Sameer Jauhar

• MBChB, BSc (Hons), FRCPsych PhD
• Senior Clinical Lecturer at King's College London

Purpose Schizophrenia (SCZ) is a severe psychiatric disorder marked by abnormal dopamine synthesis, measurable through [ ¹⁸ F]FDOPA PET imaging. This imaging technique has been proposed as a biomarker for treatment stratification in SCZ, where one-third of patients respond poorly to standard antipsychotics. This study explores the use of radiomics...

Loss of glutamatergic terminals is hypothesised to contribute to excitation-inhibition imbalance in schizophrenia, supported by evidence that the normal positive association between glutamate concentrations and synaptic terminal density is not found in patients with chronic schizophrenia. However, it is unknown whether the relationship between syna...

Previous hypotheses for the superiority of clozapine over other antipsychotics have failed to stand the test of time. Here we describe how the unique pharmacology of clozapine in the peripheral nervous system held clues for solving the puzzle of clozapine in the central nervous system. Clozapine appears to have been the prototype for a new class of...

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 studie...

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 evide...

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 exa...

This editorial considers the value and nature of academic psychiatry by asking what defines the specialty and psychiatrists as academics. We frame academic psychiatry as a way of thinking that benefits clinical services and discuss how to inspire the next generation of academics.

Background Muscarinic receptor agonism 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...

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, the...

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 characterised their relationships with g...

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...

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 t...

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 prolo...

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 antidepress...

Background: The synaptic hypothesis is an influential theory of the pathoaetiology of schizophrenia. Supporting this, there is lower uptake of the synaptic terminal density marker UCB-J in patients with chronic schizophrenia compared to controls. However, it is unclear whether these differences are present early in the illness. To address this, we...

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 psych...

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 indivi...

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 a...

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 sub...

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 (l...

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 (l...

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 interpr...

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, P...

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 o...

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 di...

Glutamatergic dysfunction is implicated in the pathoaetiology of schizophrenia, 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 cont...

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, reportin...

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 wheth...

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),...

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 h...

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 RCBD. Method: A systematic search was co...

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...

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 pat...

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...

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 syndrom...

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 conve...

N-methyl-D-aspartate receptor (NMDAR) hypofunction is hypothesised to underlie psychosis but this has not been tested early in illness. To address this, we studied 40 volunteers (21 patients with first-episode psychosis and 19 matched healthy controls) using PET imaging with an NMDAR selective ligand, [18F]GE-179, that binds to the ketamine binding...

Background While multiple studies have examined the brain functional correlates of reward, meta-analyses have either focused on studies using the monetary incentive delay (MID) task, or have adopted a broad strategy, combining data from studies using both monetary and non-monetary reward, as probed using a wide range of tasks. Objective To meta-an...

Dopamine signaling is constrained to discrete tracts yet has brain-wide effects on neural activity. The nature of this relationship between local dopamine signaling and brain-wide neuronal activity is not clearly defined and has relevance for neuropsychiatric illnesses where abnormalities of cortical activity and dopamine signaling coexist. Using 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...

Importance: Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear. Objective: To...

A leading hypothesis for schizophrenia and related psychotic disorders proposes that cortical brain disruption leads to subcortical dopaminergic dysfunction, which underlies psychosis in the majority of patients who respond to treatment. Although supported by preclinical findings that prefrontal cortical lesions lead to striatal dopamine dysregulat...

The process of stopping antipsychotics may be causally related to relapse, potentially linked to neuroadaptations that persist after cessation, including dopaminergic hypersensitivity. Therefore, the risk of relapse on cessation of antipsychotics may be minimized by more gradual tapering. There is converging evidence that suggests that adaptations...

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 elect...

To the Editor Miklowitz et al¹ present a meta-analysis of psychosocial interventions in bipolar disorder, concluding adjunctive psychotherapy to pharmacotherapy is more effective than treatment as usual in reducing recurrence and treating depression symptoms, among other outcomes. This is an important examination with clinical implications. We high...

Mood disorders such as depression and bipolar disorder are common mental illnesses, affecting millions of patients worldwide. The application of newly available brain imaging methods to the study of mood disorders holds substantial promise in uncovering the brain mechanisms affected in these illnesses. This comprehensive and authoritative text feat...

Introduction: Early Intervention for a first episode of Psychosis (EI) is essential to improve outcomes. There is limited research describing real-world implementation of EI services. Method: Analysis of service characteristics, outcomes (described through a retrospective 2007–2017 Electronic Health Record (EHR) cohort study) and clinical research...

We agree in general with Malhi et al's forthright Editorial "Make Lithium Great Again", where they reiterate that, despite its clear efficacy and effectiveness, lithium remains under-utilised in the treatment of bipolar disorder. Possible reasons they give for this include prescription of second generation antipsychotics (SGAs), which may appear ea...

[18F]FDOPA PET imaging has shown dopaminergic function indexed as Kicer differs between antipsychotic treatment responders and non-responders. However, the theragnostic potential of this biomarker to identify non-responders has yet to be evaluated. In view of this, we aimed to evaluate this as a theragnostic test using linear and non-linear machine...

The review by Post and colleagues¹ is important. The authors, with undoubted expertise in this field, describe measures addressing clinical issues in bipolar disorders (BD). They make a number of recommendations, covering the breadth of treatments, from illness stage (first episode mania, treatment resistance) to option(therapeutic approach, a broa...

The efficacy of antidepressants in major depressive disorder has been continually questioned, mainly on the basis of studies using the sum-score of the Hamilton Depression Rating Scale as a primary outcome parameter. On this measure antidepressants show a standardised mean difference of around 0.3, which some authors suggested is below the cut-off...

Background Abnormal Cerebral Blood Flow (CBF) has been found in patients with chronic schizophrenia (SCZ), first-episode psychosis patients (FEP) and individuals at clinical high-risk (CHR). In particular, previous studies using Arterial Spin Labelling (ASL) found that SCZ have a global reduction of CBF in the cortex and increased CBF in the basal...

Background Striatal dopamine dysfunction is proposed to underlie symptoms in psychosis, yet it is not known how changes in a single neurotransmitter could underlie the heterogenous presentations that are seen clinically. One hypothesis is that the symptomatic consequences of aberrant dopamine signalling may depend on where within the striatum dysfu...

Background Cortical dysconnectivity and dysfunctional glutamatergic signalling are both implicated in the pathophysiology of psychotic illness. The relationship between these two systems, and the relevance to psychotic disorders remains unknown. Methods 50 individuals with a psychotic disorder and 54 healthy controls received baseline imaging usin...

Background Proton Magnetic Resonance Spectroscopy (1H-MRS) studies indicate that altered brain glutamate signalling contributes to the pathophysiology of schizophrenia and treatment response. However it is unclear whether clinical and demographic factors affect glutamate levels in the brain. Here we aim to determine the effects of age, antipsychoti...

Background Striatal dopamine dysfunction is thought to underlie symptoms in psychosis, yet it remains unclear how a single neurotransmitter could cause the diverse presentations that are observed clinically. One hypothesis is that the consequences of aberrant dopamine signalling vary depending on where within the striatum the dysfunction occurs. Po...

Neuroimaging studies in schizophrenia have linked elevated glutamate metabolite levels to non-remission following antipsychotic treatment, and also indicate that antipsychotics can reduce glutamate metabolite levels. However, the relationship between symptomatic reduction and change in glutamate during initial antipsychotic treatment is unclear. He...

Psychotic illnesses show variable responses to treatment. Determining the neurobiology underlying this is important for precision medicine and the development of better treatments. It has been proposed that dopaminergic differences underlie variation in response, with striatal dopamine synthesis capacity (DSC) elevated in responders and unaltered i...

Glutamatergic dysregulation is one of the leading theories regarding the pathoaetiolopy of schizophrenia. Meta-analysis of magnetic resonance spectroscopy studies in schizophrenia shows increased levels of glutamate and glutamine (Glx) in the medial frontal cortex and basal ganglia in clinical high-risk groups for psychosis and increased glutamine...

Relapse in, and recovery from, schizophrenia has been acknowledged since the disease was first described. In this review the authors summarize the long-term (>100 years) data on relapse and recovery in schizophrenia by reviewing the extant older and modern relevant literature. The authors systematically question the utility of pharmacological and n...

Converging lines of evidence suggest that glutamatergic dysfunction may contribute to the pathophysiology of first episode psychosis. We investigated whether first episode psychosis patients free from all pharmacological treatments and illicit substances show cortical glutamatergic alterations. One-hundred and eleven volunteers including 65 healthy...

One of the most statistically significant loci to result from large-scale GWAS of schizophrenia is 10q24.32. However, it is still unclear how this locus is involved in the pathoaetiology of schizophrenia. The hypothesis that presynaptic dopamine dysfunction underlies schizophrenia is one of the leading theories of the pathophysiology of the disorde...

Background: Interventions early in the course of Bipolar Disorder (BD) may have the potential to limit its functional and symptomatic impact. However, the implementation of specific early interventions for BD has been limited which may at least partly be due to the lack of guidelines focused on the early illness stages. We therefore aimed to review...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The care of people with first-episode mania has been overlooked in comparison with the care of patients with other non-affective psychoses, despite evidence suggesting targeted treatments might be of benefit for this patient group. In this Personal View, we outline the general epidemiology of first-episode mania in the context of bipolar disorder,...

Background Glutamatergic dysfunction is implicated in the pathophysiology of schizophrenia, with studies reporting elevated glutamatergic metabolites across brain regions of patients. There is consistent evidence showing a decrease in glutamate metabolites after antipsychotic administration. However, the literature on the relationship between the g...