Psychological Medicine最新文献

Background: Cognitive impairment, a major determinant of poor functioning in schizophrenia, had limited responses to existing antipsychotic drugs. The limited efficacy could be due to regional differences in the dysregulation of the dopamine system. This study investigated striatal and peripheral dopaminergic makers in schizophrenia and their relationship with cognitive impairment.

Methods: Thirty-three patients with schizophrenia and 36 age- and sex-matched healthy controls (HC) participated. We evaluated their cognitive performance, examined the availability of striatal dopamine transporter (DAT) using single-photon emission computed tomography with 99mTc-TRODAT, and measured plasma levels of dopaminergic precursors (phenylalanine and tyrosine) and three branched-chain amino acids (BCAA) that compete with precursors for brain uptake via ultra-performance liquid chromatography.

Results: Schizophrenia patients exhibited lower cognitive performance, decreased striatal DAT availability, and reduced levels of phenylalanine, tyrosine, leucine, and isoleucine, and the ratio of phenylalanine plus tyrosine to BCAA. Within the patient group, lower DAT availability in the left caudate nucleus (CN) or putamen was positively associated with attention deficits. Meanwhile, lower tyrosine levels and the ratio of phenylalanine plus tyrosine to BCAA were positively related to executive dysfunction. Among all participants, DAT availability in the right CN or putamen was positively related to memory function, and plasma phenylalanine level was positively associated with executive function.

Conclusions: This study supports the role of dopamine system abnormalities in cognitive impairment in schizophrenia. The distinct associations between different dopaminergic alterations and specific cognitive domain impairments suggest the potential need for multifaceted treatment approaches to target these impairments.

Background: Drug use Disorder (DUD), the risk for which is substantially influenced by both genetic and social factors, is geographically concentrated in high-risk regions. An important step toward understanding this pattern is to examine geographical distributions of the genetic liability to DUD and a key demographic risk factor - social deprivation.

Methods: We calculated the mean family genetic risk score (FGRS) for DUD ((FGRS_DUD) and social deprivation for each of the 5983 areas Demographic Statistical Areas (DeSO) for all of Sweden and used geospatial techniques to analyze and map these factors.

Results: Using 2018 data, substantial spatial heterogeneity was seen in the distribution of the genetic risk for DUD in Sweden as a whole and in its three major urban centers which was confirmed by hot-spot analyses. Across DeSOs, FGRS_DUD and s.d. levels were substantially but imperfectly correlated (r = + 0.63), with more scattering at higher FGRS_DUD and s.d. scores. Joint mapping across DeSOs for FGRS_DUD and s.d. revealed a diversity of patterns across Sweden. The stability of the distributions of FGRS_DUD and s.d. in DeSOs within Sweden over the years 2012-2018 was quite high.

Conclusions: The geographical distribution of the genetic risk to DUD is quite variable in Sweden. DeSO levels of s.d. and FRGS_DUD were substantially correlated but also disassociated in a number of regions. The observed patterns were largely consistent with known trends in the human geography of Sweden. This effort lays the groundwork for further studies of the sources of geographic variation in rates of DUD.

Background: Robust clinical indices of etiologic heterogeneity for psychiatric disorders are rare. We investigate whether age at onset (AAO) reflects genetic heterogeneity, utilizing Genetic Risk Ratios (GRR) derived from Family Genetic Risk Scores (FGRS).

Methods: We examined, in individuals born in Sweden 1940-2003, whether AAO for five primary disorders -- drug use disorder (DUD), alcohol use disorder (AUD), major depression (MD), bipolar disorder (BD), and schizophrenia (SZ)-- was associated with varying levels of GRRs with a range of informative secondary disorders and traits.

Results: Our disorders displayed a varying pattern of change of GRRs with increasing AAO. At one end was SZ, where all GRRs rose with increasing AAO meaning that SZ became increasing genetically heterogeneous with later AAO. The most balanced disorder was AUD where, with increasing AAO, GRRs rose for AD, BD, and MD and declined for DUD, CB, and ADHD. That is, at young AAO, AUD had high levels of genetic risk for other externalizing disorders while at older AAO, high genetic risk for internalizing disorders were more prominent. MD was at the continuum's other end where all GRRs, except for AD, decreased with higher AAO, meaning that MD became increasingly genetically homogeneous with later AAO.

Conclusions: Genetic heterogeneity was robustly associated with AAO across our five primary disorders with substantial inter-disorder differences in the observed patterns. In particular, young AAO was associated with maximal genetic homogeneity for SZ and DUD while older AAO had greater genetic homogeneity for MD with AUD falling in between.

Background: Motor activity fluctuations in healthy adults exhibit fractal patterns characterized by consistent temporal correlations across wide-ranging time scales. However, these patterns are disrupted by aging and psychiatric conditions. This study aims to investigate how fractal patterns vary across the sleep-wake cycle, differ based on individuals' recency of depression diagnosis, and change before and after a depressive episode.

Methods: Using actigraphy from two cohorts (n = 378), we examined fractal motor activity patterns both between individuals without depression and with varying recencies of depression and within individuals before and after depressive symptom recurrence. To evaluate fractal patterns, we quantified temporal correlations in motor activity fluctuations across different time scales using a scaling exponent, α. Linear mixed models were utilized to assess the influence of the sleep-wake cycle, (recency of) depression, and their interaction on α.

Results: Fractal activity patterns in all individuals varied across the sleep-wake cycle, showing stronger temporal correlations during wakefulness (larger α = 1.035 ± 0.003) and more random activity fluctuations during sleep (smaller α = 0.784 ± 0.004, p < 0.001). This sleep-wake difference was reduced in recently depressed individuals (1-6 months), leading to larger α during sleep (0.836 ± 0.017), compared to currently depressed (0.781 ± 0.018, p = 0.006), remitted (0.776 ± 0.014, p < 0.001), and never-depressed individuals (0.773 ± 0.016, p < 0.001). Moreover, remitted individuals who experienced depressive symptom recurrence during antidepressant tapering exhibited a larger α during sleep after the symptom onset as compared to before (after: α = 0.703 ± 0.022; before: α = 0.680 ± 0.022; p < 0.001).

Conclusions: These findings suggest a link between fractal motor activity patterns during sleep and depressive symptom recurrence in remitted individuals and those with recent depression.

Background: Individuals with major depressive disorder (MDD) can experience reduced motivation and cognitive function, leading to challenges with goal-directed behavior. When selecting goals, people maximize 'expected value' by selecting actions that maximize potential reward while minimizing associated costs, including effort 'costs' and the opportunity cost of time. In MDD, differential weighing of costs and benefits are theorized mechanisms underlying changes in goal-directed cognition and may contribute to symptom heterogeneity.

Methods: We used the Effort Foraging Task to quantify cognitive and physical effort costs, and patch leaving thresholds in low effort conditions (reflecting perceived opportunity cost of time) and investigated their shared versus distinct relationships to clinical features in participants with MDD (N = 52, 43 in-episode) and comparisons (N = 27).

Results: Contrary to our predictions, none of the decision-making measures differed with MDD diagnosis. However, each of the measures was related to symptom severity, over and above effects of ability (i.e. performance). Greater anxiety symptoms were selectively associated with lower cognitive effort cost (i.e. greater willingness to exert effort). Anhedonia and behavioral apathy were associated with increased physical effort costs. Finally, greater overall depression was related to decreased patch leaving thresholds.

Conclusions: Markers of effort-based decision-making may inform understanding of MDD heterogeneity. Increased willingness to exert cognitive effort may contribute to anxiety symptoms such as worry. Decreased leaving threshold associations with symptom severity are consistent with reward rate-based accounts of reduced vigor in MDD. Future research should address subtypes of depression with or without anxiety, which may relate differentially to cognitive effort decisions.

Background: Adolescents with a history of conduct problems (CP) are at heightened risk of increased service utilization as they develop. While the mechanisms underlying this association are unclear, early CP have also been linked with peer victimization and internalizing problems. The goals of the current study were: (1) to examine peer victimization and internalizing problems as potential serial mediators explaining increased medical and psychiatric service use in adolescents with a history of childhood CP, and; (2) to explore whether the proposed mediation models vary by sex.

Methods: Participants (N = 744; 53% boys, Mage = 8.39 years) from an ongoing longitudinal study that began in 2008 in Québec, Canada were recruited and assessed for CP, service use, and other behaviours via self-, parent- and teacher-reported questionnaires. Serial mediation analyses were conducted to examine the effects of peer victimization and internalizing problems on the association between childhood CP and adolescent medical and psychiatric service use, controlling for sex and household income.

Results: Adolescents with childhood CP reported higher medical and psychiatric service use than non-CP peers. Peer victimization and internalizing problems significantly mediated this association in both general medical and psychiatric service use models. The models did not vary by sex.

Conclusions: Findings support higher levels of service use in adolescents with a history of CP, mediated by peer victimization and internalizing problems. Specifically, results highlight the importance of examining peer and socioemotional factors that may explain the increased service usage observed among youth with CP, to support better health outcomes.

Background: Associations between childhood trauma, neurodevelopment, alcohol use disorder (AUD), and posttraumatic stress disorder (PTSD) are understudied during adolescence.

Methods: Using 1652 participants (51.75% female, baseline M_age = 14.3) from the Collaborative Study of the Genetics of Alcoholism, we employed latent growth curve models to (1) examine associations of childhood physical, sexual, and non-assaultive trauma (CPAT, CSAT, and CNAT) with repeated measures of alpha band EEG coherence (EEGc), and (2) assess whether EEGc trajectories were associated with AUD and PTSD symptoms. Sex-specific models accommodated sex differences in trauma exposure, AUD prevalence, and neural development.

Results: In females, CSAT was associated with higher mean levels of EEGc in left frontocentral (LFC, ß = 0.13, p = 0.01) and interhemispheric prefrontal (PFI, ß = 0.16, p < 0.01) regions, but diminished growth in LFC (ß = -0.07, p = 0.02) and PFI (ß = -0.07, p = 0.02). In males, CPAT was associated with lower mean levels (ß = -0.17, p = 0.01) and increased growth (ß = 0.11, p = 0.01) of LFC EEGc. Slope of LFC EEGc was inversely associated with AUD symptoms in females (ß = -1.81, p = 0.01). Intercept of right frontocentral and PFI EEGc were associated with AUD symptoms in males, but in opposite directions. Significant associations between EEGc and PTSD symptoms were also observed in trauma-exposed individuals.

Conclusions: Childhood assaultive trauma is associated with changes in frontal alpha EEGc and subsequent AUD and PTSD symptoms, though patterns differ by sex and trauma type. EEGc findings may inform emerging treatments for PTSD and AUD.

Background: In contemporary neuroimaging studies, it has been observed that patients with major depressive disorder (MDD) exhibit aberrant spontaneous neural activity, commonly quantified through the amplitude of low-frequency fluctuations (ALFF). However, the substantial individual heterogeneity among patients poses a challenge to reaching a unified conclusion.

Methods: To address this variability, our study adopts a novel framework to parse individualized ALFF abnormalities. We hypothesize that individualized ALFF abnormalities can be portrayed as a unique linear combination of shared differential factors. Our study involved two large multi-center datasets, comprising 2424 patients with MDD and 2183 healthy controls. In patients, individualized ALFF abnormalities were derived through normative modeling and further deconstructed into differential factors using non-negative matrix factorization.

Results: Two positive and two negative factors were identified. These factors were closely linked to clinical characteristics and explained group-level ALFF abnormalities in the two datasets. Moreover, these factors exhibited distinct associations with the distribution of neurotransmitter receptors/transporters, transcriptional profiles of inflammation-related genes, and connectome-informed epicenters, underscoring their neurobiological relevance. Additionally, factor compositions facilitated the identification of four distinct depressive subtypes, each characterized by unique abnormal ALFF patterns and clinical features. Importantly, these findings were successfully replicated in another dataset with different acquisition equipment, protocols, preprocessing strategies, and medication statuses, validating their robustness and generalizability.

Conclusions: This research identifies shared differential factors underlying individual spontaneous neural activity abnormalities in MDD and contributes novel insights into the heterogeneity of spontaneous neural activity abnormalities in MDD.

Background and hypothesis: Transition to psychosis rates within ultra-high risk (UHR) services have been declining. It may be possible to 'enrich' UHR cohorts based on the environmental characteristics seen more commonly in first-episode psychosis cohorts. This study aimed to determine whether transition rates varied according to the accumulated exposure to environmental risk factors at the individual (migrant status, asylum seeker/refugee status, indigenous population, cannabis/methamphetamine use), family (family history or parental separation), and neighborhood (population density, social deprivation, and fragmentation) level.

Methods: The study included UHR people aged 15-24 who attended the PACE clinic from 2012 to 2016. Cox proportional hazards models (frequentist and Bayesian) were used to assess the association between individual and accumulated factors and transition to psychosis. UHR status and transition was determined using the CAARMS. Benjamini-Hochberg was used to correct for multiple comparisons in frequentist analyses.

Results: Of the 461 young people included, 55.5% were female and median follow-up was 307 days (IQR: 188-557) and 17.6% (n = 81) transitioned to a psychotic disorder. The proportion who transitioned increased incrementally according to the number of individual-level risk factors present (HR = 1.51, 95% CIs 1.19-1.93, p < 0.001, p_corr = 0.01). The number of family- and neighborhood-level exposures did not increase transition risk (p > 0.05). Cannabis use was the only specific risk factor significantly associated with transition (HR = 1.89, 95% CIs 1.22-2.93, p_corr = 0.03, BF = 6.74).

Conclusions: There is a dose-response relationship between exposure to individual-level psychosis-related environmental risk factors and transition risk in UHR patients. If replicated, this could be incorporated into a novel approach to identifying the highest-risk individuals within clinical services.