Prescription and Underprescription of Clozapine in Dutch Ambulatory Care

Purpose: To our knowledge, no study has examined in a structured way the extent of underprescription of clozapine in ambulatory patients with Non-Affective Psychotic Disorder (NAPD). In the Netherlands, psychiatric care for such patients is provided by Flexible Assertive Community Treatment (FACT) teams and by early intervention teams. In 20 FACT teams and 3 early intervention teams we assessed the proportion of patients who: use clozapine (type 1 patients), previously used this drug (type 2), have an unfulfilled indication for this drug, by type of indication (type 3), or were at least markedly psychotic, but had not yet received two adequate treatments with other antipsychotic drugs (type 4). We expected to find major differences between teams. To rule out that these differences are caused by differences in severity of psychopathology, we also calculated the proportions of patients who use clozapine given an indication at any time (number of type 1 patients divided by the sum of type 1, 2, and 3 patients). Materials and methods: The nurse practitioner of each team identified the patients already on clozapine. Next, using a highly-structured decision tree, the nurse practitioner and psychiatrist assessed whether the remaining patients had an indication for this drug. Indications were treatment-resistant positive symptoms, tardive dyskinesia, aggression and suicidality. The severity of positive symptoms was determined using the Clinical Global Impression-Schizophrenia Scale (CGI-SCH). Results: In the participating FACT-teams 2,286 NAPD patients were assessed. The range among teams in proportions was: type 1: 8.8-34.7% (mean: 23.0%), type 2: 0-8.2% (mean: 3.5%), type 3: 1.7-15.6% (mean: 6.9%), type 4: 1.8-16.3% (mean: 8.6%). The range in proportions of patients using this drug given an indication was 49.0-90.9% (mean: 68.8%). These figures were lower in early intervention teams. Conclusions: The proportion of patients in FACT-teams who have an unfulfilled indication for clozapine is 6.9%. There were considerable differences between teams with respect to this proportion. Almost a third of the outpatients had at any time an indication for clozapine. If one takes type 4 patients into account, this proportion may be higher

Raloxifene augmentation in men and women with a schizophrenia spectrum disorder:A study protocol

Although acute psychotic symptoms are often reduced by antipsychotic treatment, many patients with schizophrenia are impaired in daily functioning due to the persistence of negative and cognitive symptoms. Raloxifene, a Selective Estrogen Receptor Modulator (SERM) has been shown to be an effective adjunctive treatment in schizophrenia. Yet, there is a paucity in evidence for raloxifene efficacy in men and premenopausal women. We report the design of a study that aims to replicate earlier findings concerning the efficacy of raloxifene augmentation in reducing persisting symptoms and cognitive impairment in postmenopausal women, and to extend these findings to a male and peri/premenopausal population of patients with schizophrenia. The study is a multisite, placebo-controlled, double-blind, randomised clinical trial in approximately 110 adult men and women with schizophrenia. Participants are randomised 1:1 to adjunctive raloxifene 120 mg or placebo daily during 12 weeks. The treatment phase includes measurements at three time points (week 0, 6 and 12), followed by a follow-up period of two years. The primary outcome measure is change in symptom severity, as measured with the Positive and Negative Syndrome Scale (PANSS), and cognition, as measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Secondary outcome measures include social functioning and quality of life. Genetic, hormonal and inflammatory biomarkers are measured to assess potential associations with treatment effects. If it becomes apparent that raloxifene reduces psychotic symptoms and/or improves cognition, social functioning and/or quality of life as compared to placebo, implementation of raloxifene in clinical psychiatric practice can be considered

The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder

Background: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects. Methods: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects. Results: FDRs-BD had significantly larger ICV (d = +0.16, q <.05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = −0.12, q <.05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < −0.09, q <.05 corrected); and third ventricle was larger (d = +0.15, q <.05 corrected). The findings were not explained by psychopathology in the relatives or control subjects. Conclusions: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct

The Direct and Long-Term Effects of Raloxifene as Adjunctive Treatment for Schizophrenia-Spectrum Disorders:A Double-Blind, Randomized Clinical Trial

Background and hypothesis: Several studies suggest that raloxifene, a selective estrogen receptor modulator, improves symptoms and cognition in post-menopausal women with Schizophrenia-Spectrum Disorders (SSD). We aimed to assess the effects of adjunctive raloxifene in women and men with SSD.Study design: This parallel, randomized, double-blind, placebo-controlled trial included adult SSD patients across the Netherlands and Belgium. Participants were stratified by age, sex, and global functioning and randomly assigned 1:1 to 12-week add-on raloxifene or placebo. Primary outcomes were symptom severity at 6, 12, and 38 weeks and cognition at 12 and 38 weeks, as measured with the Positive and Negative Syndrome Scale and the Brief Assessment of Cognition in Schizophrenia, respectively. Intention-to-treat analyses were performed using linear mixed-effect models.Study results: We assessed 261 patients for eligibility, of which 102 (28% female) were assigned to raloxifene (n = 52) or placebo (n = 48). Although we found no main effect of raloxifene, secondary sex-specific analysis showed that in women, raloxifene had beneficial effects on negative symptoms at week 6 (LSM -2.92; adjusted P = 0.020) and week 12 (LSM -3.12; adjusted P = 0.030), and on working memory at week 38 (LSM 0.73; adjusted P = 0.040), while having negative effects on working memory at week 38 in men (LSM -0.53; adjusted P = 0.026). The number of adverse events was similar between groups.Conclusions: Our results do not support the use of raloxifene in patients with SSD in general, but suggest female-specific beneficial effects of raloxifene on negative symptoms and working memory. Our findings encourage further research on sex-specific pharmacotherapeutic treatment.</p

The Direct and Long-Term Effects of Raloxifene as Adjunctive Treatment for Schizophrenia-Spectrum Disorders:A Double-Blind, Randomized Clinical Trial

Background and hypothesis: Several studies suggest that raloxifene, a selective estrogen receptor modulator, improves symptoms and cognition in post-menopausal women with Schizophrenia-Spectrum Disorders (SSD). We aimed to assess the effects of adjunctive raloxifene in women and men with SSD.Study design: This parallel, randomized, double-blind, placebo-controlled trial included adult SSD patients across the Netherlands and Belgium. Participants were stratified by age, sex, and global functioning and randomly assigned 1:1 to 12-week add-on raloxifene or placebo. Primary outcomes were symptom severity at 6, 12, and 38 weeks and cognition at 12 and 38 weeks, as measured with the Positive and Negative Syndrome Scale and the Brief Assessment of Cognition in Schizophrenia, respectively. Intention-to-treat analyses were performed using linear mixed-effect models.Study results: We assessed 261 patients for eligibility, of which 102 (28% female) were assigned to raloxifene (n = 52) or placebo (n = 48). Although we found no main effect of raloxifene, secondary sex-specific analysis showed that in women, raloxifene had beneficial effects on negative symptoms at week 6 (LSM -2.92; adjusted P = 0.020) and week 12 (LSM -3.12; adjusted P = 0.030), and on working memory at week 38 (LSM 0.73; adjusted P = 0.040), while having negative effects on working memory at week 38 in men (LSM -0.53; adjusted P = 0.026). The number of adverse events was similar between groups.Conclusions: Our results do not support the use of raloxifene in patients with SSD in general, but suggest female-specific beneficial effects of raloxifene on negative symptoms and working memory. Our findings encourage further research on sex-specific pharmacotherapeutic treatment.</p

Prescription and Underprescription of Clozapine in Dutch Ambulatory Care

Purpose: To our knowledge, no study has examined in a structured way the extent of underprescription of clozapine in ambulatory patients with Non-Affective Psychotic Disorder (NAPD). In the Netherlands, psychiatric care for such patients is provided by Flexible Assertive Community Treatment (FACT) teams and by early intervention teams. In 20 FACT teams and 3 early intervention teams we assessed the proportion of patients who: use clozapine (type 1 patients), previously used this drug (type 2), have an unfulfilled indication for this drug, by type of indication (type 3), or were at least markedly psychotic, but had not yet received two adequate treatments with other antipsychotic drugs (type 4). We expected to find major differences between teams. To rule out that these differences are caused by differences in severity of psychopathology, we also calculated the proportions of patients who use clozapine given an indication at any time (number of type 1 patients divided by the sum of type 1, 2, and 3 patients).Materials and methods: The nurse practitioner of each team identified the patients already on clozapine. Next, using a highly-structured decision tree, the nurse practitioner and psychiatrist assessed whether the remaining patients had an indication for this drug. Indications were treatment-resistant positive symptoms, tardive dyskinesia, aggression and suicidality. The severity of positive symptoms was determined using the Clinical Global Impression-Schizophrenia Scale (CGI-SCH).Results: In the participating FACT-teams 2,286 NAPD patients were assessed. The range among teams in proportions was: type 1: 8.8–34.7% (mean: 23.0%), type 2: 0–8.2% (mean: 3.5%), type 3: 1.7–15.6% (mean: 6.9%), type 4: 1.8–16.3% (mean: 8.6%). The range in proportions of patients using this drug given an indication was 49.0–90.9% (mean: 68.8%). These figures were lower in early intervention teams.Conclusions: The proportion of patients in FACT-teams who have an unfulfilled indication for clozapine is 6.9%. There were considerable differences between teams with respect to this proportion. Almost a third of the outpatients had at any time an indication for clozapine. If one takes type 4 patients into account, this proportion may be higher.Registration number: NTR5135 http://www.trialregister.nl/trialreg/index.as

Emotional and non-emotional mental imagery and auditory verbal hallucinations (hearing voices): a systematic review of imagery assessment tools

It is unknown to what extent mental imagery and auditory verbal hallucinations (AVHs) are related. Trials evaluating this issue used both emotional and non-emotional mental imagery tools, thereby complicating outcomes comparisons. Therefore, the present study aimed to systematically review the literature on mental imagery in individuals with AVHs to (1) inventory imagery assessment tools used in this population, (2) to collect information on the relation between emotional and non-emotional mental imagery in all sensory domains and AVHs and (3) to integrate the outcomes of this systematic review in a model of different mental imagery domains and related assessment tools. We conducted a systematic literature search in the PubMed Database. After full-text screening, 17 papers were included. Findings showed that a variety of assessment methods have been used to assess various aspects of mental imagery in people with AVHs, suggesting that there is a lack of agreed theoretical conceptualization of mental imagery and AVHs. In addition, the studies confirmed as was expected that non-emotional mental imagery seemed unrelated to AVHs whereas emotional mental imagery was related to AVHs. Lastly, we proposed a model of mental imagery domains and corresponding assessment methods distinguishing between emotional and non-emotional mental imagery

Default Mode Network Connectivity as a Function of Familial and Environmental Risk for Psychotic Disorder

Research suggests that altered interregional connectivity in specific networks, such as the default mode network (DMN), is associated with cognitive and psychotic symptoms in schizophrenia. In addition, frontal and limbic connectivity alterations have been associated with trauma, drug use and urban upbringing, though these environmental exposures have never been examined in relation to DMN functional connectivity in psychotic disorder.Resting-state functional MRI scans were obtained from 73 patients with psychotic disorder, 83 non-psychotic siblings of patients with psychotic disorder and 72 healthy controls. Posterior cingulate cortex (PCC) seed-based correlation analysis was used to estimate functional connectivity within the DMN. DMN functional connectivity was examined in relation to group (familial risk), group × environmental exposure (to cannabis, developmental trauma and urbanicity) and symptomatology.There was a significant association between group and PCC connectivity with the inferior parietal lobule (IPL), the precuneus (PCu) and the medial prefrontal cortex (MPFC). Compared to controls, patients and siblings had increased PCC connectivity with the IPL, PCu and MPFC. In the IPL and PCu, the functional connectivity of siblings was intermediate to that of controls and patients. No significant associations were found between DMN connectivity and (subclinical) psychotic/cognitive symptoms. In addition, there were no significant interactions between group and environmental exposures in the model of PCC functional connectivity.Increased functional connectivity in individuals with (increased risk for) psychotic disorder may reflect trait-related network alterations. The within-network "connectivity at rest" intermediate phenotype was not associated with (subclinical) psychotic or cognitive symptoms. The association between familial risk and DMN connectivity was not conditional on environmental exposure