Kyra-Verena Sendt

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 4β2 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.

Response to initial antipsychotic treatment in first episode psychosis is related to anterior cingulate glutamate levels: a multicentre 1H-MRS study (OPTiMiSE)

Conventional antipsychotic medication is ineffective in around a third of patients with schizophrenia, and the nature of the therapeutic response is unpredictable. We investigated whether response to antipsychotics is related to brain glutamate levels prior to treatment. Proton magnetic resonance spectroscopy was used to measure glutamate levels (Glu/Cr) in the anterior cingulate cortex (ACC) and in the thalamus in antipsychotic-naive or minimally medicated patients with first episode psychosis (FEP, n = 71) and healthy volunteers (n = 60), at three sites. Following scanning, patients were treated with amisulpride for 4 weeks (n = 65), then 1H-MRS was repeated (n = 46). Remission status was defined in terms of Positive and Negative Syndrome Scale for Schizophrenia (PANSS) scores. Higher levels of Glu/Cr in the ACC were associated with more severe symptoms at presentation and a lower likelihood of being in remission at 4 weeks (P < 0.05). There were longitudinal reductions in Glu/Cr in both the ACC and thalamus over the treatment period (P < 0.05), but these changes were not associated with the therapeutic response. There were no differences in baseline Glu/Cr between patients and controls. These results extend previous evidence linking higher levels of ACC glutamate with a poor antipsychotic response by showing that the association is evident before the initiation of treatment.

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 psychosocial interventions for adult refugees and asylum seekers

Abstract 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.

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.

S146. EFFECT OF CLOZAPINE ON REGIONAL CEREBRAL BLOOD FLOW IN TREATMENT-RESISTANT SCHIZOPHRENIA

Abstract Background Approximately one-third of schizophrenia patients will not respond adequately to conventional antipsychotic treatment; termed treatment-resistant schizophrenia (TRS). The only antipsychotic recommended for this group is clozapine, which may have unique efficacy in improving residual symptoms. The biological mechanisms underlying its efficacy are poorly understood. Previous studies have examined the effects of clozapine on regional cerebral blood flow (rCBF) using radiotracer approaches in relatively small samples of patients, showing, in particular, frontal and limbic perfusion changes1,2,3. In this study, we evaluate the effects of clozapine on rCBF, measured with a non-invasive MRI technique - pulsed continuous arterial spin labelling (pCASL) - which does not require radiotracer injection, as part of an ongoing study to identify neuroimaging predictors and mediators of clozapine response. Methods Participants ≥18 years of age with TRS were recruited at the Institute of Psychiatry, Psychology & Neuroscience, Kings College London (UK). TRS status was ascertained by the documented failure to respond to at least two different antipsychotic trials of adequate length. Participants were either clozapine-naïve or had not taken clozapine for at least three months prior to the baseline MRI scan. After baseline MRI, clozapine was administered as part of routine clinical care for 12 weeks, after which a second MRI scan was performed. Symptomatic response was defined as a reduction of 20% of the Positive and Negative Syndrome Scale (PANSS)4 score and non-response was defined as <20% decrease in PANSS score. pCASL data was acquired on a General Electric 3 Tesla MR-750 MR scanner. Arterial blood was labelled using a long, adiabatic (1.8 seconds) radio frequency pulse. After a post-labelling delay of 2.025s, perfusion images were acquired with a 3D Fast Spin Echo spiral multi-shot readout (TE 32ms/TR = 5500ms; ETL = 64). Cerebral blood flow (CBF) maps were computed with a spatial resolution of 2x2x3mm, in a total acquisition time of less than 6min. CBF maps were pre-processed using the Automatic Software for ASL processing (ASAP) toolbox5. Changes in rCBF after 12 weeks of clozapine were analysed in a full factorial ANOVA design, using SPM 12 (www.fil.ion.ucl.ac.uk/spm). Clusters of significant CBF changes were assessed at p<0.05 after Family-Wise Error correction for cluster extent, using a cluster-forming threshold of T>2.74. Results This is an interim analysis of 24 patients who completed both scans. Contrasts were examined at a whole brain, assumption-free voxel-wise analysis, restricted to grey matter and co-varied for global perfusion. Clozapine administration significantly decreased perfusion in the medial frontal gyrus. There was also a significant response x time interaction, centred in the left posterior cerebellum and extending to the bilateral visual cortex and right precuneus. Discussion These interim results indicate that pCASL may be able to identify brain regions in which activity is modulated by clozapine administration as well as areas that may mediate symptomatic improvement. A key question for future analyses will be the degree to which rCBF may predict symptomatic response to clozapine, as the ability to predict a good likelihood of response could enable earlier clozapine initiation. References 1. Lahti AC et al. Biol Psychiatry 2003; 53: 601–8. 2. Potkin SG et al. Mol Psychiatry 2003; 8: 109–13. 3. Molina V et al. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 948–54. 4. Kay SR et al. Psychiatry Res 1988; 23: 99–110. 5. Mato Abad VM et al. Magn Reson Imaging 2016; 34: 334–44.

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.

The Glutamate mGluR5 Receptor as a Pharmacological Target to Enhance Cognitive Function: Emerging Evidence from Psychosis Models

Schizophrenia is a profoundly disabling condition affecting approximately 1% of the population. Although often defined by the presence of so-called ‘positive’ symptoms of hallucinations and delusions, sufferers are typically more affected by the more insidious cognitive and ‘negative’ (social withdrawal and amotivational) symptoms. The dopaminergic hypothesis has been a dominant neurobiological model, particularly as the majority of current antipsychotic medications act upon dopamine pathways, but it is notably incomplete; noteworthy, existing medications have, at best, very limited effects upon cognitive deficits. The glutamatergic (Glu) system has attracted attention in recent times as a putative target, though modulation of this ubiquitous system in the brain is not without danger; to this end the metabotropic mGluR5 receptor has emerged as a possible mechanism through which safe Glu modification might be effected. Most data at this time have emerged from animal model studies; these are interesting, with positive results, but need replication in human samples. At present, the future use of mGluR5 modifying drugs has yet to be established.