Search

Migration is a major risk factor for schizophrenia but the neurochemical processes involved are unknown. One candidate mechanism is through elevations in striatal dopamine synthesis and release. The objective of this research was to determine whether striatal dopamine function is elevated in immigrants compared to nonimmigrants and the relationship with psychosis. Two complementary case-control studies of in vivo dopamine function (stress-induced dopamine release and dopamine synthesis capacity) in immigrants compared to nonimmigrants were performed in Canada and the United Kingdom. The Canadian dopamine release study included 25 immigrant and 31 nonmigrant Canadians. These groups included 23 clinical high risk (CHR) subjects, 9 antipsychotic naïve patients with schizophrenia, and 24 healthy volunteers. The UK dopamine synthesis study included 32 immigrants and 44 nonimmigrant British. These groups included 50 CHR subjects and 26 healthy volunteers. Both striatal stress-induced dopamine release and dopamine synthesis capacity were significantly elevated in immigrants compared to nonimmigrants, independent of clinical status. These data provide the first evidence that the effect of migration on the risk of developing psychosis may be mediated by an elevation in brain dopamine function., (© The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Objective: Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines., Method: A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus., Results: Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients., Conclusions: There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation.

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., (© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The purpose of this study was to determine whether microglial activity, measured using translocator-protein positron emission tomography (PET) imaging, is increased in unmedicated persons presenting with subclinical symptoms indicating that they are at ultra high risk of psychosis and to determine whether microglial activity is elevated in schizophrenia after controlling for a translocator-specific genetic polymorphism., Method: The authors used the second-generation radioligand [(11)C]PBR28 and PET to image microglial activity in the brains of participants at ultra high risk for psychosis. Participants were recruited from early intervention centers. The authors also imaged a cohort of patients with schizophrenia and matched healthy subjects for comparison. In total, 50 individuals completed the study. At screening, participants were genotyped to account for the rs6971 polymorphism in the gene encoding the 18Kd translocator protein. The main outcome measure was total gray matter [(11)C]PBR28 binding ratio, representing microglial activity., Results: [(11)C]PBR28 binding ratio in gray matter was elevated in ultra-high-risk participants compared with matched comparison subjects (Cohen's d >1.2) and was positively correlated with symptom severity (r=0.730). Patients with schizophrenia also demonstrated elevated microglial activity relative to matched comparison subjects (Cohen's d >1.7)., Conclusions: Microglial activity is elevated in patients with schizophrenia and in persons with subclinical symptoms who are at ultra high risk of psychosis and is related to at-risk symptom severity. These findings suggest that neuroinflammation is linked to the risk of psychosis and related disorders, as well as the expression of subclinical 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., (© The Author(s) 2015.)

Objective: To describe a practical approach to the community management of treatment-resistant schizophrenia (TRS)., Method: A descriptive review of an approach to the assessment and management of patients with TRS, including the community titration of clozapine treatment, and a report of the management recommendations for the first one hundred patients assessed by the Treatment REview and Assessment Team (TREAT)., Results: The standardized model for the community assessment, management and titration of clozapine is described. To date, 137 patients have been referred to this service and 100 patients (72%) attended for assessment. Of these, 33 have been initiated on clozapine while fifteen have had clozapine recommended but have not wished to undertake clozapine treatment. Other management options recommended have included augmentation strategies and long-acting injectable antipsychotics., Conclusion: The service had increased the number of patients receiving community assessment and initiation of clozapine by five-fold relative to the rate prior to the establishment of the service. The large number of referrals and high attendance rate indicates that there is clinical demand for the model. Systematic evaluation is required to determine the clinical and cost-effectiveness of this model and its potential application to other clinical settings., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)