Corrigendum: The effect of antipsychotics on glutamate levels in the anterior cingulate cortex and clinical response: a 1H-MRS study in first-episode psychosis patients.

[This corrects the article DOI: 10.3389/fpsyt.2022.967941.].

Discontinuation of psychotropic medication: a synthesis of evidence across medication classes.

Pharmacotherapy is an effective treatment modality across psychiatric disorders. Nevertheless, many patients discontinue their medication at some point. Evidence-based guidance for patients, clinicians, and policymakers on rational discontinuation strategies is vital to enable the best, personalized treatment for any given patient. Nonetheless, there is a scarcity of guidelines on discontinuation strategies. In this perspective, we therefore summarize and critically appraise the evidence on discontinuation of six major psychotropic medication classes: antidepressants, antipsychotics, benzodiazepines, mood stabilizers, opioids, and stimulants. For each medication class, a wide range of topics pertaining to each of the following questions are discussed: (1) Who can discontinue (e.g., what are risk factors for relapse?); (2) When to discontinue (e.g., after 1 year or several years of antidepressant use?); and (3) How to discontinue (e.g., what's the efficacy of dose reduction compared to full cessation and interventions to mitigate relapse risk?). We thus highlight how comparing the evidence across medication classes can identify knowledge gaps, which may pave the way for more integrated research on discontinuation.

Histamine-3 Receptor Availability and Glutamate Levels in the Brain: A PET-1H-MRS Study of Patients With Schizophrenia and Healthy Controls.

BACKGROUND: The histamine-3 receptor (H3R) may have a role in cognitive processes through its action as a presynaptic heteroreceptor inhibiting the release of glutamate in the brain. To explore this, we examined anterior cingulate cortex (ACC) and striatum H3R availability in patients with schizophrenia and characterized their relationships with glutamate levels in corresponding brain regions. METHODS: We employed a cross-sectional study, recruiting 12 patients with schizophrenia and 12 healthy volunteers. Participants underwent positron emission tomography using the H3R-specific radio ligand [11C]MK-8278, followed by proton magnetic resonance spectroscopy to measure glutamate levels, recorded as Glu and Glx. Based on existing literature, the ACC and striatum were selected as regions of interest. RESULTS: We found significant inverse relationships between tracer uptake and Glu (r = -0.66, P = .02) and Glx (r = -0.62, P = .04) levels in the ACC of patients, which were absent in healthy volunteers (Glu: r = -0.19, P = .56, Glx: r = 0.10, P = .75). We also found a significant difference in striatal (F1,20 = 6.00, P = .02) and ACC (F1,19 = 4.75, P = .04) Glx levels between groups. CONCLUSIONS: These results provide evidence of a regionally specific relationship between H3Rs and glutamate levels, which builds on existing preclinical literature. Our findings add to a growing literature indicating H3Rs may be a promising treatment target in schizophrenia, particularly for cognitive impairment, which has been associated with altered glutamate signaling.

Synaptic Terminal Density Early in the Course of Schizophrenia: An In Vivo UCB-J Positron Emission Tomographic Imaging Study of SV2A.

BACKGROUND: The synaptic hypothesis is an influential theory of the pathoetiology of schizophrenia (SCZ), which is supported by the finding that there is lower uptake of the synaptic terminal density marker [11C]UCB-J in patients with chronic SCZ than in control participants. However, it is unclear whether these differences are present early in the illness. To address this, we investigated [11C]UCB-J volume of distribution (VT) in antipsychotic-naïve/free patients with SCZ who were recruited from first-episode services compared with healthy volunteers. METHODS: Forty-two volunteers (SCZ n = 21, healthy volunteers n = 21) underwent [11C]UCB-J positron emission tomography to index [11C]UCB-J VT and distribution volume ratio in the anterior cingulate, frontal, and dorsolateral prefrontal cortices; the temporal, parietal and occipital lobes; and the hippocampus, thalamus, and amygdala. Symptom severity was assessed in the SCZ group using the Positive and Negative Syndrome Scale. RESULTS: We found no significant effects of group on [11C]UCB-J VT or distribution volume ratio in most regions of interest (effect sizes from d = 0.0-0.7, p > .05), with two exceptions: we found lower distribution volume ratio in the temporal lobe (d = 0.7, uncorrected p < .05) and lower VT/fp in the anterior cingulate cortex in patients (d = 0.7, uncorrected p < .05). The Positive and Negative Syndrome Scale total score was negatively associated with [11C]UCB-J VT in the hippocampus in the SCZ group (r = -0.48, p = .03). CONCLUSIONS: These findings indicate that large differences in synaptic terminal density are not present early in SCZ, although there may be more subtle effects. When taken together with previous evidence of lower [11C]UCB-J VT in patients with chronic illness, this may indicate synaptic density changes during the course of SCZ.

Does Slow and Steady Win the Race? Rates of Antipsychotic Discontinuation, Antipsychotic Dose, and Risk of Psychotic Relapse.

BACKGROUND: Antipsychotics are recommended for prevention of relapse in schizophrenia. It is unclear whether increased risk of relapse following antipsychotic discontinuation is predominantly associated with an absolute magnitude of dose reduction or rate of antipsychotic reduction. Establishing the responsible mechanism is important because prolonged withdrawal schedules have been suggested to reduce risk of relapse. STUDY DESIGN: Individual patient data from antipsychotic discontinuation studies were obtained. We estimated the occupancy of receptors over time using half-lives and median effective dose ED50 values obtained from pharmacokinetic and receptor occupancy studies. Hazard ratios for relapse events were calculated using Cox proportional hazards models to assess the influence of formulation (oral, 1-monthly, and 3-monthly injections). The change in hazard ratio over time was estimated, and the effect of time-varying covariates was calculated, including rate of occupancy reduction and absolute receptor occupancy. STUDY RESULTS: Five studies including 1388 participants with schizophrenia were identified (k = 2: oral, k = 2: 1-monthly injection, k = 1: 3-monthly injection). Withdrawal of long-acting injectable medication did not lead to a lower hazard ratio compared with withdrawal of oral medication, and this included the period immediately following randomization. Hazard ratios were not associated with the rate of decline of receptor occupancy; however, they were associated with reduced absolute occupancy in trials of long-acting injections (P = .038). CONCLUSIONS: Antipsychotic discontinuation is associated with an increased risk of psychotic relapse, related to receptor occupancy. Although relapse does not appear to be related to the rate of discontinuation, gradual discontinuation strategies may allow for easier antipsychotic reinstatement in case of symptomatic worsening.

Dopamine in major depressive disorder: A systematic review and meta-analysis of in vivo imaging studies.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of global disability. Several lines of evidence implicate the dopamine system in its pathophysiology. However, the magnitude and consistency of the findings are unknown. We address this by systematically reviewing in vivo imaging evidence for dopamine measures in MDD and meta-analysing these where there are sufficient studies. METHODS: Studies investigating the dopaminergic system using positron emission tomography or single photon emission computed tomography in MDD and a control group were included. Demographic, clinical and imaging measures were extracted from each study, and meta-analyses and sensitivity analyses were conducted. RESULTS: We identified 43 studies including 662 patients and 801 controls. Meta-analysis of 38 studies showed no difference in mean or mean variability of striatal D2/3 receptor availability (g = 0.06, p = 0.620), or combined dopamine synthesis and release capacity (g = 0.19, p = 0.309). Dopamine transporter (DAT) availability was lower in the MDD group in studies using DAT selective tracers (g = -0.56, p = 0.006), but not when tracers with an affinity for serotonin transporters were included (g = -0.21, p = 0.420). Subgroup analysis showed greater dopamine release (g = 0.49, p = 0.030), but no difference in dopamine synthesis capacity (g = -0.21, p = 0.434) in the MDD group. Striatal D1 receptor availability was lower in patients with MDD in two studies. CONCLUSIONS: The meta-analysis indicates striatal DAT availability is lower, but D2/3 receptor availability is not altered in people with MDD compared to healthy controls. There may be greater dopamine release and lower striatal D1 receptors in MDD, although further studies are warranted. We discuss factors associated with these findings, discrepancies with preclinical literature and implications for future research.

Antidepressant and antipsychotic side-effects and personalised prescribing: a systematic review and digital tool development.

BACKGROUND: Side-effects of psychiatric medication impair quality of life and functioning. Furthermore, they contribute to morbidity, mortality, stigma, and poor treatment concordance resulting in relapse of psychiatric illness. Guidelines recommend discussing side-effects with patients when making treatment decisions, but a synthesis of antidepressant and antipsychotic side-effects to guide this process is missing, and considering all side-effects is a complex, multidimensional process. We aimed to create comprehensive databases of antipsychotic and antidepressant side-effects, and a digital tool to support database navigation. METHODS: To create the databases, we did an umbrella review of Embase, PsycINFO, and MEDLINE from database inception to June 26, 2023. We included meta-analyses of randomised controlled trials examining antipsychotic monotherapy in the treatment of schizophrenia or antidepressant monotherapy in the treatment of major depressive disorder. We included meta-analyses in adults (aged ≥18 years) that assessed drugs with a common comparator. The search was complemented by a review of national and international guidelines and consensus statements for the treatment of major depressive disorder and schizophrenia in adults. Effect sizes for antipsychotic and antidepressant side-effects were extracted from meta-analyses examining the largest number of drugs. In cases of incomplete meta-analytic coverage, data were imputed on the basis of guideline-derived ordinal rankings or, if imputation was not possible, ordinal scores were extracted. Both meta-analytic and ordinal outcomes were normalised to provide values between 0 and 1. We then constructed a digital tool, the Psymatik Treatment Optimizer, to combine the side-effect databases with side-effect concerns of an individual user, to enable users to select side-effects of concern and the relative degree of concern for each side-effect. Concern weightings and the side-effect databases are synthesised via a multicriteria decision analysis method (technique for order of preference by similarity to ideal situation, or TOPSIS). FINDINGS: Of 3724 citations, 14 articles containing 68 meta-analyses of individual side-effects met inclusion criteria. After review of 19 guidelines, seven provided ordinal data. Antipsychotic data were extracted from five studies (11 meta-analyses, n=65 594 patients) and four guidelines, and antidepressant data were extracted from three guidelines. The resultant databases included data on 32 antipsychotics (14 side-effects) and 37 antidepressants (nine side-effects). The databases highlighted the clinical dilemma associated with balancing side-effects, with avoidance of one side-effect (eg, weight gain for antipsychotics) increasing the risk of others (eg, akathisia). To aid with this dilemma, the Psymatik Treatment Optimizer synthesises the side-effect databases with individual user-defined concern weights. After computing up to 5851 pairwise comparisons for antidepressants and 5142 pairwise comparisons for antipsychotics, Psymatik ranks treatments in order of preference for the individual user, with the output presented in a heatmap. INTERPRETATION: By facilitating collaborative, personalised, and evidence-based prescribing decisions, the side-effect databases and digital application supports care delivery that is consistent with international regulatory guidance for the treatment of schizophrenia and depression, and it therefore has promise for informing psychiatric practice and improving outcomes. FUNDING: National Institute for Health and Care Research, Maudsley Charity, Wellcome Trust, Medical Research Council.

The relationship between striatal dopamine and anterior cingulate glutamate in first episode psychosis changes with antipsychotic treatment.

The neuromodulator dopamine and excitatory neurotransmitter glutamate have both been implicated in the pathogenesis of psychosis, and dopamine antagonists remain the predominant treatment for psychotic disorders. To date no study has measured the effect of antipsychotics on both of these indices together, in the same population of people with psychosis. Striatal dopamine synthesis capacity (Kicer) and anterior cingulate glutamate were measured using 18F-DOPA positron emission tomography and proton magnetic resonance spectroscopy respectively, before and after at least 5 weeks' naturalistic antipsychotic treatment in people with first episode psychosis (n = 18) and matched healthy controls (n = 20). The relationship between both measures at baseline and follow-up, and the change in this relationship was analyzed using a mixed linear model. Neither anterior cingulate glutamate concentrations (p = 0.75) nor striatal Kicer (p = 0.79) showed significant change following antipsychotic treatment. The change in relationship between whole striatal Kicer and anterior cingulate glutamate, however, was statistically significant (p = 0.017). This was reflected in a significant difference in relationship between both measures for patients and controls at baseline (t = 2.1, p = 0.04), that was not present at follow-up (t = 0.06, p = 0.96). Although we did not find any effect of antipsychotic treatment on absolute measures of dopamine synthesis capacity and anterior cingulate glutamate, the relationship between anterior cingluate glutamate and striatal dopamine synthesis capacity did change, suggesting that antipsychotic treatment affects the relationship between glutamate and dopamine.

An automatic analysis framework for FDOPA PET neuroimaging.

In this study we evaluate the performance of a fully automated analytical framework for FDOPA PET neuroimaging data, and its sensitivity to demographic and experimental variables and processing parameters. An instance of XNAT imaging platform was used to store the King's College London institutional brain FDOPA PET imaging archive, alongside individual demographics and clinical information. By re-engineering the historical Matlab-based scripts for FDOPA PET analysis, a fully automated analysis pipeline for imaging processing and data quantification was implemented in Python and integrated in XNAT. The final data repository includes 892 FDOPA PET scans organized from 23 different studies. We found good reproducibility of the data analysis by the automated pipeline (in the striatum for the Kicer: for the controls ICC = 0.71, for the psychotic patients ICC = 0.88). From the demographic and experimental variables assessed, gender was found to most influence striatal dopamine synthesis capacity (F = 10.7, p < 0.001), with women showing greater dopamine synthesis capacity than men. Our automated analysis pipeline represents a valid resourse for standardised and robust quantification of dopamine synthesis capacity using FDOPA PET data. Combining information from different neuroimaging studies has allowed us to test it comprehensively and to validate its replicability and reproducibility performances on a large sample size.

Fifty years on: Serotonin and depression.

It has been over 50 years since the original serotonin hypothesis was proposed by the British Psychiatrist Alec Coppen. Recently, some authors have questioned the validity of the hypothesis. In this narrative review, we summarise the evidence for the serotonin hypothesis of depression, focusing on psychopharmacology and molecular imaging, as well as systems-level neuroscience.

Parsing neurobiological heterogeneity of the clinical high-risk state for psychosis: A pseudo-continuous arterial spin labelling study.

Introduction: The impact of the clinical high-risk for psychosis (CHR-P) construct is dependent on accurately predicting outcomes. Individuals with brief limited intermittent psychotic symptoms (BLIPS) have higher risk of developing a first episode of psychosis (FEP) compared to individuals with attenuated psychotic symptoms (APS). Supplementing subgroup stratification with information from candidate biomarkers based on neurobiological parameters, such as resting-state, regional cerebral blood flow (rCBF), may help refine risk estimates. Based on previous evidence, we hypothesized that individuals with BLIPS would exhibit increased rCBF compared to APS in key regions linked to dopaminergic pathways. Methods: Data from four studies were combined using ComBat (to account for between-study differences) to analyse rCBF in 150 age- and sex-matched subjects (n = 30 healthy controls [HCs], n = 80 APS, n = 20 BLIPS and n = 20 FEP). Global gray matter (GM) rCBF was examined in addition to region-of-interest (ROI) analyses in bilateral/left/right frontal cortex, hippocampus and striatum. Group differences were assessed using general linear models: (i) alone; (ii) with global GM rCBF as a covariate; (iii) with global GM rCBF and smoking status as covariates. Significance was set at p < 0.05. Results: Whole-brain voxel-wise analyses and Bayesian ROI analyses were also conducted. No significant group differences were found in global [F(3,143) = 1,41, p = 0.24], bilateral frontal cortex [F(3,143) = 1.01, p = 0.39], hippocampus [F(3,143) = 0.63, p = 0.60] or striatum [F(3,143) = 0.52, p = 0.57] rCBF. Similar null findings were observed in lateralized ROIs (p > 0.05). All results were robust to addition of covariates (p > 0.05). No significant clusters were identified in whole-brain voxel-wise analyses (p > 0.05FWE). Weak-to-moderate evidence was found for an absence of rCBF differences between APS and BLIPS in Bayesian ROI analyses. Conclusion: On this evidence, APS and BLIPS are unlikely to be neurobiologically distinct. Due to this and the weak-to-moderate evidence for the null hypothesis, future research should investigate larger samples of APS and BLIPS through collaboration across large-scale international consortia.

Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis.

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan's unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = -0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = -0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = -0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = -0.02, p < 0.001) and frontal white matter Glx (z = -0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.

Off the RADAR; questions regarding the trial protocol of a randomised controlled trial of antipsychotic reduction and discontinuation.

The randomised controlled trial of antipsychotic reduction and discontinuation addresses essential questions with regard to continued use of antipsychotics in schizophrenia, pertaining to social functioning and continued antipsychotic use. However, significant methodological issues stated in the trial protocol have the potential to confound interpretation of any findings. These include use of a non-blinded outcome measure, treatment as usual comparator and possible sample size issues.

Reduced cortical cerebral blood flow in antipsychotic-free first-episode psychosis and relationship to treatment response.

BACKGROUND: Altered cerebral blood flow (CBF) has been found in people at risk for psychosis, with first-episode psychosis (FEP) and with chronic schizophrenia (SCZ). Studies using arterial spin labelling (ASL) have shown reduction of cortical CBF and increased subcortical CBF in SCZ. Previous studies have investigated CBF using ASL in FEP, reporting increased CBF in striatum and reduced CBF in frontal cortex. However, as these people were taking antipsychotics, it is unclear whether these changes are related to the disorder or antipsychotic treatment and how they relate to treatment response. METHODS: We examined CBF in FEP free from antipsychotic medication (N = 21), compared to healthy controls (N = 22). Both absolute and relative-to-global CBF were assessed. We also investigated the association between baseline CBF and treatment response in a partially nested follow-up study (N = 14). RESULTS: There was significantly lower absolute CBF in frontal cortex (Cohen's d = 0.84, p = 0.009) and no differences in striatum or hippocampus. Whole brain voxel-wise analysis revealed widespread cortical reductions in absolute CBF in large cortical clusters that encompassed occipital, parietal and frontal cortices (Threshold-Free Cluster Enhancement (TFCE)-corrected <0.05). No differences were found in relative-to-global CBF in the selected region of interests and in voxel-wise analysis. Relative-to-global frontal CBF was correlated with percentage change in total Positive and Negative Syndrome Scale after antipsychotic treatment (r = 0.67, p = 0.008). CONCLUSIONS: These results show lower cortical absolute perfusion in FEP prior to starting antipsychotic treatment and suggest relative-to-global frontal CBF as assessed with magnetic resonance imaging could potentially serve as a biomarker for antipsychotic response.

Striatal dopaminergic alterations in individuals with copy number variants at the 22q11.2 genetic locus and their implications for psychosis risk: a [18F]-DOPA PET study.

Dopaminergic dysregulation is one of the leading hypotheses for the pathoetiology underlying psychotic disorders such as schizophrenia. Molecular imaging studies have shown increased striatal dopamine synthesis capacity (DSC) in schizophrenia and people in the prodrome of psychosis. However, it is unclear if genetic risk for psychosis is associated with altered DSC. To investigate this, we recruited healthy controls and two antipsychotic naive groups of individuals with copy number variants, one with a genetic deletion at chromosome 22q11.2, and the other with a duplication at the same locus, who are at increased and decreased risk for psychosis, respectively. Fifty-nine individuals (21 with 22q11.2 deletion, 12 with the reciprocal duplication and 26 healthy controls) received clinical measures and [18F]-DOPA PET imaging to index striatal Kicer. There was an inverse linear effect of copy number variant number on striatal Kicer value (B = -1.2 × 10-3, SE = 2 × 10-4, p < 0.001), with controls showing levels intermediate between the two variant groups. Striatal Kicer was significantly higher in the 22q11.2 deletion group compared to the healthy control (p < 0.001, Cohen's d = 1.44) and 22q11.2 duplication (p < 0.001, Cohen's d = 2) groups. Moreover, Kicer was positively correlated with the severity of psychosis-risk symptoms (B = 730.5, SE = 310.2, p < 0.05) and increased over time in the subject who went on to develop psychosis, but was not associated with anxiety or depressive symptoms. Our findings suggest that genetic risk for psychosis is associated with dopaminergic dysfunction and identify dopamine synthesis as a potential target for treatment or prevention of psychosis in 22q11.2 deletion carriers.