Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology

OBJECTIVE: Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines. METHODS: A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus. RESULTS: Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients. CONCLUSIONS: There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation

Evidence that duplications of 22q11.2 protect against schizophrenia.

A number of large, rare copy number variants (CNVs) are deleterious for neurodevelopmental disorders, but large, rare, protective CNVs have not been reported for such phenotypes. Here we show in a CNV analysis of 47 005 individuals, the largest CNV analysis of schizophrenia to date, that large duplications (1.5-3.0 Mb) at 22q11.2--the reciprocal of the well-known, risk-inducing deletion of this locus--are substantially less common in schizophrenia cases than in the general population (0.014% vs 0.085%, OR=0.17, P=0.00086). 22q11.2 duplications represent the first putative protective mutation for schizophrenia

Cannabis and cognitive performance in psychosis: a cross-sectional study in patients with non-affective psychotic illness and their unaffected siblings

The relationship between cannabis use and cognitive functioning in patients with psychosis has yielded contradictory findings. In individuals at genetic high risk for psychosis, information is sparse. The aim of this study was to assess the association between recency and frequency of cannabis use and cognitive functioning in patients with psychosis and their unaffected siblings.status: publishe

Analysis of auto-antibodies in psychotic disorder

OBJECTIVES: Antibodies against neuronal antigens such as N-methyl-D-aspartate receptor (NMDAr), and voltage gated potassium channel (VGKC) complexare present in various CNS excitability disorders, including cerebellar ataxia, encephalitis and epilepsy. Recently, an increasing number of reports indicatethat these types of antibodies are also seen in a subgroup of psychotic disorder patients. Yet, results of different research groups are inconsistent.We aimed to identify the presence of pathogenic autoantibodies targeting NMDAr and VGKC in sera of psychotic disorder and healthy individuals. METHODS: We analyzed the presence of NMDAr-autoantibodies of the IgG isotype in sera of 230 psychotic disorder patients and 293 controls. To this end we made use of an in-house cell based assay with HEK293 cells expressing GluN1 and GluN2B subunit of NMDAr. 120 schizophrenia patient sera were additionally screened for the presence of VGKC antibodies usingradio immuno assay (RIA) from DLDDiagnostika GmbH. Sera tested positive by RIA were subsequently retested with rat brain immunohistochemistry (IHC) and on cell based assay (CBA) of transfected HEK293 cells for the VGKC complex proteins leucine-rich glioma inactivated-1 (LGI-1) and contactin-associated protein-like 2 (CASPR2). RESULTS: No antibodies against the Nr1 subunit of the NMDAr were found in the sera of patients and controls. 4 patients were positive (>100 pmol/l) and 2 borderline positive (>50 pmol/l) for VGKC complex autoantibodies when tested by RIA. None of the positive screened sera could be confirmed as positive on rat brain IHC or CBA for CASPR2 and LGI-1. CONCLUSION: The results indicate that the presence of NMDAr-autoantibodies against Nr1 in the sera of patients with psychotic disorder is rare. Yet, we cannot rule out that these antibodies can only be detected in the cerebrospinal fluid of these patients.Autoantibodies against VGKC complex might be present in a small population of psychotic disorder patients. It has to be further investigated whether the indirect immunofluorescence is sensitive enough to detect autoantibodies in the serum or if the RIA could give false positive results.For a reliable diagnosis of patients it will be essential to improve the selectivity of the antibody detection assays as a solid basis for adequate immunosuppressive therapy.status: publishe

Evidence for genetic contribution to the increased risk of type 2 diabetes in schizophrenia.

The epidemiologic link between schizophrenia (SCZ) and type 2 diabetes (T2D) remains poorly understood. Here, we investigate the presence and extent of a shared genetic background between SCZ and T2D using genome-wide approaches. We performed a genome-wide association study (GWAS) and polygenic risk score analysis in a Greek sample collection (GOMAP) comprising three patient groups: SCZ only (n = 924), T2D only (n = 822), comorbid SCZ and T2D (n = 505); samples from two separate Greek cohorts were used as population-based controls (n = 1,125). We used genome-wide summary statistics from two large-scale GWAS of SCZ and T2D from the PGC and DIAGRAM consortia, respectively, to perform genetic overlap analyses, including a regional colocalisation test. We show for the first time that patients with comorbid SCZ and T2D have a higher genetic predisposition to both disorders compared to controls. We identify five genomic regions with evidence of colocalising SCZ and T2D signals, three of which contain known loci for both diseases. We also observe a significant excess of shared association signals between SCZ and T2D at nine out of ten investigated p value thresholds. Finally, we identify 29 genes associated with both T2D and SCZ, several of which have been implicated in biological processes relevant to these disorders. Together our results demonstrate that the observed comorbidity between SCZ and T2D is at least in part due to shared genetic mechanisms.Wellcome Trust (WT098051)

Neural correlates of reward processing in adults with 22q11 deletion syndrome

BACKGROUND: 22q11.2 deletion syndrome (22q11DS) is caused by a microdeletion on chromosome 22q11.2 and associated with an increased risk to develop psychosis. The gene coding for catechol-O-methyl-transferase (COMT) is located at the deleted region, resulting in disrupted dopaminergic neurotransmission in 22q11DS, which may contribute to the increased vulnerability for psychosis. A dysfunctional motivational reward system is considered one of the salient features in psychosis and thought to be related to abnormal dopaminergic neurotransmission. The functional anatomy of the brain reward circuitry has not yet been investigated in 22q11DS. METHODS: This study aims to investigate neural activity during anticipation of reward and loss in adult patients with 22q11DS. We measured blood-oxygen-level dependent (BOLD) activity in 16 patients with 22q11DS and 12 healthy controls during a monetary incentive delay task using a 3T Philips Intera MRI system. Data were analysed using SPM8. RESULTS: During anticipation of reward, the 22q11DS group alone displayed significant activation in bilateral middle frontal and temporal brain regions. Compared to healthy controls, significantly less activation in bilateral cingulate gyrus extending to premotor, primary motor and somatosensory areas was found. During anticipation of loss, the 22q11DS group displayed activity in the left middle frontal gyrus and anterior cingulate cortex, and relative to controls, they showed reduced brain activation in bilateral (pre)cuneus and left posterior cingulate. Within the 22q11DS group, COMT Val hemizygotes displayed more activation compared to Met hemizygotes in right posterior cingulate and bilateral parietal regions during anticipation of reward. During anticipation of loss, COMT Met hemizygotes compared to Val hemizygotes showed more activation in bilateral insula, striatum and left anterior cingulate. CONCLUSIONS: This is the first study to investigate reward processing in 22q11DS. Our preliminary results suggest that people with 22q11DS engage a fronto-temporal neural network. Compared to healthy controls, people with 22q11DS primarily displayed reduced activity in medial frontal regions during reward anticipation. COMT hemizygosity affects responsivity of the reward system in this condition. Alterations in reward processing partly underlain by the dopamine system may play a role in susceptibility for psychosis in 22q11DS