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Despite being associated with increased illness severity and suicidality compared to non-psychotic depression, psychotic depression remains under-researched, particularly in adolescents. With this article, we aim to review treatment options for psychotic depression in adolescents. We performed a multi-step narrative review, first identifying studies on adolescents with psychotic depression evaluating any intervention and with any methodological design. We subsequently complemented our search with systematic reviews and meta-analysis evaluating treatment interventions in adults with psychotic depression and adolescents with bipolar depression. Finally, we reviewed clinical guidelines to complement the evidence found and provided recommendations for clinical practice. Based on the findings, we recommend a stepped approach to the treatment of psychotic depression in adolescents. For mild cases with predominance of depressive symptoms, antidepressant monotherapy with a serotonin selective reuptake inhibitor (eg fluoxetine, sertraline or citalopram) could be trialed first. In severe presentations, antidepressant-antipsychotic combination would be the treatment of choice. The antidepressant-antipsychotic combination has been recommended by several clinical guidelines, systematic reviews and meta-analysis in this population, adolescents with bipolar depression and adults with psychotic depression. Another combination of antidepressant-antipsychotic with evidence from a case report is the fluoxetine-quetiapine combination. For those adolescents not responding to the antidepressant-antipsychotic combination, or those requiring a rapid response or unable to take medication, electroconvulsive therapy could be considered. Psychological interventions (eg cognitive behavioral therapy, family therapy or interpersonal psychotherapy training for adolescents) are recommended by clinical guidelines but require further research. Overall, literature on the field is scarce and limited, with most evidence coming from adults and other populations. Further research into effective and safe treatment of psychotic depression in adolescent population is needed., Competing Interests: Dr Aymerich received personal fees or grants from Janssen Cilag and Neuraxpharm outside the current work, and is supported by the Alicia Koplowitz Foundation. Dr Catalan has received speaking fees of Janssen-Cilag, Lundbeck-Otsuka and ROVI. Dr Jauhar reports personal fees from Boehringer-Ingelheim, Recordati, Lundbeck, Sunovian, LB pharmaceuticals, and non-financial support from British Association for Psychopharmacology, during the conduct of the study. Dr Salazar de Pablo reports personal fees from Janssen Cilag Lundbeck, Angelini and Menarini, outside the submitted work the authors report no other conflicts of interest in this work., (© 2025 Perez-Rodriguez et al.)

Background: Muscarinic receptor agonism and positive allosteric modulation is a promising mechanism of action for treating psychosis, not present in most D2R-blocking antipsychotics. Xanomeline, an M1/M4-preferring agonist, has shown efficacy in late-stage clinical trials, with more compounds being investigated. Therefore, we aim to synthesize evidence on the preclinical efficacy of muscarinic receptor agonists and positive allosteric modulators in animal models of psychosis to provide unique insights and evidence-based information to guide drug development., Methods: We plan a systematic review and meta-analysis of in vivo animal studies comparing muscarinic receptor agonists or positive allosteric modulators with control conditions and existing D2R-blocking antipsychotics in animals subjected to any method that induces behavioural changes of relevance for psychosis. We will identify eligible studies by searching multiple electronic databases. At least two independent reviewers will conduct the study selection and data extraction using prespecified forms and assess the risk of bias with the SYRCLE's tool. Our primary outcomes include locomotor activity and prepulse inhibition measured with standardized mean differences. We will examine other behavioural readouts of relevance for psychosis as secondary outcomes, such as social interaction and cognitive function. We will synthesize the data using multi-level meta-analysis with a predefined random-effects structure, considering the non-independence of the data. In meta-regressions we will explore potential sources of heterogeneity from a predefined list of characteristics of the animal population, model, and intervention. We will assess the confidence in the evidence considering a self-developed instrument thatconsiders the internal and external validity of the evidence., Protocol Registration: PROSPERO-ID: CRD42024520914., Competing Interests: Competing interests: Spyridon Siafis: None. Nobuyuki Nomura: N.N. has received manuscript fees from Sumitomo Pharma. Johannes Schneider-Thoma: None. Irene Bighelli: None. Alexandra Bannach-Brown: None. Fiona J. Ramage: None. Francesca Tinsdeall: None. Ioannis Mantas: None. Sameer Jauhar: SJ has received honoraria for educational talks given for Boehringer Ingelheim, Lundbeck, Janssen, and Sunovion, and has advised on antipsychotics to LB Pharmaceuticals. Sridhar Natesan: None. Anthony Vernon: ACV has received research support from UCB S.A and Bit.Bio (https://www.bit.bio/) and has received honoraria for seminars at GlaxoSmithKline. Andrea de Bartolomeis: AdB has received research support from Janssen, Lundbeck, and Otsuka and lecture fees for educational meeting from Chiesi, Lundbeck, Roche, Sunovion, Vitria, Recordati, Angelini and Takeda; he has served on advisory boards for Eli Lilly, Jansen, Lundbeck, Otsuka, Roche, and Takeda, Chiesi, Recordati, Angelini, Vitria. Sabine M. Hölter: None. Natascha I. Drude: None. Ulf Tölch: None. Wulf-Peter Hansen: None. Virginia Chiocchia: None. Oliver Howes: ODH has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Elysium, Heptares, Global Medical Education, Invicro, Jansenn, Karuna, Lundbeck, Merck, Neurocrine, Ontrack/ Pangea, Otsuka, Sunovion, Recordati, Roche, Rovi and Viatris/ Mylan. He was previously a part-time employee of Lundbeck A/v. Dr Howes has a patent for the use of dopaminergic imaging. Josef Priller: None. Georgia Salanti: None. Malcolm R. Macleod: None. Stefan Leucht: SL has received received honoraria for advising/consulting and/or for lectures and/or for educational material from Angelini, Boehringer Ingelheim, Eisai, Ekademia, GedeonRichter, Janssen, Karuna, Kynexis, Lundbeck, Medichem, Medscape, Mitsubishi, Otsuka, NovoNordisk, Recordati, Rovi, Teva., (Copyright: © 2025 Siafis S et al.)

Introduction: Most people with bipolar disorder (BD) experience sleep disturbances across mood states and many identify sleep changes before both depressive and manic episodes. Nearly half of all patients have multiple relapses of BD and identifying early warning signs of relapse, such as sleep changes, could benefit both patients and clinicians as a preventive strategy., Methods: A systematic search of the databases Embase, APA PsychINFO, and MEDLINE was performed to identify studies that investigated the relationship between sleep changes and mood in BD. The review was registered with PROSPERO (CRD42023405950) and followed the PRISMA guidelines. Results were categorised based on the identified relationship between sleep changes and mood, e.g. sleep and depression correlation, and these are synthesised narratively. The Newcastle-Ottawa scale was used to assess the risk of bias (RoB)., Results: The systematic literature search yielded 7159 records. 17 publications were included, describing 13 studies. Nine categories were identified describing the relationship between sleep and mood (e.g. sleep-mood correlations and comparing BD and HC on sleep duration). Regardless of sleep assessment (e.g. actigraphy), study duration or mood outcome, changes towards longer sleep, earlier onset and later wake-up were mostly followed by depressive mood, and vice versa for mania. 14 papers had a "fair" RoB rating., Discussion: Changes in sleep patterns appear to precede predictable mood changes in BD and could be used as early warning signs for patients and clinicians. The main limitation of the study is the high heterogeneity between study results, preventing the conduction of a meta-analysis., Competing Interests: Declaration of competing interest Author MB has received grants from Deutsche Forschungsgemeinschaft (DFG), Bundesministerium für Bildung und Forschung (BMBF), European Commission, Sächsische Aufbaubank, as well as sat on advisory boards for MedEd-Link Inc. Janssen Global Services, LLC, Biogen, COMPASS Pathfinder Ltd., FoGes UG, GH Research, Janssen-Cilag, Livanova, Msd Sharp & Dohme, MINDFORCE, Novartis Switzerland, Sunovion, and finally received lecture fees from Janssen-Cilag, Biogen, and FoGes UG. Author AC has received grant funding from the MRC, ADM Protexin Ltd., NIHR, European Union Horizon Europe/Innovate UK, Beckley Psytech Ltd., and Wellcome Trust, has received payment or honoraria for presentations and/or consulting from Janssen, Otsuka, COMPASS Pathways Plc., Viatris and Medscape, and is President of the International Society for Affective Disorders. Author SJ has received honoraria for educational talks given for Boehringer-Ingelheim, Lundbeck, Sunovian and Janssen. He has been an advisor to LB pharmaceuticals. He has sat on a funding panel for the Wellcome Trust, and as expert advisor for a NICE Technology Appraisal. He is a member of Council for the British Association for Psychopharmacology (unpaid). Author ES has received a grant from “Bundesministerium für Bildung und Forschung (BMBF)”. The authors report no other conflicts of interest., (Crown Copyright © 2025. Published by Elsevier B.V. All rights reserved.)

Rationale: Working memory impairment is a prominent feature of schizophrenia which predicts clinical and functional outcomes. Preclinical data suggest histamine-3 receptor (H3R) expression in cortical pyramidal neurons may have a role in working memory, and post-mortem data has found disruptions of H3R expression in schizophrenia., Objectives: We examined the role of H3R in vivo to elucidate its role on working memory impairment in schizophrenia., Methods: We used positron emission tomography (PET) with the selective H3R radioligand [ 11 C]MK-8278 to measure H3R availability, and employed a task during functional magnetic resonance imaging (fMRI) to assess working memory-evoked brain activation and cognitive task performance, in patients with schizophrenia (n = 12) and matched healthy volunteers (n = 12). We assessed the relationship between H3R availability and both task performance and working memory-evoked brain activation in regions of interest (ROIs), including the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC)., Results: Patients with schizophrenia showed a strong positive correlation, after corrections for multiple comparisons, between ACC H3R availability and task performance (rho = 0.73, p = 0.007), which was absent in the control group (rho = 0.03, p = 0.94). Further ROI analysis did not find a significant relationship between H3R availability and working memory-evoked brain activation., Conclusions: These results provide support for the role of H3R on working memory processes in patients with schizophrenia., Competing Interests: Declarations. Conflicts of interest: AA, ES, MMN, SJK, MV, and ECO have no conflicting interests to declare. In the last 3 years, SJ has given non-promotional educational talks for Lundbeck, Janssen, and Sunovion. EAR is a full-time employee of Invicro, an imaging centre conducting contract studies for pharmaceutical and biotech partners. As part of his role, EAR has consulted for numerous industry and academic entities. ODH is a part-time employee and stockholder of Lundbeck A/s. He has received investigator-initiated research funding from and/or participated in advisory/ speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Jansenn, Lundbeck, Neurocrine, Otsuka, Sunovion, Recordati, Roche and Viatris/ Mylan. ODH has a patent for the use of dopaminergic imaging., (© 2024. The Author(s).)

Background: Psychedelic drugs are a focus of interest in the treatment of depression and other disorders but there are longstanding concerns about possible adverse psychiatric consequences. Because the relevant literature is largely informal, the seriousness of these risks is difficult to evaluate., Methods: Searches were made for case reports of schizophrenia-spectrum, affective or other psychiatric disorders after use of psychedelic drugs. Case reports of flashbacks were also searched for. Individuals with recent use of other drugs (apart from cannabis and alcohol) and/or a previous history of major psychiatric disorder were excluded. Symptoms were tabulated using the Syndrome Check List of the Present State Examination (PSE-9)., Results: We found 17 case reports of schizophrenia spectrum disorder, 17 of affective disorder (depression, mania, or both), 3 cases of anxiety, 1 of depersonalization, and 1 of unclassifiable illness. The states could develop after a single use of the drug (5/17 schizophrenia; 6/17 affective disorder), and duration was highly variable. Recovery was the rule in cases of affective disorder but not in schizophrenia spectrum disorder. Twelve of 29 cases of flashbacks showed psychiatric symptomatology definitely outlasting the attacks, mainly anxiety (5 cases) and depression (8 cases). Flashback symptoms resolved within twelve months in approximately half of the cases but in a few persisted for years., Conclusions: Reliable descriptions of schizophrenia spectrum disorder and major affective disorder after psychedelic drug use disorder exist but are relatively uncommon. Flashbacks are sometimes but not always associated with psychiatric symptomatology, mainly anxiety or depression.

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., (© 2024. The Author(s).)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

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 [ 11 C]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 [ 11 C]UCB-J volume of distribution (V T ) 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 [ 11 C]UCB-J positron emission tomography to index [ 11 C]UCB-J V T 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 [ 11 C]UCB-J V T 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 V T /f p 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 [ 11 C]UCB-J V T 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 [ 11 C]UCB-J V T in patients with chronic illness, this may indicate synaptic density changes during the course of SCZ., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)

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., Competing Interests: Declaration of interests TP has participated in educational speaker meetings organised by Lundbeck, Otsuka, Sunovion, Janssen, Schwabe Pharma, ROVI Biotech, and Recordati. RAMcC has participated in advisory or speaker meetings organised by Otsuka, Karuna, Boehringer Ingelheim, and Janssen. TP and RAMcC are directors of Pharmatik that funds website hosting for Psymatik. Neither TP nor RAMcC have holdings or financial stakes in any pharmaceutical company. MH has received honoraria for advisory boards and lectures from Recordati. SJ has participated in educational speaker meetings organised by Lundbeck, Otsuka, Sunovion, Janssen, and Boehringer Ingelheim. FG has received honoraria from Lundbeck, Otsuka, Sunovion, and Boehringer Ingelheim. ODH has received investigator-initiated research funding from or participated in advisory or speaker meetings organised by Angellini, Autifony, Biogen, Boehringer Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, Rand, Recordati, Roche, Viatris (formerly Mylan), and ROVI Biotech. AHY has delivered paid lectures and advisory boards for the following companies: AstraZeneca, Boehringer Ingelheim, Eli Lilly, LivaNova, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS Pathways, Sage, Novartis, and Neurocentrx. CUC has been a consultant or advisor to or has received honoraria from AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, COMPASS Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen, Johnson & Johnson, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris; has provided expert testimony for Janssen and Otsuka; has served on a data safety monitoring board for COMPASS Pathways, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva; has received grant support from Janssen and Takeda; has received royalties from UpToDate; and is a stock option holder of Cardio Diagnostics, MindPax, LB Pharma, and Quantic. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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 D 2/3 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 D 1 receptor availability was lower in patients with MDD in two studies., Conclusions: The meta-analysis indicates striatal DAT availability is lower, but D 2/3 receptor availability is not altered in people with MDD compared to healthy controls. There may be greater dopamine release and lower striatal D 1 receptors in MDD, although further studies are warranted. We discuss factors associated with these findings, discrepancies with preclinical literature and implications for future research., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: Dr Mizuno has received fellowship grants from Canon Foundation in Europe, manuscript fees from Sumitomo Dainippon Pharma, and consultant fees from WCG Clinical and Signant Health within the past 3 years. Dr Ashok has conducted research funded by the National Institute of Health Research (Reference number: NIHR ACF-2019-14-004). Dr Bhat has no conflicting interests to declare. Dr Jauhar has received honoraria for educational talks given for Boehringer Ingelheim, Lundbeck, Janssen and Sunovion, has advised on antipsychotics to LB Pharmaceuticals, and has sat on a Wellcome Funding Panel on backwards translation in mental health. Professor Howes has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organised by Angelini, Autifony, Biogen, Boehringer Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, Rand, Recordati, Roche and Viatris/Mylan, and was a part-time employee of H Lundbeck A/S. Professor Howes has a patent for the use of dopaminergic imaging.

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 Ki cer : 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.

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.

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 (Ki cer ) 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 Ki cer (p = 0.79) showed significant change following antipsychotic treatment. The change in relationship between whole striatal Ki cer 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., (© 2023. The Author(s).)

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 Ki cer . There was an inverse linear effect of copy number variant number on striatal Ki cer value (B = -1.2 × 10 -3 , SE = 2 × 10 -4 , p < 0.001), with controls showing levels intermediate between the two variant groups. Striatal Ki cer 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, Ki cer 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., (© 2021. The Author(s).)

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., (© 2023. The Author(s).)

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.

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  > 0.05 FWE ). 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., Competing Interests: SJ has received honoraria for educational talks given for Lundbeck, Janssen, and Sunovion. OH has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organized by Angelini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, Recordati, Roche and Viatris/Mylan. OH has a patent for the use of dopaminergic imaging. OH is a part-time employee and stockholder of Lundbeck A/S. PF-P has received research funds or personal fees from Lundbeck, Angelini, Menarini, Sunovion, Boehringer Ingelheim, Mindstrong, Proxymm Science, outside the current study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Oliver, Davies, Zelaya, Selvaggi, De Micheli, Catalan, Baldwin, Arribas, Modinos, Crossley, Allen, Egerton, Jauhar, Howes, McGuire and Fusar-Poli.)

Background: Reserpine is an effective antihypertensive drug, but its role in routine practice has declined such that it is rarely used. This is largely based on the assumption that reserpine causes depression. This assumption was a foundation for the original monoamine hypothesis of depression. However, there remains conflicting evidence as to whether reserpine causes depression, and no systematic review of available evidence., Aims: We systematically reviewed evidence on effects of reserpine on depressive and related symptoms (e.g. anxiety, suicidal ideation)., Method: Electronic searches of MEDLINE, Embase and PsycINFO were conducted to identify studies up to 14 February 2021. Studies of any methodological design involving reserpine-treated and reserpine-untreated conditions, in any adult human population, were included and a narrative synthesis of findings was undertaken. Risk of bias (RoB) was examined using ROBINS-I., Results: Of the 35 studies meeting inclusion criteria, 9 were randomised controlled trials. Eleven studies reported some depressogenic effects, 13 reported no effect and 11 reported putative antidepressant effects. Studies identifying depressive effects were more likely to examine people without psychiatric disorders at baseline, while studies identifying a potential antidepressant effect tended to treat fewer participants for shorter durations, at higher doses. Around one-third of studies conducted in people with psychiatric disorders showed beneficial effects on depression symptoms. 30/35 studies were at high RoB., Conclusions: Associations between reserpine and depression are inconsistent and limited by a lack of high-quality evidence. Due to reserpine's apparently complex effects, we urge nuance rather than simplicity surrounding the monoamine hypothesis of 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.

Background: Given the likelihood of progressive illness in bipolar disorder (BD), it is important to understand the benefits and risks of interventions administered early in illness course. We conducted a systematic review of the effectiveness of interventions in the early course of BD I or II., Methods: We completed a systematic search on MEDLINE, PsycINFO, EMBASE, the Cochrane Central Register of Controlled Trials, CINAHL and Google Scholar from 1/1/1979 till 14/9/2022. We included controlled trials examining intervention effects on symptomatic, course, functional and tolerability outcomes of patients in the 'early course' of BD I or II. We classified patients to be in early course if they (a) were seeking help for the first time for a manic episode, (b) had a lifetime history of up to 3 manic episodes, or (c) had up to 6 lifetime mood episodes. Evidence quality was assessed using the GRADE approach., Results: From 4135 unique publications we included 25 reports representing 2212 participants in 16 randomized studies, and 17,714 participants from nine non-randomized studies. Available evidence suggested that in early illness course, lithium use was associated with lower recurrence risk compared with other mood stabilizers. Mood stabilizers were also associated with better global functioning, compared with the use of antipsychotics in the medium term. While summative findings regarding psychological therapies were limited by heterogeneity, family-focused and cognitive-behavioral interventions were associated with reduced recurrence risk or improved symptomatic outcomes. There was some evidence that the same pharmacological interventions were more efficacious in preventing recurrences when utilized in earlier rather than later illness course., Conclusions and Recommendations: While there are promising initial findings, there is a need for more adequately powered trials to examine the efficacy and tolerability of interventions in youth and adults in early illness course. Specifically, there is a compelling need to compare the relative benefits of lithium with other pharmacological agents in preventing recurrences. In addition to symptomatic outcomes, there should be a greater focus on functional impact and tolerability. Effective pharmacological and psychological interventions should be offered to those in early course of BD, balancing potential risks using shared decision-making approaches., (© 2023. The Author(s).)

Background: Clozapine is the only medication licenced for patients with psychosis that is resistant to conventional antipsychotic treatment. However, despite its effectiveness, it remains widely underutilised. One contributory factor for this may be clinicians' lack of confidence around the management of clozapine., Objective: We conducted a survey of clinicians working in Early Intervention in Psychosis (EIP) services to determine their training needs for clozapine management in EIP services., Methods: An electronic survey was made available to all clinicians working in EIP services in England. The survey assessed confidence and training needs regarding managing clozapine in patients with treatment-resistant psychosis. Quantitative data were analysed using total mean scores and the Mann-Whitney U test., Results: In all, 192 (27%) of approximately 700 clinicians from 35 EIP services completed the survey. Approximately half (54%) had not received training on treatment with clozapine. Experience of training was higher in prescribers than non-prescribers, and among medical than non-medical clinicians. Previous training was associated with significantly higher confidence in offering clozapine and managing treatment-resistant psychosis ( p  < 0.001). Confidence levels with managing treatment-resistant psychosis and clozapine were relatively high (mean = 4 out of 5, SD = 1). Respondents were most confident about monitoring mental health response to treatment (mean = 5, SD = 1). Participants were least confident about how to discontinue clozapine treatment safely (mean = 3, SD = 1)., Conclusion: Most clinicians working in EIP have not received training on the use of clozapine. This may account, in part, for the underutilisation of clozapine in EIP services. The provision of training in the identification of treatment-resistant psychosis and the use of clozapine will likely improve the detection and management of treatment resistance in the early phase of psychosis., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: D.T. is the Editor-in-Chief of Therapeutic Advances in Psychopharmacology; therefore, the peer-review process was managed by alternative members of the Board and the submitting Editor was not involved in the decision-making process., (© The Author(s), 2022.)

Background: Clozapine is the only drug licensed for treatment-resistant schizophrenia (TRS) but the real-world clinical and cost-effectiveness of community initiation of clozapine is unclear., Aims: The aim was to assess the feasibility and cost-effectiveness of community initiation of clozapine., Method: This was a naturalistic study of community patients recommended for clozapine treatment., Results: Of 158 patients recommended for clozapine treatment, 88 (56%) patients agreed to clozapine initiation and, of these, 58 (66%) were successfully established on clozapine. The success rate for community initiation was 65.4%; which was not significantly different from that for in-patient initiation (58.82%, χ 2 (1,88) = 0.47, P = 0.49). Following clozapine initiation, there was a significant reduction in median out-patient visits over 1 year (from 24.00 (interquartile range (IQR) = 14.00-41.00) to 13.00 visits (IQR = 5.00-24.00), P < 0.001), and 2 years (from 47.50 visits (IQR = 24.75-71.00) to 22.00 (IQR = 11.00-42.00), P < 0.001), and a 74.71% decrease in psychiatric hospital bed days ( z = -2.50, P = 0.01). Service-use costs decreased (1 year: -£963/patient ( P < 0.001); 2 years: -£1598.10/patient ( P < 0.001). Subanalyses for community-only initiation also showed significant cost reductions (1 year: -£827.40/patient ( P < 0.001); 2 year: -£1668.50/patient ( P < 0.001) relative to costs prior to starting clozapine. Relative to before initiation, symptom severity was improved in patients taking clozapine at discharge (median Positive and Negative Syndrome Scale total score: initial visit: 80 (IQR = 71.00-104.00); discharge visit 50.5 (IQR = 44.75-75.00), P < 0.001) and at 2 year follow-up (Health of Nation Outcome Scales total score median initial visit: 13.00 (IQR = 9.00-15.00); 2 year follow-up: 8.00 (IQR = 3.00-13.00), P = 0.023)., Conclusions: These findings indicate that community initiation of clozapine is feasible and is associated with significant reductions in costs, service use and symptom severity.

Objectives: Rapid cycling is a common and disabling phenomenon in individuals with bipolar disorders. In the absence of a recent literature examination, this systematic review and meta-analysis aimed to synthesise the evidence of efficacy, acceptability and tolerability of treatments for individuals with rapid cycling bipolar disorder (RCBD)., Method: A systematic search was conducted to identify randomised controlled trials assigning participants with RCBD to pharmacological and/or non-pharmacological interventions. Study inclusion and data extraction were undertaken by two reviewers independently. The primary outcome was continuous within-subject RCBD illness severity before and after treatment. Pre-post random effects meta-analyses were conducted for each outcome/intervention arm studied, generating a standardised effect size (hedge's g) and 95% confidence interval (CI)., Results: A total of 34 articles describing 30 studies were included. A total of 16 separate pharmacological treatments were examined in contrast to 1 psychological therapy study. Only quetiapine and lamotrigine were assessed in >5 studies. By assessing 95% CI overlap of within-subject efficacy effects compared to placebo, the only interventions suggesting significant depression benefits (placebo g = 0.60) were olanzapine (with/without fluoxetine; g = 1.01), citalopram (g = 1.10) and venlafaxine (g = 2.48). For mania, benefits were indicated for quetiapine (g = 1.01), olanzapine (g = 1.19) and aripiprazole (g = 1.09), versus placebo (g = 0.33). Most of these effect sizes were from only one trial per treatment. Heterogeneity between studies was variable, and 20% were rated to have a high risk of bias., Conclusions: While many interventions appeared efficacious, there was a lack of robust evidence for most treatments. Given the limited and heterogeneous evidence base, the optimal treatment strategies for people with RCBD are yet to be established., (© 2022 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Background: Evidence from post-mortem studies and in vivo imaging studies suggests there may be reduced N -methyl-d-aspartate receptor (NMDAR) levels in the hippocampus in patients with schizophrenia. Other studies have reported increased glutamate in striatum in schizophrenia patients. It has been hypothesised that NMDAR hypofunction leads to the disinhibition of glutamatergic signalling; however, this has not been tested in vivo., Methods: In this study, we investigated the relationship between hippocampal NMDAR and striatal glutamate using simultaneous positron emission tomography-magnetic resonance (PET-MR) imaging. We recruited 40 volunteers to this cross-sectional study; 21 patients with schizophrenia, all in their first episode of illness, and 19 healthy controls. We measured hippocampal NMDAR availability using the PET ligand [ 18 F]GE179. This was indexed relative to whole brain as the distribution volume ratio (DVR). Striatal glutamatergic indices (glutamate and Glx) were acquired simultaneously, using combined PET-MR proton magnetic resonance spectroscopy ( 1 H-MRS)., Results: A total of 33 individuals (15 healthy controls, 18 patients) were included in the analyses (mean (SD) age of controls, 27.31 (4.68) years; mean (SD) age of patients, 24.75 (4.33), 27 male and 6 female). We found an inverse relationship between hippocampal DVR and striatal glutamate levels in people with first-episode psychosis (rho = -0.74, p  < 0.001) but not in healthy controls (rho = -0.22, p  = 0.44)., Conclusion: This study show that lower relative NMDAR availability in the hippocampus may drive increased striatal glutamate levels in patients with schizophrenia. Further work is required to determine whether these findings may yield new targets for drug development in schizophrenia.

Introduction: Glutamatergic dysfunction is implicated in the pathophysiology of schizophrenia. It is unclear whether glutamatergic dysfunction predicts response to treatment or if antipsychotic treatment influences glutamate levels. We investigated the effect of antipsychotic treatment on glutamatergic levels in the anterior cingulate cortex (ACC), and whether there is a relationship between baseline glutamatergic levels and clinical response after antipsychotic treatment in people with first episode psychosis (FEP)., Materials and Methods: The sample comprised 25 FEP patients; 22 completed magnetic resonance spectroscopy scans at both timepoints. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS)., Results: There was no significant change in glutamate [baseline 13.23 ± 2.33; follow-up 13.89 ± 1.74; t(21) = -1.158, p = 0.260], or Glx levels [baseline 19.64 ± 3.26; follow-up 19.66 ± 2.65; t(21) = -0.034, p = 0.973]. There was no significant association between glutamate or Glx levels at baseline and the change in PANSS positive (Glu r = 0.061, p = 0.777, Glx r = -0.152, p = 0.477), negative (Glu r = 0.144, p = 0.502, Glx r = 0.052, p = 0.811), general (Glu r = 0.110, p = 0.607, Glx r = -0.212, p = 0.320), or total scores (Glu r = 0.078, p = 0.719 Glx r = -0.155, p = 0.470)., Conclusion: These findings indicate that treatment response is unlikely to be associated with baseline glutamatergic metabolites prior to antipsychotic treatment, and there is no major effect of antipsychotic treatment on glutamatergic metabolites in the ACC., Competing Interests: OH was a part-time employee of H. Lundbeck A/S and has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Jansenn, Lundbeck, Neurocrine, Otsuka, Sunovion, Rand, Recordati, Roche, and Viatris/Mylan. Neither OH or his family have holdings/a financial stake in any pharmaceutical company. OH has a patent for the use of dopaminergic imaging. RM has received honoraria for non-promotional talks for Janssen, Sunovian, Otsuka, Lundbeck. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zahid, McCutcheon, Borgan, Jauhar, Pepper, Nour, Rogdaki, Osugo, Murray, Hathway, Murray and Howes.)

Prefrontal cortex has been shown to regulate striatal dopaminergic function via glutamatergic mechanisms in preclinical studies. Concurrent disruption of these systems is also often seen in neuropsychiatric disease. The simultaneous measurement of striatal dopamine signaling, cortical gray matter, and glutamate levels is therefore of major interest, but has not been previously reported. In the current study, twenty-eight healthy subjects underwent 2 simultaneous [ 11 C]-( + )-PHNO PET-MRI scans, once after placebo and once after amphetamine in a double-blind randomized cross-over design, to measure striatal dopamine release, striatal dopamine receptor (D 2/3 R) availability, anterior cingulate glutamate+glutamine (Glx) levels, and cortical gray matter volumes at the same time. Voxel-based morphometry was used to investigate associations between neurochemical measures and gray matter volumes. Whole striatum D 2/3 R availability was positively associated with prefrontal cortex gray matter volume (pFWE corrected = 0.048). This relationship was mainly driven by associative receptor availability (pFWE corrected = 0.023). In addition, an interaction effect was observed between sensorimotor striatum D 2/3 R availability and anterior cingulate Glx, such that in individuals with greater anterior cingulate Glx concentrations, D 2/3 R availability was negatively associated with right frontal cortex gray matter volumes, while a positive D 2/3 R-gray matter association was observed in individuals with lower anterior cingulate Glx levels (pFWE corrected = 0.047). These results are consistent with the hypothesis that the prefrontal cortex is involved in regulation of striatal dopamine function. Furthermore, the observed associations raise the possibility that this regulation may be modulated by anterior cingulate glutamate concentrations., (© 2022. The Author(s).)

The D2 dopamine receptor (D2R) is the primary site of the therapeutic action of antipsychotics and is involved in essential brain functions relevant to schizophrenia, such as attention, memory, motivation, and emotion processing. Moreover, the gene coding for D2R (DRD2) has been associated with schizophrenia at a genome-wide level. Recent studies have shown that a polygenic co-expression index (PCI) predicting the brain-specific expression of a network of genes co-expressed with DRD2 was associated with response to antipsychotics, brain function during working memory in patients with schizophrenia, and with the modulation of prefrontal cortex activity after pharmacological stimulation of D2 receptors. We aimed to investigate the relationship between the DRD2 gene network and in vivo striatal dopaminergic function, which is a phenotype robustly associated with psychosis and schizophrenia. To this aim, a sample of 92 healthy subjects underwent 18 F-DOPA PET and was genotyped for genetic variations indexing the co-expression of the DRD2-related genetic network in order to calculate the PCI for each subject. The PCI was significantly associated with whole striatal dopamine synthesis capacity (p = 0.038). Exploratory analyses on the striatal subdivisions revealed a numerically larger effect size of the PCI on dopamine function for the associative striatum, although this was not significantly different than effects in other sub-divisions. These results are in line with a possible relationship between the DRD2-related co-expression network and schizophrenia and extend it by identifying a potential mechanism involving the regulation of dopamine synthesis. Future studies are needed to clarify the molecular mechanisms implicated in this relationship., (© 2022. The Author(s).)

In this Personal View, we critically appraise and summarise evidence for antipsychotic drugs and alternatives to drug treatment, with a focus on people in their first episode or acute relapses of schizophrenia and related conditions within the first 5-10 years of illness. There is a large body of generally moderate quality evidence from randomised controlled trials for antipsychotics in both treating acute psychosis and reducing relapse, in thousands of people in their first episode and in established illness. There is a much smaller evidence base, of generally low quality, in a few hundred people, for potential benefits of non-drug interventions, such as cognitive behavioural therapy, Open Dialogue, Soteria, and psychoanalytic psychotherapy., Competing Interests: Declaration of interests SJ has received honoraria for educational talks given for Sunovian, and his employer (King's College London) has received honoraria for educational talks he has given for Lundbeck. SML declares no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Schizophrenia, characterised by psychotic symptoms and in many cases social and occupational decline, remains an aetiological and therapeutic challenge. Contrary to popular belief, the disorder is modestly more common in men than in women. Nor is the outcome uniformly poor. A division of symptoms into positive, negative, and disorganisation syndromes is supported by factor analysis. Catatonic symptoms are not specific to schizophrenia and so-called first rank symptoms are no longer considered diagnostically important. Cognitive impairment is now recognised as a further clinical feature of the disorder. Lateral ventricular enlargement and brain volume reductions of around 2% are established findings. Brain functional changes occur in different subregions of the frontal cortex and might ultimately be understandable in terms of disturbed interaction among large-scale brain networks. Neurochemical disturbance, involving dopamine function and glutamatergic N-methyl-D-aspartate receptor function, is supported by indirect and direct evidence. The genetic contribution to schizophrenia is now recognised to be largely polygenic. Birth and early life factors also have an important aetiological role. The mainstay of treatment remains dopamine receptor-blocking drugs; a psychological intervention, cognitive behavioural therapy, has relatively small effects on symptoms. The idea that schizophrenia is better regarded as the extreme end of a continuum of psychotic symptoms is currently influential. Other areas of debate include cannabis and childhood adversity as causative factors, whether there is progressive brain change after onset, and the long-term success of early intervention initiatives., Competing Interests: Declaration of interests SJ has received honoraria from Sunovian for educational talks, and his institution has received honoraria for talks he has given for Lundbeck. MJ and PJM declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

There has been recent debate regarding the efficacy of electroconvulsive therapy in the treatment of depression. This has been based on narrative reviews that contradict existing systematic reviews and meta-analyses. In this special article, we highlight the mistakes that occur when interpreting evidence using narrative reviews, as opposed to conventional systematic reviews and meta-analyses.

Electroconvulsive therapy is the most effective treatment for severe, psychotic or treatment-resistant depression. However, its effectiveness continues to be questioned, both in mainstream media and narratives within the scientific literature. In this analysis, we use an evidence-based approach to demonstrate the efficacy and safety of modern electroconvulsive therapy.