affective lability may represent a psychological dimension that mediates the association between childhood traumatic experiences and the risk of a more severe or complex clinical expression of BD.

Cannabis use disorder is associated with greater illness severity in tobacco smoking patients with bipolar disorder

OBJECTIVEnCannabis use disorders (CUD) may influence the course of bipolar disorder (BD), but key confounding factors such as tobacco smoking have not been adequately addressed. This study examined whether CUD was associated with a more severe illness course in tobacco smoking BD patients.nnnMETHODSnA sample of French and Norwegian tobacco smoking patients with BD I and II (N=642) was investigated. DSM-IV diagnoses and other characteristics were obtained through personal interviews using structured questionnaires. The association between CUD and illness course was assessed in regression analyses.nnnRESULTSnIn bivariate analyses, CUD was associated with earlier BD onset, higher frequency of manic (in BD I) and depressive episodes and hospitalizations per illness year, and a higher occurrence of psychotic episodes. After controlling for potential confounders, the relationships with earlier BD onset (B=-5.60 95% CI=-7.65 to -3.64), and increased rates of manic episodes (OR=1.93, 95% CI: 1.15 to 3.23) and hospitalizations (OR=2.93, 95% CI: 1.85 to 4.64) remained statistically significant.nnnLIMITATIONSnDespite the multivariate approach, differences between the two samples may lead to spurious findings related to hidden confounders. Substance use and mood episode information was collected retrospectively, and potential birth cohort effects could not be controlled for.nnnCONCLUSIONnStudies have found associations between tobacco smoking and poorer outcomes in BD. In this study on tobacco smoking BD patients we report an association between CUD and illness severity, suggesting that CUD exacerbates the disease evolution independently of tobacco smoking. Specific treatment and prevention programs addressing CUD in BD patients are warranted.

Childhood trauma mediates the association between ethnic minority status and more severe hallucinations in psychotic disorder

BACKGROUNDnEthnic minority status and childhood trauma are established risk factors for psychotic disorders. Both are found to be associated with increased level of positive symptoms, in particular auditory hallucinations. Our main aim was to investigate the experience and effect of childhood trauma in patients with psychosis from ethnic minorities, hypothesizing that they would report more childhood trauma than the majority and that this would be associated with more current and lifetime hallucinations.nnnMETHODnIn this cross-sectional study we included 454 patients with a SCID-I DSM-IV diagnosis of non-affective or affective psychotic disorder. Current hallucinations were measured with the Positive and Negative Syndrome Scale (P3; Hallucinatory Behaviour). Lifetime hallucinations were assessed with the SCID-I items: auditory hallucinations, voices commenting and two or more voices conversing. Childhood trauma was assessed with the Childhood Trauma Questionnaire, self-report version.nnnRESULTSnPatients from ethnic minority groups (n = 69) reported significantly more childhood trauma, specifically physical abuse/neglect, and sexual abuse. They had significantly more current hallucinatory behaviour and lifetime symptoms of hearing two or more voices conversing. Regression analyses revealed that the presence of childhood trauma mediated the association between ethnic minorities and hallucinations.nnnCONCLUSIONSnMore childhood trauma in ethnic minorities with psychosis may partially explain findings of more positive symptoms, especially hallucinations, in this group. The association between childhood trauma and these first-rank symptoms may in part explain this groups higher risk of being diagnosed with a schizophrenia-spectrum diagnosis. The findings show the importance of childhood trauma in symptom development in psychosis.

Polygenic risk scores in bipolar disorder subgroups

BACKGROUNDnBipolar disorder (BD) is a genetically and clinically heterogeneous disorder. Current classifications of BD rely on clinical presentations without any validating biomarkers, making homogenous and valid subtypes warranted. This study aims at investigating whether a BD polygenic risk score (PGRS) can validate BD subtypes including diagnostic sub-categories (BD-I versus BD-II), patients with and without psychotic symptoms, polarity of first presenting episode and age at onset based groups. We also wanted to investigate whether illness severity indicators were associated with a higher polygenic risk for BD.nnnMETHODSnAnalyze differences in BD PGRS scores between suggested subtypes of BD and between healthy controls (CTR) and BD in a sample of N=669 (255 BD and 414 CTR).nnnRESULTSnThe BD PGRS significantly discriminates between BD and CTR (p<0.001). There were no differences in BD PGRS between groups defined by diagnostic sub-categories, presenting polarity and age at onset. Patients with psychotic BD had nominally significantly higher BD PGRS than patients with non-psychotic BD after controlling for diagnostic sub-category (p=0.019). These findings remained trend level significant after Bonferroni corrections (p=0.079).nnnLIMITATIONSnThe low explained variance of the current PGRS method could lead to type II errors.nnnCONCLUSIONSnThere are nominally significant differences in BD PGRS scores between patients with and without psychotic symptoms, indicating that these two forms of BD might represent distinct subtypes of BD based in its polygenic architecture and a division between BD with and without psychotic symptoms could represent a more valid subclassification of BD than current diagnostic sub-categories. If replicated, this finding could affect future research, diagnostics and clinical practice.

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.

BackgroundThe 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.MethodsNinety-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.ResultsChildhood 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.ConclusionOur 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.