Ritsaert Lieverse

Childhood Adversities Increase the Risk of Psychosis: A Meta-analysis of Patient-Control, Prospective- and Cross-sectional Cohort Studies

Evidence suggests that adverse experiences in childhood are associated with psychosis. To examine the association between childhood adversity and trauma (sexual abuse, physical abuse, emotional/psychological abuse, neglect, parental death, and bullying) and psychosis outcome, MEDLINE, EMBASE, PsychINFO, and Web of Science were searched from January 1980 through November 2011. We included prospective cohort studies, large-scale cross-sectional studies investigating the association between childhood adversity and psychotic symptoms or illness, case-control studies comparing the prevalence of adverse events between psychotic patients and controls using dichotomous or continuous measures, and case-control studies comparing the prevalence of psychotic symptoms between exposed and nonexposed subjects using dichotomous or continuous measures of adversity and psychosis. The analysis included 18 case-control studies (n = 2048 psychotic patients and 1856 nonpsychiatric controls), 10 prospective and quasi-prospective studies (n = 41 803) and 8 population-based cross-sectional studies (n = 35 546). There were significant associations between adversity and psychosis across all research designs, with an overall effect of OR = 2.78 (95% CI = 2.34–3.31). The integration of the case-control studies indicated that patients with psychosis were 2.72 times more likely to have been exposed to childhood adversity than controls (95% CI = 1.90–3.88). The association between childhood adversity and psychosis was also significant in population-based cross-sectional studies (OR = 2.99 [95% CI = 2.12–4.20]) as well as in prospective and quasi-prospective studies (OR = 2.75 [95% CI = 2.17–3.47]). The estimated population attributable risk was 33% (16%–47%). These findings indicate that childhood adversity is strongly associated with increased risk for psychosis.

Significantly reduced docosahexaenoic and docosapentaenoic acid concentrations in erythrocyte membranes from schizophrenic patients compared with a carefully matched control group

BACKGROUND Fatty acid research in schizophrenia has demonstrated an altered cell membrane phospholipid metabolism. Erythrocyte membrane phospholipid composition closest reflects that of neuronal membranes. METHODS (Poly)(un)saturated fatty acid concentrations were measured in the erythrocyte membranes of 19, consecutively admitted, medicated young schizophrenic patients and then compared with matched control subjects. Psychiatric symptomatology was rated with the Positive and Negative Symptom Scale and Montgomery-Asberg Depression Rating Scale. Because diet, hormones, and cannabis influence fatty acid metabolism, we included these factors in our study. RESULTS The most distinctive findings concerned the omega-3 series: C22:5 omega-3, C22:6 omega-3 (docosahexaenoic acid), and the sum of omega-3 fatty acids were significantly decreased. Interestingly, C20:4 omega-6 (arachidonic acid) was not lowered. In the omega-9 series, higher levels of C22:1 omega-9 and lower levels its elongation product, C24:1 omega-9 (nervonic acid), were found. Interestingly, the other arm of the desaturation-elongation sequence of C18:1 omega-9, C20:3 omega-9, was lower in patients. The total omega-9 fatty acid levels were also lower in patients. CONCLUSIONS Significant differences in erythrocyte fatty acid composition were found. The differences were not due to diet or hormonal status and could not be explained by the medication or cannabis use. No consistent pattern emerged from the different fatty acid abnormalities and the clinical symptom scores.

Elevated salivary dehydroepiandrosterone-sulfate but normal cortisol levels in medicated depressed patients: preliminary findings

Major depression is often associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. In contrast to cortisol, dehydroepiandrosterone-sulfate (DHEA-S) has been less extensively studied in depressed patients. This study examined salivary morning and evening levels of cortisol and DHEA-S in 13 medicated, unipolar, non-psychotic depressed patients and 13 healthy volunteers. Diurnal declines in cortisol and DHEA-S levels were found in both depressed and control groups. In patients compared with controls, DHEA-S was significantly elevated, in conjunction with normal cortisol levels. Based on DHEA-S at 22:00 h only, 77% of the subjects were correctly classified in a discriminant analysis as depressed or control. When simultaneously entered in a multiple regression analysis, DHEA-S (morning and evening) and cortisol (evening only) predicted symptom severity in depressed patients. These preliminary results suggest that DHEA-S may be a more sensitive indicator of depression and symptom severity than cortisol in medicated but still clinically depressed patients.

Therapygenetics in mindfulness-based cognitive therapy: do genes have an impact on therapy-induced change in real-life positive affective experiences?

Positive affect (PA) has an important role in resilience against depression and has been shown to increase with mindfulness-based cognitive therapy (MBCT). To elucidate the underlying mechanisms of change in PA as well as develop insights that may benefit personalized medicine, the current study examined the contribution of genetic variation to individual differences in change in PA in response to MBCT. Individuals (n=126) with residual depressive symptoms were randomized to either an MBCT group or treatment as usual. PA was assessed using experience sampling methodology (ESM). Single-nucleotide polymorphisms (SNPs) in genes known to be involved in reward functioning were selected. SNPs in the genes for brain-derived neurotrophic factor (BDNF), the muscarinic acetylcholine receptor M2 (CHRM2), the dopamine receptor D4 (DRD4) and the μ1 opioid receptor (OPRM1) significantly moderated the impact of treatment condition over time on PA. Genetic variation in the genes for CHRM2 and OPRM1 specifically had an impact on the level of PA following MBCT. The current study shows that variation in response to MBCT may be contingent on genetic factors associated with the regulation of PA. These findings contribute to our understanding of the processes moderating response to treatment and prediction of treatment outcome.

Effect of dehydroepiandrosterone supplementation on fatty acid and hormone levels in patients with X‐linked adrenoleucodystrophy

objective  In X‐linked adrenoleucodystrophy (X‐ALD) the peroxisomal β‐oxidation of saturated very long‐chain fatty acids (VLCFAs; carbon length > 22 atoms) is impaired. These fatty acids accumulate in blood and tissues, in particular in the nervous system, adrenal cortex and testis. Most patients have a primary adrenocortical insufficiency with low levels of cortisol and dehydroepiandrosterone (DHEA) and its sulphate ester (DHEA‐S), collectively called DHEA(S). Surprisingly, very low plasma levels of DHEA(S) may be found when plasma cortisol and ACTH levels are normal. In animal studies DHEA administration had a peroxisome proliferating effect and induced the expression of peroxisomal enzymes involved in the β‐oxidation of fatty acids.

Instrumental Assessment of Bradykinesia: A Comparison Between Motor Tasks

Bradykinesia, a common symptom in psychiatry, is characterized by reduced movement speed and amplitude. Monitoring for bradykinesia is important, as it has been associated with reductions in quality of life and medication compliance. Subtle forms of bradykinesia have been associated with treatment response in antipsychotic-naïve first episode patients. Therefore, accurate and reliable assessment is of clinical importance. Several mechanical and electronic instruments have been developed for this purpose. However, their content validity is limited. This study investigated which tasks, or combinations thereof, are most suitable for assessing bradykinesia instrumentally. Eleven motor tasks were assessed using inertial sensors. Their capability of distinguishing bradykinetic patients with schizophrenia (n = 6) from healthy controls (n = 5) was investigated. Seven tasks significantly discriminated patients from controls. The combination of tasks considered most feasible for the instrumental assessment of bradykinesia was the gait, pronation/supination, leg agility and flexion/extension of elbow tasks (effect size = 2.9).

Reliability and validity of an instrument for the assessment of bradykinesia

Bradykinesia is associated with reduced quality of life and medication non-compliance, and it may be a prodrome for schizophrenia. Therefore, screening/monitoring for subtle bradykinesia is of clinical and scientific importance. This study investigated the validity and reliability of such an instrument. Included were 70 patients with psychotic disorders. Inertial sensors captured mean cycle duration, amplitude and velocity of four movement tasks: walking, elbow flexion/extension, forearm pronation/supination and leg agility. The concurrent validity with the Unified Parkinsons Disease Rating Scale (UPDRS) bradykinesia subscale was determined using regression analysis. Reliability was investigated with the intra-class correlation coefficient. The duration, amplitude and velocities of the four tasks measured by the instrument explained 67% of the variance on the UPDRS bradykinesia subscale. The instrument test-retest reliability was high. The instrument investigated in this study is a valid and reliable alternative to observer-rated scales. It is an ideal tool for monitoring bradykinesia as it requires little training and experience to achieve reliable results.

The relation between depressive and obsessive-compulsive symptoms in obsessive-compulsive disorder: Results from a large, naturalistic follow-up study

OBJECTIVE Despite the frequent occurrence of depressive symptoms in obsessive-compulsive disorder (OCD), little is known about the reciprocal influence between depressive and obsessive-compulsive symptoms during the course of the disease. The aim of the present study is to investigate the longitudinal relationship between obsessive-compulsive and depressive symptoms in OCD patients. METHOD We used the baseline and 1-year follow-up data of the Netherlands Obsessive Compulsive Disorder Association (NOCDA) study. In 276 patients with a lifetime diagnosis of obsessive-compulsive disorder, depressive and obsessive-compulsive symptoms were assessed at baseline and at one-year follow-up with the Beck Depression Inventory (BDI) and the Yale-Brown Obsessive Compulsive Symptom (Y-BOCS) scale. Relations were investigated using a cross-lagged panel design. RESULTS The association between the severity of depressive symptoms at baseline and obsessive-compulsive symptoms at follow-up was significant (β=0.244, p<0.001), while the association between the severity of obsessive-compulsive symptoms at baseline and depressive symptoms at follow-up was not (β=0.097, p=0.060). Replication of the analyses in subgroups with and without current comorbid major depressive disorder (MDD) and subgroups with different sequence of onset (primary versus secondary MDD) revealed the same results. LIMITATIONS There may be other factors, which affect both depressive and obsessive-compulsive symptoms that were not assessed in the present study. CONCLUSION The present study demonstrates a relation between depressive symptoms and the course of obsessive-compulsive symptoms in OCD patients, irrespective of a current diagnosis of MDD and the sequence of onset of OCD and MDD.

No Evidence of Association between Childhood Urban Environment and Cortical Thinning in Psychotic Disorder.

Background The alterations in cortical morphology, such as cortical thinning, observed in psychotic disorder, may be the outcome of interacting genetic and environmental effects. It has been suggested that urban upbringing may represent a proxy environmental effect impacting cortical thickness (CT). Therefore, the current study examined whether the association between group as a proxy genetic variable (patients with psychotic disorder [high genetic risk], healthy siblings of patients [intermediate risk] and healthy control subjects [average risk]) and CT was conditional on different levels of the childhood urban environment and whether this was sex-dependent. Methods T1-weighted MRI scans were acquired from 89 patients with a psychotic disorder, 95 non-psychotic siblings of patients with psychotic disorder and 87 healthy control subjects. Freesurfer software was used to measure CT. Developmental urban exposure was classified as low, medium, and high, reflecting the population density and the number of moves between birth and the 15th birthday, using data from the Dutch Central Bureau of Statistics and the equivalent database in Belgium. Multilevel regression analyses were used to examine the association between group, sex, and urban upbringing (as well as their interactions) and cortical CT as the dependent variable. Results CT was significantly smaller in the patient group compared to the controls (B = -0.043, p <0.001), but not in the siblings compared to the controls (B = -0.013, p = 0.31). There was no main effect of developmental urbanicity on CT (B = 0.001, p = 0.91). Neither the three-way group × urbanicity × sex interaction (χ2 = 3.73, p = 0.16), nor the two-way group × urbanicity interaction was significant (χ2 = 0.51, p = 0.77). Conclusion The negative association between (familial risk for) psychotic disorder and CT was not moderated by developmental urbanicity, suggesting that reduced CT is not the outcome of familial sensitivity to the proxy environmental factor ‘urban upbringing’.

Behavioral pattern separation and its link to the neural mechanisms of fear generalization

Abstract Fear generalization is a prominent feature of anxiety disorders and post-traumatic stress disorder (PTSD). It is defined as enhanced fear responding to a stimulus that bears similarities, but is not identical to a threatening stimulus. Pattern separation, a hippocampal-dependent process, is critical for stimulus discrimination; it transforms similar experiences or events into non-overlapping representations. This study is the first in humans to investigate the extent to which fear generalization relies on behavioral pattern separation abilities. Participants (N = 46) completed a behavioral task taxing pattern separation, and a neuroimaging fear conditioning and generalization paradigm. Results show an association between lower behavioral pattern separation performance and increased generalization in shock expectancy scores, but not in fear ratings. Furthermore, lower behavioral pattern separation was associated with diminished recruitment of the subcallosal cortex during presentation of generalization stimuli. This region showed functional connectivity with the orbitofrontal cortex and ventromedial prefrontal cortex. Together, the data provide novel experimental evidence that pattern separation is related to generalization of threat expectancies, and reduced fear inhibition processes in frontal regions. Deficient pattern separation may be critical in overgeneralization and therefore may contribute to the pathophysiology of anxiety disorders and PTSD.