Changes in immunoglobulin levels during clozapine treatment in schizophrenia.

BACKGROUND AND HYPOTHESIS: Use of clozapine in treatment-resistant schizophrenia is often limited due to risk of adverse effects. Cross-sectional associations between clozapine treatment and low immunoglobulin levels have been reported, however prospective studies are required to establish temporal relationships. We tested the hypothesis that reductions in immunoglobulin levels would occur over the first 6 months following initiation of clozapine treatment. Relationships between immunoglobulin levels and symptom severity over the course of clozapine treatment were also explored. DESIGN: This prospective observational study measured immunoglobulin (Ig) levels (A, M and G) in 56 patients with treatment-resistant schizophrenia at 6-, 12- and 24-weeks following initiation with clozapine. Clinical symptoms were also measured at 12 weeks using the positive and negative syndrome scale (PANSS). RESULTS: IgA, IgG and IgM all decreased during clozapine treatment. For IgA and IgG the reduction was significant at 24 weeks (IgA: ß = -32.66, 95% CI = -62.38, -2.93, p = 0.03; IgG: ß = -63.96, 95% CI = -118.00, -9.31, p = 0.02). For IgM the reduction was significant at 12 and 24 weeks (12 weeks: ß = -23.48, 95% CI = -39.56, -7.42, p = 0.004; 24 weeks: ß = -33.12, 95 %CI = -50.30, -15.94, p = <0.001). Reductions in IgA and IgG during clozapine treatment were correlated with reductions in PANSS-total over 12 weeks (n = 32, IgA r = 0.59, p = 0.005; IgG r = 0.48, p = 0.03). CONCLUSIONS: The observed reductions in immunoglobulin levels over six months of clozapine treatment add further evidence linking clozapine to secondary antibody deficiency. Associations between Ig reduction and symptom improvement may however indicate that immune mechanisms contribute to both desirable and undesirable effects of clozapine.

A pre-post pilot study of electronic cigarettes to reduce smoking in people with severe mental illness.

BACKGROUND: Smoking is the largest single contributor to poor physical health and increased mortality in people with serious mental illnesses. The aim of the study was to investigate the utility of electronic cigarettes (e-cigarettes) as a harm reduction intervention in this population. METHOD: Fifty tobacco smokers with a psychotic disorder were enrolled onto a 24-week pilot study (ClinicalTrials.gov: NCT02212041) investigating the efficacy of a 6-week free e-cigarette intervention to reduce smoking. Cigarette and e-cigarette use was self-reported at weekly visits, and verified using carbon monoxide tests. Psychopathology, e-cigarette acceptability and adverse effects were assessed using standardised scales. RESULTS: There was a significant (⩾50%) reduction in cigarettes consumed per day between baseline and week 6 [F(2.596,116.800) = 25.878, p < 0.001], and e-cigarette use was stable during this period [F(2.932,46.504) = 2.023, p = 0.115]. These changes were verified by significant carbon monoxide reductions between these time points [F(3.335,126.633) = 5.063, p = 0.002]. CONCLUSIONS: The provision of e-cigarettes is a potentially useful harm reduction intervention in smokers with a psychotic disorder.

A systematic review of psychosocial interventions for adult refugees and asylum seekers.

Background: Europe is in the midst of the largest refugee migration since the Second World War; there is an urgent need to provide an updated systematic review of the current best evidence for managing mental distress in refugee populations.Aims: The aim of this review is to provide an exhaustive summary of the current literature on psychosocial interventions, both trauma- and non-trauma-focused, for refugee populations experiencing post-traumatic stress disorder (PTSD), depressive or anxiety symptoms. To produce recommendations for future research and current clinical practice.Method: Searches were conducted in PubMed, PsychINFO (Hosted by Ovid), PILOTS and Social Services Abstracts; 5305 articles were screened and 40 were included.Results: This review found medium to high quality evidence supporting the use of narrative exposure therapy (NET). A lack of culturally adapted treatments was apparent and there was less evidence to support standard cognitive behavioural therapy (CBT), Eye Movement Desensitisation and Reprocessing (EMDR) and multidisciplinary treatments.Conclusion: NET produced positive outcomes in refugees from a diverse range of backgrounds and trauma types. There is a general dearth of research in all intervention types: further research should include more "real-world" multidisciplinary interventions that better model clinical practice. Recommendations for evaluating local need, and creating a culturally sensitive workforce are discussed.

Anterior cingulate glutamate metabolites as a predictor of antipsychotic response in first episode psychosis: data from the STRATA collaboration.

Elevated brain glutamate has been implicated in non-response to antipsychotic medication in schizophrenia. Biomarkers that can accurately predict antipsychotic non-response from the first episode of psychosis (FEP) could allow stratification of patients; for example, patients predicted not to respond to standard antipsychotics could be fast-tracked to clozapine. Using proton magnetic resonance spectroscopy (1H-MRS), we examined the ability of glutamate and Glx (glutamate plus glutamine) in the anterior cingulate cortex (ACC) and caudate to predict response to antipsychotic treatment. A total of 89 minimally medicated patients with FEP not meeting symptomatic criteria for remission were recruited across two study sites. 1H-MRS and clinical data were acquired at baseline, 2 and 6 weeks. Response was defined as >20% reduction in Positive and Negative Syndrome Scale (PANSS) Total score from baseline to 6 weeks. In the ACC, baseline glutamate and Glx were higher in Non-Responders and significantly predicted response (P < 0.02; n = 42). Overall accuracy was greatest for ACC Glx (69%) and increased to 75% when symptom severity at baseline was included in the model. Glutamate metabolites in the caudate were not associated with response, and there was no significant change in glutamate metabolites over time in either region. These results add to the evidence linking elevations in ACC glutamate metabolites to a poor antipsychotic response. They indicate that glutamate may have utility in predicting response during early treatment of first episode psychosis. Improvements in accuracy may be made by combining glutamate measures with other response biomarkers.

Subcortical volume reduction and cortical thinning 3 months after switching to clozapine in treatment resistant schizophrenia.

The neurobiological effects of clozapine are under characterised. We examined the effects clozapine treatment on subcortical volume and cortical thickness and investigated whether macrostructural changes were linked to alterations in glutamate or N-acetylaspartate (NAA). Data were acquired in 24 patients with treatment-resistant schizophrenia before and 12 weeks after switching to clozapine. During clozapine treatment we observed reductions in caudate and putamen volume, lateral ventricle enlargement (P < 0.001), and reductions in thickness of the left inferior temporal cortex, left caudal middle frontal cortex, and the right temporal pole. Reductions in right caudate volume were associated with local reductions in NAA (P = 0.002). None of the morphometric changes were associated with changes in glutamate levels. These results indicate that clozapine treatment is associated with subcortical volume loss and cortical thinning and that at least some of these effects are linked to changes in neuronal or metabolic integrity.

Changes in Brain Glutamate on Switching to Clozapine in Treatment-Resistant Schizophrenia.

It has been suggested that the antipsychotic clozapine may modulate brain glutamate, and that this effect could contribute to its efficacy in treatment-resistant schizophrenia (TRS). The aim of this study was to examine the effects of clozapine on brain glutamate in TRS longitudinally. This study examined individuals with TRS before and 12 weeks after switching from a non-clozapine antipsychotic to treatment with clozapine as part of their normal clinical care. Proton magnetic resonance spectroscopy (1H-MRS) measured concentrations, corrected for voxel tissue content, of glutamate (Glucorr), and glutamate plus glutamine (Glxcorr) in the anterior cingulate cortex (ACC) and right caudate nucleus. Symptoms were monitored using the Positive and Negative Syndrome Scale (PANSS). Of 37 recruited patients (27 men, 39.30 years old, 84% clozapine naïve), 25 completed 1H-MRS at both timepoints. 12 weeks of clozapine was associated with a longitudinal reduction in Glucorr in the caudate (n = 23, F = 7.61 P = .01) but not in the ACC (n = 24, F = 0.02, P = .59). Percentage reduction in caudate Glucorr was positively correlated with percentage improvement in symptoms (total PANSS score, n = 23, r = .42, P = .04). These findings indicate that reductions in glutamate in the caudate nucleus may contribute to symptomatic improvement during the first months of clozapine treatment.

Symptom Remission and Brain Cortical Networks at First Clinical Presentation of Psychosis: The OPTiMiSE Study.

Individuals with psychoses have brain alterations, particularly in frontal and temporal cortices, that may be particularly prominent, already at illness onset, in those more likely to have poorer symptom remission following treatment with the first antipsychotic. The identification of strong neuroanatomical markers of symptom remission could thus facilitate stratification and individualized treatment of patients with schizophrenia. We used magnetic resonance imaging at baseline to examine brain regional and network correlates of subsequent symptomatic remission in 167 medication-naïve or minimally treated patients with first-episode schizophrenia, schizophreniform disorder, or schizoaffective disorder entering a three-phase trial, at seven sites. Patients in remission at the end of each phase were randomized to treatment as usual, with or without an adjunctive psycho-social intervention for medication adherence. The final follow-up visit was at 74 weeks. A total of 108 patients (70%) were in remission at Week 4, 85 (55%) at Week 22, and 97 (63%) at Week 74. We found no baseline regional differences in volumes, cortical thickness, surface area, or local gyrification between patients who did or did not achieved remission at any time point. However, patients not in remission at Week 74, at baseline showed reduced structural connectivity across frontal, anterior cingulate, and insular cortices. A similar pattern was evident in patients not in remission at Week 4 and Week 22, although not significantly. Lack of symptom remission in first-episode psychosis is not associated with regional brain alterations at illness onset. Instead, when the illness becomes a stable entity, its association with the altered organization of cortical gyrification becomes more defined.

Remission from antipsychotic treatment in first episode psychosis related to longitudinal changes in brain glutamate.

Neuroimaging studies in schizophrenia have linked elevated glutamate metabolite levels to non-remission following antipsychotic treatment, and also indicate that antipsychotics can reduce glutamate metabolite levels. However, the relationship between symptomatic reduction and change in glutamate during initial antipsychotic treatment is unclear. Here we report proton magnetic resonance spectroscopy (1H-MRS) measurements of Glx and glutamate in the anterior cingulate cortex (ACC) and thalamus in patients with first episode psychosis (n = 23) at clinical presentation, and after 6 weeks and 9 months of treatment with antipsychotic medication. At 9 months, patients were classified into Remission (n = 12) and Non-Remission (n = 11) subgroups. Healthy volunteers (n = 15) were scanned at the same three time-points. In the thalamus, Glx varied over time according to remission status (P = 0.020). This reflected an increase in Glx between 6 weeks and 9 months in the Non-Remission subgroup that was not evident in the Remission subgroup (P = 0.031). In addition, the change in Glx in the thalamus over the 9 months of treatment was positively correlated with the change in the severity of Positive and Negative Syndrome Scale (PANSS) positive, total and general symptoms (P<0.05). There were no significant effects of group or time on glutamate metabolites in the ACC, and no differences between either patient subgroup and healthy volunteers. These data suggest that the nature of the response to antipsychotic medication may be related to the pattern of changes in glutamatergic metabolite levels over the course of treatment. Specifically, longitudinal reductions in thalamic Glx levels following antipsychotic treatment are associated with symptomatic improvement.

Biological Predictors of Clozapine Response: A Systematic Review.

Background: Clozapine is the recommended antipsychotic for treatment-resistant schizophrenia (TRS) but there is significant variability between patients in the degree to which clozapine will improve symptoms. The biological basis of this variability is unknown. Although clozapine has efficacy in TRS, it can elicit adverse effects and initiation is often delayed. Identification of predictive biomarkers of clozapine response may aid initiation of clozapine treatment, as well as understanding of its mechanism of action. In this article we systematically review prospective or genetic studies of biological predictors of response to clozapine. Methods: We searched the PubMed database until 20th January 2018 for studies investigating "clozapine" AND ("response" OR "outcome") AND "schizophrenia." Inclusion required that studies examined a biological variable in relation to symptomatic response to clozapine. For all studies except genetic-studies, inclusion required that biological variables were measured before clozapine initiation. Results: Ninety-eight studies met the eligibility criteria and were included in the review, including neuroimaging, blood-based, cerebrospinal fluid (CSF)-based, and genetic predictors. The majority (70) are genetic studies, collectively investigating 379 different gene variants, however only three genetic variants (DRD3 Ser9Gly, HTR2A His452Tyr, and C825T GNB3) have independently replicated significant findings. Of the non-genetic variables, the most consistent predictors of a good response to clozapine are higher prefrontal cortical structural integrity and activity, and a lower ratio of the dopamine and serotonin metabolites, homovanillic acid (HVA): 5-hydroxyindoleacetic acid (5-HIAA) in CSF. Conclusions: Recommendations include that future studies should ensure adequate clozapine trial length and clozapine plasma concentrations, and may include multivariate models to increase predictive accuracy.

Association between serum levels of glutamate and neurotrophic factors and response to clozapine treatment.

Clozapine is the only available therapy for about 30% of schizophrenia patients otherwise refractory to antipsychotics. Unfortunately, the mechanism of action of the drug is still unknown and there are no biomarkers that can predict a positive response to clozapine. We aimed to examine serum neurotrophins and glutamate levels as putative biomarkers for clozapine response based on the hypothesized mode-of-action of the compound. Blood samples of 89 chronic schizophrenia patients maintained on clozapine were analyzed in a cross-sectional design. Serum brain derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), neurotrophic growth factor (NGF), glial derived neurotrophic factor (GDNF) and glutamate were determined. Differences between responders and non-responders to clozapine and correlation between clinical and biological measures were analyzed. Our sample consisted of 54 (61%) responders and 35 (39%) non-responders. Responders had higher mean BDNF levels than non-responders (2066±814 vs. 1668±820pg/ml, p<0.05. respectively) and higher serum glutamate levels (1.61±2.2 vs. 0.66±0.9pg/ml, respectively, p<0.05). Furthermore, there was a significant correlation between serum glutamate levels and positive symptoms among the clozapine-responder group (rho=0.47, p<0.005). High serum levels of BDNF and glutamate were associated with response to clozapine, while glutamate levels correlated with the psychosis severity in clozapine responders only. Large-scale, prospective longitudinal studies are needed to support these findings and the assumption that serum glutamate and BDNF can discriminate between clozapine responders and non-responders.

A systematic review of factors influencing adherence to antipsychotic medication in schizophrenia-spectrum disorders.

Adherence to antipsychotics improves outcome in schizophrenia. There is a lack of consensus on which factors most influence adherence behaviour and methodological issues hinder interpretation of existing evidence. A rigorous systematic search designed to identify robustly implicated factors emerging from methodologically rigorous studies narrowed our search to 13 observational studies (total N=6235) relating to adherence, antipsychotics and schizophrenia. Studies varied significantly, with reported adherence rates ranging from 47.2% to 95%. Positive attitude to medication and illness insight were the only factors consistently associated with better adherence, while contradictory results were found for socio-demographic characteristics, symptom severity and side effects. Only distinct aspects of the therapeutic relationship and social support in younger patients were related to good adherence. Antipsychotic type or formulation and neurocognitive functioning did not appear to impact medication adherence. Despite greater methodological rigour in determining studies to include in the present systematic review, it remains difficult to guide clinicians in this vital area and most of the work discussed contained small sample sizes. Future research in this field should therefore prioritise prospective study designs over longer periods and larger samples in naturalistic settings, providing a more appropriate and clinically meaningful framework than widely used cross-sectional designs.

Dementia praecox redux: a systematic review of the nicotinic receptor as a target for cognitive symptoms of schizophrenia.

Most individuals with schizophrenia suffer some cognitive dysfunction: such deficits are predictive of longer-term functioning; and current dopamine-blocking antipsychotics have made little impact on this domain. There is a pressing need to develop novel pharmacological agents to tackle this insidious but most disabling of problems. The acetylcholinergic system is involved in cognitive and attentional processing, and its metabotropic and nicotinic receptors are widespread throughout the brain. Deficits in acetylcholinergic functioning occur in schizophrenia, and high rates of tobacco smoking have been posited to represent a form of self-medication. The nicotinic acetylcholine receptor (nAChR) has emerged as a putative target to improve cognitive deficits in schizophrenia, and this study systematically reviewed the emerging data. Nineteen studies were identified, covering three compound classes: agonists at the α7 and α 4ß2 nAChRs, and positive allosteric modulators. Overall data are underwhelming: some studies showed significant improvements in cognition but as many studies had negative findings. It remains unclear if this represents drug limitations or nascent study methodology problems. The literature is particularly hindered by variability in inclusion of smokers, generally small sample sizes, and a lack of consensus on cognitive test batteries. Future work should evaluate longer-term outcomes, and, particularly, the effects of concomitant cognitive training.

Beyond dopamine: glutamate as a target for future antipsychotics.

The dopamine hypothesis of schizophrenia remains the primary theoretical framework for the pharmacological treatment of the disorder. Despite various lines of evidence of dopaminergic abnormalities and reasonable efficacy of current antipsychotic medication, a significant proportion of patients show suboptimal treatment responses, poor tolerability, and a subsequent lack of treatment concordance. In recent decades, intriguing evidence for the critical involvement of other neurotransmitter systems in the pathophysiology of schizophrenia has emerged, most notably of dysfunctions within the glutamate pathways. Consequently, the glutamate synapse has arisen as a promising target for urgently needed novel antipsychotic compounds-particularly in regards to debilitating negative and cognitive symptoms poorly controlled by currently available drugs. In this paper, recent findings integrating glutamatergic and dopaminergic abnormalities in schizophrenia and their implications for novel pharmacological targets are discussed. An overview of compounds in various stages of development is given: drugs enhancing NMDA receptor function as well as metabotropic glutamate receptor (mGluR) agonist and positive allosteric modulators (PAMs) are emphasised. Together with other agents more indirectly affecting glutamatergic neurotransmission, their potential future role in the pharmacotherapy of schizophrenia is critically evaluated.