Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age

Many women with schizophrenia remain symptomatic despite optimal use of current therapies. While previous studies suggest that adjunctive oestrogen therapy might be effective, large-scale clinical trials are required before clinical applications are possible. This study is the first large-scale randomized-controlled trial in women with treatment-resistant schizophrenia. This Definitive Oestrogen Patch Trial was an 8-week, three-arm, double-blind, randomized-controlled trial conducted between 2006 and 2011. The 183 female participants were aged between 18 and 45 (mean=35 years), with schizophrenia or schizoaffective disorder and ongoing symptoms of psychosis (Positive and Negative Syndrome Scale, PANSS score>60) despite a stable dose of antipsychotic medication for at least 4 weeks. Mean duration of illness was more than 10 years. Participants received transdermal estradiol 200 μg, transdermal estradiol 100 μg or an identical placebo patch. For the 180 women who completed the study, the a priori outcome measure was the change in PANSS score measured at baseline and days 7, 14, 28 and 56. Cognition was assessed at baseline and day 56 using the Repeatable Battery of Neuropsychological Status. Data were analysed using latent growth curve modelling. Both estradiol groups had greater decreases in PANSS positive, general and total symptoms compared with the placebo group (P<0.01), with a greater effect seen for 200 μg than 100 μg estradiol. The largest effect size was for the positive subscale of PANSS in the estradiol 200 μg treatment group (effect size 0.44, P<0.01). This study shows estradiol is an effective and clinically significant adjunctive therapy for women with treatment-resistant schizophrenia, particularly for positive symptoms.Molecular Psychiatry advance online publication, 15 April 2014; doi:10.1038/mp.2014.33.

The impact of insight in a first-episode mania with psychosis population on outcome at 18 months

To explore whether poor initial insight during a first episode of mania with psychotic features was predictive of poor psychosocial and clinical outcomes at 18 months.

Relationship between membrane fatty acids and cognitive symptoms and information processing in individuals at ultra-high risk for psychosis

Cognitive symptoms and impairment are central to schizophrenia and often an early sign of this condition. The present study investigated biological correlates of cognitive symptoms and performance in individuals at ultra-high risk (UHR) for psychosis. The study sample comprised 80 neuroleptic-naïve UHR individuals aged 13-25 years. Associations among erythrocyte membrane fatty acid levels, measured by gas chromatography, and cognitive functioning were investigated in UHR patients. Subjects were divided into terciles based on their scores on the cognitive factor of the Positive and Negative Syndrome Scale. The Zahlen-Verbindungs Test (ZVT) (the number-combination test) was also used as a measure of information-processing speed. Exploratory analysis was conducted to investigate the relationship between membrane fatty acid levels with the size of the intracranial area (ICA), a neurodevelopmental measure relevant to schizophrenia, in half of subjects (n=40) using magnetic resonance imaging. The adjusted analysis revealed that omega-9 eicosenoic and erucic acid levels were significantly higher, but omega-3 docosahexaenoic acid levels were significantly lower, in the cognitively impaired than in the cognitively intact group. We found a significant negative association of eicosenoic, erucic, and gamma-linoleic acids with ZVT scores. A negative association between ICA and membrane levels of eicosenoic acid was also found. This is the first study to demonstrate the relationship between membrane fatty acids and cognitive function in neuroleptic-naïve subjects at UHR for psychosis. The study findings indicate that abnormalities in membrane fatty acids may be associated with the neurodevelopmental disruption associated with the cognitive impairments of individuals at UHR for psychosis.

First aid recommendations for psychosis: using the Delphi method to gain consensus between mental health consumers, carers, and clinicians.

BACKGROUND: Members of the general public often lack the knowledge and skills to intervene effectively to help someone who may be developing a psychotic illness before appropriate professional help is received. METHODS: We used the Delphi method to determine recommendations on first aid for psychosis. An international panel of 157 mental health consumers, carers, and clinicians completed a 146-item questionnaire about how a member of the public could help someone who may be experiencing psychosis. The panel members rated each questionnaire item according to whether they believed the statement should be included in the first aid recommendations. The results were analyzed by comparing consensus rates across the 3 groups. Three rounds of ratings were required to consolidate consensus levels. RESULTS: Eighty-nine items were endorsed by >or=80% of panel members from all 3 groups as essential or important for psychosis first aid. These items were grouped under the following 9 headings: how to know if someone is experiencing psychosis; how to approach someone who may be experiencing psychosis; how to be supportive; how to deal with delusions and hallucinations; how to deal with communication difficulties; whether to encourage the person to seek professional help; what to do if the person does not want help; what to do in a crisis situation when the person has become acutely unwell; what to do if the person becomes aggressive. CONCLUSIONS: These recommendations will improve the provision of first aid to individuals who are developing a psychotic disorder by informing the content of training courses.

Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age

Many women with schizophrenia remain symptomatic despite optimal use of current therapies. While previous studies suggest that adjunctive oestrogen therapy might be effective, large-scale clinical trials are required before clinical applications are possible. This study is the first large-scale randomized-controlled trial in women with treatment-resistant schizophrenia. This Definitive Oestrogen Patch Trial was an 8-week, three-arm, double-blind, randomized-controlled trial conducted between 2006 and 2011. The 183 female participants were aged between 18 and 45 (mean=35 years), with schizophrenia or schizoaffective disorder and ongoing symptoms of psychosis (Positive and Negative Syndrome Scale, PANSS score>60) despite a stable dose of antipsychotic medication for at least 4 weeks. Mean duration of illness was more than 10 years. Participants received transdermal estradiol 200 μg, transdermal estradiol 100 μg or an identical placebo patch. For the 180 women who completed the study, the a priori outcome measure was the change in PANSS score measured at baseline and days 7, 14, 28 and 56. Cognition was assessed at baseline and day 56 using the Repeatable Battery of Neuropsychological Status. Data were analysed using latent growth curve modelling. Both estradiol groups had greater decreases in PANSS positive, general and total symptoms compared with the placebo group (P<0.01), with a greater effect seen for 200 μg than 100 μg estradiol. The largest effect size was for the positive subscale of PANSS in the estradiol 200 μg treatment group (effect size 0.44, P<0.01). This study shows estradiol is an effective and clinically significant adjunctive therapy for women with treatment-resistant schizophrenia, particularly for positive symptoms.

Associations of obsessive-compulsive symptoms with clinical and neurocognitive features in schizophrenia according to stage of illness

This study aimed to investigate the association of obsessive-compulsive symptoms with clinical and neurocognitive features in patients with schizophrenia. This study enrolled 163 people with schizophrenia who were receiving risperidone monotherapy. Comorbid obsessive-compulsive symptoms were assessed using the Yale-Brown Obsessive-Compulsive Scale, and subjects with a score ≥ 10 constituted the obsessive-compulsive symptom group (n=30, 18.4%). The learning index was significantly higher in patients with obsessive-compulsive symptoms than in those without such symptoms after adjusting for age, stage (early and chronic), duration of illness, and CDSS score. However, there was no significant interaction between obsessive-compulsive symptoms and stage of illness. Scores on Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia, and Beck Depression Inventory were significantly higher in the obsessive-compulsive symptom group. In addition, the Subjective Well-being under Neuroleptic Treatment score was significantly lower in the obsessive-compulsive symptom group. In conclusion, comorbid obsessive-compulsive symptoms in patients with schizophrenia were associated with a higher learning ability without a significant interaction with stage of illness. However, schizophrenia patients with obsessive-compulsive symptoms had more severe psychotic and depressive symptoms and poorer quality of life.

C-reactive protein is increased in schizophrenia but is not altered by antipsychotics : meta-analysis and implications

The inflammatory hypothesis of schizophrenia (SZ) posits that inflammatory processes and neural-immune interactions are involved in its pathogenesis, and may underpin some of its neurobiological correlates. SZ is the psychiatric disorder causing the most severe burden of illness, not just owing to its psychiatric impairment, but also owing to its significant medical comorbidity. C-reactive protein (CRP) is a commonly used biomarker of systemic inflammation worldwide. There are some conflicting results regarding the behaviour of CRP in SZ. The aims of this study were to verify whether peripheral CRP levels are indeed increased in SZ, whether different classes of antipsychotics divergently modulate CRP levels and whether its levels are correlated with positive and negative symptomatology. With that in mind, we performed a meta-analysis of all cross-sectional studies of serum and plasma CRP levels in SZ compared to healthy subjects. In addition, we evaluated longitudinal studies on CRP levels before and after antipsychotic use. Our meta-analyses of CRP in SZ included a total of 26 cross-sectional or longitudinal studies comprising 85 000 participants. CRP levels were moderately increased in persons with SZ regardless of the use of antipsychotics and did not change between the first episode of psychosis and with progression of SZ (g=0.66, 95% confidence interval (95% CI) 0.43 to 0.88, P<0.001, 24 between-group comparisons, n=82 962). The extent of the increase in peripheral CRP levels paralleled the increase in severity of positive symptoms, but was unrelated to the severity of negative symptoms. CRP levels were also aligned with an increased body mass index. Conversely, higher age correlated with a smaller difference in CRP levels between persons with SZ and controls. Furthermore, CRP levels did not increase after initiation of antipsychotic medication notwithstanding whether these were typical or atypical antipsychotics (g=0.01, 95% CI -0.20 to 0.22, P=0.803, 8 within-group comparisons, n=713). In summary, our study provides further evidence of the inflammatory hypothesis of SZ. Whether there is a causal relationship between higher CRP levels and the development of SZ and aggravation of psychotic symptoms, or whether they are solely a marker of systemic low-grade inflammation in SZ, remains to be clarified.

Clozapine reverses schizophrenia-related behaviours in the metabotropic glutamate receptor 5 knockout mouse: association with N-methyl-d-aspartic acid receptor up-regulation

Abnormalities in glutamatergic signalling are proposed in schizophrenia in light of the schizophreniform psychosis elicited by NMDA antagonists. The metabotropic glutamate receptor 5 (mGluR5) interacts closely with the NMDA receptor and is implicated in several behavioural endophenotypes of schizophrenia. We have demonstrated that mice lacking mGluR5 have increased sensitivity to the hyperlocomotive effects of the NMDA antagonist MK-801. Mice lacking mGluR5 also show abnormal locomotor patterns, reduced prepulse inhibition (PPI), and deficits on performance of a short-term spatial memory task on the Y-maze. Chronic administration of the antipsychotic drug clozapine ameliorated the locomotor disruption and reversed the PPI deficit, but did not improve Y-maze performance. Chronic clozapine increased NMDA receptor binding ([3H]MK-801) but did not alter dopamine D2 ([3H]YM-09151), 5-HT2A ([3H]ketanserin), or muscarinic M1/M4 receptor ([3H]pirenzepine), binding in these mice. These results demonstrate behavioural abnormalities that are relevant to schizophrenia in the mGluR5 knockout mouse and a reversal of behaviours with clozapine treatment. These results highlight both the interactions between mGluR5 and NMDA receptors in the determination of schizophreniform behaviours and the potential for the effects of clozapine to be mediated by NMDA receptor regulation.
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Effects of omega-3 PUFA on the vitamin E and glutathione antioxidant defense system in individuals at ultra-high risk of psychosis

BACKGROUND: Oxidative stress and impaired antioxidant defenses are reported in schizophrenia and are associated with disturbed neurodevelopment, brain structural alterations, glutamatergic imbalance, increased negative symptoms, and cognitive impairment. There is evidence that oxidative stress predates the onset of acute psychotic illness. Here, we investigate the effects of omega-3 PUFA on the vitamin E and glutathione antioxidant defense system (AODS). METHOD: In 64 help-seeking UHR-individuals (13-25 years of age), vitamin E levels and glutathione were investigated before and after 12 weeks of treatment with either 1.2g/d omega-3 (PUFA-E) or saturated fatty acids (SFA-E), with each condition also containing 30.4mg/d alpha-tocopherol to ensure absorption without additional oxidative risk. RESULTS: In multivariate tests, the effects on the AODS (alpha-tocopherol, total glutathione) were not significantly different (p=0.13, p=0.11, respectively) between treatment conditions. According to univariate findings, only PUFA-E caused a significant alpha-tocopherol increase, while PUFA-E and SFA-E caused a significant gamma- and delta-tocopherol decrease. Total glutathione (GSHt) was decreased by PUFA-E supplementation. CONCLUSION: Effects of the PUFA-E condition on the vitamin E and glutathione AODS could be mechanisms underlying its clinical effectiveness. In terms of the vitamin E protection system, PUFA-E seems to directly support the antioxidative defense at membrane level. The effect of PUFA-E on GSHt is not yet fully understood, but could reflect antioxidative effects, resulting in decreased demand for glutathione. It is still necessary to further clarify which type of PUFA/antioxidant combination, and in which dose, is effective at each stage of psychotic illness.

The relationship between suicide and violence in schizophrenia: analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) dataset

Background

Suicide and violence often co-occur in the general population as well as in mentally ill individuals. Few studies, however, have assessed whether these suicidal behaviors are predictive of violence risk in mental illness.

Aims

The aim of this study is to investigate whether suicidal behaviors, including suicidal ideation, threats, and attempts, are significantly associated with increased violence risk in individuals with schizophrenia.

Method

Data for these analyses were obtained from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial, a randomized controlled trial of antipsychotic medication in 1460 adults with schizophrenia. Univariate Cox regression analyses were used to calculate hazard ratios (HRs) for suicidal ideation, threats, and attempts. Multivariate analyses were conducted to adjust for common confounding factors, including: age, alcohol or drug misuse, major depression, antisocial personality disorder, depression, hostility, positive symptom, and poor impulse control scores. Tests of discrimination, calibration, and reclassification assessed the incremental predictive validity of suicidal behaviors for the prediction of violence risk.

Results

Suicidal threats and attempts were significantly associated with violence in both males and females with schizophrenia with little change following adjustment for common confounders. Only suicidal threats, however, were associated with a significant increase in incremental validity beyond age, diagnosis with a comorbid substance use disorder, and recent violent behavior.

Conclusions

Suicidal threats are independently associated with violence risk in both males and females with schizophrenia, and may improve violence risk prediction.

Risk factors for violence in psychosis: systematic review and meta-regression analysis of 110 studies

Background

Previous reviews on risk and protective factors for violence in psychosis have produced contrasting findings. There is therefore a need to clarify the direction and strength of association of risk and protective factors for violent outcomes in individuals with psychosis.

Method

We conducted a systematic review and meta-analysis using 6 electronic databases (CINAHL, EBSCO, EMBASE, Global Health, PsycINFO, PUBMED) and Google Scholar. Studies were identified that reported factors associated with violence in adults diagnosed, using DSM or ICD criteria, with schizophrenia and other psychoses. We considered non-English language studies and dissertations. Risk and protective factors were meta-analysed if reported in three or more primary studies. Meta-regression examined sources of heterogeneity. A novel meta-epidemiological approach was used to group similar risk factors into one of 10 domains. Sub-group analyses were then used to investigate whether risk domains differed for studies reporting severe violence (rather than aggression or hostility) and studies based in inpatient (rather than outpatient) settings.

Findings

There were 110 eligible studies reporting on 45,533 individuals, 8,439 (18.5%) of whom were violent. A total of 39,995 (87.8%) were diagnosed with schizophrenia, 209 (0.4%) were diagnosed with bipolar disorder, and 5,329 (11.8%) were diagnosed with other psychoses. Dynamic (or modifiable) risk factors included hostile behaviour, recent drug misuse, non-adherence with psychological therapies (p values<0.001), higher poor impulse control scores, recent substance misuse, recent alcohol misuse (p values<0.01), and non-adherence with medication (p value <0.05). We also examined a number of static factors, the strongest of which were criminal history factors. When restricting outcomes to severe violence, these associations did not change materially. In studies investigating inpatient violence, associations differed in strength but not direction.

Conclusion

Certain dynamic risk factors are strongly associated with increased violence risk in individuals with psychosis and their role in risk assessment and management warrants further examination.

Graph analysis of dream reports is especially informative about psychosis

Early psychiatry investigated dreams to understand psychopathologies. Contemporary psychiatry, which neglects dreams, has been criticized for lack of objectivity. In search of quantitative insight into the structure of psychotic speech, we investigated speech graph attributes (SGA) in patients with schizophrenia, bipolar disorder type I, and non-psychotic controls as they reported waking and dream contents. Schizophrenic subjects spoke with reduced connectivity, in tight correlation with negative and cognitive symptoms measured by standard psychometric scales. Bipolar and control subjects were undistinguishable by waking reports, but in dream reports bipolar subjects showed significantly less connectivity. Dream-related SGA outperformed psychometric scores or waking-related data for group sorting. Altogether, the results indicate that online and offline processing, the two most fundamental modes of brain operation, produce nearly opposite effects on recollections: While dreaming exposes differences in the mnemonic records across individuals, waking dampens distinctions. The results also demonstrate the feasibility of the differential diagnosis of psychosis based on the analysis of dream graphs, pointing to a fast, low-cost and language-invariant tool for psychiatric diagnosis and the objective search for biomarkers. The Freudian notion that ‘‘dreams are the royal road to the unconscious’’ is clinically useful, after all.

Graph analysis of dream reports is especially informative about psychosis

Early psychiatry investigated dreams to understand psychopathologies. Contemporary psychiatry, which neglects dreams, has been criticized for lack of objectivity. In search of quantitative insight into the structure of psychotic speech, we investigated speech graph attributes (SGA) in patients with schizophrenia, bipolar disorder type I, and non-psychotic controls as they reported waking and dream contents. Schizophrenic subjects spoke with reduced connectivity, in tight correlation with negative and cognitive symptoms measured by standard psychometric scales. Bipolar and control subjects were undistinguishable by waking reports, but in dream reports bipolar subjects showed significantly less connectivity. Dream-related SGA outperformed psychometric scores or waking-related data for group sorting. Altogether, the results indicate that online and offline processing, the two most fundamental modes of brain operation, produce nearly opposite effects on recollections: While dreaming exposes differences in the mnemonic records across individuals, waking dampens distinctions. The results also demonstrate the feasibility of the differential diagnosis of psychosis based on the analysis of dream graphs, pointing to a fast, low-cost and language-invariant tool for psychiatric diagnosis and the objective search for biomarkers. The Freudian notion that ‘‘dreams are the royal road to the unconscious’’ is clinically useful, after all

Graph analysis of dream reports is especially informative about psychosis

Early psychiatry investigated dreams to understand psychopathologies. Contemporary psychiatry, which neglects dreams, has been criticized for lack of objectivity. In search of quantitative insight into the structure of psychotic speech, we investigated speech graph attributes (SGA) in patients with schizophrenia, bipolar disorder type I, and non-psychotic controls as they reported waking and dream contents. Schizophrenic subjects spoke with reduced connectivity, in tight correlation with negative and cognitive symptoms measured by standard psychometric scales. Bipolar and control subjects were undistinguishable by waking reports, but in dream reports bipolar subjects showed significantly less connectivity. Dream-related SGA outperformed psychometric scores or waking-related data for group sorting. Altogether, the results indicate that online and offline processing, the two most fundamental modes of brain operation, produce nearly opposite effects on recollections: While dreaming exposes differences in the mnemonic records across individuals, waking dampens distinctions. The results also demonstrate the feasibility of the differential diagnosis of psychosis based on the analysis of dream graphs, pointing to a fast, low-cost and language-invariant tool for psychiatric diagnosis and the objective search for biomarkers. The Freudian notion that ‘‘dreams are the royal road to the unconscious’’ is clinically useful, after all