JAMA Psychiatry最新文献

Importance: Accelerometry has been increasingly used as an objective index of sleep, physical activity, and circadian rhythms in people with mood disorders. However, most prior research has focused on sleep or physical activity alone without consideration of the strong within- and cross-domain intercorrelations; and few studies have distinguished between trait and state profiles of accelerometry domains in major depressive disorder (MDD).

Objectives: To identify joint and individual components of the domains derived from accelerometry, including sleep, physical activity, and circadian rhythmicity using the Joint and Individual Variation Explained method (JIVE), a novel multimodal integrative dimension-reduction technique; and to examine associations between joint and individual components with current and remitted MDD.

Design, setting, and participants: This cross-sectional study examined data from the second wave of a population cohort study from Lausanne, Switzerland. Participants included 2317 adults (1164 without MDD, 185 with current MDD, and 968 with remitted MDD) with accelerometry for at least 7 days. Statistical analysis was conducted from January 2021 to June 2023.

Main outcomes and measures: Features derived from accelerometry for 14 days; current and remitted MDD. Logistic regression adjusted for age, sex, body mass index, and anxiety and substance use disorders.

Results: Among 2317 adults included in the study, 1261 (54.42%) were female, and mean (SD) age was 61.79 (9.97) years. JIVE reduced 28 accelerometry features to 3 joint and 6 individual components (1 sleep, 2 physical activity, 3 circadian rhythms). Joint components explained 58.5%, 79.5%, 54.5% of the total variation in sleep, physical activity, and circadian rhythm domains, respectively. Both current and remitted depression were associated with the first 2 joint components that were distinguished by the salience of high-intensity physical activity and amplitude of circadian rhythm and timing of both sleep and physical activity, respectively. MDD had significantly weaker circadian rhythmicity.

Conclusions and relevance: Application of a novel multimodal dimension-reduction technique demonstrates the importance of joint influences of physical activity, circadian rhythms, and timing of both sleep and physical activity with MDD; dampened circadian rhythmicity may constitute a trait marker for MDD. This work illustrates the value of accelerometry as a potential biomarker for subtypes of depression and highlights the importance of consideration of the full 24-hour sleep-wake cycle in future studies.

Importance: The risk of mental disorders is consistently associated with variants in CACNA1C (L-type calcium channel Cav1.2) but it is not known why these channels are critical to cognition, and whether they affect the layer III pyramidal cells in the dorsolateral prefrontal cortex that are especially vulnerable in cognitive disorders.

Objective: To examine the molecular mechanisms expressed in layer III pyramidal cells in primate dorsolateral prefrontal cortices.

Design, setting, and participants: The design included transcriptomic analyses from human and macaque dorsolateral prefrontal cortex, and connectivity, protein expression, physiology, and cognitive behavior in macaques. The research was performed in academic laboratories at Yale, Harvard, Princeton, and the University of Pittsburgh. As dorsolateral prefrontal cortex only exists in primates, the work evaluated humans and macaques.

Main outcomes and measures: Outcome measures included transcriptomic signatures of human and macaque pyramidal cells, protein expression and interactions in layer III macaque pyramidal cells using light and electron microscopy, changes in neuronal firing during spatial working memory, and working memory performance following pharmacological treatments.

Results: Layer III pyramidal cells in dorsolateral prefrontal cortex coexpress a constellation of calcium-related proteins, delineated by CALB1 (calbindin), and high levels of CACNA1C (Cav1.2), GRIN2B (NMDA receptor GluN2B), and KCNN3 (SK3 potassium channel), concentrated in dendritic spines near the calcium-storing smooth endoplasmic reticulum. L-type calcium channels influenced neuronal firing needed for working memory, where either blockade or increased drive by β1-adrenoceptors, reduced neuronal firing by a mean (SD) 37.3% (5.5%) or 40% (6.3%), respectively, the latter via SK potassium channel opening. An L-type calcium channel blocker or β1-adrenoceptor antagonist protected working memory from stress.

Conclusions and relevance: The layer III pyramidal cells in the dorsolateral prefrontal cortex especially vulnerable in cognitive disorders differentially express calbindin and a constellation of calcium-related proteins including L-type calcium channels Cav1.2 (CACNA1C), GluN2B-NMDA receptors (GRIN2B), and SK3 potassium channels (KCNN3), which influence memory-related neuronal firing. The finding that either inadequate or excessive L-type calcium channel activation reduced neuronal firing explains why either loss- or gain-of-function variants in CACNA1C were associated with increased risk of cognitive disorders. The selective expression of calbindin in these pyramidal cells highlights the importance of regulatory mechanisms in neurons with high calcium signaling, consistent with Alzheimer tau pathology emerging when calbindin is lost with age and/or inflammation.

Importance: Complex biological, socioeconomic, and psychological variables combine to cause mental illnesses, with mounting evidence that early-life experiences are associated with adulthood mental health.

Objective: To evaluate whether changing neighborhood income deprivation and residential moves during childhood are associated with the risk of receiving a diagnosis of depression in adulthood.

Design, setting, and participants: This cohort study included the whole population of 1 096 916 people born in Denmark from January 1, 1982, to December 31, 2003, who resided in the country during their first 15 years of life. Individuals were followed up from 15 years of age until either death, emigration, depression diagnosis, or December 31, 2018. Longitudinal data on residential location was obtained by linking all individuals to the Danish longitudinal population register. Statistical analysis was performed from June 2022 to January 2024.

Exposures: Exposures included a neighborhood income deprivation index at place of residence for each year from birth to 15 years of age and a mean income deprivation index for the entire childhood (aged ≤15 years). Residential moves were considered by defining "stayers" as individuals who lived in the same data zone during their entire childhood and "movers" as those who did not.

Main outcomes and measures: Multilevel survival analysis determined associations between neighborhood-level income deprivation and depression incidence rates after adjustment for individual factors. Results were reported as incidence rate ratios (IRRs) with 95% credible intervals (95% CrIs). The hypotheses were formulated before data collection.

Results: A total of 1 096 916 individuals (563 864 male participants [51.4%]) were followed up from 15 years of age. During follow-up, 35 098 individuals (23 728 female participants [67.6%]) received a diagnosis of depression. People living in deprived areas during childhood had an increased risk of depression (IRR, 1.10 [95% CrI, 1.08-1.12]). After full individual-level adjustment, the risk was attenuated (IRR, 1.02 [95% CrI, 1.01-1.04]), indicating an increase of 2% in depression incidence for each 1-SD increase in income deprivation. Moving during childhood, independent of neighborhood deprivation status, was associated with significantly higher rates of depression in adulthood compared with not moving (IRR, 1.61 [95% CrI, 1.52-1.70] for 2 or more moves after full adjustment).

Conclusions and relevance: This study suggests that, rather than just high or changing neighborhood income deprivation trajectories in childhood being associated with adulthood depression, a settled home environment in childhood may have a protective association against depression. Policies that enable and support settled childhoods should be promoted.

Importance: Characterizing mental health service use trajectories preceding diagnosis of a psychotic disorder may help identify individuals at highest risk and in which settings they are at highest risk.

Objective: To examine mental health service use and diagnostic trajectories before first diagnosis of psychotic disorder and identify utilization and diagnostic patterns.

Design, setting, and participants: This population-based, retrospective cohort study used linked provincial health administrative data. The sample included individuals aged 15 to 29 years diagnosed with a psychotic disorder in Ontario, Canada, between April 1, 2012, and March 31, 2018. These individuals were matched to individuals with a diagnosis of a mood disorder. Data were analyzed from November 2018 to November 2019.

Main outcomes and measures: The main outcomes were rates, timing, and setting of mental health-related service use and associated diagnoses in the 3 years before the index disorder among individuals first diagnosed with a psychotic disorder compared with those first diagnosed with a mood disorder.

Results: A total of 10 501 individuals with a first diagnosis of psychotic disorder were identified (mean [SD] age, 21.55 [3.83] years; 72.1% male). A total of 72.2% of individuals had at least 1 mental health service visit during the 3 years before their first psychotic disorder diagnosis, which was significantly more than matched controls with a first mood disorder diagnosis (66.8%) (odds ratio [OR], 1.34; 95% CI, 1.26-1.42). Compared with individuals diagnosed with a mood disorder, individuals diagnosed with a psychotic disorder were significantly more likely to have had mental health-related hospital admissions (OR, 3.98; 95% CI, 3.43-4.62) and emergency department visits (OR, 2.27; 95% CI, 2.12-2.43) in the preceding 3 years. Those with psychotic disorders were more likely to have had prior diagnoses of substance use disorders (OR, 2.57; 95% CI, 2.35-2.81), other disorders (personality disorders, developmental disorders) (OR, 1.75; 95% CI, 1.61-1.90), and self-harm (OR, 1.64; 95% CI, 1.36-1.98) in the past 3 years compared with those diagnosed with mood disorders.

Conclusions and relevance: This study found that in the 3 years prior to an index diagnosis, individuals with a first diagnosis of psychotic disorder had higher rates of mental health service use, particularly emergency department visits and hospitalizations, compared with individuals with a first diagnosis of a mood disorder. Individuals with psychotic disorders also had a greater number of premorbid diagnoses. Differences in health service utilization patterns between those with a first psychotic disorder diagnosis vs a first mood disorder diagnosis suggest distinct premorbid trajectories that could be useful for next steps in prediction and prevention research.

Importance: Bipolar disorder (BD) is chronic and disabling, with depression accounting for the majority of time with illness. Recent research demonstrated a transformative advance in the clinical efficacy of transcranial magnetic stimulation for treatment-resistant major depressive disorder (MDD) using an accelerated schedule of intermittent theta-burst stimulation (aiTBS), but the effectiveness of this treatment for treatment-refractory BD is unknown.

Objective: To evaluate the effectiveness of aiTBS for treatment-refractory BD.

Design, setting, and participants: This randomized clinical trial, conducted from March 2022 to February 2024, included individuals with treatment-resistant BD with moderate to severe depressive episodes referred from the Penn Bipolar outpatient clinic. Included patients had 2 or more prior failed antidepressant trials by Antidepressant Treatment History Form criteria and no other primary psychiatric diagnosis, were receiving a mood stabilizer for 4 or more weeks, and had a Montgomery-Åsberg Depression Rating Scale (MADRS) score of 20 or higher.

Intervention: Prior to treatment, resting-state functional magnetic resonance imaging was used to compute personalized left dorsolateral prefrontal cortex target by connectivity to subgenual anterior cingulate cortex. Patients were randomized 1:1 to 10 sessions per day of imaging-guided active or sham aiTBS for 5 days with 1 session per hour at 90% resting motor threshold for 90 000 pulses total.

Main outcome and measures: The main outcome was repeated MADRS scores before and after treatment.

Results: A total of 24 participants (12 [50%] female; 12 [50%] male; mean [SD] age, 43.3 [16.9] years) were randomized to active (n = 12) or sham (n = 12) aiTBS. All participants completed treatment and 1-month follow-up. MADRS scores were significantly lower in the active group (mean [SD], 30.4 [4.8] at baseline; 10.5 [6.7] after treatment) than in the sham group (28.0 [5.4] at baseline; 25.3 [6.7] after treatment) at treatment end (estimated difference, -14.75; 95% CI, -19.73 to -9.77; P < .001; Cohen d, -2.19).

Conclusion and relevance: In this randomized clinical trial, aiTBS was more effective than sham stimulation for depressive symptom reduction in patients with treatment-resistant BD. Further trials are needed to determine aiTBS durability and to compare with other treatments.

Trial registration: ClinicalTrials.gov Identifier: NCT05228457.

Importance: Bipolar disorder (BD) often first appears in adolescence after onset of major depressive disorder (MDD), but diagnosis and treatment are commonly delayed. This delay is a concern because untreated BD is associated with adverse long-term outcomes, a more recurrent disease course and difficult-to-treat illness, and suicide attempts and deaths.

Objective: To examine the association of age at MDD onset with early transition to BD and the subsequent use of psychiatric inpatient services as a severity indicator.

Design, setting, and participants: This retrospective cohort study analyzed comprehensive data sourced from the Stockholm MDD Cohort data from 1997 to 2018, which encompass both outpatient and inpatient care. Individuals with an initial MDD episode from January 1, 2010, to December 31, 2013, who transitioned to BD by December 31, 2018, were identified. Data were analyzed between September 5 and December 28, 2023.

Exposures: Post MDD assessments included a depression severity index, comorbidities, psychotherapy, psychotropic drugs, and electroconvulsive therapy.

Main outcomes and measures: The main outcome was the transition from MDD to BD, dichotomized as occurring early (within 3 years of MDD onset) or late (3 years after MDD onset). Secondary outcomes encompassed the use of psychiatric inpatient services post transition and patterns of medication usage. A robust propensity score matching framework was used to estimate outcomes.

Results: The final balanced cohort included 228 individuals, with an equal distribution between adults (n = 114; mean [SD] age, 24.5 [6.3] years; 96 female [84.2%]; 20 experiencing an early transition to BD [17.5%]) and youths (n = 114; mean [SD] age, 15.3 [1.6] years; 93 female [81.6%]; 8 experiencing an early transition to BD [7.0%]). Youths were substantially less likely to transition early (odds ratio, 0.42; 95% CI, 0.20-0.88; P = .02), despite having more outpatient visits (mean [SD] visits per month, 1.21 [1.07] vs 0.97 [0.98] for adults; P = .01). Both groups experienced substantially reduced inpatient care following a BD diagnosis, concurring with a marked decline in antidepressant use without increased lithium use.

Conclusions and relevance: These findings suggest that adolescents may experience delayed BD progression and that diagnosis substantially reduced inpatient care in all age groups, which coincided with a reduction in the use of antidepressants. These findings may inform pharmacologic strategies in patients with first-episode MDD at risk for BD.