Maria Rogdaki

A Test of the Transdiagnostic Dopamine Hypothesis of Psychosis Using Positron Emission Tomographic Imaging in Bipolar Affective Disorder and Schizophrenia

Importance The dopamine hypothesis suggests that dopamine abnormalities underlie psychosis, irrespective of diagnosis, implicating dopamine dysregulation in bipolar affective disorder and schizophrenia, in line with the research domain criteria approach. However, this hypothesis has not been directly examined in individuals diagnosed with bipolar disorder with psychosis. Objectives To test whether dopamine synthesis capacity is elevated in bipolar disorder with psychosis and how this compares with schizophrenia and matched controls and to examine whether dopamine synthesis capacity is associated with psychotic symptom severity, irrespective of diagnostic class. Design, Setting, and Participants This cross-sectional case-control positron emission tomographic study was performed in the setting of first-episode psychosis services in an inner-city area (London, England). Sixty individuals participated in the study (22 with bipolar psychosis [18 antipsychotic naive or free], 16 with schizophrenia [14 antipsychotic naive or free], and 22 matched controls) and underwent fluorodihydroxyphenyl-L-alanine ([18F]-DOPA) positron emission tomography to examine dopamine synthesis capacity. Standardized clinical measures, including the Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning, were administered. The study dates were March 2013 to November 2016. Main Outcomes and Measures Dopamine synthesis capacity (Kicer) and clinical measures (Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning). Results The mean (SD) ages of participants were 23.6 (3.6) years in 22 individuals with bipolar psychosis (13 male), 26.3 (4.4) years in 16 individuals with schizophrenia (14 male), and 24.5 (4.5) years in controls (14 male). There was a significant group difference in striatal dopamine synthesis capacity (Kicer) (F2,57 = 6.80, P = .002). Kicer was significantly elevated in both the bipolar group (mean [SD], 13.18 [1.08] × 10−3 min−1; P = .002) and the schizophrenia group (mean [SD], 12.94 [0.79] × 10−3 min−1; P = .04) compared with controls (mean [SD], 12.16 [0.92] × 10−3 min−1). There was no significant difference in striatal Kicer between the bipolar and schizophrenia groups. Kicer was significantly positively correlated with positive psychotic symptom severity in the combined bipolar and schizophrenia sample experiencing a current psychotic episode, explaining 27% of the variance in symptom severity (n = 32, r = 0.52, P = .003). There was a significant positive association between Kicer and positive psychotic symptom severity in individuals with bipolar disorder experiencing a current psychotic episode (n = 16, r = 0.60, P = .01), which remained significant after adjusting for manic symptom severity. Conclusions and Relevance These findings are consistent with a transdiagnostic role for dopamine dysfunction in the pathoetiology of psychosis and suggest dopamine synthesis capacity as a potential novel drug target for bipolar disorder and schizophrenia.

Regulation of dopaminergic function: an [(18)F]-DOPA PET apomorphine challenge study in humans

Dopaminergic function has a key role in normal brain function, dopaminergic dysfunction being implicated in numerous neuropsychiatric disorders. Animal studies show that dopaminergic stimulation regulates dopaminergic function, but it is not known whether this exists in humans. In the first study (study 1), we measured dopamine synthesis capacity (indexed as Kicer) to identify the relationship between baseline and change in Kicer under resting conditions for comparison with effects of dopaminergic stimulation. In the second study (study 2), we used a within-subjects design to test effects of dopaminergic stimulation on dopamine synthesis capacity. In study 1, eight volunteers received two 18F-DOPA scans on separate days, both at rest. In study 2, 12 healthy male volunteers received two 18F-DOPA positron emission tomographic (PET) scans after treatment with either the dopamine partial agonist apomorphine (0.03 or 0.005 mg kg−1) or placebo. In study 1, no significant correlation was found between baseline and change in dopamine synthesis capacity between scans (r=−0.57, n=8, P=0.17, two-tailed). In study 2, a significant negative correlation was found between baseline dopamine synthesis capacity and percentage change in dopamine synthesis capacity after apomorphine challenge (r=−0.71, n=12, P=0.01, two-tailed). This correlation was significantly different (P<0.01) from the correlation between baseline and change in dopamine synthesis capacity under unstimulated conditions. One-way repeated-measures analysis of variance showed a significant group (study 1/study 2) × time interaction (F(1,18)=11.5, P=0.003). Our findings suggest that regulation of dopamine synthesis capacity by apomorphine depends on baseline dopamine function, consistent with dopamine stimulation stabilizing dopaminergic function. Loss of this autoregulation may contribute to dopaminergic dysfunction in brain disorders such as schizophrenia, substance dependence, and Parkinsons disease.

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.

Determinants of treatment response in first-episode psychosis: an 18 F-DOPA PET study

Psychotic illnesses show variable responses to treatment. Determining the neurobiology underlying this is important for precision medicine and the development of better treatments. It has been proposed that dopaminergic differences underlie variation in response, with striatal dopamine synthesis capacity (DSC) elevated in responders and unaltered in non-responders. We therefore aimed to test this in a prospective cohort, with a nested case-control comparison. 40 volunteers (26 patients with first-episode psychosis and 14 controls) received an 18F-DOPA Positron Emission Tomography scan to measure DSC (Kicer) prior to antipsychotic treatment. Clinical assessments (Positive and Negative Syndrome Scale, PANSS, and Global Assessment of Functioning, GAF) occurred at baseline and following antipsychotic treatment for a minimum of 4 weeks. Response was defined using improvement in PANSS Total score of >50%. Patients were followed up for at least 6 months, and remission criteria applied. There was a significant effect of group on Kicer in associative striatum (F(2, 37) = 7.9, p = 0.001). Kicer was significantly higher in responders compared with non-responders (Cohen’s d = 1.55, p = 0.01) and controls (Cohen’s d = 1.31, p = 0.02). Kicer showed significant positive correlations with improvements in PANSS-positive (r = 0.64, p < 0.01), PANSS negative (rho = 0.51, p = 0.01), and PANSS total (rho = 0.63, p < 0.01) ratings and a negative relationship with change in GAF (r = −0.55, p < 0.01). Clinical response is related to baseline striatal dopaminergic function. Differences in dopaminergic function between responders and non-responders are present at first episode of psychosis, consistent with dopaminergic and non-dopaminergic sub-types in psychosis, and potentially indicating a neurochemical basis to stratify psychosis.

Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology:

An expert review of the aetiology, assessment, and treatment of autism spectrum disorder, and recommendations for diagnosis, management and service provision was coordinated by the British Association for Psychopharmacology, and evidence graded. The aetiology of autism spectrum disorder involves genetic and environmental contributions, and implicates a number of brain systems, in particular the gamma-aminobutyric acid, serotonergic and glutamatergic systems. The presentation of autism spectrum disorder varies widely and co-occurring health problems (in particular epilepsy, sleep disorders, anxiety, depression, attention deficit/hyperactivity disorder and irritability) are common. We did not recommend the routine use of any pharmacological treatment for the core symptoms of autism spectrum disorder. In children, melatonin may be useful to treat sleep problems, dopamine blockers for irritability, and methylphenidate, atomoxetine and guanfacine for attention deficit/hyperactivity disorder. The evidence for use of medication in adults is limited and recommendations are largely based on extrapolations from studies in children and patients without autism spectrum disorder. We discuss the conditions for considering and evaluating a trial of medication treatment, when non-pharmacological interventions should be considered, and make recommendations on service delivery. Finally, we identify key gaps and limitations in the current evidence base and make recommendations for future research and the design of clinical trials.

The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: a cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study

Summary Background The pathophysiology of psychosis is incompletely understood. Disruption in cortical glutamatergic signalling causing aberrant striatal dopamine synthesis capacity is a proposed model for psychosis, but has not been tested in vivo. We therefore aimed to test the relationship between cortical glutamate concentrations and striatal dopamine synthesis capacity, and psychotic symptoms. Methods In this cross-sectional multimodal imaging study, 28 individuals with first-episode psychosis and 28 healthy controls underwent 18F-DOPA PET (measuring striatal dopamine synthesis capacity), and proton magnetic resonance spectroscopy (measuring anterior cingulate cortex glutamate concentrations). Participants were recruited from first-episode psychosis services in London, UK and were required to be in the first episode of a psychotic illness, with no previous illness or treatment episodes. Exclusion criteria for all participants were: history of substantial head trauma, dependence on illicit substances, medical comorbidity (other than minor illnesses), and contraindications to scanning (such as pregnancy). Symptoms were measured using the Positive and Negative Syndrome Scale. The primary endpoint was the relationship between anterior cingulate cortex glutamate concentrations and striatal dopamine synthesis capacity in individuals with their first episode of psychosis as shown by imaging, examined by linear regression. Linear regression was used to examine relationships between measures. Findings Glutamate concentrations showed a significant inverse relationship with striatal dopamine synthesis capacity in patients with psychosis (R2=0·16, p=0·03, β −1·71 × 10−4, SE 0·76 × 10−4). This relationship remained significant after the addition of age, gender, ethnicity, and medication status to the model (p=0·015). In healthy controls, there was no significant relationship between dopamine and glutamate measures (R2=0·04, p=0·39). Positive and Negative Syndrome Scale positive psychotic symptoms were positively associated with striatal dopamine synthesis capacity (R2=0·14, p=0·046, β 2546, SE 1217) and showed an inverse relationship with anterior cingulate glutamate concentrations (R2=0·16, p=0·03, β −1·71 × 10−4, SE 7·63 × 10−5). No relationships were seen with negative symptoms (positive symptoms, mean [SD] −18·4 (6·6) negative symptoms, mean [SD] −15·4 [6·1]). Interpretation These observations are consistent with the hypothesis that cortical glutamate dysfunction is related to subcortical dopamine synthesis capacity and psychosis. Although the precise mechanistic relationship between cortical glutamate and dopamine in vivo remains unclear, our findings support further studies to test the effect of modulating cortical glutamate in the treatment of psychosis. Funding Medical Research Council, Wellcome Trust, Biomedical Research Council, South London and Maudsley NHS Foundation Trust, JMAS Sim Fellowship, Royal College of Physicians (Edinburgh) (SJ).

O3.5. TESTING THE DOPAMINE HYPOTHESIS OF PSYCHOSIS USING POSITRON EMISSION TOMOGRAPHIC IMAGING IN FIRST EPISODE BIPOLAR AFFECTIVE DISORDER AND SCHIZOPHRENIA

Abstract Background The dopamine hypothesis of psychosis suggests that dopamine abnormalities are present in psychotic illness, irrespective of diagnostic class. Meta-analyses of Positron Emission Tomography (PET) studies of the dopamine system have shown elevated dopamine synthesis capacity in schizophrenia, though there is a dearth of studies examining this in other psychotic disorders. We therefore sought to answer the question of whether abnormalities of the presynaptic dopamine system are seen in bipolar psychosis, how this compared to schizophrenia, and whether positive psychotic symptoms were associated with dopamine synthesis capacity, irrespective of diagnostic class. Methods Cross-sectional, case-control 18F-DOPA Positron Emission Tomography (PET) study in people with first episode bipolar psychosis, schizophrenia and control subjects. Clinical measures included the Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale and Global Assessment of Functioning (GAF). Results Mean (SD) ages were 23.6 (3.6) years in 22 people with bipolar psychosis (13 male), 26.3 (4.4) years in 16 people with schizophrenia (14 male), and 24.5 (4.5) years in controls (14 male). There was a significant group difference in striatal dopamine synthesis capacity (Kicer) (F2,57=6.80, P=.002), post-hoc tests indicating Kicer was significantly elevated in both the bipolar group (mean [SD], 13.18 [1.08]×10–3 min-1; P=.002) and the schizophrenia group (mean [SD], 12.94 [0.79]×10–3 min-1; P=.04) compared with controls (mean [SD], 12.16 [0.92]×10–3 min-1). Kicer was positively correlated with positive psychotic symptom severity in the combined bipolar and schizophrenia sample currently experiencing psychosis, explaining 27% of the variance in symptom severity (n=32, r=0.52, P=.003). Discussion This is the first study to examine the presynaptic dopamine system in bipolar psychosis, finding an elevation compared to controls, equivalent to schizophrenia, from first onset of illness. A relationship was found between dopamine synthesis capacity and positive psychotic symptoms, across diagnostic classes, indicating a transdiagnostic role for dopamine synthesis capacity and positive psychotic symptoms.

The Effects of Antipsychotic Treatment on Presynaptic Dopamine Synthesis Capacity in First-Episode Psychosis: A Positron Emission Tomography Study

Background Elevated striatal dopamine synthesis capacity has been implicated in the etiology and antipsychotic response in psychotic illness. The effects of antipsychotic medication on dopamine synthesis capacity are poorly understood, and no prospective studies have examined this question in a solely first-episode psychosis sample. Furthermore, it is unknown whether antipsychotic efficacy is linked to reductions in dopamine synthesis capacity. We conducted a prospective [18F]-dihydroxyphenyl-L-alanine positron emission tomography study in antipsychotic naïve/free people with first-episode psychosis commencing antipsychotic treatment. Methods Dopamine synthesis capacity (indexed as influx rate constant) and clinical symptoms (measured using Positive and Negative Syndrome Scale) were measured before and after at least 5 weeks of antipsychotic treatment in people with first-episode psychosis. Data from a prior study indicated that a sample size of 13 would have >80% power to detect a statistically significant change in dopamine synthesis capacity at alpha = .05 (two tailed). Results A total of 20 people took part in the study, 17 of whom were concordant with antipsychotic medication at therapeutic doses. There was no significant effect of treatment on dopamine synthesis capacity in the whole striatum (p = .47), thalamus, or midbrain, nor was there any significant relationship between change in dopamine synthesis capacity and change in positive (ρ = .35, p = .13), negative, or total psychotic symptoms. Conclusions Dopamine synthesis capacity is unaltered by antipsychotic treatment, and therapeutic effects are not mediated by changes in this aspect of dopaminergic function.