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Background: Although both pharmacotherapy and psychological treatments are considered to be efficacious in the treatment of major depressive disorder (MDD), one third of patients do not respond to treatment and many experience residual symptoms post-treatment. In this double-blind placebo-controlled randomized control trial (RCT), we assessed whether intranasal oxytocin (OT) augments the therapeutic efficacy of psychotherapy for MDD and improves the therapeutic alliance., Methods: Twenty-three volunteers (12 female) with MDD underwent 16 sessions of interpersonal therapy. Prior to each session, volunteers self-administered 24 International Units of intranasal OT ( n = 12; Syntocinon ) or placebo ( n = 11). Depressive symptoms were assessed with the Inventory of Depressive Symptomatology at pre- and post-treatment, and at a six month follow-up., Results: Multilevel modeling found a significant effect of OT on the negative slope of depressive symptoms over time ( p < 0.05), with medium-large effect sizes at post-treatment (Cohen's d = 0.75) and follow-up (Cohen's d = 0.82). Drug intervention also predicted the intercept when examining the weekly ratings of the therapeutic alliance ( p < 0.05), such that volunteers receiving OT, relative to placebo, reported improved therapeutic alliance at session 1. The agreement of goals between therapists and participants, a facet of the therapeutic alliance, mediated the relationship between drug intervention and clinical outcome., Conclusion: In this pilot study, the administration of intranasal OT, relative to placebo, improved the therapeutic alliance at the beginning of therapy and therapeutic efficacy of psychotherapy in persons with MDD. Future RCTs should attempt to replicate these findings in larger samples with different therapeutic modalities ( ClinicalTrials.gov: NCT02405715 ).

Background: Social anxiety (SA), a prevalent comorbid condition in psychotic disorders with a negative impact on functioning, requires adequate intervention relatively early. Using a randomized controlled trial, we tested the efficacy of a group cognitive-behavioral therapy intervention for SA (CBT-SA) that we developed for youth who experienced the first episode of psychosis (FEP). For our primary outcome, we hypothesized that compared to the active control of group cognitive remediation (CR), the CBT-SA group would show a reduction in SA that would be maintained at 3- and 6-month follow-ups. For secondary outcomes, it was hypothesized that the CBT-SA group would show a reduction of positive and negative symptoms and improvements in recovery and functioning., Method: Ninety-six patients with an FEP and SA, recruited from five different FEP programs in the Montreal area, were randomized to 13 weekly group sessions of either CBT-SA or CR intervention., Results: Linear mixed models revealed that multiple measures of SA significantly reduced over time, but with no significant group differences. Positive and negative symptoms, as well as functioning improved over time, with negative symptoms and functioning exhibiting a greater reduction in the CBT-SA group., Conclusions: While SA decreased over time with both interventions, a positive effect of the CBT-SA intervention on measures of negative symptoms, functioning, and self-reported recovery at follow-up suggests that our intervention had a positive effect that extended beyond symptoms specific to SA.ClinicalTrials.gov identifier: NCT02294409.

Background: Rapid progression from the first identifiable symptom to the onset of first-episode psychosis (FEP) allows less time for early intervention. The aim of this study was to examine the association between the first identifiable symptom and the subsequent speed of illness progression., Methods: Data were available for 390 patients attending a catchment-based early intervention service for FEP. Exposure to non-psychotic and subthreshold psychotic symptoms was retrospectively recorded using semi-structured interviews. Outcomes following the onset of the first identifiable symptom were (1) time to onset of FEP and (2) symptom incidence rate (i.e. number of symptoms emerging per person-year until FEP onset). These outcomes were respectively analyzed with Cox proportional hazards and negative binomial regressions., Results: After Bonferroni correction, having a subthreshold psychotic ( v. non-psychotic) symptom as the first symptom was not associated with time to FEP onset [hazard ratio (HR) = 1.39; 95% CI 0.94-2.04] but was associated with higher symptom incidence [incidence rate ratio (IRR) = 1.92; 95% CI 1.10-3.48]. A first symptom of suspiciousness was associated with shorter time to FEP onset (HR = 2.37; 95% CI 1.38-4.08) and higher symptom incidence rate (IRR = 3.20; 95% CI 1.55-7.28) compared to other first symptoms. In contrast, a first symptom of self-harm was associated with lower symptom incidence rate (IRR = 0.06; 95% CI 0.01-0.73) compared to other first symptoms. Several associations between symptoms and illness progression were moderated by the age at symptom onset., Conclusions: Appreciating the content and timing of early symptoms can identify windows and treatment targets for early interventions in psychosis.

Background: It is unknown whether patient disengagement from early intervention services for psychosis is as prevalent in low- and middle-income countries (LMICs) like India, as it is in high-income countries (HICs). Addressing this gap, we studied two first-episode psychosis programs in Montreal, Canada and Chennai, India. We hypothesized lower service disengagement among patients and higher engagement among families in Chennai, and that family engagement would mediate cross-site differences in patient disengagement., Methods: Sites were compared on their 2-year patient disengagement and family engagement rates conducting time-to-event analyses and independent samples t tests on monthly contact data. Along with site and family involvement, Cox proportional hazards regression included known predictors of patient disengagement (e.g. gender)., Results: The study included data about 333 patients (165 in Montreal, 168 in Chennai) and their family members (156 in Montreal, 168 in Chennai). More Montreal patients (19%) disengaged before 24 months than Chennai patients (1%), χ 2 (1, N = 333) = 28.87, p < 0.001. Chennai families had more contact with clinicians throughout treatment (Cohen's d = -1.28). Family contact significantly predicted patient disengagement in Montreal (HR = 0.87, 95% CI 0.81-0.93). Unlike in Chennai, family contact declined over time in Montreal, with clinicians perceiving such contact as not necessary (Cohen's d = 1.73)., Conclusions: This is the first investigation of early psychosis service engagement across a HIC and an LMIC. Patient and family engagement was strikingly higher in Chennai. Maintaining family contact may benefit patient engagement, irrespective of context. Findings also suggest that differential service utilization may underpin cross-cultural variations in psychosis outcomes.

Background: Longitudinal studies of first episode of psychosis (FEP) patients are critical to understanding the dynamic clinical factors influencing functional outcomes; negative symptoms and verbal memory (VM) deficits are two such factors that remain a therapeutic challenge. This study uses white-gray matter contrast at the inner edge of the cortex, in addition to cortical thickness, to probe changes in microstructure and their relation with negative symptoms and possible intersections with verbal memory., Methods: T1-weighted images and clinical data were collected longitudinally for patients (N = 88) over a two-year period. Cognitive data were also collected at baseline. Relationships between baseline VM (immediate/delayed recall) and rate of change in two negative symptom dimensions, amotivation and expressivity, were assessed at the behavioral level, as well as at the level of brain structure., Results: VM, particularly immediate recall, was significantly and positively associated with a steeper rate of expressivity symptom decline (r = 0.32, q = 0.012). Significant interaction effects between baseline delayed recall and change in expressivity were uncovered in somatomotor regions bilaterally for both white-gray matter contrast and cortical thickness. Furthermore, interaction effects between immediate recall and change in expressivity on cortical thickness rates were uncovered across higher-order regions of the language processing network., Conclusions: This study shows common neural correlates of language-related brain areas underlying expressivity and VM in FEP, suggesting deficits in these domains may be more linked to speech production rather than general cognitive capacity. Together, white-gray matter contrast and cortical thickness may optimally inform clinical investigations aiming to capture peri-cortical microstructural changes.

Background: Specialized early intervention (EI) following a first episode of psychosis (FEP) are effective at reducing negative symptoms, although its trajectory warrants systematic assessment. However, findings are equivocal as to whether extended gains are made post 2 years of EI and whether there is additional benefit of extending EI for an additional 3 years., Methods: Data on 178 FEP patients, from a randomized controlled trial of a 3-year extension of EI service v. transfer to regular care following 2 years of EI service, were used for this report. Repeated measures analysis of variance were conducted separately for the initial 2 years of treatment in an EI service, and for the 3-year post-randomization to examine trajectories of negative symptoms over the two periods in the two arms of the study., Results: There were significant improvements in total negative symptoms over the first 2 years of EI F(4.612, 797.905) = 25.263, p &lt; 0.001 and in domains of 'expressivity' and 'motivation'. In the following 3 years, there were further significant improvements in negative symptoms F(4.318, 759.908) = 4.182, p = 0.002 with no difference between groups F(4.318, 759.908) = 1.073, p = 0.371. Changes in negative symptoms over the extension period were driven by expressivity F(4.01, 674.73) = 7.19, p &lt; 0.01, but not motivation F(6.58, 1112.18) = 0.95, p = 0.46., Conclusion: Negative symptoms improve significantly over the first 2 years of EI. Subsequent amelioration was largely the result of expressivity. Motivation deficits remained stable. Extended EI offered no advantage over regular care post-randomization.