Journal of Psychiatric Research

As the global prevalence of trauma rises, there is a growing need for accessible and scalable treatments for trauma-related disorders like posttraumatic stress disorder (PTSD). Trauma-related intrusive memories (TR-IMs) are a central PTSD symptom and a target of exposure-based therapies, gold-standard treatments that are effective but resource-intensive. This study examined whether a brief ecological momentary assessment (EMA) protocol assessing the phenomenology of TR-IMs could reduce intrusion symptoms in trauma-exposed adults. Participants (N=131) experiencing at least 2 TR-IMs per week related to a DSM-5 criterion A trauma completed a 2-week EMA protocol during which they reported on TR-IM properties three times per day, and on posttraumatic stress symptoms at the end of each day. Longitudinal symptom measurements were entered into linear mixed-effects models to test the effect of Time on TR-IMs. Over the 2-week EMA protocol, intrusion symptom severity (cluster B scores) significantly declined (t = -2.78, p = 0.006), while other symptom cluster scores did not significantly change. Follow-up analyses demonstrated that this effect was specific to TR-IMs (t = -4.02, p < 0.001), and was not moderated by survey completion rate, total PTSD symptom severity, or ongoing treatment. Our findings indicate that implementing an EMA protocol assessing intrusive memories could be an effective trauma intervention. Despite study limitations like its quasi-experimental design and absence of a control group, the specificity of findings to intrusive memories argues against a mere regression to the mean. Overall, an EMA approach could provide a cost-effective and scalable treatment option targeting intrusive memory symptoms.

BackgroundRumination is a transdiagnostic problem that is common in major depressive disorder (MDD). Rumination Focused Cognitive Behavioral Therapy (RF-CBT) explicitly targets the ruminative habit. This study examined changes in brain activation during a rumination induction task in adolescents with remitted MDD following RF-CBT. We also evaluated the reliability of the rumination task among adolescents who received treatment as usual (TAU). MethodFifty-five adolescents ages 14-17 completed a self-relevant rumination induction fMRI task and were then randomized to either RF-CBT (n = 30) or TAU (n = 25). Participants completed the task a second time either following 10-14 sessions of RF-CBT or the equivalent time delay for the TAU group. We assessed activation change in the RF-CBT group using paired-samples t-tests and reliability by calculating intraclass correlation coefficients (ICCs) of five rumination-related ROIs during each of three blocks for the TAU and RF-CBT groups separately (Rumination Instruction, Rumination Prompt, and Distraction). ResultsFollowing treatment, participants in the RF-CBT group demonstrated an increase in activation of the left precuneus during Rumination Instruction and the left angular and superior temporal gyri during Rumination Prompt (p < .01). The TAU group demonstrated fair to excellent reliability (M = .52, range = .27-.86) across most ROIs and task blocks. In contrast, the RF-CBT group demonstrated poor reliability across most ROIs and task blocks (M = .21, range = -.19-.69). ConclusionRF-CBT appears to lead to rumination-related brain change. We demonstrated that the rumination induction task has fair to excellent reliability among individuals who do not receive an intervention that explicitly targets the ruminative habit, whereas reliability of this task is largely poor in the context of RF-CBT. This has meaningful implications in longitudinal and intervention studies, particularly when conceptualizing it as an important target for intervention. It also suggests one of many possible mechanisms for why fMRI test-retest reliability can be low that appears unrelated to the methodology itself.

BackgroundSelf-directed passive aggression (SD-PAB) is defined as any behaviour harming one-self by inactivity and omission of own needs. Depressive disorders are a severe mental disorder that results from the interaction between stress exposure, coping strategies, and vulnerability. Previous cross-sectional studies found SD-PAB to be associated with depressive symptoms and to represent a mediator of the relationship between cognitive risk factors and depressive symptoms. Therefore, SD-PAB may be a potential target of prevention or treatment in the context of depressive disorders. However, prospective studies on the relationship between depressive symptoms and SD-PAB are lacking. The current study aimed at closing this gap by examining the associations of subjective stress, SD-PAB, and depressive symptoms cross-sectionally and over time. MethodIn two assessment cohorts students participated three times [M1: start of the semester (n = 352); M2: start of the exam period (n = 293); M3 = end of the exam period (n = 276)] in an online survey (depressive symptoms; self-perceived stress; SD-PAB). Cross-sectional data was analysed using regression models. Longitudinal data was analysed using Random Intercept Cross-lagged Panel Models. ResultsAcross all time points, SD-PAB demonstrated a unique cross-sectional association with depressive symptoms when controlled for self-perceived stress ({beta} = .27 - .33; all ps < .001). Furthermore, at M2 [{beta} = .14, t(289) = 3.71, p < .001] and M3 [{beta} = .15, t(272) = 3.51, p < .001] the relationship between depressive symptoms and self-perceived stress was stronger for individuals reporting higher levels of SD-PAB. Depressive symptoms at M1 are a marginal significant predictor of SD-PAB at M2 ({beta} = .31; p = .067) and depressive symptoms at M2 are a marginal significant predictor for SD-PAB at M3 ({beta} = .17; p = .074). However, there was no evidence for SD-PAB predicting the course of depressive symptoms. ConclusionSD-PAB may represent a symptom of depressive disorders and a moderator of unsuccessful stress coping but does not predict the course of depressive symptoms over time.

Childhood Adversity (CA) is one of the strongest factors associated with the onset of Major Depressive Disorder (MDD), and both CA and MDD have been linked to altered hippocampal structure/function. The current study aimed to explore the relationships between retrospectively reported childhood emotional neglect (CEN), current wellbeing and depressive symptoms, and a range of hippocampal-dependent cognitive functions i.e., anterograde learning and memory, episodic memory recollection, and imagination (episodic future thinking and scene construction). In two-wave recruitment periods at undergraduate intake 2014-15 (Cohort 1) and 2016-17 (Cohort 2), a combined cohort of n=1485 university students completed online surveys, with n=64 further participating in experimental testing session. As anticipated, higher CEN ratings consistently correlated with poorer current wellbeing and higher depressive symptoms. However, whilst the anticipated relationships between CEN, current wellbeing, and subjectively reported estimates of hippocampal-dependent cognitions were observed in the data reported in the online survey, an unexpectedly circumscribed pattern was observed on formal in-person examination of these cognitive functions. More specifically, higher CEN related to less vivid and less detailed imagined future/scene constructions and with an attenuated sense of presence and emotional valence during these simulations. A similar pattern was not evidence when participants simulated experienced past events (i.e. episodic memories). Current depression scores did not consistently correlate with vividness, detail, or emotional valence. In addition, and contrary to expectation, no relationship between CEN, depressive symptoms, and the spatial coherence of imagined or recollected events was seen. Moreover, neither CEN nor depressive symptoms correlated with many key measures of anterograde memory. Hence, we observed a highly specific constellation of impairment related to CEN when explored on a simulation per simulation basis, that was not obviously linked to altered hippocampal function, indicating that the relationship between CEN, hippocampal function, and subsequent psychopathology may not readily explained by either spatial or mnemonic hippocampal- related deficits. We consider whether the observed experiential differences in the qualia of imagined simulations may represent an important therapeutic target to decrease a CEN-driven latent vulnerability to MDD.

BackgroundRepetitive transcranial magnetic stimulation (TMS) is now widely accepted as an effective non-pharmacologic treatment for treatment-resistant depression. However, whether repeated acute TMS courses can recapture the antidepressant effects of the initial acute course is still an open question, especially in the Veteran population. We present here a retrospective analysis of a specialty clinic within the Veteran Affairs Hospital System to help address this question. AimsFollowing an acute treatment course of TMS, we sought to determine the treatment response of a subsequent TMS course. We hypothesized that those who responded to an initial acute TMS course would respond in a similar manner to a subsequent treatment course. Methods116 cases referred for evaluation for TMS between September 2017 to April 2021 were reviewed. 63 Veterans completed at least one acute course of TMS and 12 completed at least two courses and met inclusion criteria for this review. Symptoms were evaluated via self-reported scales at baseline and weekly throughout treatment. Clinical response to subsequent treatment (>50% symptom reduction as measured by the PHQ-9) was compared to initial treatment response. ResultsOf the initial treatment responders (n = 6), all six responded to a second acute course, with an 85.3% symptom reduction. Of the initial treatment nonresponders (n = 6), three responded to a second acute course. Exploratory regression analysis predicted change in depression symptoms (PHQ-9) during a second TMS course using initial treatment response, time into treatment, and baseline symptom severity. Together, these factors explained 72% of the variance. No adverse events were reported in those who completed a second course, and the Veterans tolerated the treatment well. ConclusionsOur findings support the growing understanding that a second acute TMS treatment course for treatment-resistant depression is safe, well-tolerated, and effective in initial responders and some non-responders. Despite multiple confounders in a naturalistic setting, robust initial treatment response was sustained in a second acute course. Low power limits generalizability, and larger powered, prospective studies are needed.

BackgroundBeck observed overgeneralized thinking as a key vulnerability factor for excessive self-blame/-criticism in major depressive disorder (MDD). Whilst the contribution of reduced access to specific autobiographical memory episodes has often been considered, the role of more abstract semantic memory systems remains elusive. Here, we investigated the individual ability to differentiate between the meaning of abstract social concepts when interpreting behavior (e.g. "critical" vs. "faultfinding") and its contribution to vulnerability to self-blaming biases and MDD using a previously developed cognitive task. MethodsCognitive testing in 96 participants (n=60 medication-free remitted MDD and n=36 control) and fMRI scanning in 75 participants employed self- and other-blame-evoking conditions. A priori right anterior temporal lobe (ATL) seed and bilateral anterior subgenual cingulate and dorsolateral prefrontal cortex regions-of-interest were defined. ResultsAs expected, the MDD group exhibited greater self-blame-selective conceptual overgeneralization and stronger interdependency of conceptual overgeneralization with negative emotional valence relative to the control group. Individuals with this depressogenic interdependency showed higher self-blame-selective right anterior subgenual cingulate and primary motor cortex activations across groups, potentially corresponding to stronger self-blame and self-agency attributions, respectively, when conceptually overgeneralizing the interpretation of their negative actions. Individuals with higher self-blame-selective conceptual overgeneralization displayed lower right ATL activation for self-vs. other-blame, suggesting reduced access to differentiated conceptual representations. ConclusionsFuture studies are needed to confirm the hypothesis that self-blame-selective conceptual overgeneralization characterizes a distinct neurocognitive subtype of primary MDD vulnerability which may be modulated by depressive state and thus serves as a personalized treatment target.

BackgroundThe sense of agency, or the belief in action causality, is an elusive construct that impacts day-to-day experience and decision-making. Despite its relevance in a range of neuropsychiatric disorders, it is widely under-studied and remains difficult to measure objectively in patient populations. We developed and tested a novel cognitive measure of valence-modulated agency perception in an in-person and online cohort. MethodsThe in-person cohort consisted of 52 healthy control subjects and 20 subjects with depression and anxiety disorders (DA), including major depressive disorder and generalized anxiety disorder. The online sample consisted of 254 participants. The task consisted of an effort task for monetary rewards with computerized visual feedback interference and trial-by-trial ratings of self versus other agency. ResultsAll subjects across both cohorts demonstrated higher self-agency after receiving positive-win feedback, compared to negative-loss feedback when the level of computer inference was kept constant. Patients with DA showed reduced positive valence-dependent agency compared to healthy controls. Finally, in both cohorts, lower self-agency following negative-loss feedback was associated with worse anhedonia symptoms. ConclusionTogether this work suggests how positive and negative environmental information impacts the sense of self-agency in healthy subjects, and how it is perturbed in patients with depression and anxiety.

The existing gold standard assessments of depression suffer various issues, which include the evaluation of constructs extraneous to the core symptoms of the illness, and low sensitivity to change over time. Members of our team developed a new, simple visual analogue scale that aims to address these issues (M3VAS). Initial validation of the scale demonstrated good internal consistency and convergent validity. Still, we have not yet investigated how well it assesses changes in the severity of depressive symptoms over time. This project will analyse data from a longitudinal study (Hampsey et al., 2022), aiming to ascertain whether the M3VAS is sensitive to change i.e., how well it detects either a worsening or improvement of symptoms over a number of weeks (repeated measures). Validating this scales longitudinal validity could provide a better way for future longitudinal (observational and interventional) studies to identify changes in the severity of depressive illness.

ObjectiveObsessive-compulsive disorder (OCD) and posttraumatic-stress disorder (PTSD) are often comorbid. While exposure-based treatments can be effective for each, given that comorbid OCD and PTSD symptoms often interact dynamically, concurrent treatment may be most beneficial. The aim of the current analysis was to examine the naturalistic effectiveness of concurrently-delivered exposure and response prevention (ERP) and prolonged exposure (PE) therapy among individuals with comorbid OCD and PTSD. MethodsAdult patients (N=181) diagnosed with comorbid OCD and PTSD were treated with concurrent ERP and PE as part of a video therapy service specializing in treating comorbid OCD and PTSD. Treatment outcomes for both conditions were assessed at three timepoints: (1) at session 20, (2) at session 40, and (3) the final assessment timepoint completed by each patient. ResultsAt all three timepoints, there were significant reductions in OCD and PTSD symptoms. By the final timepoint, median percent improvement was 40.9% [IQR: 11.5-70.7%] for PTSD and 50.0% [IQR: 25-67.6%] for OCD. By the final timepoint, 67.4% of patients met criteria for a full PTSD response, 64.1% met criteria for a full OCD response, and 49.2% met criteria for a full response for both conditions. Analyses of secondary treatment outcomes showed significant reductions in depressive and anxiety symptoms, disability, and showed improvements in quality of life. ConclusionConcurrent ERP and PE, delivered remotely via video therapy in a real-world setting, appears to be a clinically effective treatment approach for individuals with comorbid OCD and PTSD.

BackgroundFatigue is a central symptom of major depressive disorder (MDD). Research in healthy individuals has shown that heightened feelings of fatigue are associated with a reduced willingness to exert effort. However, it remains unclear how fatigue affects effort-based decision-making in individuals with MDD. In this study, we explore how cognitive effort is traded for rewards in MDD and how feelings of fatigue and depressed mood symptoms influence this decision-making process. MethodsHealthy participants (n = 26) and individuals with MDD (n = 18) took part in a forced-choice paradigm, where they decided to perform either a low-effort cognitive effort task for a small reward or a more cognitively effortful task for a larger reward. Participants also completed the Beck Depression Inventory and the Modified Fatigue Impact Scale, which were used in a factor analysis to generate combined scores for depressed mood and fatigue for each participant. These factor scores were then incorporated into hierarchical mixed-effects models of choice data to explain behavioral differences between participants with MDD. ResultsOur findings reveal that individuals with MDD exhibited significantly higher preferences for low-effort/low-reward options compared to their healthy counterparts. This difference was linked to increased feelings of fatigue, which raised the perceived cost of cognitive effort. Variations in fatigue questionnaire scores showed stronger associations with effort-based choice behavior than those from questionnaires assessing depressive mood, indicating that fatigue is a key symptom with specific ties to effort in MDD. ConclusionsThese findings illuminate how fatigue might lead to decreases in goal-directed behavior in MDD, thereby deepening our understanding of diminished motivation in MDD and suggesting potential pathways for more effective treatment.

BackgroundSuicidal ideation (SI) is a major global concern, yet its dynamic interplay with other symptoms remains poorly understood. ObjectiveTo identify symptoms that co-fluctuate with or temporally precede SI to improve warning signal detection and intervention. MethodsLongitudinal data from three Dutch psychiatric cohorts with lifetime internalizing disorders (16 waves from April 2020 until February 2022) were collected during the COVID-19 pandemic. We analyzed depressive, happiness, anxiety, loneliness, worry symptoms, and COVID-19-specific items only in those participants with SI fluctuations. Dynamic Time Warping (DTW) quantified within-person similarity between symptom trajectories and SI, and results were aggregated at group level. FindingsThe 307 participants (mean age 44.8 years; 61.6% female) showed increasing SI over time (p < .001). SI aligned with four depressive symptoms (i.e., sad mood, low self-esteem, low interest, and reduced happiness), two anxiety-related symptoms (i.e., fear of losing control, faintness), feeling abandoned, and overwhelming worrying. In directed DTW analysis, sad mood, hypersomnia, worrying about projects, and numbness/tingling showed significant temporal precedence before SI. ConclusionSI is embedded in a broad symptom network beyond depression. These results underscore the value of time-sensitive, idiographic monitoring using tools like DTW to capture the person-specific temporal pathways through which SI emerges and intensifies. Clinical implicationsThis study suggests a core group of affective, cognitive, and interpersonal symptoms that could serve as informative signals for evaluating changes in SI and may represent actionable targets for intervention. Summary BoxO_ST_ABSWhat is already known on this topic?C_ST_ABSO_LISuicidal ideation (SI) is a dynamic phenomenon, yet traditional research often relies on static, group-level averages that do not capture individual fluctuations. C_LIO_LIWhile SI is linked to depression, it can emerge independently through complex interactions with other affective and interpersonal states C_LI What this study adds?O_LIThis study identifies a set of affective, cognitive, and interpersonal symptoms, sad mood, overwhelming worry, and feelings of abandonment, that significantly co-fluctuate with SI over weeks and months. Additionally four specific "leading" symptoms, sad mood, hypersomnia, worrying about projects, and somatic numbness, were found that precede increases in SI. C_LI How this study might affect research, practice or policy?O_LIThe identified co-fluctuations and precursors serve as informative "(early) warning signals" that can improve individual risk stratification and clinical monitoring and may represent targets for intervention. C_LIO_LIThe results support a shift toward network-based models in suicidology, emphasizing the need for time-sensitive monitoring to capture the complex and dynamic nature of suicidality. C_LI

BackgroundMajor depression comprises two discrete subtypes, major (MDMD) and simple (SDMD) dysmood disorder. MDMD, but not SDMD, patients were identified to have highly sensitized cytokine/growth factor networks using stimulated whole blood cultures. However, no information regarding serum cytokines/chemokines/growth factors in SDMD is available. ObjectivesThis case-control study compares 48 serum cytokines/chemokines/growth factors in academic students with SDMD (n=64) and first episode (FE)-SDMD (n=47) to those of control students (n=44) using a multiplex assay. FindingsBoth FE-SDMD and SDMD exhibit a notable inhibition of immune profiles, such as the compensatory immunoregulatory response system (CIRS) and alternative M2 macrophage and T helper-2 (Th-2) profiles. We observed a substantial reduction in the serum concentrations of five proteins: interleukin (IL)-4, IL-10, soluble IL-2 receptor (sIL-2R), IL-12p40, and macrophage colony-stimulating factor. A significant proportion of the variability observed in suicidal behaviors (26.7%) can be accounted for by serum IL-4, IL-10, and sIL-2R (all decreased), and CCL11 (eotaxin) and granulocyte CSF (both increased). The same biomarkers (except for IL-10), accounted for 25.5% of the variance in SDMS severity. A significant correlation exists between decreased levels of IL-4 and elevated ratings of the brooding type of rumination. ConclusionsThe immune profile of SDMD and FE-SDMD exhibits a significant deviation from that observed in MDMD, providing additional evidence that SDMD and MDMD represent distinct phenotypes. SDMD is characterized by the suppression of the CIRS profile, which signifies a disruption of immune homeostasis and tolerance, rather than the presence of an inflammatory response.

ObjectiveFew studies have investigated the neurological underpinnings of social-emotional processing among individuals with non-suicidal self-injury (NSSI), despite the range of interpersonal impairments associated with the behavior. This study aims to identify NSSI-specific patterns of resting state functional connectivity (RSFC) and neural activation during an emotional facial expression task. MethodsParticipants were currently depressed, antidepressant-free adolescents with and without lifetime history of NSSI. Left and right amygdala were specified as seed regions for RSFC analysis (n=43 NSSI, n=9 clinical controls). The emotional faces task presented participants with neutral, happy, and sad faces. Whole-brain analyses examined neural activation during the task, and groups were compared on post-scan ratings of facial emotional intensity (n=39 NSSI, n=9 clinical controls). ResultsGroups did not differ in RSFC analyses. Adolescents with NSSI showed attenuated neural activation to happy (versus neutral) faces in areas of the occipital lobe and cerebellum, and rated neutral and sad faces as more negative than clinical controls. ConclusionsWhile groups did not differ in baseline limbic connectivity, neurological and behavioral findings revealed NSSI-specific alterations in processing of social-emotional stimuli. Depressed adolescents with NSSI interpreted ambiguous or negative social stimuli more negatively than depressed controls, and had an attenuated neural response to positive social stimuli. This negative bias likely contributes to the myriad interpersonal difficulties associated with NSSI. Adolescents with NSSI may benefit from treatments which combat these negative social interpretations and improve control over emotional responses to interpersonal stress.

BackgroundNeuropsychological deficits are common in obsessive-compulsive disorder (OCD) and may influence functional and treatment outcomes. Only a few studies have effectively targeted these deficits, with most failing to show broad transfer of training. This study aimed to evaluate the efficacy of an integrated cognitive control training (ICCT) program on neuropsychological functioning in OCD patients and assess related changes in clinical and socio-occupational functions. MethodA single-group open-label design with pre-, mid-, post-treatment, and follow-up assessments was employed with 38 participants diagnosed with OCD, who were on stable doses of serotonin reuptake inhibitors (SRIs). The ICCT program, integrating task- and game-based cognitive stimulation with metacognitive strategy training and generalization exercises, included 24 hours of training over eight weeks across therapist-guided and homework sessions. The intervention was systematically adapted and validated, and its efficacy was examined across neuropsychological, clinical, and socio-occupational domains. ResultsThe intervention demonstrated moderate to large improvements in neuropsychological functioning (R{superscript 2}M range = .15 to .27) and self-reported cognitive difficulties (R{superscript 2}M = .58) and further demonstrated transfer to untrained domains such as OCD symptom reduction (R{superscript 2}M = .54), anxiety (R{superscript 2}M = .61), depression (R{superscript 2}M = .60), metacognitive regulation (R{superscript 2}M = .30), and socio-occupational functioning (R{superscript 2}M = .26). However, response inhibition saw only small improvements (R{superscript 2}M = .11). ConclusionThe ICCT program achieved both near and far transfer of cognitive training, improving neuropsychological, clinical, and socio-occupational outcomes. This contrasts with prior interventions with limited transfer of training. The small effect on response inhibition may reflect the trait nature of the deficit, assessment limitations, or gaps in the intervention. Future studies should use randomized control designs to validate and compare ICCT with other interventions.

BackgroundMajor depressive disorder (MDD) is associated with maladaptive self-reported interoception, i.e., abnormal bodily self-experience. Although diminished body trusting predicts suicidal ideation, interoceptive measures have not been considered in depressed inpatients, whose suicide risk regularly peaks post-discharge. This study aims to explore interoceptive characteristics at admission that help identify inpatients at risk for suicidal ideation at discharge, thereby preventing fatal outcomes. MethodsThe observational study included 87 depressed inpatients providing self-ratings at both hospital admission (T0) and discharge (T1) on the following scales: Multidimensional Assessment of Interoceptive Awareness (MAIA-2); Beck Depression Inventory-II (BDI-II). A hierarchical logistic regression analysis estimated the longitudinal association between self-reported interoception (T0) and suicidal ideation (T1). The optimal cutpoints for predicting suicidal ideation were calculated using ROC curve analysis. ResultsSuicidal ideation was found in 17.24% patients at discharge, who reported lower baseline MAIA-2 Trusting scores than non-ideators (p=0.01). Diminished body trusting (OR=0.19), somatic comorbidity (OR=16.77), and baseline suicidal ideation (OR=24.01) significantly predicted suicidal ideation (T1). For body trusting, we estimated an optimal classification of subsequent suicidal ideation for the cutpoint[&le;]2.33 (AUC=0.70 [95% CI 0.57, 0.83], sensitivity=0.87, specificity=0.44, positive predictive value=0.25, negative predictive value=0.94). LimitationsDue to the exploratory nature of the study, the findings should be replicated in pre-registered trials with larger sample sizes. ConclusionsDiminished body trusting is, with acceptable sensitivity, a significant predictor for post-treatment suicidal ideation in depressed inpatients. This finding emphasizes the importance of incorporating body-centered approaches into multimodal treatment strategies especially in inpatients under risk to prevent suicidal incidents.

Neuroticism, a personality trait, can predict major depressive disorder (MDD). The current study aims to determine whether a) neuroticism is a feature of the acute state of MDD, including suicidal behaviors (SB); and b) adverse childhood experiences (ACEs) are associated with neuroticism in MDD. This study included 133 participants, 67 normal controls and 66 MDD patients, and assessed the Big 5 Inventory (BFI), ACEs using the ACE Questionnaire, and the phenome of depression using the Hamilton Depression (HAMD) Rating Scale (HAMD), Beck Depression Inventory (BDI), The State-Trait Anxiety Inventory (STAI) and Columbia Suicide Severity Rating Scale (C-SSRS) scores to assess current SB. Neuroticism was significantly higher in MDD than controls, and it explained 64.9% of the variance in the depression phenome (a latent vector extracted from HAMD, BDI, STAI, and current SB scores). The other BFI domains had much less (extraversion, agreeableness) or no effect (openness, conscientiousness). One latent vector could be extracted from the phenome, lifetime dysthymia, lifetime anxiety disorders and neuroticism scores. Neglect (physical and emotional) and abuse (physical, neglect and sexual) account for approximately 30% of the variance in this latent vector. Partial Least Squares analysis showed that the effects of neglect on the phenome were partially mediated by neuroticism, whereas the effects of abuse were completely mediated by neuroticism. Neuroticism (trait) and the MDD phenome (state) are both manifestations of the same latent core, with neuroticism being a less severe manifestation of major depression, which in fact is a multiplicative manifestation of neuroticism.

BackgroundTreatment resistant depression (TRD) is one of the leading causes of disability in Canada and is associated with significant societal costs. Repetitive transcranial magnetic stimulation (rTMS) is an approved, safe, and well-tolerated intervention for TRD. In the setting of the COVID-19 pandemic, reducing the number of visits to the clinic is a potential approach to significantly minimize exposure and transmission risks to patients. This can be accomplished by administering multiple treatment sessions in a single day, using an rTMS protocol known as accelerated intermittent theta burst stimulation (aiTBS). The objective of this novel study is to assess the feasibility, acceptance and clinical outcomes of a practical high-dose aiTBS protocol, including tapering treatments and symptom-based relapse prevention treatments, in patients with unipolar depression previously responsive to electroconvulsive therapy (ECT) or patients warranting ECT due to symptom severity. MethodsAll patients with unipolar depression referred to the brain stimulation service at the Centre for Addiction and Mental Health (CAMH) who warrant ECT will be offered screening to assess for eligibility to enroll in this trial. This open label, single group trial consists of 3 phases. In the acute treatment phase, treatment will occur 8 times daily for 5 days a week, until symptom remission is achieved or a maximum of 10 days of treatment. In the tapering phase, treatments will be reduced to 2 treatment days per week for 2 weeks, followed by 1 treatment day per week for 2 weeks. Patients will then enter the symptom-based relapse prevention phase including virtual check-ins and a treatment schedule based on symptom level. Remission, response and change in scores on several clinical measures from baseline to the end of the acute, tapering and relapse prevention phases represent the clinical outcomes of interest. DiscussionFindings from this novel clinical trial may provide support for the use of aiTBS, including tapering treatments and symptom-based relapse prevention treatments, as a safe and effective alternative intervention for patients needing ECT during the COVID-19 pandemic. Trial registrationClinicaltrials.gov: NCT04384965

ObjectiveRepetitive transcranial magnetic stimulation (rTMS) is an effective, evidence-based treatment for major depressive disorder (MDD) and is publicly funded in Australia. However, there is no published data to date concerning its use in private TMS service provider clinics in Australia. There is further limited data as to its efficacy and safety in treating MDD in youth populations. MethodsThis retrospective study examined routinely collected data of 46 outpatients aged 17 to 25 years old, who received rTMS treatment for MDD in a private TMS clinic. Primary outcomes measures were the Montgomery-Asberg Depression Rating Scale (MADRS) and the depression subscale of the 21-item Depression, Anxiety and Stress Scale (DASS-21). Secondary measures included the anxiety and stress sub-scales of the DASS-21, a measure of Quality of Life (QoL) Enjoyment and Satisfaction Questionnaire, and the Cognitive Failures Questionnaire (CFQ). ResultsA 4-7-week course of rTMS significantly reduce symptoms of self-reported depression (42.5% response) and clinician-assessed depression (40.7% response). Both anxiety and stress significantly reduced across the course of rTMS treatment and significant improvements to QoL and self-reported cognition were observed. Reported side effects following rTMS in youth included a mild headache and fatigue. ConclusionsThe findings of this naturalistic study suggest that an acute course of rTMS provided in private clinical settings is safe and effective - resulting in similar response rates in youth patients as reported in adult patients. In real world practice, rTMS proves to be a well-tolerated and highly effective intervention for MDD in youth, across diverse clinical settings. Implications and ContributionThe findings of this naturalistic study suggest that in real world practice, rTMS proves to be a well-tolerated and highly effective intervention for treating depression and anxiety in youth (17-25-year-olds), with additional benefits to cognitive symptoms of depression and overall well-being.

Early flow cytometry studies revealed T cell activation in major depressive disorder (MDD) (Maes et al., 1990-1993). MDD is characterised by activation of the immune-inflammatory response system (IRS) and the compensatory immunoregulatory system (CIRS), including deficits in T regulatory (Treg) cells. This study examines the number of cannabinoid type 1 (CB1) and type 2 (CB2) receptor bearing T/B lymphocytes in MDD, and the effects of in vitro cannabidiol (CBD) administration on CB1/CB2. Using flow cytometry, we determined the percentage of CD20+CB2+, CD3+CB2+, CD4+CB2+, CD8+CB2 and FoxP3+CB1+ cells in 19 healthy controls and 29 MDD patients in 5 conditions: baseline, stimulation with anti-CD3/CD28 with or without 0.1 {micro}g/mL, 1.0 {micro}g/mL or 10.0 {micro}g/mL CBD. We found that CB2+ was significantly higher in CD20+ than CD3+ and CD4+, and CD8+ cells. Stimulation with anti-CD3/CD8 beads increases the number of CB2-bearing CD3+, CD4+, and CD8+ cells, as well as CB1-bearing FoxP3+ cells. There was an inverse association between the number of reduced CD4+CB2+ and IRS profiles, including M1 macrophage, T helper-(Th)-1 and Th-17 phenotypes. MDD is characterized by lowered basal FoxP3+CB1+% and higher CD20+CB2+%. 33.2% of the variance in the depression phenome (including severity of depression, anxiety, and current suicidal behaviors) is explained by CD20+CB2+% (positively) and CD3+CB2+% (inversely). All 5 immune cell populations were significantly increased by 10 {micro}g/mL CBD administration. In conclusion, reductions in FoxP3+CB1+% and CD3+/CD4+CB2+% contribute to deficits in immune homeostasis in MDD, while increased CD20+CB2+% may contribute to the pathophysiology of MDD by activating T-independent humoral immunity. SummationsO_LILowered CD4+CB2+ T cells are associated with increased immune-inflammatory responses (IRS) in major depressive disorder (MDD) C_LIO_LILowered CD3+CB2+% and increased CD20+CB2+% predict severity of depression and suicidal behaviors C_LIO_LILowered CD3/CD4+CB2+ may impact the immune homeostatic processes leading to enhanced IRS in MDD C_LIO_LIIncreased CD20+CB2+% may activate T-independent humoral immunity and enhance IRS responses. C_LI ConsiderationsO_LIDepletion of CB1 bearing T regulatory and CB2 bearing T and T helper cells and increased CB2+ bearing B cells are new drug targets in MDD. C_LIO_LIThe findings deserve replication in other countries and cultures. C_LIO_LIFuture research should examine CB2 bearing macrophages, dendritic cells, and natural killer cells in MDD C_LI

Individuals with obsessive-compulsive disorder (OCD) exhibit nonspecific deficits in executive function. Internal preoccupations with obsessive-compulsive themes (OCs) may prevent individuals with OCD from fully engaging in externally oriented tasks, explaining these deficits - an executive overload model of OCD. This study reports data from 43 individuals with OCD and 54 healthy individuals collected using the revised Attention Network Test (ANT-R) that is consistent with predictions of the executive overload model. During ANT-R, externally orienting cues enhanced individual readiness to respond to external stimuli (alerting benefits), but alerting benefits were negatively associated with severity of internal preoccupations (e.g., neutralizing and obsessing symptoms). Alerting cues improved efficacy of conflict processing (executive benefits), more in individuals with OCD than in healthy controls. These executive benefits correlated positively with the severity of contamination. Internal preoccupation with OCs could also contribute to poor engagement with exposure and response prevention (ERP) exercises and, consequently, might explain the limited efficacy of ERP-based interventions in some patients. This study describes two clinical cases to illustrate how personalized externally orienting cues may augment ERP exercises to improve patients engagement in therapeutic interventions. The study concludes with discussion of broader implications of the results and with new hypotheses for future investigations. HighlightsO_LIInternal preoccupations negatively impact executive function in OCD. C_LIO_LIExternally orienting cues improve readiness to respond to external stimuli in OCD. C_LIO_LIExternally orienting cues improve efficacy of conflict processing in OCD. C_LIO_LIEffects of externally orienting cues vary across obsessive-compulsive themes. C_LIO_LIEfficacy of ERP could be improved by augmenting with externally orienting cues. C_LI