Neural correlates of stress-reactive rumination in depression - The role of childhood trauma and social anxiety.

Recent work showed an association of prefrontal dysfunctions in patients with Major Depressive Disorder (MDD) and social stress induced rumination. However, up to date it is unclear which etiological features of MDD might cause prefrontal dysfunctions. In the study at hand, we aimed to replicate recent findings, that showed prefrontal activation alterations during the Trier Social Stress Test (TSST) and subsequently increased stress-reactive rumination in MDD compared to healthy controls. Moreover, we aimed to explore the role of adverse childhood experiences and other clinical variables in this relationship. N = 55 patients currently suffering from MDD and n = 42 healthy controls (HC) underwent the TSST, while cortical activity in areas of the Cognitive Control Network (CCN) was measured via functional near-infrared spectroscopy (fNIRS). The TSST successfully induced a stress reaction (physiologically, as well as indicated by subjective stress ratings) and state rumination in all subjects with moderate to large effect sizes. In comparison to HC, MDD patients showed elevated levels of state rumination with large effect sizes, as well as a typical pattern of reduced cortical oxygenation during stress in the CCN with moderate effect sizes. Self-reported emotional abuse and social anxiety were moderately positively associated with increased stress-reactive rumination. Within the MDD sample, emotional abuse was negatively and social anxiety positively associated with cortical oxygenation within the CCN with moderate to large effect sizes. In conclusion, our results replicate previous findings on MDD-associated prefrontal hypoactivity during stress and extends the research toward specific subtypes of depression.

Trait-dependent effects of theta burst stimulation after psychosocial stress: a sham-controlled study in healthy individuals.

OBJECTIVE: Previous studies suggest that theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation (rTMS), applied to the left dorsolateral prefrontal cortex (DLPFC) might be a promising approach to modulate stress-reactive rumination and the associated psychophysiological stress response. Crucially, individuals showing higher levels of trait rumination might benefit more from prefrontal stimulation. METHODS: In this sham-controlled study, 127 healthy individuals, with varying ruminative tendencies, received a single-session of intermittent TBS (iTBS), continuous TBS (cTBS) or sham TBS (sTBS) over the left DLPFC before being confronted with a Trier Social Stress Test. RESULTS: Results showed significant TBS effects on salivary cortisol as a function of trait rumination. cTBS, as compared to sTBS and iTBS, resulted in an attenuated stress-induced cortisol response in high compared to low trait ruminators. Although independent of trait rumination levels, cTBS showed positive effects on stress-related changes in mood and, both cTBS and iTBS (versus sham) presented an enhanced heart rate recovery following the stressor. We found no evidence for (trait rumination-dependent) TBS effects on stress-reactive rumination, negative affect, subjective stress or heart rate variability. CONCLUSIONS: cTBS shows beneficial effects on certain measures of stress, especially in high trait ruminators. SIGNIFICANCE: These findings highlight the importance of accounting for individual differences when examining TBS effects.

In situ fNIRS measurements during cognitive behavioral emotion regulation training in rumination-focused therapy: A randomized-controlled trial.

Repetitive negative thinking (RNT), including rumination, plays a key role in various psychopathologies. Although several psychotherapeutic treatments have been developed to reduce RNT, the neural correlates of those specific treatments and of psychotherapy in general are largely unknown. Functional near-infrared spectroscopy (fNIRS) offers the potential to investigate the neural correlates of psychotherapeutic techniques in situ. Therefore, in this study we investigated the efficacy and neural correlates of a fNIRS adapted Mindfulness-based Emotion Regulation Training (MBERT) for the treatment of depressive rumination in 42 subjects with major depressive disorder (MDD) in a cross-over designed randomized controlled trial. Using psychometric measures, subjective ratings and fNIRS, we analyzed in situ changes in depressive symptom severity, ruminative thoughts and cortical activity in the Cognitive Control Network (CCN). Our results show that MBERT is effective in treating depressive symptoms and rumination. On a neural level, we found consistently higher cortical activation during emotion regulation training compared to control trials in the bilateral inferior frontal gyrus (IFG) and dorsolateral prefrontal cortex (DLPFC). Furthermore, cortical oxygenation decreased from session to session in the bilateral DLPFC. The relevance of the results for the psychotherapeutic treatment of MDD as well as further necessary investigations are discussed.

Hypnotherapy for agoraphobia-Feasibility and efficacy investigated in a pilot study.

A number of case studies describing hypnotherapy in the treatment of anxiety disorder patients have already been published. Only a few randomized controlled trials (RCTs) investigated the efficacy of hypnotherapy but focused mainly on symptoms rather than specific mental disorders. The goal of this study was to investigate whether hypnotherapy (HT) was superior to a waitlist control group (WL) in the reduction of agoraphobia-related symptoms. Further goals were to report the feasibility of hypnotherapy as well as attrition and completion rates and detect (epi-)genetic variables, which might play a role in treatment outcome. This pilot study was based on a monocentric two-armed randomized controlled rater-blind clinical trial that was conducted between 2018 and 2020 with a waitlist control group. A total of 36 patients diagnosed with agoraphobia were randomized to either HT or WL. Patients in HT received individual outpatient treatment with hypnotherapy with 8 to 12 sessions for a period of 3 months. Patients in WL received HT after 3 months. Agoraphobia-related symptoms were assessed at baseline, after the treatment, and 3 months later in both groups with a clinician rating. The primary hypothesis concerning the difference between groups in the individual percentage symptom reduction could be confirmed in the intention-to-treat, not the per-protocol sample. Additionally, we applied repeated-measures analyses of variance and found a higher symptom decrease in HT compared with WL patients in three of the five imputed datasets. The dropout rate was low, and satisfaction with the treatment was high. HT patients experienced a strong symptom reduction after receiving hypnotherapy. WL patients improved slightly during the waiting period. The COMT Val108/158Met genotype had an effect on the agoraphobia-related symptoms as well as on COMT DNA methylation levels. This is the first study to indicate that hypnotherapy performed better than a waitlist control group regarding the reduction in anxiety symptoms in an RCT. Future studies should confirm the efficacy of hypnotherapy and compare the treatment with a standard treatment for anxiety disorders in a larger trial. Future studies should also investigate whether hypnotic susceptibility is associated with COMT Val108/158Met genotype and could predict treatment success for HT. Clinical trial registration: https://classic.clinicaltrials.gov/ct2/show/NCT03684577, identifier: NCT03684577.

Blood transcriptome analysis suggests an indirect molecular association of early life adversities and adult social anxiety disorder by immune-related signal transduction.

Social anxiety disorder (SAD) is a psychiatric disorder characterized by severe fear in social situations and avoidance of these. Multiple genetic as well as environmental factors contribute to the etiopathology of SAD. One of the main risk factors for SAD is stress, especially during early periods of life (early life adversity; ELA). ELA leads to structural and regulatory alterations contributing to disease vulnerability. This includes the dysregulation of the immune response. However, the molecular link between ELA and the risk for SAD in adulthood remains largely unclear. Evidence is emerging that long-lasting changes of gene expression patterns play an important role in the biological mechanisms linking ELA and SAD. Therefore, we conducted a transcriptome study of SAD and ELA performing RNA sequencing in peripheral blood samples. Analyzing differential gene expression between individuals suffering from SAD with high or low levels of ELA and healthy individuals with high or low levels of ELA, 13 significantly differentially expressed genes (DEGs) were identified with respect to SAD while no significant differences in expression were identified with respect to ELA. The most significantly expressed gene was MAPK3 (p = 0.003) being upregulated in the SAD group compared to control individuals. In contrary, weighted gene co-expression network analysis (WGCNA) identified only modules significantly associated with ELA (p ≤ 0.05), not with SAD. Furthermore, analyzing interaction networks of the genes from the ELA-associated modules and the SAD-related MAPK3 revealed complex interactions of those genes. Gene functional enrichment analyses indicate a role of signal transduction pathways as well as inflammatory responses supporting an involvement of the immune system in the association of ELA and SAD. In conclusion, we did not identify a direct molecular link between ELA and adult SAD by transcriptional changes. However, our data indicate an indirect association of ELA and SAD mediated by the interaction of genes involved in immune-related signal transduction.

Sex-dependent multimodal response profiles to psychosocial stress.

INTRODUCTION: Sex differences in stress reactions are often reported in the literature. However, the sex-dependent interplay of different facets of stress is still not fully understood. Particularly in neuroimaging research, studies on large samples combining different indicators of stress remain scarce. MATERIALS AND METHODS: In a functional magnetic resonance imaging study, a sample of 140 healthy participants (67 females using oral contraceptives) underwent a standardized stress induction protocol, the ScanSTRESS. During the experiment, salivary cortisol and subjective ratings were obtained at multiple time points and heart rate was recorded. RESULTS: Sex differences emerged in different facets of the stress response:Women reacted with enhanced subjective feelings of stress and increases in heart rate, while men showed more pronounced neural activation in stress-related brain regions such as the inferior frontal gyrus and insula. Subjective feelings of stress and (para) hippocampal activity were negatively related in women,whereas a slightly positive association was observed in men. DISCUSSION: These results provide further insight in the sex-specific stress response patterns. Moreover, they emphasize the role of the hippocampus in the regulation of the stress response. This paves the way for the identification of sex-dependent vulnerability factors that can, in the future, be implemented in the prevention and treatment of stress-related disorders.

Corrigendum: GH responsiveness is not correlated to IGF1 P2 promoter methylation in children with Turner syndrome, GHD and SGA short stature.

[This corrects the article DOI: 10.3389/fendo.2022.897897.].

OXTR DNA methylation differentiates men on the obesity spectrum with and without binge eating disorder.

BACKGROUND: The neuropeptide oxytocin (OXT) plays a role in the regulation of eating behavior and metabolism. OXT functioning is altered in patients with eating and weight disorders, and a variant of the oxytocin receptor gene (OXTR) has been associated with impulsive eating behavior as it is seen in patients with binge eating disorder (BED). Gene × environment interactions could play a role in BED. One mechanism mediating this interaction is the epigenetic alteration of gene expression. We therefore investigated if DNA methylation of the OXTR differs between individuals with obesity depending on a comorbid BED. We analyzed DNA methylation of the OXTR in peripheral blood of 227 individuals on the obesity spectrum (mean age: 40.3 ± 13.1 yrs; mean BMI: 38.6 ± 7.3 kg/m2), 130 of which were diagnosed with BED. RESULTS: There were no overall differences in OXTR methylation between participants with and those without BED (p > 0.05), while both subgroups were comparable regarding age and body mass index (BMI), but significantly differed in sex distribution (p = 0.035). We found no relationship between mean DNA methylation and BMI or self-reported eating disorder (ED) pathology. Analyzing potential sex differences revealed a significantly lower OXTR DNA methylation in male participants with BED as compared to those without BED (p = 0.017). No such difference was found in the female subsample (p > 0.05). CONCLUSIONS: Clinically significant binge eating pathology might be associated with lower OXTR DNA methylation exclusively in males. The differential DNA methylation of OXTR in males with BED supports the view that BED represents a phenotype within the obesity spectrum that is characterized by specific vulnerability factors. A better understanding of the epigenetic underpinnings of the OXT system might contribute to the refinement of OXT administration approaches as potential interventions in eating and weight disorders.

GH Responsiveness Is not Correlated to IGF1 P2 Promoter Methylation in Children With Turner Syndrome, GHD and SGA Short Stature.

Background: The methylation of IGF1 promoter P2 was reported to negatively correlate with serum IGF-1 concentration and rhGH treatment response in children with idiopathic short stature. These findings have not yet been confirmed. Objective: This study aimed to determine IGF1 promoter P2 methylation in short children treated with rhGH and correlate clinical parameters with the methylation status. In addition, long-term stability of methylation during rhGH treatment was studied. Design: This was a single tertiary center study analyzing clinical GH response and IGF-1 serum concentration changes in patients with GHD (n=40), SGA short stature (n=36), and Turner syndrome (n=16) treated with rhGH. Data were correlated to the methylation of two cytosine residues (-137, +97) of the P2 promoter of IGF1 in blood cells measured by pyrosequencing in 443 patient samples. Results: Basal and stimulated IGF-1 concentrations, first year increment in height velocity and studentized residuals of a prediction model did not correlate to the methylation of -137 und +97 in IGF1 P2 promoter. The methylation of these two sites was relatively stable during treatment. Conclusions: This study did not confirm IGF1 P2 promotor being a major epigenetic locus for GH responsiveness in patients treated with a normal dose of rhGH. Additional studies are warranted.

Validity of chronotype questionnaires in adolescents: Correlations with actigraphy.

There are only a few validated chronotype and morningness-eveningness questionnaires for adolescents. We evaluated three such questionnaires, namely Morningness-Eveningness Stability Scale improved; reduced Morningness-Eveningness Questionnaire for Children and Adolescents; and Composite Scale of Morningness in adolescents against actigraphy. Fifty-five healthy 13- to 16-year-old adolescents completed the Morningness-Eveningness Stability Scale improved, reduced Morningness-Eveningness Questionnaire for Children and Adolescents, Composite Scale of Morningness, and Pediatric Daytime Sleepiness Scale, and provided a 7-day actigraphy and sleep diary recording about their sleep-wake patterns. We examined the correlations between sleep-wake and activity parameters, and the questionnaires. The influence of age and sex on chronotype classification was studied using uni- and multivariate analyses. All three chronotype questionnaires showed good internal consistency and convergent validity. Spearman correlations reflected less daytime sleepiness, earlier sleep times, midpoints of sleep, and acrophase in morning-oriented participants. Evening-oriented participants had more sleepiness and later respective sleep-wake times. Chronotype classification differed significantly between questionnaires. The Composite Scale of Morningness classified more participants as morning types when compared with the reduced Morningness-Eveningness Questionnaire for Children and Adolescents (12 versus 7, respectively), and fewer adolescents as evening types (5 versus 9, respectively). Age and sex had no significant influence on questionnaire scores. The Morningness-Eveningness Stability Scale improved, reduced Morningness-Eveningness Questionnaire for Children and Adolescents, and Composite Scale of Morningness are valid instruments to determine circadian preference in adolescents; however, chronotype classification from the Composite Scale of Morningness and reduced Morningness-Eveningness Questionnaire for Children and Adolescents cannot be used interchangeably.

Neural correlates of attentional control in social anxiety disorder: the impact of early-life adversity and DNA methylation.

BACKGROUND: Social anxiety disorder is characterized by intense fear and avoidance of social interactions and scrutiny by others. Although alterations in attentional control seem to play a central role in the psychopathology of social anxiety disorder, the neural underpinnings in prefrontal brain regions have not yet been fully clarified. METHODS: The present study used functional MRI in participants (age 18-50 yr) with social anxiety disorder (n = 42, 31 female) and without (n = 58, 33 female). It investigated the interrelation of the effects of social anxiety disorder and early-life adversity (a main environmental risk factor of social anxiety disorder) on brain activity during an attentional control task. We applied DNA methylation analysis to determine whether epigenetic modulation in the gene encoding the glucocorticoid receptor, NR3C1, might play a mediating role in this process. RESULTS: We identified 2 brain regions in the left and medial prefrontal cortex that exhibited an interaction effect of social anxiety disorder and early-life adversity. In participants with low levels of early-life adversity, neural activity in response to disorder-related stimuli was increased in association with social anxiety disorder. In participants with high levels of early-life adversity, neural activity was increased only in participants without social anxiety disorder. NR3C1 DNA methylation partly mediated the effect of social anxiety disorder on brain activity as a function of early-life adversity. LIMITATIONS: The absence of behavioural correlates associated with social anxiety disorder limited functional interpretation of the results. CONCLUSION: These findings demonstrate that the neurobiological processes that underlie social anxiety disorder might be fundamentally different depending on experiences of early-life adversity. Long-lasting effects of early-life adversity might be encoded in NR3C1 DNA methylation and entail alterations in social anxiety disorder-related activity patterns in the neural network of attentional control.

Polygenic risk scores across the extended psychosis spectrum.

As early detection of symptoms in the subclinical to clinical psychosis spectrum may improve health outcomes, knowing the probabilistic susceptibility of developing a disorder could guide mitigation measures and clinical intervention. In this context, polygenic risk scores (PRSs) quantifying the additive effects of multiple common genetic variants hold the potential to predict complex diseases and index severity gradients. PRSs for schizophrenia (SZ) and bipolar disorder (BD) were computed using Bayesian regression and continuous shrinkage priors based on the latest SZ and BD genome-wide association studies (Psychiatric Genomics Consortium, third release). Eight well-phenotyped groups (n = 1580; 56% males) were assessed: control (n = 305), lower (n = 117) and higher (n = 113) schizotypy (both groups of healthy individuals), at-risk for psychosis (n = 120), BD type-I (n = 359), BD type-II (n = 96), schizoaffective disorder (n = 86), and SZ groups (n = 384). PRS differences were investigated for binary traits and the quantitative Positive and Negative Syndrome Scale. Both BD-PRS and SZ-PRS significantly differentiated controls from at-risk and clinical groups (Nagelkerke's pseudo-R2: 1.3-7.7%), except for BD type-II for SZ-PRS. Out of 28 pairwise comparisons for SZ-PRS and BD-PRS, 9 and 12, respectively, reached the Bonferroni-corrected significance. BD-PRS differed between control and at-risk groups, but not between at-risk and BD type-I groups. There was no difference between controls and schizotypy. SZ-PRSs, but not BD-PRSs, were positively associated with transdiagnostic symptomology. Overall, PRSs support the continuum model across the psychosis spectrum at the genomic level with possible irregularities for schizotypy. The at-risk state demands heightened clinical attention and research addressing symptom course specifiers. Continued efforts are needed to refine the diagnostic and prognostic accuracy of PRSs in mental healthcare.

Dynamic DNA Methylation Changes in the COMT Gene Promoter Region in Response to Mental Stress and Its Modulation by Transcranial Direct Current Stimulation.

Changes in epigenetic modifications present a mechanism how environmental factors, such as the experience of stress, can alter gene regulation. While stress-related disorders have consistently been associated with differential DNA methylation, little is known about the time scale in which these alterations emerge. We investigated dynamic DNA methylation changes in whole blood of 42 healthy male individuals in response to a stressful cognitive task, its association with concentration changes in cortisol, and its modulation by transcranial direct current stimulation (tDCS). We observed a continuous increase in COMT promotor DNA methylation which correlated with higher saliva cortisol levels and was still detectable one week later. However, this lasting effect was suppressed by concurrent activity-enhancing anodal tDCS to the dorsolateral prefrontal cortex. Our findings support the significance of gene-specific DNA methylation in whole blood as potential biomarkers for stress-related effects. Moreover, they suggest alternative molecular mechanisms possibly involved in lasting behavioral effects of tDCS.

The association of the 5-HTTLPR polymorphism and the response to different stressors in healthy males.

The experience of stress is related to individual wellbeing and vulnerability to psychopathology. Therefore, understanding the determinants of individual differences in stress reactivity is of great concern from a clinical perspective. The functional promotor polymorphism of the serotonin transporter gene (5-HTTLPR/rs25531) is such a factor, which has been linked to the acute stress response as well as the adverse effect of life stressors. In the present study, we compared the impact of two different stress induction protocols (Maastricht Acute Stress Test and ScanSTRESS) and the respective control conditions on affective ratings, salivary cortisol levels and cognitive performance. To this end, 156 healthy young males were tested and genotyped for the 5-HTTLPR/rs25531 polymorphism. While combined physiological and psychological stress in the MAST led to a greater cortisol increase compared to control conditions as well as the psychosocial ScanSTRESS, subjective stress ratings were highest in the ScanSTRESS condition. Stress induction in general affected working memory capacity but not response inhibition. Subjective stress was also influenced by 5-HTTLPR/rs25531 genotype with the high expression group showing lower stress ratings than lower expression groups. In line with previous research, we identified the low expression variant of the serotonin transporter gene as a risk factor for increased stress reactivity. While some dimensions of the human stress response may be stressor specific, cognitive outcomes such as working memory performance are influenced by stress in general. Different pathways of stress processing and possible underlying mechanisms are discussed.

Treatment of major depressive disorder with bilateral theta burst stimulation: study protocol for a randomized, double-blind, placebo-controlled multicenter trial (TBS-D).

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (dlPFC) is currently evolving as an effective and safe therapeutic tool in the treatment of major depressive disorder (MDD). However, already established rTMS treatment paradigms are rather time-consuming. With theta burst stimulation (TBS), a patterned form of rTMS, treatment time can be substantially reduced. Pilot studies and a randomized controlled trial (RCT) demonstrate non-inferiority of TBS to 10 Hz rTMS and support a wider use in MDD. Still, data from placebo-controlled multicenter RCTs are lacking. In this placebo-controlled multicenter study, 236 patients with MDD will be randomized to either intermittent TBS (iTBS) to the left and continuous TBS (cTBS) to the right dlPFC or bilateral sham stimulation (1:1 ratio). The treatment will be performed with 80% resting motor threshold intensity over six consecutive weeks (30 sessions). The primary outcome is the treatment response rate (Montgomery-Asberg Depression Rating Scale reduction ≥ 50%). The aim of the study is to confirm the superiority of active bilateral TBS compared to placebo treatment. In two satellite studies, we intend to identify possible MRI-based and (epi-)genetic predictors of responsiveness to TBS therapy. Positive results will support the clinical use of bilateral TBS as an advantageous, efficient, and well-tolerated treatment and pave the way for further individualization of MDD therapy.Trial registration: ClinicalTrials.gov (NCT04392947).

Insights from a laboratory and naturalistic investigation on stress, rumination and frontal brain functioning in MDD: An fNIRS study.

Recent research has emphasized rumination as an important maintaining factor in various mental disorders. However, operationalization and therefore induction of rumination in experimental settings poses a major challenge in terms of ecological validity. As stress seems to play a key role in everyday situations eliciting rumination, we conducted two stress paradigms while assessing behavioral and neurophysiological measures. Aiming to replicate previous findings on induced rumination by means of the Trier Social Stress Test (TSST) and comparing them to physiological (pain) stress, a clinical sample of patients with Major Depressive Disorder (MDD; n = 22) and healthy controls (HC; n = 23) was recruited. Cortical blood oxygenation was assessed during the stress paradigms using functional near-infrared spectroscopy (fNIRS). Further, we used ecological momentary assessment (EMA) of stress, rumination and mood to be able to correlate ruminative responses during induced stress and everyday rumination. Our results showed that social stress but not physiological stress induced depressive rumination in MDD but not in HC. Further, rumination reactivity in response to social stress but not to physiological stress was significantly associated with rumination reactivity in everyday life as assessed with EMA. With respect to cortical oxygenation, MDD subjects showed hypoactivity in the Cognitive Control Network during the TSST, which mediated the differences between MDD and HC in post-stress rumination. Our findings emphasize the role of negative social triggers in depressive rumination and validate the TSST as an induction method for depressive rumination. The results inform future developments in psychotherapeutic treatment for depressive rumination.

DNA methylation differences associated with social anxiety disorder and early life adversity.

Social anxiety disorder (SAD) is a psychiatric disorder characterized by extensive fear in social situations. Multiple genetic and environmental factors are known to contribute to its pathogenesis. One of the main environmental risk factors is early life adversity (ELA). Evidence is emerging that epigenetic mechanisms such as DNA methylation might play an important role in the biological mechanisms underlying SAD and ELA. To investigate the relationship between ELA, DNA methylation, and SAD, we performed an epigenome-wide association study for SAD and ELA examining DNA from whole blood of a cohort of 143 individuals using DNA methylation arrays. We identified two differentially methylated regions (DMRs) associated with SAD located within the genes SLC43A2 and TNXB. As this was the first epigenome-wide association study for SAD, it is worth noting that both genes have previously been associated with panic disorder. Further, we identified two DMRs associated with ELA within the SLC17A3 promoter region and the SIAH3 gene and several DMRs that were associated with the interaction of SAD and ELA. Of these, the regions within C2CD2L and MRPL28 showed the largest difference in DNA methylation. Lastly, we found that two DMRs were associated with both the severity of social anxiety and ELA, however, neither of them was found to mediate the contribution of ELA to SAD later in life. Future studies are needed to replicate our findings in independent cohorts and to investigate the biological pathways underlying these effects.

An Investigation of Psychosis Subgroups With Prognostic Validation and Exploration of Genetic Underpinnings: The PsyCourse Study.

Importance: Identifying psychosis subgroups could improve clinical and research precision. Research has focused on symptom subgroups, but there is a need to consider a broader clinical spectrum, disentangle illness trajectories, and investigate genetic associations. Objective: To detect psychosis subgroups using data-driven methods and examine their illness courses over 1.5 years and polygenic scores for schizophrenia, bipolar disorder, major depression disorder, and educational achievement. Design, Setting, and Participants: This ongoing multisite, naturalistic, longitudinal (6-month intervals) cohort study began in January 2012 across 18 sites. Data from a referred sample of 1223 individuals (765 in the discovery sample and 458 in the validation sample) with DSM-IV diagnoses of schizophrenia, bipolar affective disorder (I/II), schizoaffective disorder, schizophreniform disorder, and brief psychotic disorder were collected from secondary and tertiary care sites. Discovery data were extracted in September 2016 and analyzed from November 2016 to January 2018, and prospective validation data were extracted in October 2018 and analyzed from January to May 2019. Main Outcomes and Measures: A clinical battery of 188 variables measuring demographic characteristics, clinical history, symptoms, functioning, and cognition was decomposed using nonnegative matrix factorization clustering. Subtype-specific illness courses were compared with mixed models and polygenic scores with analysis of covariance. Supervised learning was used to replicate results in validation data with the most reliably discriminative 45 variables. Results: Of the 765 individuals in the discovery sample, 341 (44.6%) were women, and the mean (SD) age was 42.7 (12.9) years. Five subgroups were found and labeled as affective psychosis (n = 252), suicidal psychosis (n = 44), depressive psychosis (n = 131), high-functioning psychosis (n = 252), and severe psychosis (n = 86). Illness courses with significant quadratic interaction terms were found for psychosis symptoms (R2 = 0.41; 95% CI, 0.38-0.44), depression symptoms (R2 = 0.28; 95% CI, 0.25-0.32), global functioning (R2 = 0.16; 95% CI, 0.14-0.20), and quality of life (R2 = 0.20; 95% CI, 0.17-0.23). The depressive and severe psychosis subgroups exhibited the lowest functioning and quadratic illness courses with partial recovery followed by reoccurrence of severe illness. Differences were found for educational attainment polygenic scores (mean [SD] partial η2 = 0.014 [0.003]) but not for diagnostic polygenic risk. Results were largely replicated in the validation cohort. Conclusions and Relevance: Psychosis subgroups were detected with distinctive clinical signatures and illness courses and specificity for a nondiagnostic genetic marker. New data-driven clinical approaches are important for future psychosis taxonomies. The findings suggest a need to consider short-term to medium-term service provision to restore functioning in patients stratified into the depressive and severe psychosis subgroups.