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Background: Unipolar treatment-resistant depression (MDD-TRD) is associated with neurocognitive impairment. Ketamine, an emerging treatment for MDD-TRD, may have neurocognitive benefits, but evidence remains limited., Methods: We conducted a systematic search on EMBASE, Google Scholar, PsycINFO, and PubMed and included studies exploring the cognitive effects of intravenous (IV) ketamine treatment in the management of MDD-TRD following the PRISMA guidelines. We analyzed cognitive scale score changes pre- and post-IV ketamine treatment and the quality of the evidence using the Cochrane risk of bias tool and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE)., Results: Out of 1171 identified studies, fourteen studies were included in this study. Most studies reported positive cognitive outcomes post-ketamine treatment, including improvements in processing speed, working memory, verbal and visual memory, executive function, attention, emotional processing, and auditory verbal episodic memory. Variability existed, with one study reporting negative effects on verbal memory. Overall, studies exhibited a low risk of bias., Limitations: Several limitations impacted the results observed, including confining our scope to articles in English, heterogeneity of the included studies, small sample sizes, and the predominance of a female, Western, and Caucasian population, constraining the generalizability of the findings., Conclusions: IV ketamine treatment shows promise in improving neurocognitive function in MDD-TRD patients. However, further research is warranted to elucidate long-term effects, control for confounders such as concomitant medications, and explore neurocognitive subgroups within the TRD population. These findings underscore the need for comprehensive assessment and management of cognitive symptoms in TRD, informing future clinical practice., Competing Interests: Declaration of competing interest No author or immediate family member has financial relationships with any commercial organization that might appear to represent a potential conflict of interest with the material presented., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Persons with Major Depressive Disorder (MDD), notably treatment-resistant depression (TRD), are differentially affected by type 2 diabetes mellitus and associated morbidity. Ketamine is highly efficacious in the treatment of adults living with MDD, notably TRD. Herein, we sought to determine the effect of ketamine on metabolic parameters in animal stress paradigms and human studies., Methods: We performed a comprehensive search on PubMed, OVID, and Scopus databases for primary research articles from inception to May 5, 2024. Study screening and data extraction were performed by two reviewers (S.W. and G.H.L.). Both preclinical and clinical studies were included in this review., Results: Results from the preclinical studies indicate that in experimental diabetic conditions, ketamine does not disrupt glucose-insulin homeostasis. Within adults with MDD, ketamine is associated with GLUT3 transporter upregulation and differentially affects metabolomic signatures. In adults with TRD, ketamine induces increased brain glucose uptake in the prefrontal cortex. Available evidence suggests that ketamine does not adversely affect metabolic parameters., Limitations: There are a paucity of clinical studies evaluating the effects of ketamine on glucose-insulin homeostasis in adults with MDD., Conclusions: Our results indicate that ketamine is not associated with significant and/or persistent disruptions in metabolic parameters. Available evidence indicates that ketamine does not adversely affect glucose-insulin homeostasis. These results underscore ketamine's efficacy and safety as an antidepressant treatment that is not associated with metabolic disturbances commonly reported with current augmentation therapies., Competing Interests: Declaration of competing interest Roger S. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals,Viatris, Abbvie, Atai Life Sciences. Dr. Roger McIntyre is a CEO of Braxia Scientific Corp. Rodrigo B. Mansur has received research grant support from the Canadian Institute of Health Research; Physicians' Services Incorporated Foundation; the Baszucki Brain Research Fund; and the Academic Scholar Awards, Department of Psychiatry, University of Toronto. Joshua D. Rosenblat has received research grant support from the Canadian Institute of Health Research (CIHR), Physician Services, Inc. (PSI) Foundation, Labatt Brain Health Network, Brain and Cognition Discovery Foundation (BCDF), Canadian Cancer Society, Canadian Psychiatric Association, Academic Scholars Award, American Psychiatric Association, American Society of Psychopharmacology, University of Toronto, University Health Network Center for Mental Health, Joseph M. West Family Memorial Fund, and Timeposters Fellowship and industry funding for speaker/consultation/research fees from iGan, Boehringer Ingelheim, Janssen, Allergan, Lundbeck, Sunovion, Braxia Health, Braxia Scientific Corp., and COMPASS. Kayla M. Teopiz has received fees from Braxia Scientific Corp., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Deep transcranial magnetic stimulation (dTMS) is an Food and Drug Administration-approved treatment for treatment-resistant depression (TRD). Our study aims to examine the impact of baseline insomnia severity on mood outcomes of dTMS and the impact of dTMS on comorbid insomnia in patients with treatment-resistant depression using a retrospective analysis. Twenty-five patients with treatment-resistant depression who underwent dTMS were divided into two groups: "low insomnia" and "high insomnia," depending on Insomnia Severity Index scores at baseline. Significant improvements in depression and anxiety from baseline to final dTMS session were noted in both groups. Baseline insomnia severity was not associated with poorer treatment outcomes after dTMS. Final insomnia scores of the two groups were not significantly different, suggesting dTMS alleviated insomnia symptoms in patients with treatment-resistant depression. Further research incorporating a prospective study design in a multicenter setting is warranted to replicate these findings and elucidate the mechanistic action of dTMS on insomnia outcomes., Citation: Chopra A, Singal P, Kodya S. Impact of deep transcranial magnetic stimulation on insomnia outcomes in patients with treatment-resistant depression: a retrospective study. J Clin Sleep Med . 2024;20(5):813-815., (© 2024 American Academy of Sleep Medicine.)

Objective: Psychomotor retardation is a core clinical component of Major Depressive Disorder responsible for disability and is known as a treatment response marker of biological treatments for depression. Our objective was to describe cognitive and motoric measures changes during a treatment by repetitive Transcranial Magnetic Stimulation (rTMS) within the THETAD-DEP trial for treatment-resistant depression (TRD), and compare those performances at the end of treatment and one month after between responders (>50% improvement on MADRS score), partial responders (25-50%) and non-reponders (no clinically relevant improvement). Our secondary aim was to investigate baseline psychomotor performances associated with non-response and response even partial., Methods: Fifty-four patients with treatment-resistant unipolar depression and treated by either high frequency 10 Hz rTMS or iTBS for 4 weeks (20 sessions) underwent assessment including French Retardation Rating Scale for Depression (ERD), Verbal Fluency test, and Trail Making Test A. before, just after treatment and one month later., Results: 20 patients were responders (R, 21 partial responders (PR) and 13 non-responders (NR). rTMS treatment improved psychomotor performances in the R and PR groups unlike NR patients whose psychomotor performance was not enhanced by treatment. At baseline, participants, later identified as partial responders, showed significantly higher performances than non-responders., Conclusion: Higher cognitivo-motor performances at baseline may be associated with clinical improvement after rTMS treatment. This work highlights the value of objective psychomotor testing for the identification of rTMS responders and partial responders, and thus may be useful for patient selection and protocol individualization such as treatment continuation for early partial responders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Previous studies have found an association between klotho, an anti-aging hormone, and major depressive disorder. However, whether low-dose ketamine infusion alters klotho levels among patients with treatment-resistant depression (TRD) remains unknown., Methods: In total, 48 patients with TRD and strong suicidal ideation were randomly assigned to a single 0.5 mg/kg ketamine or 0.045 mg/kg midazolam regimen and were subjected to a 2-week follow-up. Depressive and suicidal symptoms were assessed before the infusion and during the follow-up. The serum levels of klotho were assessed at baseline and 3 days postinfusion., Results: A generalized linear model with adjustment of baseline klotho levels showed that, despite the fact that ketamine did not significantly increase levels of klotho, patients in the ketamine group had higher levels of klotho at Day 3 postinfusion than patients in the midazolam group (p = 0.043). However, we found no association between changes in klotho levels and changes in depressive and suicidal symptoms (all p > 0.05). Higher klotho levels at baseline were associated with poorer antidepressant effect of low-dose ketamine during postinfusion follow-up., Discussion: Klotho may play a role in the antidepressant effect of low-dose ketamine. Additional molecular studies are necessary to elucidate the neuromechanisms of TRD, ketamine, and klotho., Competing Interests: Declaration of competing interest None of the authors in this study had any conflict of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose/background: Quetiapine is a first-line augmenting agent for treatment-resistant depression (TRD) and is used off-label in insomnia. Quetiapine and its active metabolite norquetiapine act mostly on 5-HT2A, 5-HT2C, H1, and D2 as antagonists and on 5-HT1A as partial agonists. Patients with TRD often have comorbid personality disorder (PD), and evidence suggests an association between sleep disturbance and recovery among patients with PD. Here, we aimed to evaluate the effects of quetiapine on sleep in TRD patients with and without PD (PD+/PD-)., Methods/procedures: We reviewed health records of 38 patients with TRD (20 TRD/PD+) who had been treated with a pharmacotherapy regimen including quetiapine. Clinical outcomes were determined by comparing changes in sleep items of the Hamilton Depression Rating Scale at the beginning (T0) and after 3 months of an unchanged treatment (T3)., Findings/results: Patients with TRD/PD+ and TRD/PD- taking quetiapine showed significant improvement in sleep items from T0 to T3 (P < 0.001, ηp2 ≥ 0.19). There was a significant personality × time interaction for sleep-maintenance insomnia (P = 0.006, ηp2 = 0.23), with TRD/PD+ showing a greater improvement at T3 compared with TRD/PD- (P = 0.01). While exploring other sleep items, no personality × time interaction was found. In the TRD/PD- group, improvement in sleep items was associated with an overall improvement in depressive symptoms (r = 0.55, P = 0.02)., Implications/conclusions: Quetiapine induced greater improvements in sleep-maintenance insomnia among TRD/PD+ patients than TRD/PD-. These findings suggest quetiapine could have a therapeutic role for insomnia in PD underscoring a distinct underlying neurobiological mechanism of sleep disturbance in people living with PD., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: M.A.A. received travel costs and accommodation from Livanova company for attending VNS workshop. The other authors have no conflicts of interest or financial disclosures to report.

Esketamine, the S-enantiomer of ketamine, has recently emerged as a therapy for treatment-resistant depression (TRD), showing both rapid antidepressant action and good efficacy and high safety. It is also indicated for the acute short-term treatment of psychiatric emergency due to major depressive disorder (MDD) and for depressive symptoms in adults with MDD with acute suicidal thoughts/behavior. We here provide preliminary insights on esketamine nasal spray (ESK-NS) effectiveness and safety among patients with a substance use disorder (SUD) within the sample of patients with TRD collected for the observational, retrospective, multicentre REAL-ESK study. Twenty-six subjects were retrospectively selected according to the presence of a SUD in comorbidity. Subjects enrolled completed the three different follow-up phases (T0/baseline, T1/after one month, and T2/after three months) and there were no dropouts. A decrease in Montgomery-Asberg depression rating scale (MADRS) scores was recorded, thus highlighting the antidepressant efficacy of ESK-NS (MADRS decreased from T0 to T1, t = 6.533, df=23, p<0.001, and from T1 to T2, t = 2.029, df=20, p = 0.056). Considering tolerability and safety issues, one or more side effects were reported by 19/26 subjects (73%) after treatment administration. All reported side effects were time-dependent and did not cause significant sequelae; among them, dissociative symptoms (38%) and sedation (26%) were the most frequently reported. Finally, no cases of abuse or misuse of ESK-NS were reported. Despite study limitations related to the inherent nature of the study, a limited number of patients, and a short follow-up period, ESK-NS showed to be effective and safe in patients diagnosed with TRD comorbid with a SUD., Competing Interests: Declaration of Competing Interest Giovanni Martinotti has been a consultant and/or a speaker and/or has received research grants from Angelini, Doc Generici, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Servier, and Recordati. Ileana Andriola was speaker at Janssen-sponsored conferences. Bernardo Dell'Osso has received lecture honoraria from Angelini, Lundbeck, Janssen, Pfizer, Neuraxpharm, Arcapharma, and Livanova. Antonio Vita received grant/research support and speaker/consultant fees from Angelini, Boheringer Ingelheim, Innovapharma, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Recordati, Roche, Rovi Pharma, and Takeda. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Major depression is common in older adults (≥ 60 years of age), termed late-life depression (LLD). Up to 30% of these patients will have treatment-resistant late-life depression (TRLLD), defined as depression that persists despite two adequate antidepressant trials. TRLLD is challenging for clinicians, given several etiological factors (eg, neurocognitive conditions, medical comorbidities, anxiety, and sleep disruption). Proper assessment and management is critical, as individuals with TRLLD often present in medical settings and suffer from cognitive decline and other marks of accelerated aging. This article serves as an evidence-based guide for medical practitioners who encounter TRLLD in their practice., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Borderline personality disorder (BPD) has high rates of comorbidity with mood disorders, including treatment-resistant depression (TRD). Comorbidity of BPD with depression is associated with poorer response to antidepressants. Intravenous ketamine is a novel treatment for TRD that has not been specifically evaluated in patients with comorbid BPD. In this retrospective analysis of data collected from participants who received care at the Canadian Rapid Treatment Centre of Excellence (CRTCE; Braxia Health; ClinicalTrials.gov: NCT04209296), we evaluated the effectiveness of intravenous ketamine in a TRD population with comorbid BPD (N=100; n=50 BPD-positive compared with n=50 BPD-negative). Participants were administered four doses of intravenous ketamine (0.5-0.75mg/kg over 40 minutes) over two weeks. The primary outcome measures were changes in depressive symptom severity (as measured by Quick Inventory of Depressive Symptomatology-Self Report 16-item (QIDS-SR 16 )) and borderline symptom severity (as measured by Borderline Symptom List 23-item (BSL-23)). Both BPD-positive and BPD-negative groups improved significantly on the QIDS-SR 16 , QIDS-SR 16 suicide ideation item, anxiety, and functionality scales with large effect sizes. There was no significant difference between groups. The BPD-positive group exhibited significant reduction of 0.64 on BSL-23 scores and a significant reduction of 5.95 on QIDS-SR 16 scores. Patients with TRD and comorbid BPD receiving ketamine exhibited a significant reduction in symptoms of depression, borderline personality, suicidality, and anxiety., Competing Interests: Declaration of Competing Interest Dr. Joshua D Rosenblat has received research grant support from the Canadian Institute of Health Research (CIHR), Physician Services Inc (PSI) Foundation, Labatt Brain Health Network, Brain and Cognition Discovery Foundation (BCDF), Canadian Cancer Society, Canadian Psychiatric Association, Academic Scholars Award, American Psychiatric Association, American Society of Psychopharmacology, University of Toronto, University Health Network Centre for Mental Health, Joseph M. West Family Memorial Fund and Timeposters Fellowship and industry funding for speaker/consultation/research fees from iGan, Boehringer Ingelheim, Janssen, Allergan, Lundbeck, Sunovion and COMPASS. He is the Chief Medical and Scientific Officer of Braxia Scientific and the medical director of the Canadian Rapid Treatment Centre of Excellence (Braxia Health). Kevin Kratiuk is the Vice President of Operations at Braxia Health and is a shareholder of Braxia Scientific Corp. Dr. Roger McIntyre has received research grant support from Global Alliance for Chronic Diseases/Canadian Institutes of Health Research (CIHR)/National Natural Science Foundation of China's Mental Health Team Grant; speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie. Dr. Roger McIntyre is a CEO of Braxia Scientific Corp. Kayla M. Teopiz has received personal fees from Braxia Scientific Corp. All other authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Tinnitus, a frequent disorder, is the conscious perception of a sound in the absence of a corresponding external acoustic sound source in the sense of a phantom sound. Although the majority of people who perceive a tinnitus sound can cope with it and are only minimaly impaired in their quality of lfe, 2-3% of the population perceive tinnitus as a major problem. Recently it has been proposed that the two groups should be differentiated by distict terms: "Tinnitus" describes the auditory or sensory component, whereas "Tinnitus Disorder" reflects the auditory component and the associated suffering. There is overwhelming evidence that a high tinnitus burden is associated with the increased occurrence of comorbidities, including depression. Since no causal therapeutic options are available for patients with tinnitus at the present time, the identification and adequate treatment of relevant comorbidities is of great importance for the reduction of tinnitus distress. This chapter deals with the relationship between tinnitus and depression. The neuronal mechanisms underlying tinnitus will first be discussed. There will also be an overview about depression and treatment resistant depression (TRD). A comprehensive review about the state-of-the-art evidences of the relationship between tinnitus and TRD will then be provided., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The antidepressant effect of low-dose ketamine infusion on Taiwanese patients with anxious vs nonanxious treatment-resistant depression (ANX-TRD vs NANX-TRD) has remained unknown., Methods: In total, 71 patients with TRD were randomized to three groups. Each group had participants who received saline infusions mixed with 0 (a normal saline infusion), 0.2, and 0.5 mg/kg of ketamine. Participants were followed up for 2 weeks. Anxious depression was defined as major depressive disorder with a total score of 7 or more on the 17-item Hamilton Depression Rating Scale Anxiety-Somatization factor. Generalized estimating equation models were used to investigate the effects of treatment (ketamine vs placebo) and depression type (ANX-TRD vs NANX-TRD) in the reduction of depressive symptoms during the follow-up period., Results: Patients with ANX-TRD were less likely to respond to a single low-dose ketamine infusion than those with NANX-TRD. Among patients with NANX-TRD, low-dose ketamine infusion was significantly superior to placebo for reducing depressive symptoms. However, among patients with ANX-TRD, ketamine was not superior to placebo; nonetheless, approximately 30% of the patients responded to ketamine infusion compared to 13% who responded to the placebo., Conclusions: Low-dose ketamine infusion was effective for Taiwanese patients with NANX-TRD but not so effective for those with ANX-TRD. A higher level of anxiety severity accompanying depression was related to greater depression severity. This may confound and reduce the antidepressant effect of ketamine infusion.

This case report describes successful maintenance treatment with oral S-ketamine in a patient with severe depression, who previously was resistant to electroconvulsive therapy and deep brain stimulation, and who also had comorbid psychotic and obsessive compulsive symptoms., Competing Interests: Competing interests: JKEV received a speaker's honorarium from Janssen, outside the submitted work. RAS has received research funding for two randomised clinical trials with generic oral esketamine from the Netherlands Organisation for Health Research & Development and the National Health Care Institute, a speaker's fee from Janssen and consultancy fee from Clexio Biosciences, both outside the submitted work., (© BMJ Publishing Group Limited 2020. Re-use permitted under CC BY. Published by BMJ.)

Objective: To assess the burden of treatment-resistant depression (TRD) among privately insured patients with anxiety disorder and/or substance use disorders (SUD)., Methods: Adults <65 years old were identified in the Optum Health Care Solutions Inc. database (July 2009-March 2017). Among those with major depressive disorder (MDD) and antidepressant use, patients who initiated a third antidepressant (index date) after two regimens at adequate dose and duration were classified in the TRD cohort and patients without evidence of TRD were classified in the non-TRD MDD control cohort. The non-MDD control cohort comprised patients without MDD. In the non-TRD MDD and non-MDD cohorts, the index date was imputed to mimic the distribution of time in the TRD cohort from the first antidepressant to the index date or from the start of eligibility to the index date, respectively. Patients with <6 months of continuous insurance eligibility pre-/post-index, psychosis, schizophrenia, bipolar disorder and related conditions, dementia, and development disorders, and/or no baseline anxiety disorder and/or SUD were excluded. Patients with TRD were matched 1:1 to patients with non-TRD MDD and patients without MDD, based on exact matching factors (i.e. availability of work loss data) and propensity scores computed based on characteristics measured pre-index. Outcomes, including healthcare resource use (HRU) and costs, work productivity loss and related costs measured per patient per year ≤24 months post-index were compared between matched TRD, non-TRD MDD and non-MDD cohorts., Results: A total of 3166 patients were identified in the TRD cohort and matched to non-TRD MDD and non-MDD cohorts. Among patients with TRD (mean age 39 years, 60.5% female), 87.3% had an anxiety disorder, 24.1% had SUD. The TRD cohort had higher HRU vs non-TRD MDD and non-MDD cohorts: 0.32 vs 0.20 and 0.14 inpatient admissions, 0.91 vs 0.73 and 0.58 emergency department visits, and 23.8 vs 16.8 and 11.6 outpatient visits, respectively (all p  < .01). The TRD cohort had higher healthcare costs ($16,674) vs non-TRD MDD ($10,945) and non-MDD ($6493) cohorts (all p  < .01). Among patients with work loss data ( N  = 310/cohort), patients with TRD had more work loss days (54) and higher work loss-related costs ($13,674) vs patients with non-TRD MDD (32 days; $7131) and without MDD (17 days; $4798; all p  < .01)., Conclusions: In patients with an anxiety disorder and/or SUD, TRD was associated with higher HRU, healthcare costs, work loss days and work loss-related costs.

Purpose/background: Major depressive disorder (MDD) and obesity commonly co-occur. We sought to assess the impact of body mass index (BMI) on the acute antidepressant effects of ketamine in patients with treatment-resistant depression., Methods/procedures: Post hoc analyses were conducted from a multisite, randomized, double-blind, placebo-controlled trial designed to assess the rapid-onset effects of intravenous ketamine. Patients (n = 99) were randomized to a single dose administration of ketamine 0.1 mg/kg (n = 18), ketamine 0.2 mg/kg (n = 20), ketamine 0.5 mg/kg (n = 22), ketamine 1.0 mg/kg (n = 20), or active placebo, midazolam 0.045 mg/kg (n = 19). Patients were stratified for BMI. For patients randomized to ketamine (n = 80), BMI was assessed as a continuous variable and also categorically (obese, overweight, not obese/overweight [reference]). The primary outcome measure was the change on the 6-item Hamilton Depression Rating Scale 24 hours after treatment. Outcomes at day 3 were also assessed., Findings/results: The 6-item Hamilton Depression Rating Scale change scores at 24 hours were inversely associated with BMI (-0.28 ± 0.12, P = 0.02). With BMI operationalized categorically, both obese (-4.15 ± 1.41, P = 0.004) and overweight (-1.99 ± 1.14, P = 0.08) categories were inversely related to the 6-item Hamilton Depression Rating Scale change score at 24 hours, statistically significant for the obese category, as compared with the reference group. Similar but weaker findings were observed at 72 hours after infusion., Implications/conclusions: Higher BMI and obesity were associated with a more robust acute antidepressant response to ketamine. This may have clinical relevance for a great number of patients who have both MDD and obesity., Clinical Trial Registration: NCT01920555.

Study Objectives: Sleep disruption is a significant symptom of major depressive disorder (MDD). To our knowledge, no prior work has examined the impact of repetitive transcranial magnetic stimulation (rTMS) on sleep disturbances in adolescents with MDD., Methods: Seventeen adolescents with treatment-resistant depression received 30 daily sessions of 10-Hz rTMS applied to the left dorsolateral prefrontal cortex (L-DLPFC). Clinical symptoms were assessed at baseline; after 10, 20, and 30 treatments; and at a 6-month follow-up visit. Insomnia was measured with a 3-item subscale of the Quick Inventory of Depressive Symptomatology-Adolescent (17 Item)-Self Report (QIDS-A 17 -SR). Hypersomnia was measured with a single QIDS-A 17 -SR item. Depression severity was rated with the Children's Depression Rating Scale, Revised (CDRS-R). The effect of rTMS on sleep was examined via linear mixed model analyses, with fixed effects of time (as a proxy of treatment), depression severity, age, and hypnotic medication use., Results: No significant main effect of time was observed on the insomnia subscale (F 4,43.442  = 1.078, p = 0 .379). However, there was a significant main effect of time on the QIDS-A 17 -SR hypersomnia score (F 4,46.124  = 2.733, p = 0 .040), with significant improvement from baseline to treatment 10 (p adj  = 0.019) and from baseline to 6-month follow-up (p adj  = 0.044). In exploratory sensitivity analyses, response/nonresponse to rTMS for overall depressive symptoms had no significant effect on sleep outcomes., Conclusions: rTMS may have intrinsic effects on hypersomnia apart from its antidepressant effects in depressed adolescents. Future work should utilize sham controls and objective, quantitative measurements of sleep architecture to assess effects of rTMS in depressed adolescents., Clinical Trial Registry: Clinicaltrials.gov identifiers are NCT00587639, NCT01502033, NCT01804270., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: There is a practical need for the identification of pretreatment clinical and epidemiological response predictors to repeat ketamine infusions. Response predictors can serve to guide clinical inclusion of patients and weigh risks versus benefits for those receiving maintenance ketamine. Previous studies indicate a link between obesity, depression, and treatment response. We sought to investigate if body mass index (BMI) or metabolic syndrome could predict treatment response to ketamine., Methods: Patients aged 18 to 72 years who were electroconvulsive therapy nonresponders were given a subanesthetic ketamine hydrochloride dose of 0.5 mg/kg delivered intravenously for 40 minutes for an acute series of 3 to 6 infusions every other day. If patients reported at least a 50% decrease in depression symptoms after the acute series, they were moved to a maintenance series of infusions, on an individualized basis. To assess if BMI or metabolic syndrome could predict response, logistic regression models were run to analyze initial responders, sustained responders, and nonresponders. Models were adjusted for age, sex, and baseline depression severity., Results: Of the 150 patients analyzed, 56 did not respond to the acute phase, 38 initially responded to the acute phase but relapsed during the maintenance phase, and 56 sustained their response for 1 year. In unadjusted models, BMI was not shown to be a predictor of initial or sustained response. Alternatively, metabolic syndrome defined by a diagnosis of hypertension, hyperglycemia, or hyperlipidemia was determined to be significantly associated with diminished initial response but not sustained response., Conclusions: In our patient group, results support the literature that outcome in antidepressant therapy is affected by the presence of metabolic syndrome rather than obesity itself. Although BMI did not predict initial response to ketamine, the presence of metabolic syndrome was significantly negatively associated with the initial response to an acute series of ketamine infusions.

Background: Recent studies have suggested that neurocognition is changed after repeated infusions of ketamine in patients with treatment-resistant depression (TRD). The objective of this study was to investigate whether differences existed in the neurocognitive effect of six ketamine infusions in patients with anxious and nonanxious TRD and to determine the association between baseline neurocognition and changes in symptoms after the infusions., Method: Patients with anxious (n = 30) and nonanxious TRD (n = 20) received six intravenous infusions of ketamine (0.5 mg/kg over 40 min) over 12 days. Speed of processing (SOP), working memory (WM), verbal learning and memory (VBM), visual learning and memory (VSM) and the severity of depressive and anxious symptoms were assessed at baseline, one day after the last infusion (day 13) and two weeks after the completion of the serial infusions (day 26). A linear mixed model was used to determine whether the neurocognitive changes differed between the two groups. Pearson correlation analysis was used to determine the relationship between baseline neurocognition and the changes in the symptomatic scores., Results: Patients with anxious TRD had significant increases in SOP on day 13 and day 26 (both p < 0.001), and in VBM on day 13 (p = 0.028). However, no significant increase in any neurocognitive domain was found in patients with nonanxious TRD. Faster SOP at baseline was associated with greater improvement of anxious symptoms in patients with anxious TRD, and better VSM at baseline was associated with greater improvement of depressive symptoms in patients with nonanxious TRD., Limitation: The major limitation of this study is the open-label design., Conclusion: After six ketamine infusions, neurocognitive improvement was observed in patients with anxious TRD but not in patients with nonanxious TRD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Repetitive transcranial magnetic stimulation (rTMS) has demonstrated antidepressant efficacy but has limited evidence in depression associated with traumatic brain injury (TBI). Here, we investigate the use of rTMS targeted with individualized resting-state network mapping (RSNM) of dorsal attention network (DAN) and default mode network (DMN) in subjects with treatment-resistant depression associated with concussive or moderate TBI. The planned sample size was 50 with first interim analysis planned at 20, but only 15 were enrolled before the study was terminated for logistical reasons. Subjects were randomized to 20 sessions of bilateral rTMS (4000 left-sided excitatory pulses, 1000 right-sided inhibitory pulses) or sham. Treatment was targeted to the dorsolateral prefrontal cluster with maximal difference between DAN and DMN correlations based on resting-state functional magnetic resonance imaging with individualized RSNM. Mean improvement in the primary outcome, Montgomery-Asberg Depression Rating Scale (MADRS), was 56% ± 14% (n = 9) with active treatment and 27% ± 25% (n = 5) with sham (Cohen's d = 1.43). One subject randomized to sham withdrew before starting treatment. There were no seizures or other significant adverse events. MADRS improvement was inversely correlated with functional connectivity between the right-sided stimulation site and the subgenual anterior cingulate cortex (sgACC; r = -0.68, 95% confidence interval 0.03-0.925). Active treatment led to increased sgACC-DMN connectivity (d = 1.55) and increased sgACC anti-correlation with the left- and right-sided stimulation sites (d = -1.26 and -0.69, respectively). This pilot study provides evidence that RSNM-targeted rTMS is feasible in TBI patients with depression. Given the dearth of existing evidence-based treatments for depression in this patient population, these preliminarily encouraging results indicate that larger controlled trials are warranted.

About 20 to 30 percent of patients with Major Depressive Disorder (MDD) do not respond to standard treatment and are considered treatment-resistant. The N-methyl-d-aspartate (NMDA) glutamate receptor antagonist ketamine has demonstrated rapid antidepressant effects in treatment-resistant MDD, but it is unknown whether its acute psychological effects are related to the later antidepressant effect. Therefore, we investigated the association between antidepressant responses to ketamine and the quality of ketamine-induced psychological experiences in MDD. A total of 31 patients (M = 49.5 ± 11.2 years, 16 women) were treated with three ketamine infusions per week (0.5 mg/ kg over 40 min) administered for two consecutive weeks. Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline, after four and 24 h and at end of treatment. The 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC) was applied four hours after the first infusion to assess the subjective quality of acute psychological effects. Patients with a ≥ 50% MADRS reduction from baseline to end of treatment were considered as responders. After six infusions, 17 of 31 patients (55%) showed a response to ketamine treatment, while 14 patients (45%) had no response. Anxiety-related experiences induced by ketamine were significantly higher in non-responders. Percentage MADRS reduction after four hours and individual levels of ketamine-induced anxiety were predictive of a response at end of treatment. The study demonstrated the considerable impact of ketamine-induced anxiety on the antidepressant efficacy of ketamine. It underpins the importance of considering patients' subjective experiences and underlines the possibility of a phenotypic response predictor., (Copyright © 2019. Published by Elsevier B.V.)

Objective: To examine the effect of high baseline anxiety on response to ketamine versus midazolam (active placebo) in treatment-resistant depression (TRD)., Methods: In a multisite, double-blind, placebo-controlled trial, 99 subjects with TRD were randomized to one of five arms: a single dose of intravenous ketamine 0.1, 0.2, 0.5, 1.0 mg/kg, or midazolam 0.045 mg/kg. The primary outcome measure was change in the six-item Hamilton Rating Scale for Depression (HAMD6). A linear mixed effects model was used to examine the effect of anxious depression baseline status (defined by a Hamilton Depression Rating Scale Anxiety-Somatization score ≥7) on response to ketamine versus midazolam at 1 and 3 days postinfusion., Results: N = 45 subjects had anxious TRD, compared to N = 54 subjects without high anxiety at baseline. No statistically significant interaction effect was found between treatment group assignment (combined ketamine treatment groups versus midazolam) and anxious/nonanxious status on HAMD6 score at either days 1 or 3 postinfusion (Day 1: F(1, 84) = 0.02, P = 0.88; Day 3: F(1, 82) = 0.12, P = 0.73)., Conclusion: In contrast with what is observed with traditional antidepressants, response to ketamine may be similar in both anxious and nonanxious TRD subjects. These pilot results suggest the potential utility of ketamine in the treatment of anxious TRD., (© 2018 Wiley Periodicals, Inc.)

Background: Several studies indicate that ketamine has rapid antidepressant effects in patients with treatment-resistant depression (TRD). The extent to which repeated doses of ketamine (versus placebo) reduce depression in the short and long term among outpatients with TRD and chronic, current suicidal ideation remains unknown., Methods: Twenty-six medicated outpatients with severe major depressive disorder with current, chronic suicidal ideation were randomized in a double-blind fashion to six ketamine infusions (0.5 mg/kg over 45 minutes) or saline placebo over three weeks. Depression and suicidal ideation were assessed at baseline, 240 min post-infusion, and during a three-month follow-up phase., Results: During the infusion phase, there was no differences in depression severity or suicidal ideation between placebo and ketamine (p = 0.47 and p = 0.32, respectively). At the end of the infusion phase, two patients in the ketamine group and one in the placebo group met criteria for remission of depression. At three-month follow-up, two patients in each group met criteria for remission from depression., Limitations: Limitations include the small sample size, uncontrolled outpatient medication regimens, and restriction to outpatients, which may have resulted in lower levels of suicidal ideation than would be seen in emergency or inpatient settings., Conclusions: Repeated, non-escalating doses of ketamine did not outperform placebo in this double-blind, placebo controlled study of patients with severe TRD and current, chronic suicidal ideation. This result may support our previously published open-label data that, in this severely and chronically ill outpatient population, the commonly used dose of 0.5 mg/kg is not sufficient., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Inpatient psychotherapy might trigger adverse effects among others due to short but intensive treatment. Thus, in this pilot study, certain adverse effects of the multidisciplinary inpatient Cognitive Behavioral Analysis System of Psychotherapy (CBASP) for treatment-resistant chronically depressed patients as well as their relationship to treatment outcome (response-, remission-, and relapse-rates) are examined., Material and Methods: 50 patients with treatment-resistant and chronic depression completed the structured 12-weeks inpatient treatment program. Adverse effects were assessed by 1) deterioration of depressive symptoms (measured by the Hamilton Depression Rating Scale, HDRS) at discharge and 2) a self-report questionnaire measuring Adverse Effects of Inpatient Psychotherapy (ADEFIP), which were filled out 6 to 12 months after discharge by the patients., Results: After 12 weeks of treatment, 84% could be classified as responder, of whom 44% fulfilled the remission criterion. 16% were Non-Responder. According to HDRS, none of the patients showed objective deterioration of the depressive symptoms. Six months after discharge, 40% of the responders suffered from relapse. Concerning the ADEFIP, 66% of the patients reported transient deterioration of symptoms. These patients were less likely to achieve remission. Over 50% reported interpersonal conflicts with treatment team members or other patients without any relation to outcome. Finally, more than half of the patients reported significant changes in social relationships after discharge. These patients were less likely to relapse. Overall, 94% of the patients reported at least one of the in this study assessed adverse effects., Conclusions: Despite some limitations, this pilot study suggests that the CBASP inpatient program could indeed cause adverse effects. However, only subjective transient deterioration appeared to have a negative impact on the individual treatment outcome in the short-term. Results encourage further research concerning adverse treatment effects in the context of short- and long-term treatment outcome investigating how relevant adverse effects are., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: One third of patients with major depressive disorder (MDD) fail to respond to currently available antidepressant medications. Inflammation may contribute to treatment non-response through effects on neurotransmitter systems relevant to antidepressant efficacy. In post-hoc analyses, increased concentrations of inflammatory markers prior to treatment predict poor antidepressant response. However, limited data exists on whether depressed patients with multiple failed treatment trials in their current episode of depression exhibit increased inflammation., Methods: Plasma concentrations of inflammatory markers were measured in unmedicated, medically stable patients with MDD (n = 98) and varying numbers of adequate antidepressant treatment trials in the current depressive episode as measured by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire. Covariates including age, sex, race, education, body mass index (BMI) and severity of depression were included in statistical models where indicated., Results: A significant relationship was found between number of failed treatment trials and tumor necrosis factor (TNF), soluble TNF receptor 2 (sTNF-R2) and interleukin (IL)-6 (all p < 0.05 in multivariate analyses). Post hoc pairwise comparisons with correction for multiple testing revealed that patients with 3 or more failed trials in the current episode had significantly higher plasma TNF, sTNF-R2 and IL-6 compared to individuals with 0 or 1 trial (all p < 0.05). High sensitivity c-reactive protein was also associated with a greater number of treatment failures, but only in models with BMI excluded., Conclusions: Measuring inflammatory markers and targeting inflammation or its downstream mediators may be relevant for depressed patients with multiple failed antidepressant treatment trials in their current depressive episode., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Augmentation with aripiprazole is an effective pharmacotherapy for treatment-resistant late-life depression (LLD). However, aripiprazole can cause extrapyramidal symptoms (EPS) such as akathisia and parkinsonism; these symptoms are distressing and can contribute to treatment discontinuation. We investigated the clinical trajectories and predictors of akathisia and parkinsonism in older patients receiving aripiprazole augmentation for treatment-resistant LLD., Methods: Between 2009 and 2013, depressed older adults who did not remit with venlafaxine were randomized to aripiprazole or placebo in a 12-week trial. Participants were 60 years or older and met DSM-IV-TR criteria for major depressive episode with at least moderate symptoms. The presence of akathisia and parkinsonism was measured at each visit using the Barnes Akathisia Scale (BAS) and Simpson-Angus Scale (SAS), respectively. In an exploratory analysis, we examined a broad set of potential clinical predictors and correlates: age, sex, ethnicity, weight, medical comorbidity, baseline anxiety severity, depression severity, concomitant medications including rescue medications, and aripiprazole dosage., Results: Twenty-four (26.7%) of 90 participants randomized to aripiprazole and who had akathisia scores available developed akathisia compared to 11 (12.2%) of 90 randomized to placebo. Greater depression severity was the main predictor of treatment-emergent akathisia. Most participants who developed akathisia improved over time, especially with reductions in dosage. Fifteen (16.5%) of 91 participants taking aripiprazole and who had parkinsonism scores available developed parkinsonism, but no clinical predictors or correlates were identified., Conclusions: Akathisia is a common side effect of aripiprazole, but it is typically mild and responds to dose reduction. Patients with greater baseline depression may warrant closer monitoring for akathisia. More research is needed to understand the course and predictors of treatment-emergent EPS with antipsychotic augmentation for treatment-resistant LLD., Trial Registration: ClinicalTrials.gov identifier: NCT00892047., (© Copyright 2018 Physicians Postgraduate Press, Inc.)

Introduction: Pharmacotherapy for the treatment of depressive disorders in Alzheimer's Disease (AD) represents a clinical challenge. pharmacological options are often attempted after a period of watchful waiting (8-12 weeks). monoaminergic antidepressant drugs have shown only modest or null clinical benefits, maybe because the etiology of depressive symptoms in ad patients is fundamentally different from that of nondemented subjects., Areas Covered: The following article looks at the selective serotonin reuptake inhibitor sertraline, which is one of the most frequently studied antidepressant medications in randomized controlled trials (RCTs). It also discusses many other pharmacological approaches that have proven to be inadequate (antipsychotics, acetylcholinesterase inhibitors, anticonvulsants, hormone replacement therapy) and new drug classes (mainly affecting glutamate transmission) that are being studied for treating depression in AD. It also gives discussion to the phase II RCT on the alternative drug S47445 and the potential effect on cognition of the multimodal antidepressant vortioxetine in older depressed patients. Finally, it discusses the N-methyl-D-aspartate antagonist ketamine., Expert Opinion: The present RCT methodologies are too disparate to draw firm conclusions. Future studies are required to identify effective and multimodal pharmacological treatments that efficiently treat depression in AD. Genotyping may boost antidepressant treatment success.

Objective: Sleep disturbances are common in late life depression; however, changes in insomnia symptoms during antidepressant treatment need to be characterized further. The objective of this study was two-fold: 1) to describe longitudinal trajectories of insomnia symptoms in older adults receiving antidepressant treatment and 2) to examine whether baseline depressive symptoms were associated with trajectories of sleep over time., Methods: Data was obtained from 680 older adults (aged ≥ 60) with major depression who participated in one of two protocolized open-label antidepressant treatment clinical trials (Maintenance Therapies in Late Life Depression [MTLD-3]; Incomplete Response in Late Life Depression: Getting to Remission [IRL-GRey]). Depression (total score minus sleep items) and sleep (sum of sleep items) outcomes were derived from the Hamilton Depression Rating Scale in the MLTD-3 and Montgomery-Asberg Depression Rating Scale in the IRL-GRey., Results: Both datasets identified 5 possible trajectories of insomnia symptoms with about half of the older adults having clinically significant baseline sleep disturbances and minimal improvement following a course of antidepressant treatment (i.e., sub-optimal sleep trajectory). Furthermore, across both datasets, worse baseline depression severity was associated with sub-optimal sleep trajectories., Conclusion: In older adults receiving antidepressant treatment, those with clinically significant baseline sleep disturbances and greater depression severity may require adjunctive sleep-focused treatment to ameliorate sleep symptoms., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Your patients taking antipsychotics may be at risk for developing tardive dyskinesia. In this Case and Comment activity, follow Martha, a 60-year-old woman being treated with an antipsychotic medication for her treatment-resistant depression., (© Copyright 2018 Physicians Postgraduate Press, Inc.)

Background: The relationship between severe inflammation and clinical depression in the context of major medical illnesses has been addressed, but the relationship between inflammation caused by mild infections and clinical depression is unclear. We aimed to examine whether a history of repeated low-grade infections (RLGI) in medically healthy subjects (MHS) could increase their vulnerability to major depressive disorder (MDD) (ICD-9-CM) and whether RLGI could be associated with higher resistance to antidepressants in those developing MDD., Method: A nationwide, population-based cohort study (January 1996 to December 2011) was conducted for MHS with and without a history of RLGI. The rates of MDD during an up to 8-year follow-up period were compared between the 2 groups in 2 independent cohorts. The stratified responses to adequate antidepressant trials, including easy-to-treat (ETT) and difficult-to-treat (DTT) responses, were also compared in the MDD patients., Results: During the follow-up, the 2 cohorts consistently revealed that the RLGI(+) (ie, high-inflammation; n = 727) group had a significantly higher chance of developing MDD over time than the RLGI(-) (ie, low-inflammation; n = 443) group: Cox proportional hazards regression models showed that the hazard ratio associated with a history of RLGI was 1.369 to 1.911 (P < .001), after adjusting for confounding factors. The RLGI(+) group was consistently associated with a higher likelihood of DTT responses than was the RLGI(-) group (Cohort-2002: 11.5% vs 7.6%; Cohort-2004: 11.8% vs 4.3%; P < .05 by Wald χ² tests in both cohorts)., Conclusions: This is the first large-scale retrospective cohort study to report a reliable temporal association between a history of RLGI and subsequent diagnosis of MDD and poor responses to antidepressants in 2 independent cohorts. Our data support the view that repeated mild infections play a role in the pathophysiology of MDD and antidepressant-resistant depression., (© Copyright 2017 Physicians Postgraduate Press, Inc.)

We previously found that electrical stimulation in the anterior limb of the internal capsule/bed nucleus of the stria terminalis (IC/BST) alleviates depressive symptoms in severe treatment-resistant obsessive-compulsive disorder (OCD) patients. Here we tested the hypothesis that electrical stimulation in either IC/BST or in the inferior thalamic peduncle (ITP) effectively reduces depressive symptoms in treatment-resistant major depressive disorder (TRD). In a double-blind crossover design, the effects of electrical stimulation at both targets were compared in TRD patients. The 17-item Hamilton Depression Rating scale (HAM-D) was the primary outcome measure. During the first crossover, patients received IC/BST stimulation versus no stimulation in random order (2 × 1 weeks). During the second crossover (3 × 2 months), patients received IC/BST versus ITP versus no stimulation. Patients and evaluators were blinded for stimulation conditions. All patients (n=7) were followed up for at least 3 years (3-8 years) after implantation. Six patients completed the first crossover and five patients completed the second. During the first crossover, mean (s.d.) HAM-D scores were 21.5 (2.7) for no stimulation and 11.5 (8.8) for IC/BST stimulation. During the second crossover, HAM-D scores were 15.4 (7.5) for no stimulation, 7.6 (3.8) for IC/BST stimulation and 11.2 (7.5) for ITP stimulation. The final sample size was too small to statistically analyze this second crossover. At last follow-up, only one patient preferred ITP over IC/BST stimulation. Two patients, with a history of suicide attempts before implantation, committed suicide during the follow-up phases of this study. Our data indicate that, in the long term, both ITP and IC/BST stimulation may alleviate depressive symptoms in patients suffering from TRD.

Background: Preliminary studies report no negative and a possible positive impact of deep brain stimulation (DBS) on cognition of patients with treatment-resistant depression (TRD). However, these studies neither controlled for practice effects nor compared active with sham stimulation., Method: To address these limitations, we compared 25 TRD patients, who underwent DBS of the ventral anterior limb of the internal capsule (vALIC), with 21 healthy controls (HCs) matched on gender, age and education level. Both groups did subtests of the Cambridge Neuropsychological Test Automated Battery assessing verbal and visuospatial memory, attention, cognitive flexibility, psychomotor functioning, planning and object naming. TRD patients were tested 3 weeks prior to DBS surgery (baseline), 3 weeks following surgery (T1) and following 52 weeks of DBS optimization (T2). HCs were tested at baseline, 6 weeks following baseline (T1) and 20-24 weeks following baseline (T2). Subsequently, TRD patients entered a randomized, double-blind crossover phase, in which they were tested in an active and a sham stimulation phase., Results: TRD patients did not improve on a test of immediate verbal recognition from baseline to T1, whereas HCs did (group x time: p = 0.001). Both TRD patients and HCs improved over sessions on tests measuring delayed verbal recall, visuospatial memory, planning and object naming (all p < 0.01). Active and sham stimulation did not have an impact on any of the tests differentially., Conclusions: vALIC DBS neither has a lasting positive nor negative impact on cognition in TRD patients. DBS surgery might have a temporary negative effect on verbal memory.

Background: The present study was conducted to examine the hypothesis based on our previous studies, that the multiple diagnoses of comorbid anxiety disorders (ADs) and higher interpersonal sensitivity predict treatment-resistant depression (TRD)., Methods: The participants were 199 consecutive outpatients with major depressive disorder (MDD), who were comprehensively diagnosed using the Mini International Neuropsychiatric Interview (MINI). TRD was defined as the failure to achieve remission with two or more adequate antidepressant trials. Using multiple logistic regression, the clinical features including the number of comorbid ADs and the Interpersonal Sensitivity Measure (IPSM) score of the TRD group (N=31) were compared with those of the remission group (N=123)., Results: Comorbid ADs (odds ratio (OR), 4.5), higher IPSM score (OR, 4.1), suicidal risk (OR, 3.9), and non-melancholic features (OR, 3.3) were identified as the most discriminative variables associated with TRD. All the participants with two or more comorbid ADs (N=12) belonged to the TRD group., Conclusion: The results showed that the multiple diagnoses of comorbid ADs and higher interpersonal sensitivity were associated with TRD, suggesting that considering the concept of MDD with "anxious distress," which appears in DSM-5, may be useful for managing TRD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Cognitive dysfunction in major depressive disorder (MDD) is identified as a primary therapeutic target; no current treatment is approved for the treatment of cognitive dysfunction in MDD. We examined whether intranasal insulin offered a beneficial effect across measures of cognitive function in adults with MDD., Methods: Thirty-five adults (18-65 years of age: 47.09±9.89) meeting criteria for a major depressive episode as per the Diagnostic and Statistical Manual (DSM)-IV-Treatment Revised were included in this randomized, double blind, placebo-controlled, crossover design study. Subjects were not stratified based on baseline cognitive deficit. Subjects were randomized to 4 weeks of either intranasal insulin 40 International Units (IU) taken four times a day (i.e., morning, afternoon, evening, and before bed) (QID) (n=19) or placebo (n=16)., Results: No between group differences were observed in change from baseline on total Montgomery Åsberg Depression Rating Scale (MADRS) score (25.98±2.81), in either of the Positive or Negative subscales of the Positive and Negative Affect Schedule (PANAS), or on a global index of neurocognition. The possibility of practice and/or carry over effect could not be excluded. Methodological refinement (e.g., stratification of subjects based on baseline cognitive deficit) may have augmented assay sensitivity., Conclusion: Intranasal insulin did not demonstrate statistically significant improvements on overall mood, aspects of emotional processing, neurocognitive function, or self-reported quality of life patient reported outcomes., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Disturbed sleep may confer risk for suicidal behaviors. Polysomnographic (PSG) sleep parameters have not been systematically evaluated in association with suicidal ideation (SI) among individuals with treatment-resistant depression (TRD)., Methods: This secondary data analysis included 54 TRD individuals (N=30 with major depressive disorder (MDD) and N=24 with bipolar depression (BD)). PSG sleep parameters included Sleep Efficiency (SE), Total Sleep Time (TST), Wakefulness After Sleep Onset (WASO), REM percent/latency, and non-REM (NREM) Sleep Stages 1-4. The Hamilton Depression Rating Scale (HAM-D) was used to group participants according to presence or absence of SI. Sleep abnormalities were hypothesized among those with current SI. ANOVA analyses were conducted before (Model 1) and after adjusting for depression (Model 2) and diagnostic variables (Model 3)., Results: Significant differences in PSG parameters were observed in Model 1; those with SI had less NREM Stage 4 sleep (p<.05). After adjusting for central covariates, Models 2 and 3 revealed significantly less NREM Stage 4 sleep, lower SE (P<.05), and higher WASO (P<.05) among those with SI. BD participants with SI also had less NREM Stage 4 and more NREM Stage 1 sleep., Limitations: 1) a predominantly white sample; 2) exclusion of imminent suicide risk; 3) concomitant mood stabilizer use among BD patients; and 4) single-item SI assessment., Conclusions: Independent of depression severity, SI was associated with less NREM Stage 4 sleep, and higher nocturnal wakefulness across diagnostic groups. Sleep may warrant further investigation in the pathogenesis of suicide risk, particularly in TRD, where risk may be heightened., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Obstructive sleep apnea (OSA) is frequently comorbid with late-life depression. The purpose of this project was to determine, using a sample of older adults with major depressive disorder, whether patient-reported diagnosis of OSA was associated with rate of response to venlafaxine., Methods: Participants from this multisite study were adults ≥60 years old (n = 468) with major depressive disorder and a Montgomery Asberg Depression Rating Scale (MADRS) score of ≥15. Depression response was the outcome variable, defined as a MADRS score of ≤10 for two consecutive assessments at the end of 12 weeks of open-label treatment with venlafaxine 300 mg/day. To assess OSA, participants were asked if they had been diagnosed with OSA using polysomnography., Results: Eighty participants (17.1%) reported a diagnosis of OSA prior to baseline. Participants with OSA were more likely to be male, report greater impairment on measures of health, experience a longer duration of the index episode, and receive an adequate antidepressant trial prior to entering the study. During the 12 weeks of treatment, 40.8% responded to treatment with venlafaxine (43.6%, n = 169/388 of the no OSA group, and 27.5%, n = 22/80 of the OSA group). Participants without OSA were 1.79 times more likely to respond to treatment (HR: 1.79 [95%CI: 1.13-2.86], P < .05) compared to those with OSA., Conclusions: OSA may impair response to antidepressant pharmacotherapy in depressed older adults. Future studies of antidepressant response rates among depressed older adults with OSA should both prospectively diagnose OSA and monitor adherence to treatments such as continuous positive airway pressure., (© 2016 Wiley Periodicals, Inc.)