Marise W.J. Machielsen

Polyunsaturated Fatty Acid Concentration Predicts Myelin Integrity in Early-Phase Psychosis

BACKGROUND White matter (WM) abnormalities have been implicated in schizophrenia, yet the mechanisms underlying these abnormalities are not fully understood. Several lines of evidence suggest that polyunsaturated fatty acids (PUFAs) play a role in myelination, and there is substantial evidence documenting decreased PUFA concentrations in schizophrenia. We therefore hypothesized that lower membrane PUFA concentrations may be related to reduced WM integrity in schizophrenia and related disorders. METHODS In 30 male patients with a recent-onset psychotic disorder, erythrocyte membrane PUFA concentrations were assessed and diffusion tensor imaging was performed with voxelwise analysis. RESULTS Lower total PUFA concentration was associated with lower fractional anisotropy (FA) throughout the corpus callosum and bilateral parietal, occipital, temporal and frontal WM (P < .05, corrected). Of the individual PUFAs, lower arachidonic acid concentration, and to a lesser extent, lower nervonic acid, linoleic acid, and docosapentaenoic acid concentration were significantly associated with lower FA. PUFA concentrations were inversely associated with radial diffusivity but showed little association with axial diffusivity. Greater severity of negative symptoms was associated with lower nervonic acid concentration and lower FA values. CONCLUSIONS Membrane PUFA concentrations appear to be robustly related to brain WM integrity in early phase psychosis. These findings may provide a basis for studies to investigate the effects of PUFA supplementation on WM integrity and associated symptomatology in early psychosis.

Cannabis Use in Patients with a First Psychotic Episode and Subjects at Ultra High Risk of Psychosis: Impact on Psychotic- and Pre-Psychotic Symptoms

Objectives: Co-morbidity with cannabis use disorder is common in patients with a psychotic disorder and is associated with adverse outcome. This study aimed to determine prevalence of cannabis use disorder among patients with a psychotic disorder and subjects at ultra high risk of psychosis and to study the influence of cannabis use on severity of (pre-)psychotic symptomatology, psychosocial functioning and variables related to the course of the disorder in these patients. Methods: In this study 169 consecutively assessed patients with a psychotic disorder were included as well as 59 consecutively assessed subjects at ultra high risk of psychosis. Results: 45% of the patients with a psychotic disorder and 27% of the UHR patients were diagnosed with a co-morbid cannabis use disorder. Patients with cannabis use disorders did not differ from patients without cannabis use disorder in severity of psychotic symptoms. However, excluding patients with substance use disorder other than cannabis use disorder resulted in higher scores on positive symptom levels for patients with cannabis use disorder compared to patients without any substance use disorder. Regarding ultra high risk patients, subjects with cannabis use disorder did not differ from subjects without cannabis use disorder on severity of pre-psychotic symptomatology. However, a negative correlation was found between the amount of cannabis used recently and scores on the pre-psychotic negative subscale. Conclusion: Our results suggest a specific association between cannabis abuse and psychotic symptomatology.

Differences in craving for cannabis between schizophrenia patients using risperidone, olanzapine or clozapine

Substance abuse and psychotic disorders have a high rate of comorbidity. Both disorders are associated with changes in the dopaminergic transmission in the mesocorticolimbic pathways of the brain. Since antipsychotic medications interact with the dopamine receptors in these pathways, these medications could affect craving for substances. In the current study, the effect of clozapine (n = 27, mean dosage 350 mg), risperidone (n = 54, mean dosage 3.46 mg) and olanzapine (n = 60, mean dosage 13.78 mg) on subjective craving for cannabis was compared in 123 patients with cannabis dependence and psychotic disorder. Patients treated with risperidone reported significantly more craving compared with patients treated with clozapine (Z = −3.19, p = .001) or olanzapine (Z = −2.24, p = .025). No significant differences in craving between clozapine and olanzapine were found. These results are in concordance with findings in the literature on this subject and could be explained by differences in three dopamine mediated mechanisms of these compounds: 1) occupancy rate of dopamine D2 receptors, 2) dissociation rate of dopamine D2 receptors, 3) D1/D2 occupancy ratio. Risperidone and clozapine show a maximal difference in D2 receptor occupancy rate, dissociation rate and D1/D2 ratio. Olanzapine is intermediate between risperidone and clozapine in these characteristics.

Obsessive-compulsive symptoms in patients with schizophrenia: a naturalistic cross-sectional study comparing treatment with clozapine, olanzapine, risperidone, and no antipsychotics in 543 patients.

OBJECTIVE To compare the prevalence of obsessive-compulsive symptoms (OCS) in a population of patients with schizophrenia taking clozapine, olanzapine, or risperidone or taking no antipsychotic medication. METHOD Baseline data of the Genetic Risk and Outcome of Psychosis study were collected between April 2005 and October 2008. We conducted a naturalistic cross-sectional study of 543 patients with schizophrenia and related disorders, who were recruited from multiple mental health centers, including inpatient and outpatient clinics, across The Netherlands. The patients met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and were taking no antipsychotic medication or taking clozapine, olanzapine, or risperidone. OCS severity was measured with the Yale-Brown Obsessive Compulsive Scale. We compared patients to a sample of 575 healthy controls. RESULTS Prevalence of OCS in patients was significantly higher than in the control sample, 23.4% versus 4.9% (χ(2) = 73.8, P < .001). Patients taking clozapine reported OCS significantly more often during the last week (38.9%), when compared to patients taking olanzapine (20.1%, χ(2) = 10.02, P = .002) or risperidone (23.2%, χ(2) = 5.96, P = .015) and patients taking no antipsychotics (19.6%, χ(2) = 8.20, P = .004). Patients taking clozapine for 6 months or longer reported OCS significantly more often than patients taking clozapine for less than 6 months, 47.3% versus 11.8% (χ(2) = 6.89, P = .009). CONCLUSIONS Treatment with clozapine in patients with schizophrenia is associated with a higher prevalence of OCS, especially when patients have been taking clozapine for 6 months or longer. We cannot rule out the possibility that this association is related to illness characteristics. Patients treated with risperidone or olanzapine or without treatment with antipsychotic medication had comparable prevalence of OCS, all significantly higher than the control sample.

Cannabis use in patients at clinical high risk of psychosis: impact on prodromal symptoms and transition to psychosis.

BACKGROUND The relation between cannabis use and psychotic disorders has been investigated extensively. A series of meta-analytic reviews reveal a robust association between cannabis use and the development of psychosis and schizophrenia. However, the actual impact of cannabis use in subjects at high clinical risk for psychosis (CHR) is still unclear. METHOD We conducted a systematic review of publications measuring the impact of cannabis use on CHR symptomatology and transition to a first psychotic episode. RESULTS Of 729 potentially relevant papers, 11 met inclusion criteria. The results of these studies were mixed. In some studies, cannabis use was associated with more severe symptoms at baseline, increased pre-psychotic symptoms immediately after intoxication, and earlier onset of certain high-risk symptoms. In others, no significant association between cannabis use and baseline symptomatology was found. In one study, cannabis use was even significantly associated with a decrease in pre-psychotic negative symptoms, and with fewer symptoms of depression and anxiety. Four out of 5 studies reported no significant effect of cannabis use on transition to psychosis. CONCLUSIONS Cannabis use seems to provoke and enhance subclinical symptoms in CHR subjects. However, the results provide no consistent evidence for an association between cannabis use and transition to a first psychosis in CHR subjects.

Grey Matter Changes Associated with Heavy Cannabis Use: A Longitudinal sMRI Study

Cannabis is the most frequently used illicit drug worldwide. Cross-sectional neuroimaging studies suggest that chronic cannabis exposure and the development of cannabis use disorders may affect brain morphology. However, cross-sectional studies cannot make a conclusive distinction between cause and consequence and longitudinal neuroimaging studies are lacking. In this prospective study we investigate whether continued cannabis use and higher levels of cannabis exposure in young adults are associated with grey matter reductions. Heavy cannabis users (N = 20, age baseline M = 20.5, SD = 2.1) and non-cannabis using healthy controls (N = 22, age baseline M = 21.6, SD = 2.45) underwent a comprehensive psychological assessment and a T1- structural MRI scan at baseline and 3 years follow-up. Grey matter volumes (orbitofrontal cortex, anterior cingulate cortex, insula, striatum, thalamus, amygdala, hippocampus and cerebellum) were estimated using the software package SPM (VBM-8 module). Continued cannabis use did not have an effect on GM volume change at follow-up. Cross-sectional analyses at baseline and follow-up revealed consistent negative correlations between cannabis related problems and cannabis use (in grams) and regional GM volume of the left hippocampus, amygdala and superior temporal gyrus. These results suggests that small GM volumes in the medial temporal lobe are a risk factor for heavy cannabis use or that the effect of cannabis on GM reductions is limited to adolescence with no further damage of continued use after early adulthood. Long-term prospective studies starting in early adolescence are needed to reach final conclusions.

The effect of clozapine and risperidone on attentional bias in patients with schizophrenia and a cannabis use disorder: An fMRI study

Cannabis use disorders (CUDs) are highly comorbid in patients with schizophrenia and are associated with poor outcome. Clozapine has been put forward as the first choice antipsychotic in this comorbid group. However, little is known about the mechanisms underlying the assumed superiority of clozapine. We compared the effects of clozapine and risperidone on attentional bias, subjective craving and associated regional brain activity in patients with schizophrenia and CUD. Overall, 36 patients with schizophrenia and 19 healthy controls were included. Patients were randomised to antipsychotic treatment with clozapine or risperidone. At baseline and after 4 weeks of medication use, regional brain responses were measured during a classical Stroop and a cannabis word Stroop using functional magnetic resonance imaging. Clozapine-treated CUD patients showed a larger reduction in craving and in activation of the insula during the cannabis word Stroop, while risperidone-treated patients showed a larger decrease in activation of the right anterior cingulate cortex during the classical Stroop. A significant association was found between decreases in subjective craving and decreases in insula activation during the cannabis word Stroop. These findings strongly suggest that clozapine may be a better treatment choice in patients with schizophrenia and CUD than risperidone.

Longitudinal study of hippocampal volumes in heavy cannabis users

Background: Cannabis exposure, particularly heavy cannabis use, has been associated with neuroanatomical alterations in regions rich with cannabinoid receptors such as the hippocampus in some but not in other (mainly cross-sectional) studies. However, it remains unclear whether continued heavy cannabis use alters hippocampal volume, and whether an earlier age of onset and/or a higher dosage exacerbate these changes. Methods: Twenty heavy cannabis users (mean age 21 years, range 18–24 years) and 23 matched non-cannabis using healthy controls were submitted to a comprehensive psychological assessment and magnetic resonance imaging scan at baseline and at follow-up (average of 39 months post-baseline; standard deviation=2.4). Cannabis users started smoking around 16 years and smoked on average five days per week. A novel aspect of the current study is that hippocampal volume estimates were obtained from manual tracing the hippocampus on T1-weighted anatomical magnetic resonance imaging scans, using a previously validated protocol. Results: Compared to controls, cannabis users did not show hippocampal volume alterations at either baseline or follow-up. Hippocampal volumes increased over time in both cannabis users and controls, following similar trajectories of increase. Cannabis dose and age of onset of cannabis use did not affect hippocampal volumes. Conclusions: Continued heavy cannabis use did not affect hippocampal neuroanatomical changes in early adulthood. This contrasts with prior evidence on alterations in this region in samples of older adult cannabis users. In young adults using cannabis at this level, cannabis use may not be heavy enough to affect hippocampal neuroanatomy.

Structural MRI Differences between Patients with and without First Rank Symptoms: A Delusion?

Objective It has been suggested that specific psychotic symptom clusters may be explained by patterns of biological abnormalities. The presence of first rank symptoms (FRS) has been associated with cognitive abnormalities, e.g., deficits in self-monitoring or in the experience of agency, suggesting that a specific network of neural abnormalities might underlie FRS. Here, we investigate differences in cortical and subcortical brain volume between patients with and without FRS. Methods Three independent patient samples (referred to as A, B, and C) with different mean ages and in different illness stages were included, leading to a total of 348 patients within the schizophrenia-spectrum. All underwent magnetic resonance imaging of the brain. In addition, the presence of FRS was established using a diagnostic interview. Patients with (FRS+, A: n = 63, B: n = 129, and C: n = 96) and without FRS (FRS−, A: n = 35, B: n = 17, and C: n = 8) were compared on global and local cortical volumes as well as subcortical volumes, using a whole brain (cerebrum) approach. Results Nucleus accumbens volume was significantly smaller in FRS+ as compared with FRS− in sample A (p < 0.005). Furthermore, FRS+ showed a smaller volume of the pars-opercularis relative to FRS− in sample B (p < 0.001). No further significant differences were found in cortical and subcortical volumes between FRS+ and FRS− in either one of the three samples after correction for multiple comparison. Conclusion Brain volume differences between patients with and without FRS are, when present, subtle, and not consistent between three independent samples. Brain abnormalities related to FRS may be too subtle to become visible through structural brain imaging.