Johan Arends

HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia: a replication study.

In a previous study, we found an association between 5-hydroxytryptamine (serotonin) receptor 2C (HTR2C) polymorphisms and the occurrence of the metabolic syndrome in patients using antipsychotics. In the current study, we set out to replicate our findings in another sample of patients and to explore in a pooled analysis of both samples the influence of the effect of individual antipsychotics. Data for this cross-sectional study came from 2 different samples, the original sample (n = 112) and the replication sample (n = 164). Primary end point was the prevalence of the metabolic syndrome as classified by a modified version of the National Cholesterol Education Programs Adult Treatment Panel III. Primary determinants were polymorphisms in the promoter region of the HTR2C gene [HTR2C:c.1−142948(GT)n, rs3813929 (−759 C/T), and rs518147 (−697 G/C)] and an intragenic polymorphism (rs1414334:C>G). The variants of HTR2C:c.1−142948(GT)n (odds ratio [OR], 1.69; 95% confidence interval [CI], 0.75-3.81) and rs1414334 (OR, 2.35; 95% CI, 0.96-5.77) were not significantly associated with the metabolic syndrome in the replication sample but did show significance in the pooled analysis (OR, 2.09; 95% CI, 1.12-3.91; and OR, 2.35; 95% CI, 1.19-4.62, respectively). The variant rs1414334 C allele was specifically associated with the metabolic syndrome in patients using clozapine (OR, 9.20; 95% CI, 1.95-43.45) or risperidone (OR, 5.35; 95% CI, 1.26-22.83). This study extends previous findings to a larger sample of patients and implicates specific antipsychotic drugs. The increased risk for the metabolic syndrome is particularly strong in carriers of the rs1414334 C allele using clozapine or risperidone.

The association between HTR2C polymorphisms and obesity in psychiatric patients using antipsychotics: a cross-sectional study.

The use of antipsychotics is associated with an increased risk of obesity. This consideration makes it important to search for determinants that can predict the risk for antipsychotic-induced obesity. In this cross-sectional study, we investigated whether polymorphisms in the HTR2C gene were associated with obesity (body mass index >30 kg/m2) in patients using antipsychotics. We examined polymorphisms in the promoter region of the HTR2C gene ((HTR2C:c.1–142948(GT)n, rs3813928 (−997 G/A), rs3813929 (−759 C/T), rs518147 (−697 G/C)) and an intragenic polymorphism (rs1414334:C>G). The results of the logistic regression were expressed as adjusted odds ratios (OR). In total, we included 127 patients mainly diagnosed with schizophrenia or schizoaffective disorder (89%). The results indicate that a combined genotype carrying the variant HTR2C:c.1–142948(GT)n 13 repeat allele, the common allele rs3813929 C, the variant allele rs518147 C and the variant allele rs1414334 C is significantly related to an increased risk of obesity (OR 3.71 (95% confidence interval: 1.24–11.12)).

Association between HTR2C gene polymorphisms and the metabolic syndrome in patients using antipsychotics : a replication study

In two previous studies we found an association between HTR2C polymorphisms and the prevalence of the metabolic syndrome in patients using antipsychotics. In this study, we set out to replicate our findings in a third separate sample of patients. Data for this cross-sectional study came from the ongoing Pharmacotherapy Monitoring and Outcome survey study, investigating the association between schizophrenia and metabolic or cardiovascular risk factors. Primary end point was the prevalence of the metabolic syndrome. Primary determinants were two polymorphisms in the HTR2C gene: rs3813929 (−759 C/T) and rs1414334:C>G. Carriership of the variant rs1414334 C-allele was significantly associated with an increase prevalence of the metabolic syndrome (odds ratio (OR) 3.73; 95% confidence interval (CI) 1.29–10.79, P=0.015). No association was found between the HTR2C −759 C/T polymorphism and the metabolic syndrome. This study confirms previous findings that the variant C-allele of the rs1414334 polymorphism is associated with the metabolic syndrome.

Treatment of negative symptoms: Where do we stand, and where do we go?

Negative symptoms, e.g. social withdrawal, reduced initiative, anhedonia and affective flattening, are notoriously difficult to treat. In this review, we take stock of recent research into treatment of negative symptoms by summarizing psychosocial as well as pharmacological and other biological treatment strategies. Major psychosocial approaches concern social skills training, cognitive behavior therapy for psychosis, cognitive remediation and family intervention. Some positive findings have been reported, with the most robust improvements observed for social skills training. Although cognitive behavior therapy shows significant effects for negative symptoms as a secondary outcome measure, there is a lack of data to allow for definite conclusions of its effectiveness for patients with predominant negative symptoms. With regard to pharmacological interventions, antipsychotics have been shown to improve negative symptoms, but this seems to be limited to secondary negative symptoms in acute patients. It has also been suggested that antipsychotics may aggravate negative symptoms. Recent studies have investigated glutamatergic compounds, e.g. glycine receptor inhibitors and drugs that target the NMDA receptor or metabotropic glutamate 2/3 (mGlu2/3) receptor, but no consistent evidence of improvement of negative symptoms was found. Finally, some small studies have suggested improvement of negative symptoms after non-invasive electromagnetic neurostimulation, but this has only been partly replicated and it is still unclear whether these are robust improvements. We address methodological issues, in particular the heterogeneity of negative symptoms and treatment response, and suggest avenues for future research. There is a need for more detailed studies that focus on different dimensions of negative symptoms.

Practical Implications of Metacognitively Oriented Psychotherapy in Psychosis: Findings From a Pilot Study

Abstract In preparation for a multicenter randomized controlled trial, a pilot study was conducted investigating the feasibility and acceptance of a shortened version (12 vs. 40 sessions) of an individual metacognitive psychotherapy (Metacognitive Reflection and Insight Therapy [MERIT]). Twelve participants with a diagnosis of schizophrenia were offered 12 sessions of MERIT. Effect sizes were calculated for changes from baseline to treatment end for metacognitive capacity measured by the Metacognition Assessment Scale—Abbreviated. Nine of twelve patients finished treatment. However, nonsignificant moderate to large effect sizes were obtained on the primary outcome measure. This study is among the first to suggest that patients with schizophrenia will accept metacognitive therapy and evidence improvements in metacognitive capacity. Despite limitations typical to a pilot study, including a small sample size and lack of a control group, sufficient evidence of efficacy was obtained to warrant further investigation.

Association Between the 1291-C/G Polymorphism in the Adrenergic α-2a Receptor and the Metabolic Syndrome

The prevalence of the metabolic syndrome is increased in patients with schizophrenia compared with the general population. The strong interindividual differences in susceptibility to developing the metabolic syndrome suggests that the genetic makeup is a modulating factor. Part of the genetic puzzle can possibly be explained by variations in the gene coding for the adrenergic &agr;-2a receptor (ADRA2A) because this receptor plays an important role in lipolysis. Three studies have found an association between the &agr;-2a 1291-C/G polymorphism and antipsychotic induced weight gain, with conflicting results between whites and Asians. No studies have been published investigating the association between the 1291-C/G polymorphism and the metabolic syndrome. The primary objective of this cross-sectional study was to investigate the association between the ADRA2A 1291-C/G polymorphism and the metabolic syndrome in 470 patients using antipsychotic drugs. There was no significant association between carriership of the variant 1291-G allele and prevalence of the metabolic syndrome (odds ratio, 0.73; 95% confidence interval, 0.49-1.15). Exploratory analysis showed an association between carriership of the variant 1291-G allele and a reduced prevalence of the metabolic syndrome in patients not currently using antipsychotics (odds ratio, 0.05; 95% confidence interval, 0.003-0.97; P = 0.048). In conclusion, this study shows that the ADRA2A 1291-C/G polymorphism does not seem to be a strong predictor for long-term occurrence of the metabolic syndrome in antipsychotic using patients. Studies investigating this association using a prospective, or retrospective, design, as well as studies investigating this association in a nonpsychiatric population, are warranted.

Association between the ROBO1 gene and body mass index in patients using antipsychotics

Background Weight gain is one of the major problems in patients using antipsychotic medication, leading to relevant morbidities and reduced compliance to pharmacotherapy. Recently, an association has been reported between a single nucleotide polymorphism (rs1455832) of the roundabout axon guidance receptor, homolog 1 (ROBO1) gene and body mass index (BMI) in persons younger than 30 years. The aim of this study is to investigate the association between BMI and rs1455832 in patients with a psychotic disorder using antipsychotics. Methods A cross-sectional design was used in a pooled sample of Caucasian psychiatric patients obtained from three comparable Dutch psychiatric populations. Patients were eligible for inclusion in this study if they met the Diagnostic and Statistical Manual of Mental Disorders-IV criteria for a nonaffective psychotic disorder, were 18 years or older, and used one or more antipsychotics. Genotyping was performed according to standard protocols. Linear (for BMI) and logistic (for obesity, defined as BMI>30) regression analyses, corrected for age and sex, were applied in the statistical analyses. Results A total of 435 patients were included in this association analyses. The rs1455832 polymorphism studied was significantly associated with BMI and obesity in female patients. Female patients had a statistically significant (P=0.025) decrease of 1.76 kg/m2 in BMI values per C allele. In contrast to female patients, this association was not exhibited in male patients. Conclusion The rs1455832 polymorphism may play a role in inducing obesity in female patients using antipsychotics.

Metacognitive reflection and insight therapy (MERIT) for patients with schizophrenia

BACKGROUND Impaired metacognition is associated with difficulties in the daily functioning of people with psychosis. Metacognition can be divided into four domains: Self-Reflection, Understanding the Others Mind, Decentration, and Mastery. This study investigated whether Metacognitive Reflection and Insight Therapy (MERIT) can be used to improve metacognition. METHODS This study is a randomized controlled trial. Patients in the active condition (n = 35) received forty MERIT sessions, the control group (n = 35) received treatment as usual. Multilevel intention-to-treat and completers analyses were performed for metacognition and secondary outcomes (psychotic symptomatology, cognitive insight, Theory of Mind, empathy, depression, self-stigma, quality of life, social functioning, and work readiness). RESULTS Eighteen out of 35 participants finished treatment, half the drop-out stemmed from therapist attrition (N = 5) or before the first session (N = 4). Intention-to-treat analysis demonstrated that in both groups metacognition improved between pre- and post-measurements, with no significant differences between the groups. Patients who received MERIT continued to improve, while the control group returned to baseline, leading to significant differences at follow-up. Completers analysis (18/35) showed improvements on the Metacognition Assessment Scale (MAS-A) scales Self Reflectivity and metacognitive Mastery at follow-up. No effects were found on secondary outcomes. CONCLUSIONS On average, participants in the MERIT group were, based on MAS-A scores, at follow-up more likely to recognize their thoughts as changeable rather than as facts. MERIT might be useful for patients whose self-reflection is too limited to benefit from other therapies. Given how no changes were found in secondary measures, further research is needed. Limitations and suggestions for future research are discussed.

Towards a comprehensive routine outcome monitoring program for people with psychotic disorders : The Pharmacotherapy Monitoring and Outcome Survey (PHAMOUS)

BACKGROUND Patients with psychotic disorders are at risk of developing mental health and social problems, and physical disorders. To monitor and treat these problems when indicated, an annual routine outcome monitoring program, Pharmacotherapy Monitoring and Outcome Survey (PHAMOUS), was developed. This paper presents the background and content of PHAMOUS, implementation of PHAMOUS, characteristics of the patients screened in 2015, and the outcome of patients with three annual screenings between 2011 and 2015. METHODS PHAMOUS was implemented in four mental health institutions in the Northern Netherlands in 2006. During the PHAMOUS screening, patients are assessed on socio-demographics, psychiatric symptoms, medication, physical parameters, lifestyle, (psycho)social functioning and quality of life, using internationally validated instruments. RESULTS In 2015, 1955 patients with psychotic disorders were enrolled in the PHAMOUS screening. The majority (72%) was receiving mental healthcare for ten years or longer. A small group was hospitalized (10%) in the past year. Half of the patients were in symptomatic remission. Less than 10% had a paid job. More than half of the patients fulfilled the criteria for metabolic syndrome (54%). The subsample with three annual screenings from 2011 to 2015 (N = 1230) was stable, except the increasing prevalence of high glucose levels and satisfaction with social relationships (Cochrans Q = 16.33, p = .001 resp. Q = 14.79, p = .001). CONCLUSION The annual PHAMOUS screening enables to follow the mental, physical and social health problems of patients, which offers a good basis for shared-decision making with regard to updating the annual treatment plan, next to a wealth of data for scientific research.

F50. METACOGNITIVE REFLECTION AND INSIGHT THERAPY: A MULTICENTER RANDOMIZED CONTROLLED TRIAL

Abstract Background Difficulties in metacognition, or the ability to think about thinking and feeling, form an impediment to daily life functioning for persons with a psychotic disorder. In the past years, our research team has undertaken a multicenter, randomized controlled trial to investigate the efficacy of a new intervention designed to assist persons with a psychotic disorder to improve their metacognitive functioning (Metacognitive Reflection and Insight Therapy; MERIT). Methods After training thirteen therapists from seven mental healthcare institutes in the Netherlands, participants (n=70) with a DSM-IV-TR diagnosis of schizophrenia or schizoaffective disorder were included and randomized into either the MERIT condition or a treatment-as-usual condition. Persons randomized into the MERIT condition received 40 sessions of metacognitive psychotherapy, while persons in the control condition received care as usual. Measures of primary outcome (metacognition), secondary outcomes (empathy, depression, insight, stigma, social functioning, symptoms and quality of life) and control variables (neurocognition, premorbid IQ) were collected at baseline (pre), directly after therapy end (post) and at 6-month follow-up. After the follow-up measurement, research assistants were unblinded in order to conduct an interview with the participants regarding their experience of the therapy. Results Multilevel intention-to-treat and sensitivity analyses demonstrated that in both groups metacognition had improved, with no significant differences between the groups (χ2 (1)=0.435, p=.51). At 6-month follow-up, however, participants in the MERIT condition demonstrated they had continued to improve on metacognition, while scores from the control condition dipped back down (χ2 (1)=3.763, p=.05). Gains mainly seemed to be on metacognitive Self-Reflectivity (χ2 (1)=10.295, p=.001). No effects were found on secondary measures in either condition. Discussion During this presentation, we will discuss our findings and the therapy protocol, including a discussion of the clinical relevance of the current intervention, analysis of post-therapy interviews surrounding the participant’s experiences of the therapy, as well as practical limitations that were encountered during this five-year trial. Note S. de Jong (speaker) and R.J.M van Donkersgoed are early career scientists, expected to defend their dissertations in 2018.