Katherine Beck

Impaired Glucose Homeostasis in First-Episode Schizophrenia: A Systematic Review and Meta-analysis.

Importance Schizophrenia is associated with an increased risk of type 2 diabetes. However, it is not clear whether schizophrenia confers an inherent risk for glucose dysregulation in the absence of the effects of chronic illness and long-term treatment. Objective To conduct a meta-analysis examining whether individuals with first-episode schizophrenia already exhibit alterations in glucose homeostasis compared with controls. Data Sources The EMBASE, MEDLINE, and PsycINFO databases were systematically searched for studies examining measures of glucose homeostasis in antipsychotic-naive individuals with first-episode schizophrenia compared with individuals serving as controls. Study Selection Case-control studies reporting on fasting plasma glucose levels, plasma glucose levels after an oral glucose tolerance test, fasting plasma insulin levels, insulin resistance, and hemoglobin A1c (HbA1c) levels in first-episode antipsychotic-naive individuals with first-episode schizophrenia compared with healthy individuals serving as controls. Two independent investigators selected the studies. Data Extraction Two independent investigators extracted study-level data for a random-effects meta-analysis. Standardized mean differences in fasting plasma glucose levels, plasma glucose levels after an oral glucose tolerance test, fasting plasma insulin levels, insulin resistance, and HbA1c levels were calculated. Sensitivity analyses examining the effect of body mass index, diet and exercise, race/ethnicity, and minimal (⩽2 weeks) antipsychotic exposure were performed. Data Synthesis Of 3660 citations retrieved, 16 case-control studies comprising 15 samples met inclusion criteria. The overall sample included 731 patients and 614 controls. Fasting plasma glucose levels (Hedges g = 0.20; 95% CI, 0.02 to 0.38; P = .03), plasma glucose levels after an oral glucose tolerance test (Hedges g = 0.61; 95% CI, 0.16 to 1.05; P = .007), fasting plasma insulin levels (Hedges g = 0.41; 95% CI, 0.09 to 0.72; P = .01), and insulin resistance (homeostatic model assessment of insulin resistance) (Hedges g = 0.35; 95% CI, 0.14 to 0.55; P = .001) were all significantly elevated in patients compared with controls. However, HbA1c levels (Hedges g = −0.08; CI, −0.34 to 0.18; P = .55) were not altered in patients compared with controls. Conclusions and Relevance These findings show that glucose homeostasis is altered from illness onset in schizophrenia, indicating that patients are at increased risk of diabetes as a result. This finding has implications for the monitoring and treatment choice for patients with schizophrenia.

Treatment-Resistant Schizophrenia Patients Show Elevated Anterior Cingulate Cortex Glutamate Compared to Treatment-Responsive

INTRODUCTION Resistance to antipsychotic treatment is a significant clinical problem in patients with schizophrenia with approximately 1 in 3 showing limited or no response to repeated treatments with antipsychotic medication. The neurobiological basis for treatment resistance is unknown but recent evidence implicates glutamatergic function in the anterior cingulate cortex. We examined glutamate levels of chronically ill treatment-resistant patients directly compared to treatment-responsive patients. METHODS We acquired proton magnetic resonance spectroscopy (1H-MRS) at 3 Tesla from 21 treatment-resistant and 20 treatment-responsive patients. All participants had a DSM-IV diagnosis of schizophrenia. Treatment-resistant patients were classified using the modified Kane criteria. The groups were matched for age, sex, smoking status, and illness duration. RESULTS Glutamate to creatine ratio levels were higher in treatment-resistant patients (Mean [SD] = 1.57 [0.24]) than in treatment-responsive patients (Mean[SD] = 1.38 [0.23]), (T[35] = 2.34, P = .025, 2-tailed), with a large effect size of d = 0.76. A model assuming 2 populations showed a 25% improvement in the fit of the Akaike weights (0.55) over a model assuming 1 population (0.44), producing group values almost identical to actual group means. DISCUSSION Increased anterior cingulate glutamate level is associated with treatment-resistant schizophrenia. This appears to be a stable neurobiological trait of treatment-resistant patients. We discuss possible explanations for glutamatergic dysfunction playing a significant role in resistance to conventional antipsychotic treatments, which are all dopamine-2 receptor blockers. Our findings suggest that glutamatergic treatments may be particularly effective in resistant patients and that 1H-MRS glutamate indices can potentially have clinical use.

Autoantibodies to central nervous system neuronal surface antigens: psychiatric symptoms and psychopharmacological implications

RationaleAutoantibodies to central nervous system (CNS) neuronal surface antigens have been described in association with autoimmune encephalopathies which prominently feature psychiatric symptoms in addition to neurological symptoms. The potential role of these autoantibodies in primary psychiatric diseases such as schizophrenia or bipolar affective disorder is of increasing interest.ObjectivesWe aimed to review the nature of psychiatric symptoms associated with neuronal surface autoantibodies, in the context of autoimmune encephalopathies as well as primary psychiatric disorders, and to review the mechanisms of action of these autoantibodies from a psychopharmacological perspective.ResultsThe functional effects of the autoantibodies on their target antigens are described; their clinical expression is at least in part mediated by their effects on neuronal receptor function, primarily at the synapse, usually resulting in receptor hypofunction. The psychiatric effects of the antibodies are related to known functions of the receptor target or its complexed proteins, with reference to supportive genetic and pharmacological evidence where relevant. Evidence for a causal role of these autoantibodies in primary psychiatric disease is increasing but remains controversial; relevant methodological controversies are outlined. Non-receptor-based mechanisms of autoantibody action, including neuroinflammatory mechanisms, and therapeutic implications are discussed.ConclusionsAn analysis of the autoantibodies from a psychopharmacological perspective, as endogenous, bioactive, highly specific, receptor-targeting molecules, provides a valuable opportunity to understand the neurobiological basis of associated psychiatric symptoms. Potentially, new treatment strategies will emerge from the improving understanding of antibody-antigen interaction within the CNS.

The practical management of refractory schizophrenia--the Maudsley Treatment REview and Assessment Team service approach.

To describe a practical approach to the community management of treatment‐resistant schizophrenia (TRS).

Presynaptic Dopamine Capacity in Patients with Treatment-Resistant Schizophrenia Taking Clozapine: An [(18)F]DOPA PET Study.

Some patients with schizophrenia show poor response to first-line antipsychotic treatments and this is termed treatment-resistant schizophrenia. The differential response to first-line antipsychotic drugs may reflect a different underlying neurobiology. Indeed, a previous study found dopamine synthesis capacity was significantly lower in patients with treatment-resistant schizophrenia. However, in this study, the treatment-resistant patients were highly symptomatic, whereas the responsive patients showed no or minimal symptoms. The study could not distinguish whether this was a trait effect or reflected the difference in symptom levels. Thus, we aimed to test whether dopaminergic function is altered in patients with a history of treatment resistance to first-line drugs relative to treatment responders when both groups are matched for symptom severity levels by recruiting treatment-resistant patients currently showed low symptom severity with the clozapine treatment. Healthy controls (n=12), patients treated with clozapine (n=12) who had not responded to first-line antipsychotics, and patients who had responded to first-line antipsychotics (n=12) were recruited. Participants were matched for age and sex and symptomatic severity level in patient groups. Participants’ dopamine synthesis capacity was measured by using [18F]DOPA PET. We found that patients treated with clozapine show lower dopamine synthesis capacity than patients who have responded to first-line treatment (Cohen’s d=0.9191 (whole striatum), 0.7781 (associative striatum), 1.0344 (limbic striatum), and 1.0189 (sensorimotor striatum) in line with the hypothesis that the dopaminergic function is linked to treatment response. This suggests that a different neurobiology may underlie treatment-resistant schizophrenia and that dopamine synthesis capacity may be a useful biomarker to predict treatment responsiveness.

Cholesterol and triglyceride levels in first-episode psychosis: systematic review and meta-analysis

Background The extent of metabolic and lipid changes in first-episode psychosis (FEP) is unclear. Aims To investigate whether individuals with FEP and no or minimal antipsychotic exposure show lipid and adipocytokine abnormalities compared with healthy controls. Method We conducted a meta-analysis of studies examining lipid and adipocytokine parameters in individuals with FEP and no or minimal antipsychotic exposure v. a healthy control group. Studies reported fasting total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and leptin levels. Results Of 2070 citations retrieved, 20 case-control studies met inclusion criteria including 1167 patients and 1184 controls. Total cholesterol and LDL cholesterol levels were significantly decreased in patients v. controls, corresponding to an absolute reduction of 0.26 mmol/L and 0.15 mmol/L respectively. Triglyceride levels were significantly increased in the patient group, corresponding to an absolute increase of 0.08 mmol/L. However, HDL cholesterol and leptin levels were not altered in patients v. controls. Conclusions Total and LDL cholesterol levels are reduced in FEP, indicating that hypercholesterolaemia in patients with chronic disorder is secondary and potentially modifiable. In contrast, triglycerides are elevated in FEP. Hypertriglyceridaemia is a feature of type 2 diabetes mellitus, therefore this finding adds to the evidence for glucose dysregulation in this cohort. These findings support early intervention targeting nutrition, physical activity and appropriate antipsychotic prescription.

Prevalence of serum N-methyl-d-aspartate receptor autoantibodies in refractory psychosis

N-methyl-d-aspartate receptor (NMDA-R) autoantibodies have been reported in people with acute psychosis. We hypothesised that their presence may be implicated in the aetiology of treatment-refractory psychosis. We sought to ascertain the point prevalence of NMDA-R antibody positivity in patients referred to services for treatment-refractory psychosis. We found that 3 (7.0%) of 43 individuals had low positive NMDA-R antibody titres. This suggests that NMDA-R autoantibodies are unlikely to account for a large proportion of treatment-refractory psychosis.

Targeting glutamate to treat schizophrenia: lessons from recent clinical studies

On the face of it, the treatment of schizophrenia offers lots of choice: there are more than 30 antipsychotic drugs licensed for first-line treatment. However, as they all essentially use the same common mechanism of action, D2 antagonism, from a mechanistic perspective, there is little choice (Howes andKapur 2009). This is a problem because one third of patients do not respond to standard medications (Beck et al. 2014), and the drugs have limited efficacy for negative and cognitive symptoms. This is not surprising as both treatment resistance and negative and cognitive symptoms seem to involve other neurotransmitter systems (Mouchlianitis et al. 2015). Therefore, there is a need to develop novel treatments targeting other neurotransmitters. Emerging evidence suggests a key role for glutamate dysfunction in the pathophysiology of schizophrenia—in particular, N-methyl-D-aspartate-receptor (NMDAR) hypofunction (Javitt and Zukin 1991; Coyle 1996). NMDAR antagonists are able to mimic the full range of symptoms seen in schizophrenia (Krystal et al. 1994), and genetic, post mortem and animal studies lend further support to the NMDAR hypothesis. This has led to a drive to develop drugs targeting the NMDAR. One approach has been to target the NMDAR’s glycine binding site. Glycine is required to bind at the same time as glutamate to allow the activation of the NMDAR (Kleckner and Dingledine 1988). Increasing glycine occupancy has the potential to increase NMDAR neurotransmission (Danysz and Parsons 1998). Early clinical trials conducted at single sites found that glycine administered in combination with antipsychotics could reduce negative and cognitive symptoms when compared with antipsychotics alone (Javitt et al. 1994; HerescoLevy et al. 1996, 1999, 2004). However, a multi-centre study did not show separation from placebo (Buchanan et al. 2007). Furthermore, glycine does not easily cross the blood–brain barrier, necessitating high doses, affecting its tolerability. Alternative approaches to increasing brain glycine have been sought. Of particular interest is the glycine transporter 1 (GlyT1), which is postulated to be a key regular of synaptic glycine (Supplisson and Bergman 1997). A number of GlyT1 inhibitors have been synthesised and trialled. However, only the Hoffmann-La Roche compound, bitopertin, has reached phase III clinical trials (Singer et al. 2015). Bitopertin is a selective and potent glycine reuptake inhibitor (GRI). A phase II proof of concept study, of patients with schizophrenia with predominant negative symptoms, found that bitopertin (at doses of 10 and 30 mg daily) moderately reduced negative symptoms (Umbricht et al. 2014). However, this was not significant in the intention-to-treat analysis. A clinical trial programme called BSearchLyte^ was instigated. It consisted of six phase III studies. Three of these targeted the drug’s ability to treat patients with persistent negative symptoms. The other three studies were designed to determine the drug’s ability to reduce positive symptoms in patients who had not responded to the antipsychotic drugs currently available. Two of the trials were discontinued after * Katherine Beck katherine.beck@kcl.ac.uk

Treatment resistant or resistant to treatment? Antipsychotic plasma levels in patients with poorly controlled psychotic symptoms

A large proportion of individuals with schizophrenia show an inadequate response to treatment with antipsychotics. It can be unclear whether this is secondary to subtherapeutic antipsychotic plasma levels or to medication ineffectiveness. The purpose of the present study was to determine the extent of subtherapeutic antipsychotic plasma levels in a group of patients clinically identified as treatment-resistant. In addition we investigated the frequency of antipsychotic plasma level monitoring in standard clinical practice. Antipsychotic plasma levels were measured in 36 patients identified as having treatment-resistant schizophrenia by their treating clinicians. Sixteen (44%) patients showed either undetectable (19%) or subtherapeutic levels (25%), and 20 (56%) patients had levels in the therapeutic range. Subtherapeutic plasma levels were significantly associated with black ethnicity, shorter duration of current treatment and antipsychotics other than olanzapine and amisulpride. Antipsychotic plasma levels had been measured in only one patient in the year prior to our study. We found over one-third of patients identified as treatment-resistant have subtherapeutic antipsychotic levels. This indicates that they may be under-treated rather than treatment-resistant, and thus should receive different management. Currently the measurement of antipsychotic levels may be under-utilised.

Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia

Treatment resistance is a challenge for the management of schizophrenia. It is not always clear whether inadequate response is secondary to medication ineffectiveness, as opposed to medication underexposure due to non‐adherence or pharmacokinetic factors. We investigated the prevalence of subtherapeutic antipsychotic plasma levels in patients identified as treatment‐resistant by their treating clinician.