Functional neuroimaging biomarkers of anhedonia response to escitalopram plus adjunct aripiprazole treatment for major depressive disorder.

BACKGROUND: Identifying neuroimaging biomarkers of antidepressant response may help guide treatment decisions and advance precision medicine. AIMS: To examine the relationship between anhedonia and functional neurocircuitry in key reward processing brain regions in people with major depressive disorder receiving aripiprazole adjunct therapy with escitalopram. METHOD: Data were collected as part of the CAN-BIND-1 study. Participants experiencing a current major depressive episode received escitalopram for 8 weeks; escitalopram non-responders received adjunct aripiprazole for an additional 8 weeks. Functional magnetic resonance imaging (on weeks 0 and 8) and clinical assessment of anhedonia (on weeks 0, 8 and 16) were completed. Seed-based correlational analysis was employed to examine the relationship between baseline resting-state functional connectivity (rsFC), using the nucleus accumbens (NAc) and anterior cingulate cortex (ACC) as key regions of interest, and change in anhedonia severity after adjunct aripiprazole. RESULTS: Anhedonia severity significantly improved after treatment with adjunct aripiprazole.There was a positive correlation between anhedonia improvement and rsFC between the ACC and posterior cingulate cortex, ACC and posterior praecuneus, and NAc and posterior praecuneus. There was a negative correlation between anhedonia improvement and rsFC between the ACC and anterior praecuneus and NAc and anterior praecuneus. CONCLUSIONS: Eight weeks of aripiprazole, adjunct to escitalopram, was associated with improved anhedonia symptoms. Changes in functional connectivity between key reward regions were associated with anhedonia improvement, suggesting aripiprazole may be an effective treatment for individuals experiencing reward-related deficits. Future studies are required to replicate our findings and explore their generalisability, using other agents with partial dopamine (D2) agonism and/or serotonin (5-HT2A) antagonism.

An empirical analysis of structural neuroimaging profiles in a staging model of depression.

We examine structural brain characteristics across three diagnostic categories: at risk for serious mental illness; first-presenting episode and recurrent major depressive disorder (MDD). We investigate whether the three diagnostic groups display a stepwise pattern of brain changes in the cortico-limbic regions. Integrated clinical and neuroimaging data from three large Canadian studies were pooled (total n = 622 participants, aged 12-66 years). Four clinical profiles were used in the classification of a clinical staging model: healthy comparison individuals with no history of depression (HC, n = 240), individuals at high risk for serious mental illness due to the presence of subclinical symptoms (SC, n = 80), first-episode depression (FD, n = 82), and participants with recurrent MDD in a current major depressive episode (RD, n = 220). Whole-brain volumetric measurements were extracted with FreeSurfer 7.1 and examined using three different types of analyses. Hippocampal volume decrease and cortico-limbic thinning were the most informative features for the RD vs HC comparisons. FD vs HC revealed that FD participants were characterized by a focal decrease in cortical thickness and global enlargement in amygdala volumes. Greater total amygdala volumes were significantly associated with earlier onset of illness in the FD but not the RD group. We did not confirm the construct validity of a tested clinical staging model, as a differential pattern of brain alterations was identified across the three diagnostic groups that did not parallel a stepwise clinical staging approach. The pathological processes during early stages of the illness may fundamentally differ from those that occur at later stages with clinical progression.

Engagement in meaningful activities post suicide loss: A scoping review protocol.

RATIONALE: Each day, more than 10 Canadians die by suicide. Each suicide leaves entire communities to manage the traumatic aftermath of this loss. Individuals bereaved by suicide loss are at a higher risk of experiencing negative mental health outcomes. Current research suggests that engagement in meaningful activities may be an avenue to protecting mental health. It is important to understand if this is also the case for those experiencing bereavement post suicide loss. To date, there has not been a synthesis of the literature examining suicide loss and the nature and extent of engagement in meaningful activities post loss. OBJECTIVES: 1) To describe the nature and extent of the peer-reviewed suicide loss and bereavement literature related to engagement in meaningful activities; and 2) to identify facilitators and barriers that may impact engagement in meaningful activities post loss. METHODS: This paper describes a scoping review protocol that will be completed using stages identified by Arksey and O'Malley and updated by Levac and colleagues. Joanna Briggs Institute framework will also guide this review. Four electronic databases will be searched for suicide bereavement/loss concepts. Two reviewers will apply inclusion and exclusion criteria to identify articles discussing engagement in meaningful activities of everyday living post loss. Data will be descriptively summarized and analyzed using inductive content analysis. Results will be reported following PRISMA Extension for Scoping Reviews. EXPECTED RESULTS: A descriptive summary and conceptual map describing the current state of the peer-reviewed literature will be constructed. CONCLUSION: Experiencing a suicide loss increases the risk of negative mental health outcomes. A synthesis of literature is required to map the current available evidence related to suicide bereavement and engagement in meaningful activities, with potential implications for improving supports and services for those bereaved. This protocol is register with Open Science Framework Registries (10.17605/OSF.IO/M2NES).

Polish adaptation of the Dimensional Anhedonia Rating Scale (DARS) - validation in the clinical sample.

Background: Anhedonia is the core symptom of depression. Its presence has been linked to worsened prognosis. The Dimensional Anhedonia Rating Scale (DARS) is a scale measuring desire, motivation, effort and consummatory pleasure across different domains. The aim of this paper was to confirm factor structure, assess reliability and validity of the Polish adaptation of the DARS in a clinical sample of patients with mood disorders and healthy controls (HC). Methods: The study sample included 161 participants aged 18-65 years - 34 HC, 72 patients with bipolar disorder and 55 with major depressive disorder (in depressive episode or remission). Reliability of the Polish adaptation of the DARS was assessed using Cronbach's α and the average inter-item correlation (AIC). Convergent and divergent validity was established by Pearson's correlations between the DARS and the Snaith-Hamilton Pleasure Scale (SHAPS), the Quick Inventory of Depressive Symptomatology- self-report (QIDS-SR), the Hospital Anxiety and Depression Scale (HADS). The structure of the scale was examined by factor analysis. Results: The factor structure was consistent with the original scale. Strong internal consistency for the DARS total score (Cronbach's α = 0.95) and all subscales (0.86-0.93) was observed. The DARS demonstrated good convergent (moderate to strong correlations with measures of anhedonia and depression) and divergent validity (weak correlations with anxiety level). Conclusion: The Polish DARS demonstrated excellent internal consistency and very good validity. The scale is a valuable contribution to the psychometrics of anhedonia measures in patients with mood disorders.

Risk-Sensitive Decision-Making and Self-Harm in Youth Bipolar Disorder.

Background: Youth with bipolar disorder (BD) are at high risk for suicide and have high rates of self-harm, which includes both suicide attempts and non-suicidal self-injury. Greater risk-taking has been associated with suicide attempts in youth with major depression, although there are no studies examining the relationship between risk-related decision-making and self-harm in youth with BD. We aimed to examine the association of suicide risk with risk-sensitive decision-making in a controlled sample of youth with BD.Methods: Eighty-one youth with BD (based on DSM-IV criteria; 52 youth with a history of self-harm [BDSH+]; 29 without a history of self-harm [BDSH-]) and 82 age- and sex-matched control youth aged 13-20 years were recruited between 2012 and 2020. Decision-making and risk-taking performance were assessed via the Cambridge Gambling Task within the Cambridge Neuropsychological Test Automated Battery (CANTAB). General linear models were used to examine differences between groups with control for age, sex, and IQ.Results: There was a significant difference in the overall proportion of points bet (F2,157 = 3.87, P = .02, η2 = 0.23) such that BDSH- youth performed better than both BDSH+ (P = .02) and control youth (P = .04). Mean latency was significant (F3,156 = 4.12, P = .017, η2 = 0.03), with BDSH- youth deliberating longer than controls (P = .03). Risk-taking significantly differed between groups (F2,157 = 3.83, P = .02, η2 = 0.23), with BDSH- youth showing greater self-control compared to BDSH+ (P = .01) and control youth (P = .01).Conclusions: BDSH- youth had greater self-control and lower risk-taking. We speculate this finding may be reflective of a compensatory process among BDSH- youth serving a protective role in suicide risk. Future longitudinal studies are needed to examine the temporal association of neurocognition and self-harm among youth with BD.

Pro-inflammatory markers are associated with response to sequential pharmacotherapy in major depressive disorder: a CAN-BIND-1 report.

OBJECTIVE: There is limited literature on associations between inflammatory tone and response to sequential pharmacotherapies in major depressive disorder (MDD). METHODS: In a 16-week open-label clinical trial, 211 participants with MDD were treated with escitalopram 10-20 mg daily for 8 weeks. Responders continued escitalopram while non-responders received adjunctive aripiprazole 2-10 mg daily for 8 weeks. Plasma levels of pro-inflammatory markers-C-reactive protein, interleukin (IL)-1ß, IL-6, IL-17, interferon-gamma (IFN)-Γ, tumor necrosis factor (TNF)-α, and Chemokine C-C motif ligand-2 (CCL-2)-measured at baseline, and after 2, 8 and 16 weeks were included in logistic regression analyzes to assess associations between inflammatory markers and treatment response. RESULTS: Pre-treatment IFN-Γ and CCL-2 levels were significantly associated with a lower of odds of response to escitalopram at 8 weeks. Increases in CCL-2 levels from weeks 8 to 16 in escitalopram non-responders were significantly associated with higher odds of non-response to adjunctive aripiprazole at week 16. CONCLUSION: Higher pre-treatment levels of IFN-Γ and CCL-2 were associated with non-response to escitalopram. Increasing levels of these pro-inflammatory markers may be associated with non-response to adjunctive aripiprazole. These findings require validation in independent clinical populations.

Resting-state neural mechanisms of capability for suicide and their interaction with pain - A CAN-BIND-05 Study.

BACKGROUND: Suicidal ideation is highly prevalent in Major Depressive Disorder (MDD). However, the factors determining who will transition from ideation to attempt are not established. Emerging research points to suicide capability (SC), which reflects fearlessness of death and increased pain tolerance, as a construct mediating this transition. This Canadian Biomarker Integration Network in Depression study (CANBIND-5) aimed to identify the neural basis of SC and its interaction with pain as a marker of suicide attempt. METHODS: MDD patients (n = 20) with suicide risk and healthy controls (n = 21) completed a self-report SC scale and a cold pressor task measuring pain threshold, tolerance, endurance, and intensity at threshold and tolerance. All participants underwent a resting-state brain scan and functional connectivity was examined for 4 regions: anterior insula (aIC), posterior insula (pIC), anterior mid-cingulate cortex (aMCC) and subgenual anterior cingulate cortex (sgACC). RESULTS: In MDD, SC correlated positively with pain endurance and negatively with threshold intensity. Furthermore, SC correlated with the connectivity of aIC to the supramarginal gyrus, pIC to the paracingulate gyrus, aMCC to the paracingulate gyrus, and sgACC to the dorsolateral prefrontal cortex. These correlations were stronger in MDD compared to controls. Only threshold intensity mediated the correlation between SC and connectivity strength. LIMITATIONS: Resting-state scans provided an indirect assessment of SC and the pain network. CONCLUSIONS: These findings highlight point to a neural network underlying SC that is associated with pain processing. This supports the potential clinical utility of pain response measurement as a method to investigate markers of suicide risk.

The Differential Relation of Emotional, Physical, and Sexual Abuse Histories to Antidepressant Treatment Remission and Persistence of Anhedonia in Major Depression: A CAN-BIND-1 Report.

OBJECTIVE: Childhood maltreatment is a potent enviromarker of risk for poor response to antidepressant medication (ADM). However, childhood maltreatment is a heterogeneous construct that includes distinct exposures that have distinct neurobiological and psychological correlates. The purpose of the current study is to examine the differential associations of emotional, physical, and sexual maltreatment to ADM outcome and to examine the unique role of anhedonia in driving poor response in patients with specific maltreatment histories. METHODS: In a multicentre clinical trial of major depression, 164 individuals were assessed for childhood emotional, physical, and sexual maltreatment with a contextual interview with independent, standardized ratings. All individuals received 8 weeks of escitalopram, with nonresponders subsequently also receiving augmentation with aripiprazole, with outcomes measured with depression rating scales and an anhedonia scale. RESULTS: Greater severity of emotional maltreatment perpetrated by the mother was a significant and direct predictor of lower odds of week 16 remission (odds ratio [OR] = 1.68, P = 0.02). In contrast, the relations of paternal-perpetrated emotional maltreatment and physical maltreatment to week 16 remission were indirect, mediated through greater severity of anhedonia at week 8. CONCLUSIONS: We identify emotional maltreatment as a specific early exposure that places patients at the greatest risk for nonremission following pharmacological treatment. Further, we suggest that anhedonia is a key symptom domain driving nonremission in patients with particular maltreatment histories.

The BEACON study: an update to the protocol for a cohort study as part of an evaluation of the effectiveness of smartphone-assisted problem-solving therapy in men who present with intentional self-harm to emergency departments in Ontario.

BACKGROUND: Men who present to the emergency department (ED) with self-harm are at high risk of dying by suicide, with 2.7% of men dying in the year following their presentation, more than double the rate for women (1.2%). Despite this, care received after an ED visit is highly variable and many are not assessed for psychological needs. Furthermore, the limited psychological care that is available is often not covered by provincial health insurance. Even when referrals for follow-up care are made, engagement rates are low. Previous recommendations to improve engagement include written discharge plans, caring contacts, and focused interventions targeting middle-aged men at elevated risk of dying by suicide. Blended care, the incorporation of technology into traditional care, has also been proposed as a method to increase engagement in and clinical benefits from psychotherapy. This project aims to determine whether the delivery of an evidence based treatment (problem-solving therapy (PST)) is enhanced by the addition of a custom smartphone application (BEACON) compared to usual care. Due to the impact of the COVID-19 pandemic on site participation and the planned implementation, we have made several changes to the study design, primary outcome, and implementation. METHOD: We originally proposed a cohort study nested within a larger cluster randomized trial wherein intervention sites would deliver the blended care, and control sites, whose personnel were not aware of their participation, would continue delivering usual care. The cohort study evaluated participant level outcomes as previously described by Hatcher et al. (2020). Due to pandemic-related constraints, our number of participating sites dropped to five potential sites which left the cohort study underpowered. As such, we changed the study design to a multi-site, individual randomized controlled trial (RCT) among the five remaining sites. Participants will be randomized to six sessions of therapy (PST) alone, or to the therapy plus BEACON, and followed up for 6 months. Our primary outcome was changed to evaluate feasibility and acceptability with the aim of designing a definitive RCT. Study implementation was reimagined to allow for completely virtual/online conduct to comply with local COVID-19 and institutional restrictions on in-person activities. CONCLUSION: This updated protocol will provide strong results for the planning of a definitive RCT of the blended care intervention in the future, addressing areas of difficulty and concern prior to its implementation. We will evaluate the feasibility of the study intervention, assess recruitment and retention of participants, and address challenges with implementing the protocol. Lastly, we will evaluate the appropriateness of our primary outcome measure and accurately determine a sample size for a definitive RCT. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03473535 . Registered on March 22, 2018.

Neuroimaging Correlates of Treatment Response with Psychedelics in Major Depressive Disorder: A Systematic Review.

Preliminary evidence supports the use of psychedelics for major depressive disorder (MDD). However, less attention has been given to the neural mechanisms behind their effects. We conducted a systematic review examining the neuroimaging correlates of antidepressant response following psychedelic interventions for MDD. Through MEDLINE, Embase, and APA PsycINFO, 187 records were identified and 42 articles were screened. Six published studies and one conference abstract were included. Five ongoing trials were included from subjective outcomesTrials.gov. Our search covered several psychedelics, though included studies were specific to psilocybin, ayahuasca, and lysergic acid diethylamide. Three psilocybin studies noted amygdala activity and functional connectivity (FC) alterations that correlated with treatment response. Two psilocybin studies reported that FC changes in the medial and ventromedial prefrontal cortices correlated with treatment response. Two trials from a single study reported global decreases in brain network modularity which correlated with antidepressant response. One ayahuasca study reported increased activity in the limbic regions following treatment. Preliminary evidence suggests that the default mode and limbic networks may be a target for future research on the neural mechanisms of psychedelics. More data is required to corroborate these initial findings as the evidence summarized in this review is based on four datasets.

Define and characterize the anhedonia in major depressive disorder: An explorative study.

BACKGROUND: Although anhedonia is a key symptom of major depressive disorder (MDD), there is neither a concise nor effective method to distinguish and define anhedonia in MDD. The current study attempts to answer two questions based on validating the Dimensional Anhedonia Rating Scale (DARS) in Chinese MDD patients: 1) whether anhedonia subgroup can be identified? 2) whether patients with anhedonia display unique psychosocial and clinical features? METHODS: In the discovery sample, 533 MDD patients and 124 healthy controls were recruited into a multicenter study. For replication, a further 112 first-episode, drug-naïve MDD patients were recruited. Latent profile analysis (LPA) was used to identify the latent subgroups based on their hedonic function measured by the DARS. According to the categorization, ROC curves were applied to find the cut-off value. Lasso regression was performed to characterize psychological and clinical features linked to anhedonia. RESULTS: The data-driven approach identified and validated the anhedonia subgroup, and proposed that the cut-off value for distinguishing anhedonia was 28.5 based on the total score of DARS. Lasso regression demonstrated that melancholia, lower levels of positive affect and education, more severe depressive symptoms, older age were associated with anhedonia in MDD patients. CONCLUSION: This study used a data-driven approach to propose a new and convenient method for distinguishing the anhedonia of MDD patients with unique psychological and clinical features. Identifying the subtype may contribute to pinpointing more specific biomarkers in shedding light on the mechanisms of anhedonia in MDD. TRIAL REGISTRATION: TNDTAD study, NCT03294525; TOSD study, NCT03148522.

Clinical and Preclinical Assessments of Anhedonia in Psychiatric Disorders.

Anhedonia is a prevalent symptom across many psychiatric disorders. The contemporary scope of anhedonia across various models includes interest, reward anticipation, motivation, effort expenditure, reward valuation, expectation, pleasure, satiation, and learning. In order to further elucidate the impact of anhedonia on treatment outcomes, quality of life, as well as brain function, validated tools to probe the various facets of anhedonia are necessary. This chapter evaluates assessment tools for anhedonia in clinical populations and in animals. Subjective clinical scales have been in use for decades, and as the construct of anhedonia evolved, contemporary scales were developed to integrate these new concepts. Clinical scales are useful for understanding the subjective experience of anhedonia but do not account for objective aspects of anhedonia, including implicit learning. Behavioral tasks that probe responses to rewarding stimuli have been useful to fill this gap and to delineate the specific brain processes underlying facets of anhedonia. Although there have been translational challenges in the assessments of anhedonia and reward deficits from preclinical to clinical (and vice versa), the multifaceted clinical scales and reward tasks provide valuable insights into the conceptualization of anhedonia and its neural basis across psychiatric disorders.

Structuro-functional surrogates of response to subcallosal cingulate deep brain stimulation for depression.

Subcallosal cingulate deep brain stimulation produces long-term clinical improvement in approximately half of patients with severe treatment-resistant depression. We hypothesized that both structural and functional brain attributes may be important in determining responsiveness to this therapy. In a treatment-resistant depression subcallosal cingulate deep brain stimulation cohort, we retrospectively examined baseline and longitudinal differences in MRI-derived brain volume (n = 65) and 18F-fluorodeoxyglucose-PET glucose metabolism (n = 21) between responders and non-responders. Support vector machines were subsequently trained to classify patients' response status based on extracted baseline imaging features. A machine learning model incorporating preoperative frontopolar, precentral/frontal opercular and orbitofrontal local volume values classified binary response status (12 months) with 83% accuracy [leave-one-out cross-validation (LOOCV): 80% accuracy] and explained 32% of the variance in continuous clinical improvement. It was also predictive in an out-of-sample subcallosal cingulate deep brain stimulation cohort (n = 21) with differing primary indications (bipolar disorder/anorexia nervosa; 76% accuracy). Adding preoperative glucose metabolism information from rostral anterior cingulate cortex and temporal pole improved model performance, enabling it to predict response status in the treatment-resistant depression cohort with 86% accuracy (LOOCV: 81% accuracy) and explain 67% of clinical variance. Response-related patterns of metabolic and structural post-deep brain stimulation change were also observed, especially in anterior cingulate cortex and neighbouring white matter. Areas where responders differed from non-responders-both at baseline and longitudinally-largely overlapped with depression-implicated white matter tracts, namely uncinate fasciculus, cingulum bundle and forceps minor/rostrum of corpus callosum. The extent of patient-specific engagement of these same tracts (according to electrode location and stimulation parameters) also served as an independent predictor of treatment-resistant depression response status (72% accuracy; LOOCV: 70% accuracy) and augmented performance of the volume-based (88% accuracy; LOOCV: 82% accuracy) and combined volume/metabolism-based support vector machines (100% accuracy; LOOCV: 94% accuracy). Taken together, these results indicate that responders and non-responders to subcallosal cingulate deep brain stimulation exhibit differences in brain volume and metabolism, both pre- and post-surgery. Moreover, baseline imaging features predict response to treatment (particularly when combined with information about local tract engagement) and could inform future patient selection and other clinical decisions.

A qualitative systematic review of neurocognition in suicide ideators and attempters: Implications for cognitive-based psychotherapeutic interventions.

BACKGROUND: Growing evidence suggests cognitive deficits may represent neurocognitive markers with predictive utility in identifying those at risk for suicide. Characterizing these deficits may offer the opportunity to develop targeted interventions. AIM: The aim of this systematic qualitative review is to provide a synthesis of the published data on neurocognition in suicide ideators and attempters in order to clarify which neurocognitive targets may be most relevant to address using cognitive-based psychotherapeutic strategies in patients at risk for suicide. RESULTS: A total of 63 studies met criteria for inclusion. The most consistent findings were in depressed suicide attempters, where deficits in executive subdomains of inhibition, selective attention and decision-making, as well as in working memory, were identified. In contrast, no clear pattern of neurocognitive deficits emerged from studies in suicide ideators across diagnoses. CONCLUSIONS: More studies are needed to clarify the role of cognitive deficits in specific subtypes of individuals at risk for suicide. The findings are discussed in the context of promising research on cognitive remediation and other psychological interventions.

Comparative study of the pencil-and-paper and digital formats of the Spanish DARS scale.

The Dimensional Anhedonia Rating Scale (DARS) is a novel questionnaire to assess anhedonia of recent validation. In this work, we aim to study the equivalence between the traditional paper-and-pencil and the digital format of DARS. Sixty-nine patients filled the DARS in a paper-based and digital versions. We assessed differences between formats (Wilcoxon test), validity of the scales [Kappa and intraclass correlation coefficients (ICCs)], and reliability (Cronbach's alpha and Guttman's coefficient). We calculated the comparative fit index and the root mean squared error (RMSE) associated with the proposed one-factor structure. Total scores were higher for paper-based format. Significant differences between both formats were found for three items. The weighted Kappa coefficient was approximately 0.40 for most of the items. Internal consistency was greater than 0.94, and the ICC for the digital version was 0.95 and 0.94 for the paper-and-pencil version (F = 16.7, p < 0.001). Comparative Adjustment Index was 0.97 for the digital DARS and 0.97 for the paper-and-pencil DARS, and RMSE was 0.11 for the digital DARS and 0.10 for the paper-and-pencil DARS. We concluded that the digital DARS is consistent in many respects with the paper-and-pencil questionnaire, but equivalence with this format cannot be assumed without caution.

Gatekeeper training for friends and family of individuals at risk of suicide: A systematic review.

AIMS: Gatekeeper training (GKT) is an important suicide prevention strategy. Studies have evaluated the effectiveness of GKT in different populations, often neglecting family and friends who play a vital role in caring for people with suicide risk. This review evaluated GKT programs targeting family and friends to determine their effectiveness in this specific population. METHODS: Academic databases were searched for studies on GKT programs. Programs involving family and friends caring for people with suicide risk were assessed for any impact on knowledge, self-efficacy, attitudes, and suicide prevention skills. RESULTS: Seventeen studies were reviewed. GKT showed significant gains on outcomes of interest. Three studies targeted family and friends, with one involving them in program creation and conduction and another adjusting the program after their input. CONCLUSIONS: GKT programs have potentially positive effects on family and friends caring for people with suicide risk. Few programs address the specific needs of this group, and programs adapted specifically for them are scarce. Future program development recommendations are discussed.

Reward processing as a common diathesis for chronic pain and depression.

Pain disorders and psychiatric illness are strongly comorbid, particularly in the context of Major Depressive Disorder (MDD). While these disorders account for a significant amount of global disability, the mechanisms of their overlap remain unclear. Understanding these mechanisms is of vital importance to developing prevention strategies and interventions that target both disorders. Of note, brain reward processing may be relevant to explaining how the comorbidity arises, given pain disorders and MDD can result in maladaptive reward responsivity that limits reward learning, appetitive approach behaviours and consummatory response. In this review, we discuss this research and explore the possibility of reward processing deficits as a common diathesis to explain the manifestation of pain disorders and MDD. Specifically, we hypothesize that contextual physical or psychological events (e.g. surgery, divorce) in the presence of a reward impairment diathesis worsens symptoms and results in a negative feedback loop that increases the chronicity and probability of developing the other disorder. We also highlight the implications for treatment and provide a framework for future research.

Anhedonia as a central factor in depression: Neural mechanisms revealed from preclinical to clinical evidence.

Anhedonia is one of the core symptoms of major depressive disorder (MDD), which is often inadequately treated by traditional antidepressants. The modern framework of anhedonia extends the definition from impaired consummatory pleasure or interest in rewards to a broad spectrum of deficits that impact functions such as reward anticipation, approach motivation, effort expenditure, reward valuation, expectation, and reward-cue association learning. Substantial preclinical and clinical research has explored the neural basis of reward deficits in the context of depression, and has implicated mesocorticolimbic reward circuitry comprising the nucleus accumbens, ventral pallidum, ventral tegmental area, amygdala, hippocampus, anterior cingulate, insula, orbitofrontal cortex, and other prefrontal cortex regions. Dopamine modulates several reward facets including anticipation, motivation, effort, and learning. As well, serotonin, norepinephrine, opioids, glutamate, Gamma aminobutyric acid (GABA), and acetylcholine are also involved in anhedonia, and medications targeting these systems may also potentially normalize reward processing in depression. Unfortunately, whereas reward anticipation and reward outcome are extensively explored by both preclinical and clinical studies, translational gaps remain in reward motivation, effort, valuation, and learning, where clinical neuroimaging studies are in the early stages. This review aims to synthesize the neurobiological mechanisms underlying anhedonia in MDD uncovered by preclinical and clinical research. The translational difficulties in studying the neural basis of reward are also discussed.

The BEACON study: protocol for a cohort study as part of an evaluation of the effectiveness of smartphone-assisted problem-solving therapy in men who present with intentional self-harm to emergency departments in Ontario.

BACKGROUND: Patients who present to emergency departments after intentional self-harm are at an increased risk of dying by suicide. This applies particularly to men, who represent nearly two-thirds of those who die by suicide in Ontario. One way of potentially addressing this gap is to offer a course of blended problem-solving therapy, comprised of a brief course of evidence-based psychotherapy for individuals at risk for suicide, facilitated by the use of a patient-facing smartphone application and a clinician-facing "dashboard." This approach has the potential to combine the benefits of face-to-face therapy and technology to create a novel intervention. METHODS: This is a cohort study nested within a larger pragmatic multicentre pre- and post-design cluster randomised trial. Suicidal ideation assessed by the Beck Scale for Suicide Ideation is the primary outcome variable. Secondary outcome measures include depression (Patient Health Questionnaire-9), anxiety (Generalized Anxiety Disorder 7-item scale), post-traumatic stress disorder (Primary Care PTSD Screen), health-related quality of life (EuroQol 5-dimension 5-level questionnaire), meaning in life (Experienced Meaning in Life Scale), perceived social supports (Multidimensional Scale of Perceived Social Support), alcohol use (Alcohol Use Disorders Identification Test), drug use (Drug Abuse Screening Test Short Form 10), problem-solving skills (Social Problem-Solving Inventory-Revised Short Form), and self-reported healthcare costs, as well as health service use measured using Ontario administrative health data. A process evaluation will also be conducted following study completion. DISCUSSION: The cohort study will test whether better adherence to the intervention results in better outcomes. The value of the cohort study design is that we can examine in more detail certain subgroups or other variables that are not available in the larger cluster randomised trial. This trial will aim to improve standards by informing best practice in management of men who self-harm and present to hospitals in Ontario. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03473535 . Registered on March 22, 2018.

Understanding the effects of chronic benzodiazepine use in depression: a focus on neuropharmacology.

Benzodiazepines are frequently prescribed on an ongoing basis to individuals with depression, mainly to alleviate anxiety or insomnia, despite current guideline recommendations that continuous use should not exceed 4 weeks. Currently, there are no efficacy trials published beyond 8 weeks. Several antidepressant trials demonstrate that the concomitant use of a benzodiazepine is associated with poorer depressive outcomes and functional status; however, it is unclear why this is the case. Patients with depression receiving a benzodiazepine may reflect a more ill or high anxiety group, although even within anxiety disorders, the use of a benzodiazepine is associated with poorer outcomes. The neuroadaptive consequences of long-term benzodiazepine use may be a factor underlying these findings. Chronic benzodiazepine use results in decreased gamma-aminobutyric acid and monoaminergic function, as well as interference with neurogenesis, which are all purported to play a role in antidepressant efficacy. This review will discuss the oppositional neuropharmacological interactions between chronic benzodiazepine use and antidepressant mechanism of action, which could result in reduced antidepressant efficacy and function in depression.