Robert McCutcheon

Glutamate and dopamine in schizophrenia: An update for the 21st century

The glutamate and dopamine hypotheses are leading theories of the pathoaetiology of schizophrenia. Both were initially based on indirect evidence from pharmacological studies supported by post-mortem findings, but have since been substantially advanced by new lines of evidence from in vivo imaging studies. This review provides an update on the latest findings on dopamine and glutamate abnormalities in schizophrenia, focusing on in vivo neuroimaging studies in patients and clinical high-risk groups, and considers their implications for understanding the biology and treatment of schizophrenia. These findings have refined both the dopamine and glutamate hypotheses, enabling greater anatomical and functional specificity, and have been complemented by preclinical evidence showing how the risk factors for schizophrenia impact on the dopamine and glutamate systems. The implications of this new evidence for understanding the development and treatment of schizophrenia are considered, and the gaps in current knowledge highlighted. Finally, the evidence for an integrated model of the interactions between the glutamate and dopamine systems is reviewed, and future directions discussed.

Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology

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.

The Role of Genes, Stress, and Dopamine in the Development of Schizophrenia

The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia. Because it was initially based on indirect evidence and findings in patients with established schizophrenia, it was unclear what role dopamine played in the onset of the disorder. However, recent studies in people at risk of schizophrenia have found elevated striatal dopamine synthesis capacity and increased dopamine release to stress. Furthermore, striatal dopamine changes have been linked to altered cortical function during cognitive tasks, in line with preclinical evidence that a circuit involving cortical projections to the striatum and midbrain may underlie the striatal dopamine changes. Other studies have shown that a number of environmental risk factors for schizophrenia, such as social isolation and childhood trauma, also affect presynaptic dopaminergic function. Advances in preclinical work and genetics have begun to unravel the molecular architecture linking dopamine, psychosis, and psychosocial stress. Included among the many genes associated with risk of schizophrenia are the gene encoding the dopamine D2 receptor and those involved in the upstream regulation of dopaminergic synthesis, through glutamatergic and gamma-aminobutyric acidergic pathways. A number of these pathways are also linked to the stress response. We review these new lines of evidence and present a model of how genes and environmental factors may sensitize the dopamine system so that it is vulnerable to acute stress, leading to progressive dysregulation and the onset of psychosis. Finally, we consider the implications for rational drug development, in particular regionally selective dopaminergic modulation, and the potential of genetic factors to stratify patients.

Inflammation and the neural diathesis-stress hypothesis of schizophrenia: a reconceptualization

An interaction between external stressors and intrinsic vulnerability is one of the longest standing pathoaetiological explanations for schizophrenia. However, novel lines of evidence from genetics, preclinical studies, epidemiology and imaging have shed new light on the mechanisms that may underlie this, implicating microglia as a key potential mediator. Microglia are the primary immune cells of the central nervous system. They have a central role in the inflammatory response, and are also involved in synaptic pruning and neuronal remodeling. In addition to immune and traumatic stimuli, microglial activation occurs in response to psychosocial stress. Activation of microglia perinatally may make them vulnerable to subsequent overactivation by stressors experienced in later life. Recent advances in genetics have shown that variations in the complement system are associated with schizophrenia, and this system has been shown to regulate microglial synaptic pruning. This suggests a mechanism via which genetic and environmental influences may act synergistically and lead to pathological microglial activation. Microglial overactivation may lead to excessive synaptic pruning and loss of cortical gray matter. Microglial mediated damage to stress-sensitive regions such as the prefrontal cortex and hippocampus may lead directly to cognitive and negative symptoms, and account for a number of the structural brain changes associated with the disorder. Loss of cortical control may also lead to disinhibition of subcortical dopamine—thereby leading to positive psychotic symptoms. We review the preclinical and in vivo evidence for this model and consider the implications this has for treatment, and future directions.

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).

Brain-imaging studies of treatment-resistant schizophrenia: a systematic review

Around 30% of patients with schizophrenia show an inadequate response to antipsychotics-ie, treatment resistance. Neuroimaging studies can help to uncover the underlying neurobiological reasons for such resistance and identify these patients earlier. Additionally, studies examining the effect of clozapine on the brain can help to identify aspects of clozapine that make it uniquely effective in patients with treatment resistance. We did a systematic search of PubMed between Jan 1, 1980, and April 13, 2015, to identify all neuroimaging studies that examined treatment-resistant patients or longitudinally assessed the effects of clozapine treatment. We identified 330 articles, of which 61 met the inclusion criteria. Replicated differences between treatment-resistant and treatment-responsive patients include reductions in grey matter and perfusion of frontotemporal regions, and increases in white matter and basal ganglia perfusion, with effect sizes ranging from 0·4 to greater than 1. Clozapine treatment led to reductions in caudate nucleus volume in three separate studies. The available evidence supports the hypothesis that some of the neurobiological changes seen in treatment-resistant schizophrenia lie along a continuum with treatment-responsive schizophrenia, whereas other differences are categorical in nature and have potential to be used as biomarkers. However, further replication is needed, and for neuroimaging findings to be clinically translatable, future studies need to focus on a-priori hypotheses and be adequately powered.

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.

Is psychosis a multisystem disorder? A meta-review of central nervous system, immune, cardiometabolic, and endocrine alterations in first-episode psychosis and perspective on potential models

People with psychotic disorders show abnormalities in several organ systems in addition to the central nervous system (CNS); and this contributes to excess mortality. However, it is unclear how strong the evidence is for alterations in non-CNS systems at the onset of psychosis, how the alterations in non-CNS systems compare to those in the CNS, or how they relate to symptoms. Here, we consider these questions, and suggest potential models to account for findings. We conducted a systematic meta-review to summarize effect sizes for both CNS (focusing on brain structural, neurophysiological, and neurochemical parameters) and non-CNS dysfunction (focusing on immune, cardiometabolic, and hypothalamic–pituitary–adrenal (HPA) systems) in first-episode psychosis (FEP). Relevant meta-analyses were identified in a systematic search of Pubmed and the methodological quality of these was assessed using the AMSTAR checklist (A Measurement Tool to Assess Systematic Reviews). Case–control data were extracted from studies included in these meta-analyses. Random effects meta-analyses were re-run and effect size magnitudes for individual parameters were calculated, as were summary effect sizes for each CNS and non-CNS system. We also grouped studies to obtain overall effect sizes for non-CNS and CNS alterations. Robustness of data for non-CNS and CNS parameters was assessed using Rosenthal’s fail-safe N. We next statistically compared summary effect size for overall CNSand overall non-CNS alterations, as well as for each organ system separately. We also examined how non-CNS alterations correlate CNS alterations, and with psychopathological symptoms. Case-control data were extracted for 165 studies comprising a total sample size of 13,440. For people with first episode psychosis compared with healthy controls, we observed alterations in immune parameters (summary effect size: g = 1.19), cardiometabolic parameters (g = 0.23); HPA parameters (g = 0.68); brain structure (g = 0.40); neurophysiology (g = 0.80); and neurochemistry (g = 0.43). Grouping non-CNS organ systems together provided an effect size for overall non-CNS alterations in patients compared with controls (g = 0.58), which was not significantly different from the overall CNS alterations effect size (g = 0.50). However, the summary effect size for immune alterations was significantly greater than that for brain structural (P < 0.001) and neurochemical alterations (P < 0.001), while the summary effect size for cardiometabolic alterations was significantly lower than neurochemical (P = 0.04), neurophysiological (P < 0.001), and brain structural alterations (P = 0.001). The summary effect size for HPA alterations was not significantly different from brain structural (P = 0.14), neurophysiological (P = 0.54), or neurochemical alterations (P = 0.22). These outcomes remained similar in antipsychotic naive sensitivity analyses. We found some, but limited and inconsistent, evidence that non-CNS alterations were associated with CNS changes and symptoms in first episode psychosis. Our findings indicate that there are robust alterations in non-CNS systems in psychosis, and that these are broadly similar in magnitude to a range of CNS alterations. We consider models that could account for these findings and discuss implications for future research and treatment.

Defining the Locus of Dopaminergic Dysfunction in Schizophrenia: A Meta-analysis and Test of the Mesolimbic Hypothesis

Abstract Background Studies using positron emission tomography to image striatal dopamine function, have demonstrated that individuals with schizophrenia display increases in presynaptic function. Mesolimbic dysfunction specifically, has previously been suggested to underlie psychotic symptoms. This has not been directly tested in vivo, and the precise anatomical locus of dopamine dysfunction within the striatum remains unclear. The current article investigates the magnitude of dopaminergic abnormalities in individuals with schizophrenia, and determines how the magnitude of abnormality varies across functional subdivisions of the striatum. Methods EMBASE, PsychINFO, and MEDLINE were searched from January 1, 1960, to December 1, 2016. Inclusion criteria were molecular imaging studies that had measured presynaptic striatal dopamine functioning. Effects sizes for whole striatum and functional subdivisions were calculated separately. The magnitude of difference between functional subdivisions in patients and controls was meta-analyzed. Results Twenty-one eligible studies were identified, including 269 patients and 313 controls. Individuals with schizophrenia (Hedges’ g = 0.68, P < .001) demonstrated elevated presynaptic dopamine functioning compared to controls. Seven studies examined functional subdivisions. These demonstrated significant increases in patients compared to controls in associative (g = 0.73, P = .002) and sensorimotor (g = 0.54, P = .005) regions, but not limbic (g = 0.29, P = .09). The magnitude of the difference between associative and limbic subdivisions was significantly greater in patients compared to controls (g = 0.39, P = .003). Conclusion In individuals with schizophrenia dopaminergic dysfunction is greater in dorsal compared to limbic subdivisions of the striatum. This is inconsistent with the mesolimbic hypothesis and identifies the dorsal striatum as a target for novel treatment development.