Richard Bruggeman

Common variants conferring risk of schizophrenia

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the ‘genomic disorders’, have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

Deep Brain Stimulation in Tourette's Syndrome: Two Targets?

In this report, we describe the effects of bilateral thalamic stimulation in one patient and of bilateral pallidal stimulation in another patient. Both patients suffered from intractable Tourette’s syndrome (TS). Any conservative treatment had failed or had been stopped because of unbearable side effects in the 2 patients. In both cases, there was no comorbidity except for associated behavioral symptoms (compulsions). Electrodes were implanted at the level of the medial part of the thalamus (centromedian nucleus, the substantia periventricularis, and the nucleus ventro‐oralis internus) in one patient and in the posteroventral part of the globus pallidus internus (GPi) in the other patient. In both cases, deep brain stimulation (DBS) resulted in a substantial reduction of tics and compulsions. These data show that bilateral DBS of the thalamus as well as of the GPi can have a good effect on tics and behavioral symptoms in patients suffering from intractable TS.

A randomized open-label study of the impact of quetiapine versus risperidone on sexual functioning

Objective: To compare sexual functioning in patients treated with quetiapine or risperidone. Methods: This open-label study included patients with schizophrenia or a related psychotic illness who were randomized to quetiapine (200-1200 mg/d) or risperidone (1-6 mg/d) for 6 weeks. Sexual dysfunction was assessed by a semistructured interview, the Antipsychotics and Sexual Functioning Questionnaire (ASFQ), based upon the Utvalg for Kliniske Undersogelser (UKU). Results: Four of 25 quetiapine-treated patients (16%) and 12 of 24 risperidone-treated patients (50%) reported sexual dysfunction (χ 2 = 6.4; df = 1; P = 0.006) on the ASFQ. Six patients (11.7%; 4 on risperidone, 2 on quetiapine) spontaneously reported sexual dysfunction. The mean ± SD dose was 580 ± 224 mg/d for quetiapine and 3.2 ± 1.3 mg/d for risperidone. Mean ± SD prolactin levels in quetiapine- and risperidone-treated patients were 13.8 ± 17.9 and 57.7 ± 39.7 ng/mL, respectively. Conclusion: Sexual dysfunction was less common in patients treated with quetiapine than with risperidone. Direct questioning about sexual functioning is necessary to avoid underestimating the frequency of sexual side effects in patients with schizophrenia and related psychotic disorders.

Effects of bilateral repetitive transcranial magnetic stimulation on treatment resistant auditory-verbal hallucinations in schizophrenia: a randomized controlled trial.

BACKGROUND Neuroimaging findings implicate bilateral superior temporal regions in the genesis of auditory-verbal hallucinations (AVH). This study aimed to investigate whether 1 Hz repetitive transcranial magnetic stimulation (rTMS) of the bilateral temporo-parietal region would lead to increased effectiveness in the management of AVH, compared to left rTMS or placebo. METHODS 38 patients with schizophrenia (DSM-IV) and medication-resistant AVH were randomly assigned to 1 Hz rTMS treatment of the left temporo-parietal region, bilateral temporo-parietal regions, or placebo. Stimulation was conducted over 6 days, twice daily for 20 min, at 90% of the motor threshold. Effect measures included the Auditory Hallucination Rating Scale (AHRS), Positive and Negative Affect Scale (PANAS), and a score for hallucination severity obtained from the Positive and Negative Syndrome Scale (PANSS). RESULTS All groups showed some improvement on the total AHRS. Hallucination frequency was significantly reduced in the left rTMS group only. The bilateral rTMS group demonstrated the most remarkable reduction in self-reported affective responsiveness to AVH. A modest, but significant decrease on the PANSS hallucination item was observed in the combined rTMS treatment group, whereas no change occurred in the placebo group. The left rTMS group showed a significant reduction on the general psychopathology subscale. CONCLUSION Compared to bilateral or sham stimulation, rTMS of the left temporo-parietal region appears most effective in reducing auditory hallucinations, and additionally may have an effect on general psychopathology. Placebo effects should however not be ruled out, since sham stimulation also led to improvement on a number of AVH parameters.

Evidence that familial liability for psychosis is expressed as differential sensitivity to cannabis - an analysis of patient-sibling and sibling-control pairs

CONTEXT Individual differences in cannabis sensitivity may be associated with genetic risk for psychotic disorder. OBJECTIVES To demonstrate and replicate, using 2 conceptually different genetic epidemiological designs, that (familial) liability to psychosis is associated with sensitivity to cannabis. DESIGN, SETTING, AND PARTICIPANTS Sibling-control and cross-sibling comparisons using samples of patients with a psychotic disorder (n = 1120), their siblings (n = 1057), and community controls (n = 590) in the Netherlands and Flanders. MAIN OUTCOME MEASURES Positive and negative schizotypy using the Structured Interview for Schizotypy-Revised (for siblings and controls) and self-reported positive and negative psychotic experiences using the Community Assessment of Psychic Experiences (for siblings and patients). Cannabis use was assessed as current use (by urinalysis) and lifetime frequency of use (by Composite International Diagnostic Interview). RESULTS In the sibling-control comparison, siblings displayed more than 15 times greater sensitivity to positive schizotypy associated with particularly current cannabis use by urinalysis (adjusted B = 0.197, P < .001) than controls (adjusted B = 0.013, P = .86) (P interaction = .04) and a similar difference in sensitivity to its effect on negative schizotypy (siblings: adjusted B = 0.120, P < .001; controls: B = -0.008, P = .87; P interaction = .03). Similarly, siblings exposed to cannabis resembled their patient relative nearly 10 times more closely in the positive psychotic dimension of the Community Assessment of Psychic Experiences (adjusted B = 0.278, P < .001) compared with nonexposed siblings (adjusted B = 0.025, P = .12) (P interaction < .001). No significant effect was apparent for the Community Assessment of Psychic Experiences negative domain, although the association was directionally similar (2 times more resemblance; P interaction = .17). Cross-sibling, cross-trait analyses suggested that the mechanism underlying these findings was moderation (familial risk increasing sensitivity to cannabis) rather than mediation (familial risk increasing use of cannabis). CONCLUSIONS Genetic risk for psychotic disorder may be expressed in part as sensitivity to the psychotomimetic effect of cannabis. Cannabis use may synergistically combine with preexisting psychosis liability to cause positive and negative symptoms of psychosis.

The effectiveness of peer support groups in psychosis: a randomized controlled trial

Objective:  To investigate the effect of a (minimally) guided peer support group (GPSG) for people with psychosis on social network, social support, self‐efficacy, self‐esteem, and quality of life, and to evaluate the intervention and its economic consequences.

The detection of CMV pp65 and IE1 in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a highly lethal brain tumor affecting children and adults, with the majority of affected individuals dying from their disease by 2 years following diagnosis. Other groups have reported the association of cytomegalovirus (CMV) with GBM, and we sought to confirm these findings in a large series of patients with primary GBM from our institution. Immunohistochemical analysis of paraffin embedded tissue sections was performed on 49 newly diagnosed GBM tumors, the largest series reported to date. We confirmed the presence of CMV pp65 on 25/49 (51%) and of IE1 on 8/49 (16%) of these tumors. While pp65 and IE1 are generally found in the nucleus of cells that are permissibly infected by CMV, GBM in this series had mostly cytoplasmic staining, with only 16% having nuclear staining for one or both of these antigens. We infected GBM cell lines with a laboratory strain of CMV, and found that most of the staining was cytoplasmic, with some perinuclear localization of IE1. To test the potential for CMV infected GBM cells to be recognized by CMV pp65 and IE1 specific cytotoxic T lymphocytes (CTL), we used CMV infected GBM cell lines in cytotoxicity assays with human leukocyte antigen partially matched CMV CTL. Lysis of CMV infected GBM tumor cells was accentuated by pre-treating these cell lines with either the demethylating agent decitabine or interferon-γ, both of which were shown to increase MHC Class I and II expression on tumor cells in vitro. These studies confirm the presence of CMV pp65 or IE1 on approximately half of GBM, with the possibility that CMV positive tumor cells can be recognized by CMV pp65/IE1 specific T cells.

Neural correlates of alexithymia: A meta-analysis of emotion processing studies

Alexithymia is a personality trait characterized by difficulties in the experience and cognitive processing of emotions. It is considered a risk factor for a range of psychiatric and neurological disorders. Functional neuroimaging studies investigating the neural correlates of alexithymia have reported inconsistent results. To integrate previous findings, we conducted a parametric coordinate-based meta-analysis including fifteen neuroimaging studies on emotion processing in alexithymia. During the processing of negative emotional stimuli, alexithymia was associated with a diminished response of the amygdala, suggesting decreased attention to such stimuli. Negative stimuli additionally elicited decreased activation in supplementary motor and premotor brain areas and in the dorsomedial prefrontal cortex, possibly underlying poor empathic abilities and difficulties in emotion regulation associated with alexithymia. Positive stimuli elicited decreased activation in the right insula and precuneus, suggesting reduced emotional awareness in alexithymia regarding positive affect. Independent of valence, higher (presumably compensatory) activation was found in the dorsal anterior cingulate possibly indicating increased cognitive demand. These results suggest valence-specific as well as valence-independent effects of alexithymia on the neural processing of emotions.

Insight in Psychosis: Relationship With Neurocognition, Social Cognition and Clinical Symptoms Depends on Phase of Illness

Reduced insight has been reported in a majority of patients with a psychotic disorder. Most studies have focused on associations with neurocognition, neglecting relations with social cognition. Two hundred seventy patients with nonaffective psychosis participated in this study, which was part of the GROUP (Genetic Risk and OUtcome of Psychosis)-project. Linear regression analyses were performed to investigate the predictive value of composite measures of neurocognition, social cognition, and clinical symptoms. The moderating effect of phase of illness was also investigated. Insight was measured with a composite measure, based on the insight item on the Positive And Negative Syndrome Scale (PANSS) and the Birchwood Insight Scale (BIS). Insight on the BIS and the PANSS correlated significantly (r = .406). All independent variables correlated with the insight composite measure. The additional effect of social cognition and clinical symptoms were both significant. Phase of illness was a moderating variable: In patients with recent-onset psychosis (ROP), none of the independent variables explained variance. In patients with multiple episode or chronic psychosis, both social cognition and clinical symptoms had additional effects and explained insight, along with neurocognition, together explaining 20% of the variance. These findings indicate that multiple factors are associated with insight in psychosis. Specifically, associations of insight with social cognitive and clinical symptom measures were observed, over and above a contribution of neurocognition. This supports theories that imply a role for deficient emotion recognition and mentalizing in reduced insight. Further studies need to investigate insight in ROP into more detail.

A systematic review of instruments to measure depressive symptoms in patients with schizophrenia

BACKGROUND Depressive symptoms require accurate recognition and monitoring in clinical practice of patients with schizophrenia. Depression instruments developed for use in depressed patients may not discriminate depressive symptoms from negative psychotic symptoms. OBJECTIVE We reviewed depression instruments on their reliability and validity in patients with schizophrenia. METHODOLOGY A systematic literature search was carried out in three electronic databases. Psychometric properties were extracted for those instruments of which reliability, divergent, concurrent and predictive validity were reported in one or more publications. RESULTS Forty-eight publications described the reliability and validity of six depression instruments in patients with schizophrenia. The only self-report was the Beck Depression Inventory (BDI). The Brief Psychiatric Rating Scale-Depression subscale (BPRS-D), Positive and Negative Syndrome Scale-Depression subscale (PANSS-D), Hamilton Rating Scale for Depression (HAMD), Montgomery Asberg Depression Rating Scale (MADRS) and Calgary Depression Scale for Schizophrenia (CDSS) were clinician rated. All instruments were reliable for the measurement of depressive symptoms in patients with schizophrenia. The CDSS most accurately differentiated depressive symptoms from other symptoms of schizophrenia (divergent validity), correlated well with other depression instruments (concurrent validity), and was least likely to miss cases of depression or misdiagnose depression (predictive validity). CONCLUSIONS We would recommend to use the CDSS for the measurement of depressive symptoms in research and in daily clinical practice of patients with schizophrenia. A valid self-report instrument is to be developed for the use in clinical practice.