Search

Objectives: Treatment-emergent sexual dysfunction is frequently reported by individuals with major depressive disorder (MDD) on antidepressants, which negatively impacts treatment adherence and efficacy. We investigated the association of polymorphisms in pharmacokinetic genes encoding cytochrome-P450 drug-metabolizing enzymes, CYP2C19 and CYP2D6 , and the transmembrane efflux pump, P-glycoprotein (i.e., ABCB1 ), on treatment-emergent changes in sexual function (SF) and sexual satisfaction (SS) in the Canadian Biomarker Integration Network in Depression 1 (CAN-BIND-1) sample., Methods: A total of 178 adults with MDD received treatment with escitalopram (ESC) from weeks 0-8 (Phase I). At week 8, nonresponders were augmented with aripiprazole (ARI) (i.e., ESC + ARI, n  = 91), while responders continued ESC (i.e., ESC-Only, n  = 80) from weeks 8-16 (Phase II). SF and SS were evaluated using the sex effects (SexFX) scale at weeks 0, 8, and 16. We assessed the primary outcomes, SF and SS change for weeks 0-8 and 8-16, using repeated measures mixed-effects models., Results: In ESC-Only, CYP2C19 intermediate metabolizer (IM) + poor metabolizers (PMs) showed treatment-related improvements in sexual arousal, a subdomain of SF, from weeks 8-16, relative to CYP2C19 normal metabolizers (NMs) who showed a decline, F (2,54) = 8.00, p  < 0.001, q  = 0.048. Specifically, CYP2C19 IM + PMs reported less difficulty with having and sustaining vaginal lubrication in females and erection in males, compared to NMs. Furthermore, ESC-Only females with higher concentrations of ESC metabolite, S-desmethylcitalopram (S-DCT), and S-DCT/ESC ratio in serum demonstrated more decline in SF ( r  = -0.42, p  = 0.004, q  = 0.034) and SS ( r  = -0.43, p  = 0.003, q  = 0.034), respectively, which was not observed in males. ESC-Only females also demonstrated a trend for a correlation between S-DCT and sexual arousal change in the same direction ( r  = -0.39, p  = 0.009, q  = 0.052)., Conclusions: CYP2C19 metabolizer phenotypes may be influencing changes in sexual arousal related to ESC monotherapy. Thus, preemptive genotyping of CYP2C19 may help to guide selection of treatment that circumvents selective serotonin reuptake inhibitor-related sexual dysfunction thereby improving outcomes for patients. Additionally, further research is warranted to clarify the role of S-DCT in the mechanisms underlying ESC-related changes in SF and SS. This CAN-BIND-1 study was registered on clinicaltrials.gov (Identifier: NCT01655706) on 27 July 2012.

Preclinical research implicates stress-induced upregulation of the enzyme, serum- and glucocorticoid-regulated kinase 1 (SGK1), in reduced hippocampal volume. In the current study, we tested the hypothesis that greater SGK1 mRNA expression in humans would be associated with lower hippocampal volume, but only among those with a history of prolonged stress exposure, operationalized as childhood maltreatment (physical, sexual, and/or emotional abuse). Further, we examined whether baseline levels of SGK1 and hippocampal volume, or changes in these markers over the course of antidepressant treatment, would predict treatment outcomes in adults with major depression [MDD]. We assessed SGK1 mRNA expression from peripheral blood, and left and right hippocampal volume at baseline, as well as change in these markers over the first 8 weeks of a 16-week open-label trial of escitalopram as part of the Canadian Biomarker Integration Network in Depression program (MDD [n = 161] and healthy comparison participants [n = 91]). Childhood maltreatment was assessed via contextual interview with standardized ratings. In the full sample at baseline, greater SGK1 expression was associated with lower hippocampal volume, but only among those with more severe childhood maltreatment. In individuals with MDD, decreases in SGK1 expression predicted lower remission rates at week 16, again only among those with more severe maltreatment. Decreases in hippocampal volume predicted lower week 16 remission for those with low childhood maltreatment. These results suggest that both glucocorticoid-related neurobiological mechanisms of the stress response and history of childhood stress exposure may be critical to understanding differential treatment outcomes in MDD. ClinicalTrials.gov: NCT01655706 Canadian Biomarker Integration Network for Depression Study., Competing Interests: Declaration of Competing Interest RM, SC, SH, LF, NN, BNF, KH reported no relevant conflict of interests. RVM has received consulting and speaking honoraria from AbbVie, Allergan, Eisai, Janssen, KYE, Lallemand, Lundbeck, Otsuka, and Sunovion, and research grants from CAN-BIND, Canadian Institutes for Health Research, Janssen, Lallemand, Lundbeck, Nubiyota, Ontario Brain Institute and Ontario Mental Health Foundation. RWL has received honoraria for ad hoc speaking or advising/consulting, or received research funds, from Asia-Pacific Economic Cooperation, BC Leading Edge Foundation, Canadian Institutes for Health Research, Canadian Network for Mood and Anxiety Treatments, Healthy Minds Canada, Janssen, Lundbeck, Lundbeck Institute, Michael Smith Foundation for Health Research, MITACS, Myriad Neuroscience, Ontario Brain Institute, Otsuka, Pfizer, Sanofi, Unity Health, and VGH-UBCH Foundation. SCS received funding from the Ontario Brain Institute and Canadian Institutes for Health Research (MOP137097) for neuroimaging analysis in CAN-BIND, and SCS is a Senior Scientific Advisor and co-owner of ADMdx, Inc., a neuroimaging consulting company. SRA has carried out consultancy work for Indoc Research. SR holds a patent "Teneurin C-Terminal Associated Peptides (TCAP) and methods and uses thereof. Inventors: David Lovejoy, R.B. Chewpoy, Dalia Barsyte, Susan Rotzinger." SHK has received research funding or honoraria from the following sources: Abbott, Alkermes, Abbvie, Brain Canada, Canadian Institutes for Health Research, Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute, Ontario Research Fund, Otsuka, Pfizer, Servier, Sunovion and Xian-Janssen and holds stock in Field Trip Health., (Copyright © 2023 Elsevier B.V. and ECNP. All rights reserved.)

Background: Prediction of treatment outcomes is a key step in improving the treatment of major depressive disorder (MDD). The Canadian Biomarker Integration Network in Depression (CAN-BIND) aims to predict antidepressant treatment outcomes through analyses of clinical assessment, neuroimaging, and blood biomarkers., Methods: In the CAN-BIND-1 dataset of 192 adults with MDD and outcomes of treatment with escitalopram, we applied machine learning models in a nested cross-validation framework. Across 210 analyses, we examined combinations of predictive variables from three modalities, measured at baseline and after 2 weeks of treatment, and five machine learning methods with and without feature selection. To optimize the predictors-to-observations ratio, we followed a tiered approach with 134 and 1152 variables in tier 1 and tier 2 respectively., Results: A combination of baseline tier 1 clinical, neuroimaging, and molecular variables predicted response with a mean balanced accuracy of 0.57 (best model mean 0.62) compared to 0.54 (best model mean 0.61) in single modality models. Adding week 2 predictors improved the prediction of response to a mean balanced accuracy of 0.59 (best model mean 0.66). Adding tier 2 features did not improve prediction., Conclusions: A combination of clinical, neuroimaging, and molecular data improves the prediction of treatment outcomes over single modality measurement. The addition of measurements from the early stages of treatment adds precision. Present results are limited by lack of external validation. To achieve clinically meaningful prediction, the multimodal measurement should be scaled up to larger samples and the robustness of prediction tested in an external validation dataset.

The P-glycoprotein efflux pump, encoded by the ABCB1 gene, has been shown to alter concentrations of various antidepressants in the brain. In this study, we conducted a systematic review and meta-analysis to investigate the association between six ABCB1 single-nucleotide polymorphisms (SNPs; rs1045642, rs2032582, rs1128503, rs2032583, rs2235015, and rs2235040) and antidepressant treatment outcomes in individuals with major depressive disorder (MDD), including new data from the Canadian Biomarker and Integration Network for Depression (CAN-BIND-1) cohort. For the CAN-BIND-1 sample, we applied regression models to investigate the association between ABCB1 SNPs and antidepressant treatment response, remission, tolerability, and antidepressant serum levels. For the meta-analysis, we systematically summarized pharmacogenetic evidence of the association between ABCB1 SNPs and antidepressant treatment outcomes. Studies were included in the meta-analysis if they investigated at least one ABCB1 SNP in individuals with MDD treated with at least one antidepressant. We did not find a significant association between ABCB1 SNPs and antidepressant treatment outcomes in the CAN-BIND-1 sample. A total of 39 studies were included in the systematic review. In the meta-analysis, we observed a significant association between rs1128503 and treatment response (T vs. C-allele, odds ratio = 1.30, 95% confidence interval = 1.15-1.48, P value (adjusted) = 0.024, n = 2,526). We did not find associations among the six SNPs and treatment remission nor tolerability. Our findings provide limited evidence for an association between common ABCB1 SNPs and antidepressant outcomes, which do not support the implementation of ABCB1 genotyping to inform antidepressant treatment at this time. Future research, especially on rs1128503, is recommended., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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., Competing Interests: Conflict of interest Dr. Sidney H. Kennedy has received research funding or honoraria from Abbott, Alkermes, Allergan, Boehringer Ingelheim, Brain Canada, Canadian Institutes for Health Research (CIHR), Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute, Ontario Research Fund (ORF), Otsuka, Pfizer, Servier, Sunovion and Xian-Janssen. He also has received stock options from Field Trip Health. Over the past 3 years, Dr. Shane J. McInerney has received research funding from The National Office of Suicide Prevention (NOSP) in Ireland. Over the past 3 years, Dr. Diego A. Pizzagalli has received consulting fees from BlackThorn Therapeutics, Boehringer Ingelheim, Compass Pathway, Concert Pharmaceuticals, Engrail Therapeutics, Neurocrine Biosciences, Neuroscience Software, Otsuka Pharmaceuticals, and Takeda Pharmaceuticals; one honorarium from Alkermes, and research funding from NIMH, Dana Foundation, Brain and Behavior Research Foundation, Millennium Pharmaceuticals. In addition, he has received stock options from BlackThorn Therapeutics and Compass Pathways. All views expressed are solely those of the authors. All other authors report no financial relationships with commercial interest. DAP was also partially supported by R37 2R37MH068376 and P50 MH119467 from the National Institute of Mental Health. Dr. Mark Sinyor receives funding through Academic Scholar Awards from the Departments of Psychiatry at Sunnybrook Health Sciences Centre and the University of Toronto. Dr. Sakina J. Rizvi has received research funding or honoraria from Pfizer Canada, Quintiles, Janssen, Neurocrine Inc., Allergan, and Takeda. Ms. Shijing Wang, Ms. Amanda K. Ceniti, Dr. Yvonne Bergmans, Dr. Tim V. Salomons, Dr. Gustavo Turecki, Dr. Norman Farb, Dr. Nathan Churchill, and Dr. Tom A. Schweizer declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Major depressive disorder (MDD) is associated with various cognitive impairments, including response inhibition. Deficits in response inhibition may also underlie poor antidepressant treatment response. Recent studies revealed that the neurobiological correlates of response inhibition can predict response to pharmacological treatments. However, the generalizability of this finding to first-line nonpharmacological treatments, particularly cognitive behavioral therapy, remains to be investigated., Methods: Data from two independent treatment protocols were combined, one in which 65 patients with MDD underwent treatment with escitalopram, and the other in which 41 patients with MDD underwent a course of cognitive behavioral therapy. A total of 25 healthy control subjects were also recruited. Neural correlates of response inhibition were captured by participants completing a Go/NoGo task during electroencephalography recording. Response inhibition-related measures of interest included the amplitudes of the N2 and P3 event-related potentials., Results: Pretreatment P3 amplitude, which has been linked to both the motor and cognitive aspects of response inhibition, was a significant predictor of change in depressive symptoms following escitalopram and cognitive behavioral therapy treatment. A greater pretreatment P3 amplitude was associated with a greater reduction in depressive severity. In addition, the pretreatment P3 amplitude was found to be significantly greater at baseline in remitters than in nonremitters and healthy control subjects., Conclusions: The integrity of response inhibition may be critical for a successful course of pharmacological or psychological treatment for MDD. Electrophysiological correlates of response inhibition may have utility as a general prognostic marker of treatment response in MDD. Future studies may investigate the benefit of preceding first-line treatments with interventions that improve response inhibition in MDD., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: An increasing number of studies are examining the link between the endocannabinoidome and major depressive disorder (MDD). We conducted an exploratory analysis of this system to identify potential markers of treatment outcomes., Methods: The dataset of the Canadian Biomarker Integration Network in Depression-1 study, consisting of 180 patients with MDD treated for eight weeks with escitalopram followed by eight weeks with escitalopram alone or augmented with aripiprazole was analyzed. Association between response Montgomery-Asberg Depression Rating Scale (MADRS; score reduction≥50%) or remission (MADRS score≤10) at weeks 8 and 16 and single nucleotide polymorphisms (SNPs), methylation, and mRNA levels of 33 endocannabinoid markers were examined. A standard genome-wide association studies protocol was used for identifying SNPs, and logistic regression was used to assess methylation and mRNA levels., Results: Lower methylation of CpG islands of the diacylglycerol lipase alpha gene ( DAGLA ) was associated with non-remission at week 16 ( DAGLA ; OR=0.337, p<0.003, q=0.050). Methylation of DAGLA was correlated with improvement in Clinical Global Impression (p=0.026), Quick Inventory of Depressive Symptomatology (p=0.010), and Snaith-Hamilton Pleasure scales (p=0.028). We did not find any association between SNPs or mRNA levels and treatment outcomes., Discussion: Methylation of DAGLA is a promising candidate as a marker of treatment outcomes for MDD and needs to be explored further., Competing Interests: There was no role of the following granting agencies/sponsors in the design, collection of data, analysis, interpretation of data, writing of this paper, and decision to submit the paper for publication. Muhammad I. Husain receives research support from the Brain and Behavior Research Foundation, Canadian Institutes of Health Research, CAMH Foundation, the PSI Foundation, and the University of Toronto. He has provided consultancy to Mindset Pharma, PsychEd Therapeutics, and Wake Network. He holds stock/stock options in Mindset Pharma. Raymond W. Lam has received honoraria for ad hoc speaking or advising/consulting or received research funds from: Asia-Pacific Economic Cooperation, BC Leading Edge Foundation, Canadian Institutes of Health Research, Canadian Network for Mood and Anxiety Treatments, Grand Challenges Canada, Healthy Minds Canada, Janssen, Lundbeck, Lundbeck Institute, Medscape, Michael Smith Foundation for Health Research, MITACS, Myriad Neuroscience, Ontario Brain Institute, Otsuka, Pfizer, Sanofi, Unity Health, Vancouver Coastal Health Research Institute, and VGH-UBCH Foundation. Claudio N. Soares received/has pending grants that include Canadian Institutes for Health Research, Ontario Brain Institute, Ontario Research Fund, and Eisai. He also receives consulting feed or honorarium from Lundbeck, Otsuka, Pfizer, Bayer, and Eisai. Sagar V. Parikh reports research support in the past three years from Takeda, Sage, Janssen, Merck, the Ontario Brain Institute, and the Canadian Institutes for Health Research; honoraria from Aifred, Assurex, Janssen, Lundbeck, Mensante, Neonmind, Otsuka, and Sage; and shares in Neonmind and Mensante. Roumen Milev has received consulting and speaking honoraria from AbbVie, Allergan, Eisai, Janssen, KYE, Lallemand, Lundbeck, Neonmind, Otsuka, and Sunovion, and research grants from CAN-BIND, CIHR, Janssen, Lallemand, Lundbeck, Nubiyota, OBI and OMHF. Jane A. Foster receives consulting and speaking fees from Takeda Canada and RBH. Faranak Farzan received funding from CIHR, NSER, and Michael Smith Foundation for Health Research. Benoit H. Mulsant holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He currently receives research support from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute, the US National Institute of Health, Capital Solution Design LLC (software used in a study funded by CAMH Foundation), and HAPPYneuron (software used in a study funded by Brain Canada). He has been an unpaid consultant to Myriad Neuroscience. Sidney Kennedy received grants/has pending grants, including Abbott, Allergan, Brain Canada, Canadian Institutes for Health Research, Janssen, Lundbeck, Ontario Brain Institute, Ontario Research Fund, Otsuka, Pfizer, Servier, Sunovion, and Xian-Janssen. He also receives consulting fees or honorarium from Abbott, Alkermes, Allergan, Boehringer Ingelheim, Brain Canada, Canadian Institutes for Health Research, Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute, Ontario Research Fund, Otsuka, Pfizer, Servier, Sunovion and Xian-Janssen. He has stock/stock options from Field Trip Health. Stefan Kloiber’s work has been supported by the Academic Scholar Award and the Labatt Family Innovation Fund in Brain Health, Department of Psychiatry, University of Toronto. DJM’s research work is supported by the Canadian Institutes of Health Research, the Ontario Brain Foundation, the Alternate Funding Plan of Ontario, and the Centre for Addiction and Mental Health Foundation. GZ’s work has been supported by the Academic Scholar Award and the Labatt Family Innovation Fund in Brain Health, Department of Psychiatry, University of Toronto, in addition to the Brain & Behavior Research Foundation, International Obsessive-Compulsive Disorder Foundation, and the Physicians’ Services Incorporated Foundation in Ontario, Canada. SK has received an honorarium for past consultation from EmpowerPharm. All other authors declare no conflict of interest. Helena K. Kim, Gwyneth Zai, Daniel J. Müller, Benicio N. Frey, Gustavo Turecki, and Shreejoy J. Tripathy have no conflicts to disclose., (Thieme. All rights reserved.)

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is considered one of the mechanisms underlying the development of major depressive disorder (MDD), but the exact nature of this dysfunction is unknown. We investigated the relationship between hypothalamus volume (HV) and blood-derived DNA methylation in MDD. We obtained brain MRI, clinical and molecular data from 181 unmedicated MDD and 90 healthy control (HC) participants. MDD participants received a 16-week standardized antidepressant treatment protocol, as part of the first Canadian Biomarker Integration Network in Depression (CAN-BIND) study. We collected bilateral HV measures via manual segmentation by two independent raters. DNA methylation and RNA sequencing were performed for three key HPA axis-regulating genes coding for the corticotropin-binding protein (CRHBP), glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5). We used elastic net regression to perform variable selection and assess predictive ability of methylation variables on HV. Left HV was negatively associated with duration of current episode (ρ = -0.17, p = 0.035). We did not observe significant differences in HV between MDD and HC or any associations between HV and treatment response at weeks 8 or 16, overall depression severity, illness duration or childhood maltreatment. We also did not observe any differentially methylated CpG sites between MDD and HC groups. After assessing functionality by correlating methylation levels with RNA expression of the respective genes, we observed that the number of functionally relevant CpG sites differed between MDD and HC groups in FKBP5 (χ 2 = 77.25, p < 0.0001) and NR3C1 (χ 2 = 7.29, p = 0.007). Cross-referencing functionally relevant CpG sites to those that were highly ranked in predicting HV in elastic net modeling identified one site from FKBP5 (cg03591753) and one from NR3C1 (cg20728768) within the MDD group. Stronger associations between DNA methylation, gene expression and HV in MDD suggest a novel putative molecular pathway of stress-related sensitivity in depression. Future studies should consider utilizing the epigenome and ultra-high field MR data which would allow the investigation of HV sub-fields., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Suicide is a leading cause of mortality in youth, yet the course of suicide attempts is poorly documented. We explored the vulnerable transition from adolescence to emerging adulthood to identify group trajectories and risk factors., Methods: The National Longitudinal Survey of Children and Youth is a prospective representative cohort of Canadian children. We followed participants aged 7-11 years in 1994-95 to age 23 (2008-09). We modelled self-reported past-year suicide attempts (ages 12 to 23 years) using growth mixture models. We analysed risk factors from self- and parent-report questionnaires at pre-adolescence (ages 10-11) and early adolescence (ages 12-13) using multinomial logistic regressions. Analyses were adjusted for sample non-response and attrition., Results: In 2233 participants answering questions on teen and adult suicide attempts, we identified three trajectories: never attempted (96.0%), adolescence-limited (2.0%) and persisting into adulthood (2.0%). Adolescent girls aged 12-13 with depression/anxiety symptoms, and with mothers experiencing depression had higher risks of adolescence-limited than never-attempted [relative risk RR 9.27 (95% confidence interval: 1.73-49.82); 2.03 (1.02-3.32), for each standard deviation increase; 1.07 (1.00-1.15); respectively]. Preteen ADHD symptoms increased the risk of attempts persisting into adulthood as compared to never-attempted [RR 2.05 (1.29-3.28) for each standard deviation increase]. Suicide death of schoolmate/acquaintance increased risks of an adulthood trajectory as compared to never-attempted and adolescence-limited [RR 8.41 (3.04-23.27) and 6.63 (1.29-34.06), respectively]., Conclusion: In half the participants attempting suicide, attempts continued into adulthood. We stress the need for preventive strategies in early adolescence and differential clinical/educational interventions as identified for each trajectory.

The transition from suicidal ideas to a suicide act is an important topic of research for the identification of those patients at risk of acting out. We investigated here whether specific brain activity and connectivity measures at rest may be differently associated with suicidal thoughts and behaviors. A large sample of acutely depressed patients with major depressive disorder was recruited in three different centers (Montreal/Canada, Stanford/USA, and Jena/Germany), covering four different phenotypes: patients with a past history of suicide attempt (n = 53), patients with current suicidal ideas but no past history of suicide attempt (n = 40), patients without current suicidal ideation nor past suicide attempts (n = 42), and healthy comparison subjects (n = 107). 3-T resting-state functional magnetic resonance imaging (fMRI) measures of the amplitude of low-frequency fluctuation (ALFF) and degree centrality (DC) were obtained and examined in a whole-brain data-driven analysis. Past suicide attempt was associated with a double cortico-subcortical dissociation in ALFF values. Decreased ALFF and DC values mainly in a frontoparietal network and increased ALFF values in some subcortical regions (hippocampus and thalamus) distinguished suicide attempters from suicide ideators, patient controls, and healthy controls. No clear neural differences were identified in relation to suicidal ideas. Suicide attempters appear to be a distinct subgroup of patients with widespread brain alterations in functional activity and connectivity that could represent factors of vulnerability. Our results also indirectly support at the neurobiological level the relevance of the transition model described at the psychological and clinical levels. The brain bases of suicidal ideas occurrence in depressed individuals needs further investigations.

Anhedonia is thought to reflect deficits in reward processing that are associated with abnormal activity in mesocorticolimbic brain regions. It is expressed clinically as a deficit in the interest or pleasure in daily activities. More severe anhedonia in major depressive disorder (MDD) is a negative predictor of antidepressant response. It is unknown, however, whether the pathophysiology of anhedonia represents a viable avenue for identifying biological markers of antidepressant treatment response. Therefore, this study aimed to examine the relationships between reward processing and response to antidepressant treatment using clinical, behavioral, and functional neuroimaging measures. Eighty-seven participants in the first Canadian Biomarker Integration Network in Depression (CAN-BIND-1) protocol received 8 weeks of open-label escitalopram. Clinical correlates of reward processing were assessed at baseline using validated scales to measure anhedonia, and a monetary incentive delay (MID) task during functional neuroimaging was completed at baseline and after 2 weeks of treatment. Response to escitalopram was associated with significantly lower self-reported deficits in reward processing at baseline. Activity during the reward anticipation, but not the reward consumption, phase of the MID task was correlated with clinical response to escitalopram at week 8. Early (baseline to week 2) increases in frontostriatal connectivity during reward anticipation significantly correlated with reduction in depressive symptoms after 8 weeks of treatment. Escitalopram response is associated with clinical and neuroimaging correlates of reward processing. These results represent an important contribution towards identifying and integrating biological, behavioral, and clinical correlates of treatment response. ClinicalTrials.gov: NCT01655706.

Background: Recent evidence underscores the utility of rapid-acting antidepressant interventions, such as ketamine, in alleviating symptoms of major depressive episodes (MDE). However, to date, there have been limited head-to-head comparisons of intravenous (IV) ketamine infusions with other antidepressant treatment strategies in large randomized trials. This study protocol describes an ongoing multi-centre, prospective, randomized, crossover, non-inferiority trial comparing acute treatment of individuals meeting diagnostic criteria for a major depressive episode (MDE) with ketamine and electroconvulsive therapy (ECT) on efficacy, speed of therapeutic effects, side effects, and health care resource utilization. A secondary aim is to compare a 6-month maintenance strategy for ketamine responders to standard of care ECT maintenance. Finally, through the measurement of clinical, cognitive, neuroimaging, and molecular markers we aim to establish predictors and moderators of treatment response as well as treatment-elicited effects on these outcomes., Methods: Across four participating Canadian institutions, 240 patients with major depressive disorder or bipolar disorder experiencing a MDE are randomized (1:1) to a course of ECT or racemic IV ketamine (0.5 mg/kg) administered 3 times/week for 3 or 4 weeks. Non-responders (< 50% improvement in Montgomery-Åsberg Depression Rating Scale [MADRS] scores) crossover to receive the alternate treatment. Responders during the randomization or crossover phases then enter the 6-month maintenance phase during which time they receive clinical assessments at identical intervals regardless of treatment arm. ECT maintenance follows standard of care while ketamine maintenance involves: weekly infusions for 1 month, then bi-weekly infusions for 2 months, and finally monthly infusions for 3 months (returning to bi-weekly in case of relapse). The primary outcome measure is change in MADRS scores after randomized treatment as assessed by raters blind to treatment modality., Discussion: This multi-centre study will help identify molecular, imaging, and clinical characteristics of patients with treatment-resistant and/or severe MDEs who would benefit most from either type of therapeutic strategy. In addition to informing clinical practice and influencing health care delivery, this trial will add to the robust platform and database of CAN-BIND studies for future research and biomarker discovery., Trial Registration: ClinicalTrials.gov identifier NCT03674671. Registered September 17, 2018.

Importance: Social and economic costs of depression are exacerbated by prolonged periods spent identifying treatments that would be effective for a particular patient. Thus, a tool that reliably predicts an individual patient's response to treatment could significantly reduce the burden of depression., Objective: To estimate how accurately an outcome of escitalopram treatment can be predicted from electroencephalographic (EEG) data on patients with depression., Design, Setting, and Participants: This prognostic study used a support vector machine classifier to predict treatment outcome using data from the first Canadian Biomarker Integration Network in Depression (CAN-BIND-1) study. The CAN-BIND-1 study comprised 180 patients (aged 18-60 years) diagnosed with major depressive disorder who had completed 8 weeks of treatment. Of this group, 122 patients had EEG data recorded before the treatment; 115 also had EEG data recorded after the first 2 weeks of treatment., Interventions: All participants completed 8 weeks of open-label escitalopram (10-20 mg) treatment., Main Outcomes and Measures: The ability of EEG data to predict treatment outcome, measured as accuracy, specificity, and sensitivity of the classifier at baseline and after the first 2 weeks of treatment. The treatment outcome was defined in terms of change in symptom severity, measured by the Montgomery-Åsberg Depression Rating Scale, before and after 8 weeks of treatment. A patient was designated as a responder if the Montgomery-Åsberg Depression Rating Scale score decreased by at least 50% during the 8 weeks and as a nonresponder if the score decrease was less than 50%., Results: Of the 122 participants who completed a baseline EEG recording (mean [SD] age, 36.3 [12.7] years; 76 [62.3%] female), the classifier was able to identify responders with an estimated accuracy of 79.2% (sensitivity, 67.3%; specificity, 91.0%) when using only the baseline EEG data. For a subset of 115 participants who had additional EEG data recorded after the first 2 weeks of treatment, use of these data increased the accuracy to 82.4% (sensitivity, 79.2%; specificity, 85.5%)., Conclusions and Relevance: These findings demonstrate the potential utility of EEG as a treatment planning tool for escitalopram therapy. Further development of the classification tools presented in this study holds the promise of expediting the search for optimal treatment for each patient.

Major depressive disorder (MDD) is primarily treated with antidepressants, yet many patients fail to respond adequately, and identifying antidepressant response biomarkers is thus of clinical significance. Some hypothesis-driven investigations of epigenetic markers for treatment response have been previously made, but genome-wide approaches remain unexplored. Healthy participants (n = 112) and MDD patients (n = 211) between 18-60 years old were recruited for an 8-week trial of escitalopram treatment. Responders and non-responders were identified using differential Montgomery-Åsberg Depression Rating Scale scores before and after treatment. Genome-wide DNA methylation and gene expression analyses were assessed using the Infinium MethylationEPIC Beadchip and HumanHT-12 v4 Expression Beadchip, respectively, on pre-treatment peripheral blood DNA and RNA samples. Differentially methylated positions (DMPs) located in regions of differentially expressed genes between responders (n = 82) and non-responders (n = 95) were identified, and technically validated using a targeted sequencing approach. Three DMPs located in the genes CHN2 (cg23687322, p = 0.00043 and cg06926818, p = 0.0014) and JAK2 (cg08339825, p = 0.00021) were the most significantly associated with mRNA expression changes and subsequently validated. Replication was then conducted with non-responders (n = 76) and responders (n = 71) in an external cohort that underwent a similar antidepressant trial. One CHN2 site (cg06926818; p = 0.03) was successfully replicated. Our findings indicate that differential methylation at CpG sites upstream of the CHN2 and JAK2 TSS regions are possible peripheral predictors of antidepressant treatment response. Future studies can provide further insight on robustness of our candidate biomarkers, and greater characterization of functional components.

Studies of clinical populations that combine MRI data generated at multiple sites are increasingly common. The Canadian Biomarker Integration Network in Depression (CAN-BIND; www.canbind.ca) is a national depression research program that includes multimodal neuroimaging collected at several sites across Canada. The purpose of the current paper is to provide detailed information on the imaging protocols used in a number of CAN-BIND studies. The CAN-BIND program implemented a series of platform-specific MRI protocols, including a suite of prescribed structural and functional MRI sequences supported by real-time monitoring for adherence and quality control. The imaging data are retained in an established informatics and databasing platform. Approximately 1300 participants are being recruited, including almost 1000 with depression. These include participants treated with antidepressant medications, transcranial magnetic stimulation, cognitive behavioural therapy and cognitive remediation therapy. Our ability to analyze the large number of imaging variables available may be limited by the sample size of the substudies. The CAN-BIND program includes a multimodal imaging database supported by extensive clinical, demographic, neuropsychological and biological data from people with major depression. It is a resource for Canadian investigators who are interested in understanding whether aspects of neuroimaging — alone or in combination with other variables — can predict the outcomes of various treatment modalities., Competing Interests: G. MacQueen reports consultancy/speaker fees from Lundbeck, Pfizer, Johnson & Johnson and Janssen, outside the submitted work. B. Frey reports grants and personal fees from Pfizer and personal fees from Sunovion, outside the submitted work. R. Milev reports grants, nonfinancial support and honoraria from Lundbeck, Janssen and Pfizer; personal fees and honoraria from Sunovion, Shire, Allergan and Otsuka; grants from Boehringer Ingelheim; and grants from the Ontario Brain Institute, the Canadian Institutes for Health Research and CAN-BIND, outside the submitted work. F. Vila-Rodriguez reports nonfinancial support from Magventure during the conduct of the study; grants from the Canadian Institutes for Health Research, Brain Canada, the Michael Smith Foundation for Health Research, and the Vancouver Coastal Health Research Institute; and personal fees from Janssen, outside the submitted work. S. Rizvi reports grants from Pfizer Canada, outside the submitted work. S. Strother reports grants from Canadian Biomarker Integration Network in Depression during the conduct of the study and grants from Ontario Brain Institute, outside the submitted work. He is also the chief scientific officer of the neuroimaging data analysis company ADMdx, Inc (www. admdx.com), which specializes in brain image analysis to enable diagnosis, prognosis and drug effect detection for Alzheimer disease and various other forms of dementia. R. Lam reports grants from Canadian Institutes of Health Research during the conduct of the study; grants from Asia-Pacific Economic Cooperation, VGH-UBCH Foundation, BC LEading Edge Endowment Fund, Janssen, Lundbeck, Pfizer and St. Jude Medical, outside the submitted work; personal fees from Allergan, Akili, CME Institute, Canadian Network for Mood and Anxiety Treatments, Janssen, Lundbeck, Lundbeck Institute, Pfizer, Otsuka, Medscape and Hansoh, outside the submitted work; travel expenses from Asia-Pacific Economic Cooperation outside the submitted work; and stock options from Mind Mental Health Technologies., (© 2019 Joule Inc. or its licensors)

Objective: Few studies have examined the effect of risk factor modifications on depression incidence. This study was to explore psychosocial risk factors for depression and quantify the effect of risk factor modifications on depression incidence in a large-scale, longitudinal population-based study., Methods: Data were from the Montreal Longitudinal Catchment Area study (N=2433). Multivariate modified Poisson regression was used to estimate relative risk (RR). Population attributable fractions were also used to estimate the potential impact of risk factor modifications on depression incidence., Results: The cumulative incidence rate of major depressive disorder at the 2-year follow-up was 4.8%, and 6.6% at the 4-year follow-up. Being a younger adult, female, widowed, separated or divorced, Caucasian, poor, occasional drinker, having a family history of mental health problems, having less education and living in areas with higher unemployment rates and higher proportions of visible minorities, more cultural community centres and community organisations, were consistently associated with the increased risk of incident major depressive disorder. Although only 5.1% of the disease incidence was potentially attributable to occasional drinking (vs abstainers) at the 2-year follow-up, the attribution of occasional drinking doubled at the 4-year follow-up. A 10% reduction in the prevalence of occasional drinking in this population could potentially prevent half of incident cases., Conclusions: Modifiable risk factors, both individual and societal, could be the targets for public depression prevention programmes. These programmes should also be gender-specific, as different risk factors have been identified for men and women. Public health preventions at individual levels could focus on the better management of occasional drinking, as it explained around 5%~10% of incident major depressive disorders. Neighbourhood characteristics could also be the target for public prevention programmes. However, this could be very challenging. A cost-effectiveness analysis of a variety of prevention efforts is warranted., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: Available information on risk for suicide completion in females is limited and often extrapolated from studies conducted in males. However, the validity of extending to females risk factors identified among male suicide cases is unclear. In this study, we aimed to investigate clinical and behavioral risk factors for suicide among female depressed patients and compare them to similar factors among male depressed patients., Method: We identified 201 suicide completers (160 male and 41 female) who died during an episode of major depressive disorder (MDD). Cases were compared to 127 living patients with MDD (88 male and 39 female). All subjects were characterized for Axis I and II diagnoses using the Structured Clinical Interview for DSM-IV Axis I Disorders and Structured Clinical Interview for DSM-IV Axis II Personality Disorders according to the DSM-IV, as well as behavioral and temperament dimensions using proxy-based interviews. The primary outcome was measures of impulsive and impulsive-aggressive behaviors., Results: Compared to controls, male, but not female suicide cases had higher levels of impulsive aggression (P < .05). Nonimpulsive aggression differentiated both female (P < .05) and male (P < .01) suicide cases from controls. However, nonimpulsive aggression and impulsive aggression were correlated constructs in males (r = 0.297; P < .001), yet uncorrelated among females (r = 0.121; P = .390). Established risk factors for suicide, such as alcohol and substance dependence, cluster B disorders, and elevated hostility and aggression, were replicated in the pooled-sex analyses, and, though not statistically significant in discriminating between suicide cases and controls by gender, maintained strong group differences., Conclusions: Males and females share many risk factors for suicide in MDD, yet alcohol dependence is much more specific though less sensitive among depressed females. Nonimpulsive aggression is part of a diathesis for suicide in females, which is distinct from the well-characterized impulsive aggression that is consistently reported in a portion of male suicide cases., (© Copyright 2013 Physicians Postgraduate Press, Inc.)

An altered polyamine system has been suggested to play a key role in mood disorders and suicide, a hypothesis corroborated by the evidence that lithium inhibits the polyamine mediated stress response in the rat brain. Recent post-mortem studies have shown that spermidine/spermine N1-acetyltransferase (SAT1), the key regulator of cellular polyamine content, is under-expressed in brains from suicide victims compared to controls. In our study we tested the effect of in vitro lithium treatment on SAT1 gene and protein expression in B lymphoblastoid cell lines (BLCLs) from bipolar disorder (BD) patients who committed suicide (and for which BLCLs were collected prior to their death), BD patients with high and low risk of suicide and a sample of non-psychiatric controls. Baseline mRNA levels were similar in the four groups of subjects (p > 0.05). Lithium had no effect in suicide completers (p > 0.05) while it significantly increased SAT1 expression in the high risk (p < 0.001) and low risk (p < 0.01) groups as well as in controls (p < 0.001). Protein and mRNA levels were not correlated; lithium significantly reduced protein levels only in the control sample (p < 0.05). Our findings suggest that SAT1 transcription is influenced by lithium and that this effect is altered in BD patients who completed suicide, further supporting a role for polyamines in suicide.

Background: The tropomyosin-related kinase B (TrkB)/brain-derived neurotrophic factor system has been associated with psychiatric disorders, and animal models of defects in this system suggest that it might have a particular role in anxiety., Methods: DNA sequencing and cloning were used to identify a mutation in TrkB, and four different cell lines were used to assess functionality. Clinical samples were from a 22-year longitudinal cohort representative of the Quebec general population (n = 640 subjects), randomly selected when they were in kindergarten. Anxiety-related traits were measured with the Social Behaviour Questionnaire, the Diagnostic Assessment of Personality Pathology-Brief Questionnaire, and the Diagnostic Interview Schedule for DSM-IIIR., Results: An 11 base pair deletion in TrkB is significantly associated with increases in anxiety traits during childhood and the development of anxiety disorders in adulthood. We found that this deletion impaired transcription in some human cell lines., Conclusions: The identification of this deletion provides additional support for the role of TrkB in modulating anxiety-related traits in human., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Suicide completion rates are significantly higher in males than females in most societies. Although gender differences in suicide rates have been partially explained by environmental and behavioral factors, it is possible that genetic factors, through differential expression between genders, may also help explain gender moderation of suicide risk. This study investigated X-linked genes in suicide completers using a two-step strategy. We first took advantage of the genetic structure of the French-Canadian population and genotyped 722 unrelated French-Canadian male subjects, of whom 333 were suicide completers and 389 were non-suicide controls, using a panel of 37 microsatellite markers spanning the entire X chromosome. Nine haplotype windows and several individual markers were associated with suicide. Significant results aggregated primarily in two regions, one in the long arm and another in the short arm of chromosome X, limited by markers DXS8051 and DXS8102, and DXS1001 and DXS8106, respectively. The second stage of the study investigated differential brain expression of genes mapping to associated regions in Brodmann areas 8/9, 11, 44 and 46, in an independent sample of suicide completers and controls. Six genes within these regions, Rho GTPase-activating protein 6, adaptor-related protein complex 1 sigma 2 subunit, glycoprotein M6B, ribosomal protein S6 kinase 90  kDa polypeptide 3, spermidine/spermine N(1)-acetyltransferase 1 and THO complex 2, were found to be differentially expressed in suicide completers.

Background: The polyamine system has been implicated in a number of psychiatric conditions, which display both alterations in polyamine levels and altered expression of genes related to polyamine metabolism. Studies have identified associations between genetic variants in spermidine/spermine N1-acetyltransferase (SAT1) and both anxiety and suicide, and several polymorphisms appear to play important roles in determining gene expression., Methodology/principal Findings: We genotyped 63 polymorphisms, spread across four polyaminergic genes (SAT1, spermine synthase (SMS), spermine oxidase (SMOX), and ornithine aminotransferase like-1 (OATL1)), in 1255 French-Canadian individuals who have been followed longitudinally for 22 years. We assessed univariate associations with anxiety, mood disorders, and attempted suicide, as assessed during early adulthood. We also investigated the involvement of gene-environment interactions in terms of childhood abuse, and assessed internalizing and externalizing symptoms as endophenotypes mediating these interactions. Overall, each gene was associated with at least one main outcome: anxiety (SAT1, SMS), mood disorders (SAT1, SMOX), and suicide attempts (SAT1, OATL1). Several SAT1 polymorphisms displayed disease-specific risk alleles, and polymorphisms in this gene were involved in gene-gene interactions with SMS to confer risk for anxiety disorders, as well as gene-environment interactions between childhood physical abuse and mood disorders. Externalizing behaviors demonstrated significant mediation with regards to the association between OATL1 and attempted suicide, however there was no evidence that externalizing or internalizing behaviors were appropriate endophenotypes to explain the associations with mood or anxiety disorders. Finally, childhood sexual abuse did not demonstrate mediating influences on any of our outcomes., Conclusions/significance: These results demonstrate that genetic variants in polyaminergic genes are associated with psychiatric conditions, each of which involves a set of separate and distinct risk alleles. As several of these polymorphisms are associated with gene expression, these findings may provide mechanisms to explain the alterations in polyamine metabolism which have been observed in psychiatric disorders.

Alterations in the levels of spermine synthase (SMS) and spermine oxidase (SMOX), two enzymes involved in polyamine metabolism, have previously been observed in brains of suicide completers. To characterize the roles played by genetic and epigenetic factors in determining expression levels of these genes, as well as to identify potential mechanisms by which to explain our findings in suicide completers, we (1) assessed the role of promoter polymorphisms in determining expression in the brain and in vitro, and (2) examined CpG methylation and levels of methylated histone H3 lysine-27 in the promoter regions of these genes in the prefrontal cortex of suicide completers and healthy controls. We identified several promoter haplotypes in SMS and SMOX, but found no consistent effects of haplotype on expression levels in either the brain or in reporter gene assays performed in three different cell lines. We also found no overall effects of epigenetic factors in determining expression, with the exception of a relationship between CpG methylation at one site in the promoter of SMOX and its expression in Brodmann area 8/9. In conclusion, the genetic and epigenetic factors examined in this study show little influence on the expression levels of SMS and SMOX, and do not appear to be responsible for the dysregulated expression of these genes in suicide completers.

Objective: In two related studies, we explored the prevalence of migraine and its associated clinical characteristics in patients with bipolar disorder (BD) as well as psychiatric morbidity in patients treated for migraine., Method: The first study included 323 subjects with BD type I (BD I) or BD type II (BD II), diagnosed using the Schedule for Affective Disorders and Schizophrenia, Lifetime version (SADS-L) format, or the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID). Migraine history was assessed by means of a structured questionnaire. In a second sample of 102 migraine patients, we investigated current and lifetime psychiatric morbidity using the SADS-L. Statistical analyses were conducted using nonparametric analysis and log-linear models., Results: A total of 24.5% of BD patients had comorbid migraine; those with BD II had a higher prevalence (34.8%) compared to BD I (19.1%) (p < 0.005). BD patients with comorbid migraine had significantly higher rates of suicidal behaviour, social phobia, panic disorder, generalized anxiety disorder, and obsessive-compulsive disorder (all p < 0.05). In the sample of migraine patients, 34.3% had a current psychiatric diagnosis, and 73.5% had a lifetime psychiatric diagnosis. The prevalence of BD I was 4.9%, and 7.8% for BD II., Discussion: Migraine is prevalent within the BD population, particularly among BD II subjects. It is associated with an increased risk of suicidal behaviour and comorbid anxiety disorders. Conversely, migraine sufferers have high rates of current and lifetime psychopathology. A greater understanding of this comorbidity may contribute to our knowledge of the underlying mechanisms of BD.

We identified association of restless legs syndrome (RLS) with PTPRD at 9p23-24 in 2,458 affected individuals and 4,749 controls from Germany, Austria, Czechia and Canada. Two independent SNPs in the 5' UTR of splice variants expressed predominantly in the central nervous system showed highly significant P values (rs4626664, P(nominal/lambda corrected) = 5.91 x 10(-10), odds ratio (OR) = 1.44; rs1975197, P(nominal/lambda corrected) = 5.81 x 10(-9), OR = 1.31). This work identifies PTPRD as the fourth genome-wide significant locus for RLS.

Background and Purpose: The neurotensin gene (NTS), a known dopamine modulator, is located within the candidate region for the first genetic locus of restless legs syndrome (RLS1) on chromosome 12q. Though no causative mutation was found in selected patients in a previous mutation analysis, the involvement of NTS in RLS cannot be completely excluded as a potential positional and functional candidate gene. The purpose of the current study is to further explore the NTS gene for potential functional variant(s) in its entire genomic and potential regulatory regions and their possible association with RLS symptoms., Methods and Subjects: We resequenced the coding regions and sequenced all the intronic and potential regulatory regions of the NTS gene in additional patients and controls. We carried out full scale gene-based case-control and family-based genetic association studies using the sequence variants detected during mutational analysis., Results: No coding or variants in regulatory and intronic regions compatible with a deleterious mutation were detected. Seven polymorphisms with elevated allele frequencies in the Caucasian population did not show association with RLS in two independent case-control groups and 110 RLS families., Conclusion: The NTS gene on chromosome 12q is most unlikely to play a direct role in RLS etiology.

Converging evidence from clinical observations, brain imaging and pathological findings strongly indicate impaired brain iron regulation in restless legs syndrome (RLS). Animal models with mutation in (DMT1) divalent metal transporter 1 gene, an important brain iron transporter, demonstrate a similar iron deficiency profile as found in RLS brain. The human DMT1 gene, mapped to chromosome 12q near the RLS1 locus, qualifies as an excellent functional and possible positional candidate for RLS. DMT1 protein levels were assessed in lymphoblastoid cell lines from RLS patients and controls. Linkage analyses were carried out with markers flanking and within the DMT1 gene. Selected patient samples from RLS families with compatible linkage to the RLS1 locus on 12q were fully sequenced in both the coding regions and the long stretches of UTR sequences. Finally, selected sequence variants were further studied in case/control and family-based association tests. A clinical association of anemia and RLS was further confirmed in this study. There was no detectable difference in DMT1 protein levels between RLS patient lymphoblastoid cell lines and normal controls. Non-parametric linkage analyses failed to identify any significant linkage signals within the DMT1 gene region. Sequencing of selected patients did not detect any sequence variant(s) compatible with DMT1 harboring RLS causative mutation(s). Further studies did not find any association between ten SNPs, spanning the whole DMT1 gene region, and RLS affection status. Finally, two DMT1 intronic SNPs showed positive association with RLS in patients with a history of anemia, when compared to RLS patients without anemia., ((c) 2007 Wiley-Liss, Inc.)

Suicide is known to vary according to season, with peaks in the spring and troughs in the winter. The presence of psychopathology is a significant predictor of suicidality, and it is possible that the seasonal variation of suicide completion may be related to seasonality in the manifestation of psychiatric disorders common to suicide completers. In the current study, we evaluated 115 French-Canadian male suicide completers from the Greater Montreal Area for DSM-IV psychiatric disorders using proxy-based diagnostic interviews. Subjects were assessed for seasonal differences in the prevalence of DSM-IV psychiatric diagnoses just before their deaths. Diagnoses of major depressive disorder (MDD) without comorbid cluster B personality disorders, and schizophrenia were differently distributed between seasons. Most (63.4%) subjects with MDD committed suicide in the spring/summer (P =.038). However, closer examination revealed that depressed suicides with comorbid cluster B personality disorders did not show seasonality, while 83.3% of depressed suicides without comorbid cluster B personality disorders committed suicide in the spring/summer (P =.019). 87.5% of those suicides with schizophrenia committed suicide in the fall/winter (P =.026), and the only suicide with schizophrenia who died in the spring/summer was also the only one without positive symptomology. Our study is limited to male suicide completers, and results should not be generalized to women. We conclude that seasonal variation in suicide manifests itself differently in patients with different psychopathology. These findings indicate that assessment of suicide risk may need to include consideration of possible seasonal effects, depending on psychopathology.

A new restless legs syndrome locus on chromosome 14 recently has been reported in one family of Italian origin. Our study aimed to replicate this finding and determine the importance of this locus in the French Canadian population. Markers spanning the region were genotyped in 14 large families and linkage assessed using two-point and multipoint logarithm of odds scores. Possible linkage to this locus was found in one of our kindreds providing support for the existence of this locus and indicating that this locus may be responsible for a small fraction of French Canadian restless legs syndrome.

Restless legs syndrome (RLS) is a neurological disorder characterized by leg paresthesia associated with an irresistible urge to move that often interferes with nocturnal sleep, leading to chronic sleep deprivation. To map genes that may play a role in the vulnerability to RLS, a genomewide scan was conducted in a large French-Canadian family. Significant linkage was established on chromosome 12q, for a series of adjacent microsatellite markers with a maximum two-point LOD score of 3.42 (recombination fraction.05; P=6x10(-4); autosomal recessive mode of inheritance), whereas multipoint linkage calculations yielded a LOD score of 3.59. Haplotype analysis refined the genetic interval, positioning the RLS-predisposing gene in a 14.71-cM region between D12S1044 and D12S78. These findings represent the first mapping of a locus conferring susceptibility to RLS.

In order to examine the genetic substrate of the dopamine hypothesis in restless legs syndrome, we analyzed eight genes coding for receptors and enzymes related to dopaminergic transmission, using a population of 92 patients with restless legs syndrome and 182 controls matched for ethnic background. No significant differences were found in the genotypic or allelic distributions between groups. Furthermore, no effect of the loci examined was observed with stratification using clinical parameters such as age at onset or periodic leg movements during sleep index.