Matteo Rocchetti

Treatments of Negative Symptoms in Schizophrenia: Meta-Analysis of 168 Randomized Placebo-Controlled Trials

OBJECTIVES Existing treatments for schizophrenia can improve positive symptoms, but it is unclear if they have any impact on negative symptoms. This meta-analysis was conducted to assess the efficacy of available treatments for negative symptoms in schizophrenia. METHODS All randomized-controlled trials of interventions for negative symptoms in schizophrenia until December 2013 were retrieved; 168 unique and independent placebo-controlled trials were used. Negative symptom scores at baseline and follow-up, duration of illness, doses of medication, type of interventions, and sample demographics were extracted. Heterogeneity was addressed with the I (2) and Q statistic. Standardized mean difference in values of the Negative Symptom Rating Scale used in each study was calculated as the main outcome measure. RESULTS 6503 patients in the treatment arm and 5815 patients in the placebo arm were included. No evidence of publication biases found. Most treatments reduced negative symptoms at follow-up relative to placebo: second-generation antipsychotics: -0.579 (-0.755 to -0.404); antidepressants: -0.349 (-0.551 to -0.146); combinations of pharmacological agents: -0.518 (-0.757 to -0.279); glutamatergic medications: -0.289 (-0.478 to -0.1); psychological interventions: -0.396 (-0.563 to -0.229). No significant effect was found for first-generation antipsychotics: -0.531 (-1.104 to 0.041) and brain stimulation: -0.228 (-0.775 to 0.319). Effects of most treatments were not clinically meaningful as measured on Clinical Global Impression Severity Scale. CONCLUSIONS AND RELEVANCE Although some statistically significant effects on negative symptoms were evident, none reached the threshold for clinically significant improvement.

Antipsychotics' effects on blood levels of cytokines in schizophrenia: a meta-analysis.

OBJECTIVES Evidence-based medicine suggests that schizophrenia is associated with an inflammatory syndrome, but the extent to which this syndrome is normalized by antipsychotic treatment has yet to be determined. METHODS A systematic quantitative review of the effects of antipsychotics on peripheral cytokine levels in schizophrenia was performed, using follow-up studies providing in vivo cytokine assessments before and after treatment. RESULTS We retrieved 23 studies (total of 762 subjects) which showed that antipsychotic treatment significantly increases plasma levels of soluble interleukin-2 receptor and reduces the plasma levels of interleukin-1β and interferon-γ. CONCLUSIONS These results show that antipsychotics produce anti-inflammatory effects in schizophrenia.

Prevalence of self-reported childhood abuse in psychosis: a meta-analysis of retrospective studies

There is extensive clinical literature reporting traumatic childhood experiences in patients with psychosis. A quantitative meta-analysis addressing the prevalence of self-reported childhood sexual (CSA), physical (CPA) and emotional abuse (CEA) in psychotic patients has yet to be done. We conducted, a systematic literature search to identify retrospective studies addressing self-reported childhood abuse in patients with DSM/ICD psychosis. Demographic, clinical, and methodological variables were extracted from each publication, or obtained directly from its authors. Quantitative meta-analysis of CSA, CPA, CEA in the sample of patients was performed. Statistical heterogeneity and publication bias were assessed and meta-regressions performed to control for different moderators. Twenty-three studies were retrieved and included a total of 2017 psychotic patients. The prevalence of self-reported CSA, CPA, CEA were respectively of 26%, 39% and 34%. Age, publication year, gender and substance abuse moderated CSA, while age, clinical setting and substance abuse moderated CPA. Results indicated that CEA was moderated by gender and publication year of the study. According to our meta-analysis, psychotic patients have a consistently high self-report of childhood traumatic events which are sexual, physical and emotional in nature. It is our opinion that clinicians should be trained and skilled to carefully investigate childhood abuse in psychosis.

Is cannabis neurotoxic for the healthy brain? A meta-analytical review of structural brain alterations in non-psychotic users

Despite growing research in the field of cannabis imaging, mostly in those with a psychotic illness, the possible neurotoxic effects of smoked cannabis on the healthy brain have yet to be fully understood. There appears to be a need to evaluate the existing imaging data on the neuroanatomical effects of cannabis use on non‐psychotic populations.

Peripheral oxytocin and vasopressin: Biomarkers of psychiatric disorders? A comprehensive systematic review and preliminary meta-analysis

A large array of studies have investigated peripheral oxytocin (OT) and vasopressin (ADH) as potential biomarkers of psychiatric disorders, with highly conflicting and heterogenous findings. We searched Web of KnowledgeSM and Scopus® for English original articles investigating OT and/or ADH levels in different biological fluids (plasma/serum, saliva, urine and cerebrospinal fluid) across several psychiatric disorders. Sixty-four studies were included. We conducted 19 preliminary meta-analyses addressing OT alterations in plasma/serum, saliva, urine and cerebrospinal fluid of 7 psychiatric disorders and ADH alterations in plasma/serum, saliva, urine and cerebrospinal fluid of 6 psychiatric disorders compared to controls. Hedges g was used as effect size measure, together with heterogeneity analyses, test of publication biases and quality control. None of them (except serum OT in anorexia nervosa) revealed significant differences. There is no convincing evidence that peripheral ADH or OT might be reliable biomarkers in psychiatric disorders. However, the lack of significant results was associated with high methodological heterogeneity, low quality of the studies, small sample size, and scarce reliability of the methods used in previous studies, which need to be validated and standardized.

Persistence or recurrence of non-psychotic comorbid mental disorders associated with 6-year poor functional outcomes in patients at ultra high risk for psychosis

BACKGROUND Patients at ultra-high risk for psychosis (UHR) are a highly heterogeneous group in terms of clinical and functional outcomes. Several non-psychotic mental disorders co-occur together with the UHR state. Little is known about the impact of non-psychotic comorbid mental disorders on clinical and functional outcomes of UHR patients. METHODS The sample included 154 UHR help-seeking patients (identified with the CAARMS, comprehensive assessment of the at-risk mental state), evaluated at baseline on the Ham-D, Ham-A (Hamilton depression/anxiety rating scale), and PANSS (positive and negative syndrome scale). 74 patients completed the 6-year follow-up assessment (mean=6.19, SD=1.87). Comorbid disorders at follow-up were assessed with the SCID I and II. Global functioning was rated on the global assessment of functioning (GAF) scale. RESULTS In the present sample, 6-year risk of psychosis transition was 28.4%. Among non-transitioned UHR patients, 28.3% reported attenuated psychotic symptoms (APS) and 45.3% remained functionally impaired at follow-up (GAF<60). 56.8% patients were affected by at least one comorbid disorder at follow-up. Among UHR patients who presented with some comorbid disorder at baseline, 61.5% had persistent or recurrent course. Incident comorbid disorders emerged in 45.4% of baseline UHR patients. The persistence or recurrence of non-psychotic comorbid mental disorders was associated with poorer global functional outcomes at follow-up. LIMITATIONS A substantial proportion of the initial sample was not available for follow-up interviews and some groups in the analyses had small sample size. Predictors of longitudinal outcomes were not explored. CONCLUSIONS Among UHR patients, persistence or recurrence of non-psychotic comorbid mental disorders, mostly affective disorders, is associated with 6-year poor functional outcomes.

Towards a Standard Psychometric Diagnostic Interview for Subjects at Ultra High Risk of Psychosis: CAARMS versus SIPS

Background. Several psychometric instruments are available for the diagnostic interview of subjects at ultra high risk (UHR) of psychosis. Their diagnostic comparability is unknown. Methods. All referrals to the OASIS (London) or CAMEO (Cambridgeshire) UHR services from May 13 to Dec 14 were interviewed for a UHR state using both the CAARMS 12/2006 and the SIPS 5.0. Percent overall agreement, kappa, the McNemar-Bowker χ 2 test, equipercentile methods, and residual analyses were used to investigate diagnostic outcomes and symptoms severity or frequency. A conversion algorithm (CONVERT) was validated in an independent UHR sample from the Seoul Youth Clinic (Seoul). Results. There was overall substantial CAARMS-versus-SIPS agreement in the identification of UHR subjects (n = 212, percent overall agreement = 86%; kappa = 0.781, 95% CI from 0.684 to 0.878; McNemar-Bowker test = 0.069), with the exception of the brief limited intermittent psychotic symptoms (BLIPS) subgroup. Equipercentile-linking table linked symptoms severity and frequency across the CAARMS and SIPS. The conversion algorithm was validated in 93 UHR subjects, showing excellent diagnostic accuracy (CAARMS to SIPS: ROC area 0.929; SIPS to CAARMS: ROC area 0.903). Conclusions. This study provides initial comparability data between CAARMS and SIPS and will inform ongoing multicentre studies and clinical guidelines for the UHR psychometric diagnostic interview.

Improving prognostic accuracy in subjects at clinical high risk for psychosis: systematic review of predictive models and meta-analytical sequential testing simulation

Abstract Discriminating subjects at clinical high risk (CHR) for psychosis who will develop psychosis from those who will not is a prerequisite for preventive treatments. However, it is not yet possible to make any personalized prediction of psychosis onset relying only on the initial clinical baseline assessment. Here, we first present a systematic review of prognostic accuracy parameters of predictive modeling studies using clinical, biological, neurocognitive, environmental, and combinations of predictors. In a second step, we performed statistical simulations to test different probabilistic sequential 3-stage testing strategies aimed at improving prognostic accuracy on top of the clinical baseline assessment. The systematic review revealed that the best environmental predictive model yielded a modest positive predictive value (PPV) (63%). Conversely, the best predictive models in other domains (clinical, biological, neurocognitive, and combined models) yielded PPVs of above 82%. Using only data from validated models, 3-stage simulations showed that the highest PPV was achieved by sequentially using a combined (clinical + electroencephalography), then structural magnetic resonance imaging and then a blood markers model. Specifically, PPV was estimated to be 98% (number needed to treat, NNT = 2) for an individual with 3 positive sequential tests, 71%–82% (NNT = 3) with 2 positive tests, 12%–21% (NNT = 11–18) with 1 positive test, and 1% (NNT = 219) for an individual with no positive tests. This work suggests that sequentially testing CHR subjects with predictive models across multiple domains may substantially improve psychosis prediction following the initial CHR assessment. Multistage sequential testing may allow individual risk stratification of CHR individuals and optimize the prediction of psychosis.

Neurofunctional maps of the 'maternal brain' and the effects of oxytocin: a multimodal voxel-based meta-analysis.

Several studies have tried to understand the possible neurobiological basis of mothering. The putative involvement of oxytocin, in this regard, has been deeply investigated. Performing a voxel‐based meta‐analysis, we aimed at testing the hypothesis of overlapping brain activation in functional magnetic resonance imaging (fMRI) studies investigating the mother–infant interaction and the oxytocin modulation of emotional stimuli in humans. We performed two systematic literature searches: fMRI studies investigating the neurofunctional correlates of the ‘maternal brain’ by employing mother–infant paradigms; and fMRI studies employing oxytocin during emotional tasks. A unimodal voxel‐based meta‐analysis was performed on each database, whereas a multimodal voxel‐based meta‐analytical tool was adopted to assess the hypothesis that the neurofunctional effects of oxytocin are detected in brain areas implicated in the ‘maternal brain.’ We found greater activation in the bilateral insula extending to the inferior frontal gyrus, basal ganglia and thalamus during mother–infant interaction and greater left insular activation associated with oxytocin administration versus placebo. Left insula extending to basal ganglia and frontotemporal gyri as well as bilateral thalamus and amygdala showed consistent activation across the two paradigms. Right insula also showed activation across the two paradigms, and dorsomedial frontal cortex activation in mothers but deactivation with oxytocin. Significant activation in areas involved in empathy, emotion regulation, motivation, social cognition and theory of mind emerged from our multimodal meta‐analysis, supporting the need for further studies directly investigating the neurobiology of oxytocin in the mother–infant relationship.

Neurofunctional maps of the "maternal brain" and the effects of oxytocin

Several studies have tried to understand the possible neurobiological basis of mothering. The putative involvement of oxytocin, in this regard, has been deeply investigated. Performing a voxel‐based meta‐analysis, we aimed at testing the hypothesis of overlapping brain activation in functional magnetic resonance imaging (fMRI) studies investigating the mother–infant interaction and the oxytocin modulation of emotional stimuli in humans. We performed two systematic literature searches: fMRI studies investigating the neurofunctional correlates of the ‘maternal brain’ by employing mother–infant paradigms; and fMRI studies employing oxytocin during emotional tasks. A unimodal voxel‐based meta‐analysis was performed on each database, whereas a multimodal voxel‐based meta‐analytical tool was adopted to assess the hypothesis that the neurofunctional effects of oxytocin are detected in brain areas implicated in the ‘maternal brain.’ We found greater activation in the bilateral insula extending to the inferior frontal gyrus, basal ganglia and thalamus during mother–infant interaction and greater left insular activation associated with oxytocin administration versus placebo. Left insula extending to basal ganglia and frontotemporal gyri as well as bilateral thalamus and amygdala showed consistent activation across the two paradigms. Right insula also showed activation across the two paradigms, and dorsomedial frontal cortex activation in mothers but deactivation with oxytocin. Significant activation in areas involved in empathy, emotion regulation, motivation, social cognition and theory of mind emerged from our multimodal meta‐analysis, supporting the need for further studies directly investigating the neurobiology of oxytocin in the mother–infant relationship.