Deepak K. Sarpal

Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) is used as a proxy biomarker of midbrain catecholaminergic metabolism and synthesis capacity, particularly within dopaminergic nuclei. However, despite strong translational evidence for sexual dimorphism in dopaminergic systems, inconsistent sex differences in NM-MRI signal limit its interpretability as a non-invasive measure of catecholaminergic synthesis capacity. A source of variability may be the reliance on contrast-to-noise ratio (CNR) normalization, which presupposes NM-MRI signal stability within the reference region, canonically the crus cerebri. To address this limitation, the present study introduced a novel normalization framework combining a data-driven reference region with residual-based, rather than ratio-based, normalization. NM-MRI data were acquired in a transdiagnostic sample of 101 adults, aged 18–40 years, including individuals with elevated familial risk for bipolar disorder or major depressive disorder. Sex effects on NM-MRI signal were compared across the substantia nigra pars compacta (SNc), ventral tegmental area (VTA), and locus coeruleus (LC) using conventional crus cerebri-based CNR versus residual-based normalization. Residual-based normalization revealed higher NM-MRI signal in males compared with females across all catecholaminergic nuclei (SNc, VTA, LC; all adjusted p < 0.001). In contrast, conventional CNR normalization detected no sex differences in any region (all adjusted p > 0.20). Moreover, sex differences in NM-MRI signal were observed within the crus cerebri itself ( p < 0.001), indicating that the canonical reference region is not biologically invariant. Sexual dimorphism in midbrain NM-MRI signal is revealed in vivo for the first time using a novel residual-based normalization framework. By reducing reference-region bias, this approach advances NM-MRI toward candidate biomarker deployment for assessing catecholaminergic dysfunction in psychiatric and neurological disorders.

Despite growing evidence from magnetic resonance spectroscopy studies of glutamatergic and GABAergic abnormalities in schizophrenia, in vivo characterization of subcortical neurometabolites at ultra-high field and their longitudinal change across antipsychotic treatment remains limited. Ultra-high-field 7-Tesla (7 T) magnetic resonance spectroscopic imaging (MRSI) enables simultaneous multivoxel quantification of neurometabolites across subcortical regions implicated in schizophrenia, including the thalamus and dorsal caudate. Here, we leveraged 7 T MRSI to characterize subcortical neurometabolite profiles in 91 healthy individuals and 29 individuals with early-phase schizophrenia spectrum disorders (SSD) scanned while presenting with moderate to severe psychosis and following eight weeks of antipsychotic treatment. Primary analyses revealed lateralized alterations in glutamate (Glu) and GABA. In the caudate, Glu and Glx were elevated in the right hemisphere, while GABA was elevated on the right and reduced on the left, a dissociation observed in both the caudate and thalamus. Left thalamic Glx was also elevated, and Glu–GABA coupling was disrupted in the right thalamus. In secondary analyses, thalamic NAAG was markedly reduced in the left hemisphere, with elevation observed in the right thalamus, in addition to left-lateralized thalamic and caudate NAA reduction and elevated caudate GPC.Cho. In exploratory treatment-response analyses, non-remitters showed lower left thalamic and caudate NAA and GABA at baseline, with thalamic Glu declining below healthy control levels at follow-up only in non-remitters. Right thalamic NAAG elevation was restricted to the longer illness group. Collectively, these findings implicate an asymmetric disruption of astroglial–neuronal balance within subcortical regions in early-phase SSD, and across antipsychotic treatment.

Glutamatergic changes are one of the characteristic features of psychotic disorders, with changes reported in their clinical high‐risk states (CHR), first episode psychosis (FEP), and schizophrenia. Despite the abundance of literature using proton magnetic resonance ( ¹ H‐MRS) to quantify glutamate, the general pattern of changes across different brain regions is not well studied. We investigated the presence of diagnosis group effects on glutamate concentrations in 99 participants in the left dorsal lateral prefrontal cortex, anterior cingulate cortex, associative striatum, and hippocampus using ¹ H‐MRS in individuals with CHR ( n = 31), schizophrenia spectrum psychotic disorder individuals (SCZ) with minimal antipsychotic exposure ( n = 30), and healthy controls ( n = 38). ¹ H‐MRS data were normalized against white matter, gray matter, and cerebrospinal fluid fractions within regions of interest (ROI) to quantify local glutamate concentration. Our results showed no significant group differences in glutamate concentration across the four ROIs. Exploratory analyses showed a significant relationship between region and positive symptom severity on glutamate concentration. Post hoc regression analyses revealed that higher positive symptom severity was significantly associated with higher hippocampal glutamate concentrations. We conclude that glutamate concentrations may be related to positive symptoms.

In the past decade, interest in studying psychedelic compounds as potential therapeutic agents has resurged. These studies carefully exclude individuals at risk for developing psychotic symptoms in response to psychedelic use. Given the potential for psychedelics to be established as treatments in psychiatry, it is important to more robustly understand their link with psychosis and schizophrenia spectrum disorders (SSDs). In this narrative review, we examine the historical and theoretical relationship between psychedelic drugs and SSDs, including the origins of the psychotomimetic hypothesis. For key psychedelic compounds, we review their phenomenological manifestations in relation to the experiential alterations characteristic of SSDs, revealing both areas of overlap and important qualitative differences that challenge the uniform psychotomimetic classification. We also review putative neural mechanisms underlying altered experiential states associated with psychedelic use and SSDs, with attention to serotonergic, dopaminergic, and glutamatergic contributions. Clinical evidence demonstrates that psychedelics can exacerbate pre-existing psychotic illness and may trigger psychosis in vulnerable individuals, though the magnitude of these risks remains inadequately quantified. However, phenomenological and mechanistic distinctions suggest that potential therapeutic applications may exist for carefully selected symptoms (negative symptoms, depression) in stable patients using low-dose, controlled approaches. Based on published work, we provide recommendations regarding psychosis-related risk and potential avenues for the treatment of SSDs as psychedelics gain traction as therapeutics.

Objectives: Bipolar Disorder (BD)—characterized by mania, affective lability, and elevated psychosis risk—is associated with sustained attention deficits. However, evidence regarding performance on the AX‐Continuous Performance test task (AX‐CPT), a task reliably impaired in schizophrenia‐spectrum psychosis, is mixed. This study examined whether individual differences in mania/affective lability risk and psychosis risk, across cohorts of BD and BD‐at‐risk individuals, were associated with altered AX‐CPT performance. Methods: The standard measures d'context and A‐cue bias quantified AX‐CPT performance. Factors from the Mood Spectrum Self Report (MOODS‐SR‐L) indexed lifetime mania/affective lability risk (psychomotor activation, suicidality, and mixed instability) and lifetime psychosis risk. Linear regressions were performed for dimensional continuous aims (Aims 1–2) for both d'context and A‐cue bias. Tests between BD with low and high‐risk groups (Aims 3–4) were completed with ANCOVAs for both AX‐CPT output measures. Results: In the final sample of euthymic BD ( n = 27) and at‐risk individuals ( n = 121), higher levels of psychosis and mania/affective lability risk were associated with reduced target discrimination (d'context; absolute t 's > 2.015, p 's < 0.047), but not with altered A‐cue bias. Group comparisons showed no significant differences for either AX‐CPT measure. Associations with d'context from Aims 1–2 remained after covarying for current depressive symptoms but were removed when covarying for current mania severity (absolute t 's < 1.26, all p 's > 0.203). Conclusions: Target discrimination deficits were associated dimensionally with psychosis and mania/affective lability risk but not categorically with BD diagnosis. This suggests scope for dimensional risk models for understanding sustained attention deficits in BD and at‐risk individuals and highlights contributions of mania/affective lability and psychosis risk.

Background and Hypothesis: Persistent negative symptoms (PNS) often emerge early in the course of schizophrenia spectrum disorders, significantly impair long-term functional outcomes, and remain difficult to treat, with no consistently effective interventions available. The manifestation of PNS in individuals with first-episode psychosis (FEP) engaged in coordinated specialty care (CSC) in the United States remains largely unknown. This study characterizes negative symptoms in routine clinical care using data from the Early Psychosis Intervention Network’s Connection Learning Healthcare System, with a focus on a subcohort of individuals with PNS. Study Design: Practice-based data were collected every 6 months over a 2-year period from 1289 participants across 23 CSC programs using a Core Assessment Battery (CAB) comprised of clinician-rated and self-report measures. Negative symptoms were quantified across CAB items, allowing for categorization of participants into PNS (n = 79) and non-PNS groups (n = 455). Group comparisons examined outcomes across CAB items, and exploratory mediation analyses focused on the role of engagement in outcomes relative to PNS. Study Results: Individuals with PNS had higher rates of schizophrenia and lower social and role functioning compared to those in the non-PNS group. Exploratory analyses indicated that service engagement at 6 months mediated the negative relationship between PNS and 12-month social and role functioning. Conclusions: These findings highlight the challenge of PNS in individuals with FEP receiving CSC, the importance of early service engagement, and an opportunity to develop targeted interventions and refine treatment approaches to improve outcomes in this unique subgroup.