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Background We examined the cross-sectional and longitudinal relationships of motor functions with depression in older adults with type 2 diabetes (T2D). Methods Participants (n = 984) were from the longitudinal Israel Diabetes and Cognitive Decline (IDCD) study. They were initially cognitively normal and underwent evaluations of motor functions (grip strength and gait speed) and of depression (using the 15-item version of the Geriatric Depression Scale [GDS]) approximately every 18 months. We applied Hierarchical Linear Mixed Models (HLMM) to investigate the associations between motor functions and depression adjusting for sociodemographic, cardiovascular factors, overall cognitive score, and subjective report of exhaustion. Results Participants’ baseline characteristics were 72 (±5) years of age (59.6% males), 13 (±4) years of education, Mini-Mental Status Exam (MMSE) score of 28.01 (±1.78), and a GDS score of (2 ± 2.00), consistent with normal cognitive status and lack of major affective symptomatology. Slower gait speed at baseline was associated with higher GDS scores (p = .001) and with their increase over time (p = .049). A decrease in walking speed from baseline was associated with an increase in GDS scores (p = .015). Lower grip strength at baseline was associated with higher GDS scores (p = .002), but not with trajectories in GDS scores over time. A faster decrease in grip strength from baseline was associated with a faster increase in GDS scores (p = .022). Conclusions Both gait speed and grip strength are cross-sectionally associated with depression. However, only gait speed and its decrease over time can potentially be used to predict incident depression symptoms, thus facilitating the introduction of depression prevention strategies.

Understanding the relationship between different depression presentations and cognitive outcome may elucidate high-risk sub-groups for cognitive decline.In this study we utilized longitudinal data from the National Alzheimer's Coordinating Center (NACC) on 16,743 initially not demented older adults followed every 12 months for an average of 5 years. Depression dimensions were defined based on the 15-item Geriatric Depression Scale (GDS-15), that is, dysphoric mood, Withdrawal-Apathy-Vigor (WAV), anxiety, hopelessness, and subjective memory complaint (SMC).After adjustment for sociodemographic and clinical covariates, SMC and hopelessness were associated with faster decline in global cognition and all cognitive domains and WAV with decline executive function. Dysphoric mood and anxiety were not associated with a faster cognitive decline in any of the cognitive domains.Different depression dimensions had different associations with the rate of cognitive decline, suggesting distinct pathophysiology and the need for more targeted interventions.

Backgrounds The efficacy of vitamin E in prevention of diabetes-related complications differs by Haptoglobin (Hp) genotype. Objective To examine the role of Hp genotype in the relationship of vitamin E intake with brain volume in cognitively normal elderly patients with type 2 diabetes. Methods Brain volumes for the superior, middle, and inferior frontal gyri and for the middle temporal gyrus were generated from structural T1 MRI in 181 study participants (Hp 1-1: n = 24, Hp 2-1: n = 77, Hp 2-2: n = 80). Daily vitamin E intake was assessed using the Food Frequency Questionnaire. Analyses of covariance, controlling for demographic and cardiovascular variables was used to evaluate whether the association of daily vitamin E intake with brain volume was modified by Hp genotype. Results Average age was 70.8 (SD = 4.2) with 40% females, and mean Mini-Mental State Examination score of 28.17 (SD = 1.90). A significant interaction was found between vitamin E intake and Hp genotype in inferior frontal gyrus' volume; p = 0.0108. For every 1 microgram increase in vitamin E intake, the volume of the inferior frontal gyrus decreased by 0.955% for Hp 1-1 (p = 0.0348), increased by 0.429% for Hp 2-1 (p = 0.0457), and by 0.077% for Hp 2-2 (p = 0.6318). There were no significant interactions between vitamin E intake and Hp genotype for the middle (p = 0.6011) and superior (p = 0.2025) frontal gyri or for the middle temporal gyrus (p = 0.503). Conclusions The effect of dietary vitamin E on the brain may differ by Hp genotype. Studies examining the impact of vitamin E on brain-related outcomes should consider Hp genotype.

Improving Mood Promoting Access to Collaborative Treatment (IMPACT) is a well-established model for the treatment of depression in primary care. The COVID pandemic has caused increased distress and depression among the older patients in our New York City geriatric practice. This paper describes the establishment of a virtual IMPACT model during the pandemic in which IMPACT services have been provided via telephone. This effort was a multidisciplinary collaboration among geriatric medicine, geriatric psychiatry, social work, and geropsychology. Our IMPACT program uses a brief form of Interpersonal Psychotherapy (IPT) for depression as the psychosocial component instead of Problem Solving Treatment. Delivery of IMPACT by telephone appears to have enhanced engagement and sustained involvement in the program compared with prior efforts to deliver it by in-person meetings. IPT as a psychosocial modality was well-received by patients. To date, treatment outcomes have been favorable and will be reported in this presentation.

OBJECTIVE: Depression and cognitive impairment are highly prevalent in type 2 diabetes (T2D) yet little is known about how their relationship varies by sex. DESIGN: Population-based cross-sectional study. SETTING: Community. PARTICIPANTS: Eight hundred and ninety seven non-demented elderly with type 2 diabetes aged ≥ 65 participating in the Israel Diabetes and Cognitive Decline (IDCD) Study. MEASUREMENTS: Cognition was evaluated by a comprehensive neuropsychological battery and depressive symptoms were assessed by the Geriatric Depression Scale (GDS). RESULTS: In all but the executive function domain, the association of depressive symptoms with poorer cognitive function was stronger in women than men, with a significant interaction for language/semantic categorization and missed significance for episodic memory. Using a cutoff of GDS≥ 6 for clinical depression, women with depression had significantly poorer language/semantic categorization, memory and overall cognitive function. Inclusion of anti-depressants in the model did not alter substantively the associations. CONCLUSION: Our results suggest that depressed T2D women may have poorer cognitive performance, highlighting the significance of sex-specific personalized management of depression in elderly diabetics.

Objectives The APOE-e4 genotype has been associated with old-age depression, but this relationship has been rarely investigated in type 2 diabetes (T2D) older adults, who are at significantly increased risk for depression, a major contributor to T2D complications. We examined whether trajectories of depression symptoms over time differ by APOE-e4 genotype in older adults with T2D. Methods Participants [n=754 (13.1% APOE-e4 carriers)] were from the longitudinal Israel Diabetes and Cognitive Decline (IDCD) study. They were initially cognitively normal and underwent evaluations of depression approximately every 18 months using the 15-item version of the Geriatric Depression Scale (GDS) and the depression subscale of the Neuropsychiatric Inventory (NPI). APOE was defined as a dichotomy of e4 carriers and non-carriers. We used Hierarchical Linear Mixed Models (HLMM) that modeled the effects of APOE status on repeated GDS and NPI-depression scores in an unadjusted model (Model 1), adjusting for demographic factors (Model 2) and additionally adjusting for cardiovascular factors and global cognition (Model 3). Results Participants' mean age was 71.37 (SD=4.5); 38.2% female. In comparison to non-carriers, APOE-e4 carriers had lower mean GDS scores (β=-0.46, p=0.018) and lower NPI-depression scores (β=-0.170, p=0.038) throughout all study follow period. The groups did not differ in the slope of change over time in GDS (β=-0.005, p=0.252) or NPI-depression (β=-0.001, p=0.994) scores. Additional adjustment for cardiovascular factors and global cognition did not alter these results. Conclusions In older adults with T2D, APOE-e4 carriers have less depressive symptoms in successive measurements suggesting they may be less susceptible to depression. This article is protected by copyright. All rights reserved.

OBJECTIVE Depression is highly frequent in older adults with type 2 diabetes and is associated with cognitive impairment, yet little is known about how various depression dimensions differentially affect cognition. We investigated longitudinal associations of specific depression dimensions with cognitive decline. RESEARCH DESIGN AND METHODS Participants (N = 1,002) were from the Israel Diabetes and Cognitive Decline study, were ≥65 years of age, had type 2 diabetes, and were not experiencing dementia at baseline. Participants underwent a comprehensive neuropsychological battery at baseline and every 18 months thereafter, including domains of episodic memory, attention/working memory, semantic categorization/language, and executive function, and Z-scores of each domain were averaged and further normalized to calculate global cognition. Depression items from the 15-item Geriatric Depression Scale were measured at each visit and subcategorized into five dimensions: dysphoric mood, withdrawal-apathy-vigor (entitled apathy), anxiety, hopelessness, and memory complaint. Random coefficients models examined the association of depression dimensions with baseline and longitudinal cognitive functioning, adjusting for sociodemographics and baseline characteristics, including cardiovascular risk factors, physical activity, and use of diabetes medications. RESULTS In the fully adjusted model at baseline, all dimensions of depression, except for anxiety, were associated with some aspect of cognition (P values from 0.01 to 0.01). CONCLUSIONS Apathy was associated with a faster cognitive decline in executive function. These findings highlight the heterogeneity of depression as a clinical construct rather than as a single entity and point to apathy as a specific risk factor for cognitive decline among older adults with type 2 diabetes.

Older adults with type 2 diabetes (T2D) are at increased risk for depression, cognitive decline, and dementia compared to those without T2D. Little is known about the association of simultaneous changes in depression symptoms and cognitive decline over time.Subjects (n=1021; mean age 71.6 [SD=4.6]; 41.2% female) were initially cognitively normal participants of the Israel Diabetes and Cognitive Decline study who underwent evaluations of depression and cognition approximately every 18 months. Cognitive tests were summarized into four cognitive domains: episodic memory, attention/working memory, executive functions, and semantic categorization. The average of the z-scores of the four domains defined global cognition. Depression symptoms were assessed using the Geriatric Depression Scale, 15-item version. We fit a random coefficients model of changes in depression and in cognitive functions, adjusting for baseline sociodemographic and cardiovascular variables.Higher number of depression symptoms at baseline was significantly associated with lower baseline cognitive scores in global cognition (estimate = -0.1175, SE = 0.021, DF = 1,014, t = -5.59; p0.001), executive functions (estimate = -0.186, SE = 0.036, DF = 1,013, t = -5.15; p = 0.001), semantic categorization (estimate = -0.155, SE = 0.029, DF = 1,008, t = -5.3; p0.001), and episodic memory (estimate = -0.08165, SE = 0.027, DF = 1,035, t = -2.92; p = 0.0036), but not with rate of decline in any cognitive domain. During follow-up, a larger increase in number of depression symptoms, was associated with worse cognitive outcomes in global cognition (estimate = -0.1053, SE = 0.027, DF = 1,612, t = -3.77; p = 0.0002), semantic categorization (estimate = -0.123, SE = 0.036, DF = 1,583, t = -3.36; p = 0.0008), and in episodic memory (estimate = -0.165, SE = 0.055, DF = 1,622, t = -3.02; p = 0.003), but the size of this effect was constant over time.In elderly with T2D, increase in depression symptoms over time is associated with parallel cognitive decline, indicating that the natural course of the two conditions progresses concurrently and suggesting common underlying mechanisms".

Background: Type 2 diabetes (T2D) is a metabolic condition associated with poor clinical and cognitive outcomes including vascular disease, depressive symptoms, cognitive impairment, and dementia. In the general elderly population, depression has been consistently identified as a risk factor for cognitive impairment/decline. However, the association between depression and cognitive function in T2D has been understudied. Objective: We investigated the association between depression and cognitive function in a large sample of cognitively normal elderly with T2D. Methods: In this cross-sectional study, we examined 738 participants, aged 65–88 years old, enrolled in the Israel Diabetes and Cognitive Decline study. For each cognitive domain (Episodic Memory, Executive Function, Attention/Working Memory, Language/Semantic Categorization) and Overall Cognition, multiple linear regressions assessed its association with depression (score greater than 5 on the 15-item version of the Geriatric Depression Scale [GDS]), adjusting for age, sex, and education. Results: Depression (n = 66, 8.9%) was associated with worse performance on tasks of Executive Function (p = 0.004), Language/Semantic Categorization (p

OBJECTIVE This study aimed to analyze the relationship of variability in hemoglobin A1c (HbA1c) over years with subsequent depressive symptoms. RESEARCH DESIGN AND METHODS Subjects (n = 837) were participants of the Israel Diabetes and Cognitive Decline (IDCD) study, which aimed to examine the relationship of characteristics of long-term type 2 diabetes with cognitive decline. All pertain to a diabetes registry established in 1998, which contains an average of 18 HbA1c measurements per subject. The results presented here are based on the IDCD baseline examination. Symptoms of depression were assessed using the 15-item version of the Geriatric Depression Scale (GDS). To quantify the association between variability in glycemic control (measured as the SD of HbA1c measurements [HbA1c-SD]) since 1998 with the number of depression symptoms at IDCD baseline, incidence rate ratios (IRRs) and corresponding 95% CIs were estimated via negative binomial regression modeling and used to account for the overdispersion in GDS scores. RESULTS Subjects’ ages averaged 72.74 years (SD 4.63 years), and the mean number of years in the diabetes registry was 8.7 (SD 2.64 years). The mean GDS score was 2.16 (SD 2.26); 10% of subjects had a GDS score ≥6, the cutoff for clinically significant depression. Mean HbA1c significantly correlated with HbA1c-SD (r = 0.6625; P < 0.0001). The SD, but not the mean, of HbA1c measurements was significantly associated with the number of subsequent depressive symptoms. For each additional 1% increase in HbA1c-SD, the number of depressive symptoms increased by a factor of 1.31 (IRR = 1.31 [95% CI 1.03–1.67]; P = 0.03). CONCLUSIONS Variability in glycemic control is associated with more depressive symptoms.

The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine is associated with rapid but transient antidepressant effects in patients with treatment resistant unipolar depression (TRD). Based on work suggesting that ketamine and lithium may share overlapping mechanisms of action, we tested lithium compared to placebo as a continuation strategy following ketamine in subjects with TRD. Participants who met all eligibility criteria and showed at least an initial partial response to a single intravenous infusion of ketamine 0.5 mg/kg were randomized under double-blind conditions to lithium or matching placebo before receiving an additional three infusions of ketamine. Subsequent to the ketamine treatments, participants remained on lithium or placebo during a double-blind continuation phase. The primary study outcome was depression severity as measured by the Montgomery–Åsberg Depression Rating Scale compared between the two groups at Study Day 28, which occurred ~2 weeks following the final ketamine of four infusions. Forty-seven participants with TRD were enrolled in the study and underwent an initial ketamine infusion, of whom 34 participants were deemed to have at least a partial antidepressant response and were eligible for randomization. Comparison between treatment with daily oral lithium (n = 18) or matching placebo (n = 16) at the primary outcome showed no difference in depression severity between groups (t(32) = 0.11, p = 0.91, 95% CI [−7.87, 8.76]). There was no difference between lithium and placebo in continuing the acute antidepressant response to ketamine. The identification of a safe and effective strategy for preventing depression relapse following an acute course of ketamine treatment remains an important goal for future studies.

Background At least one-third of patients with major depressive disorder (MDD) have treatment-resistant depression (TRD), defined as lack of response to two or more adequate antidepressant trials. For these patients, novel antidepressant treatments are urgently needed. Methods The current study is a phase IIa open label clinical trial examining the efficacy and tolerability of a combination of dextromethorphan (DM) and the CYP2D6 enzyme inhibitor quinidine (Q) in patients with TRD. Dextromethorphan acts as an antagonist at the glutamate N-methyl-d-aspartate (NMDA) receptor, in addition to other pharmacodynamics properties that include activity at sigma-1 receptors. Twenty patients with unipolar TRD who completed informed consent and met all eligibility criteria we enrolled in an open-label study of DM/Q up to 45/10 mg by mouth administered every 12 h over the course of a 10-week period, and constitute the intention to treat (ITT) sample. Six patients discontinued prior to study completion. Results There was no treatment-emergent suicidal ideation, psychotomimetic or dissociative symptoms. Montgomery-Asberg Depression Rating Scale (MADRS) score was reduced from baseline to the 10-week primary outcome (mean change: −13.0±11.5, t19=5.0, p Limitations Open-label, proof-of-concept design. Conclusions Herein we report acceptable tolerability and preliminary efficacy of DM/Q up to 45/10 mg administered every 12 h in patients with TRD. Future larger placebo controlled randomized trials in this population are warranted.

The α-1 adrenoreceptor antagonist prazosin has shown promise in the treatment of post-traumatic stress disorder (PTSD) symptoms, but its mechanisms are not well understood. Here we administered prazosin or placebo prior to threat conditioning (day 1) and tested subsequent extinction (day 2) and reextinction (day 3) in healthy human participants. Prazosin did not affect threat conditioning but augmented stimulus discrimination during extinction and reextinction, via lower responding to the safe stimulus. These results suggest that prazosin during threat acquisition may have influenced encoding or consolidation of safety processing in particular, subsequently leading to enhanced discrimination between the safe and threatening stimuli.

BACKGROUND: Preliminary evidence suggests intravenous ketamine has rapid effects on suicidal cognition, making it an attractive candidate for depressed patients at imminent risk of suicide. In the first randomized controlled trial of ketamine using an anesthetic control condition, we tested ketamine's acute effects on explicit suicidal cognition and a performance-based index of implicit suicidal cognition (Implicit Association Test; IAT) previously linked to suicidal behavior. METHOD: Symptomatic patients with treatment-resistant unipolar major depression (inadequate response to ≥3 antidepressants) were assessed using a composite index of explicit suicidal ideation (Beck Scale for Suicidal Ideation, Montgomery-Asberg Rating Scale suicide item, Quick Inventory of Depressive Symptoms suicide item) and the IAT to assess suicidality implicitly. Measures were taken at baseline and 24 hr following a single subanesthetic dose of ketamine (n = 36) or midazolam (n = 21), a psychoactive placebo agent selected for its similar, rapid anesthetic effects. Twenty four hours postinfusion, explicit suicidal cognition was significantly reduced in the ketamine but not the midazolam group. RESULTS: Fifty three percent of ketamine-treated patients scored zero on all three explicit suicide measures at 24 hr, compared with 24% of the midazolam group (χ(2) = 4.6; P =.03). Implicit associations between self- and escape-related words were reduced following ketamine (P =.01; d =.58) but not midazolam (P =.68; d =.09). Ketamine-specific decreases in explicit suicidal cognition were largest in patients with elevated suicidal cognition at baseline, and were mediated by decreases in nonsuicide-related depressive symptoms. CONCLUSIONS: Intravenous ketamine produces rapid reductions in suicidal cognition over and above active placebo. Further study is warranted to test ketamine's antisuicidal effects in higher-risk samples. Language: en

OBJECTIVE This study aimed to analyze the relationship of variability in hemoglobin A1c (HbA1c) over years with subsequent depressive symptoms. RESEARCH DESIGN AND METHODS Subjects (n = 837) were participants of the Israel Diabetes and Cognitive Decline (IDCD) study, which aimed to examine the relationship of characteristics of long-term type 2 diabetes with cognitive decline. All pertain to a diabetes registry established in 1998, which contains an average of 18 HbA1c measurements per subject. The results presented here are based on the IDCD baseline examination. Symptoms of depression were assessed using the 15-item version of the Geriatric Depression Scale (GDS). To quantify the association between variability in glycemic control (measured as the SD of HbA1c measurements [HbA1c-SD]) since 1998 with the number of depression symptoms at IDCD baseline, incidence rate ratios (IRRs) and corresponding 95% CIs were estimated via negative binomial regression modeling and used to account for the overdispersion in GDS scores. RESULTS Subjects’ ages averaged 72.74 years (SD 4.63 years), and the mean number of years in the diabetes registry was 8.7 (SD 2.64 years). The mean GDS score was 2.16 (SD 2.26); 10% of subjects had a GDS score ≥6, the cutoff for clinically significant depression. Mean HbA1c significantly correlated with HbA1c-SD (r = 0.6625; P < 0.0001). The SD, but not the mean, of HbA1c measurements was significantly associated with the number of subsequent depressive symptoms. For each additional 1% increase in HbA1c-SD, the number of depressive symptoms increased by a factor of 1.31 (IRR = 1.31 [95% CI 1.03–1.67]; P = 0.03). CONCLUSIONS Variability in glycemic control is associated with more depressive symptoms.

Importance African American individuals have higher dementia risk than individuals of white race/ethnicity. They also have higher rates of type 2 diabetes, which may contribute to this elevated risk. This study examined the association of the following 2 classes of alleles at the haptoglobin (Hp) locus that are associated with poor cognition, cardiovascular disease, and mortality: Hp 1-1 (associated with poor cognition and cerebrovascular disease) and Hp 2-1 and Hp 2-2 (associated with greater risk of myocardial infarction and mortality). An additional polymorphism in the promoter region of the Hp 2 allele, restricted to individuals of African descent, yields a fourth genotype, Hp 2-1m. African American adults have a higher prevalence of Hp 1-1 (approximately 30%) compared with individuals of white race/ethnicity (approximately 14%), but the potential role of the Hp genotype in cognition among elderly African American individuals with type 2 diabetes is unknown. Objective To assess the association of the Hp genotypes with cognitive function and decline in elderly African American adults with type 2 diabetes. Design, Setting, and Participants This cohort study used publicly available data and specimens from the Action to Control Cardiovascular Risk in Diabetes–Memory in Diabetes (ACCORD-MIND) study to investigate the association of the Hp genotypes with cognitive function and decline in 466 elderly African American participants with type 2 diabetes. The hypothesis was that the Hp 1-1 genotype compared with the other genotypes would be associated with more cognitive impairment and faster cognitive decline in elderly African American adults with type 2 diabetes. The initial ACCORD trial was performed from October 28, 1999, to September 15, 2014. This was a multicenter clinical study performed in an academic setting. Exposures The Hp genotypes were determined from serum samples by polyacrylamide gel electrophoresis and by enzyme-linked immunosorbent assay. Main Outcomes and Measures The Mini-Mental State Examination (MMSE) was used to measure cognitive function and change after 40 months. The MMSE score ranges from 0 to 30 points; higher scores represent better cognition. Associations were examined with analysis of covariance and linear regression, adjusting for age, sex, education, baseline glycated hemoglobin level, systolic blood pressure, diastolic blood pressure, cholesterol level, creatinine level, and treatment arm (intensive vs standard). The cognitive change model adjusted also for the baseline MMSE score. Results Among 466 African American study participants (mean [SD] age, 62.3 [5.7] years), 64.8% were women, and the genotype prevalences were 29.4% (n = 137) for Hp 1-1, 36.1% (n = 168) for Hp 2-1, 10.9% (n = 51) for Hp 2-1m, and 23.6% (n = 110) for Hp 2-2. The groups differed in their baseline MMSE scores (P = .006): Hp 1-1 had the lowest MMSE score (mean [SE], 25.68 [0.23]), and Hp 2-1m had the highest MMSE score (mean [SE], 27.15 [0.36]). Using the least squares method, the 40-month decline was significant for Hp 1-1 (mean [SE], −0.41 [0.19];P = .04) and for Hp 2-2 (mean [SE], −0.68 [0.21];P = .001). However, the overall comparison across the 4 groups did not reach statistical significance for the fully adjusted model. The interaction of age with the Hp 1-1 genotype on MMSE score decline estimate per year change was significant (mean [SE], −0.87 [0.37];P = .005), whereas it was not significant for Hp 2-1 (mean [SE], 0.06 [0.37];P = .85), Hp 2-1m (mean [SE], −0.06 [0.51];P = .89), and Hp 2-2 (mean [SE], −0.44 [0.41];P = .29), indicating that cognitive decline in Hp 1-1 carriers was accentuated in older ages, whereas it was not significant for the other Hp genotypes. Conclusions and Relevance In this study, the Hp 1-1 genotype, which is 2-fold (approximately 30%) more prevalent among African American individuals than among individuals of white race/ethnicity, was associated with poorer cognitive function and greater cognitive decline than the other Hp genotypes. The Hp gene polymorphism may explain the elevated dementia risk in African American adults. The neuropathological substrates and mechanisms for these associations merit further investigation.

Mood disorders are common and debilitating, resulting in a significant public health burden. Current treatments are only partly effective and patients who have failed to respond to trials of existing antidepressant agents (eg, those who suffer from treatment-resistant depression [TRD]) require innovative therapeutics with novel mechanisms of action. Although neuroscience research has elucidated important aspects of the basic mechanisms of antidepressant action, most antidepressant drugs target monoaminergic mechanisms identified decades ago. Glutamate, the major excitatory neurotransmitter in the central nervous system, and glutamatergic dysfunction has been implicated in mood disorders. These data provide a rationale for the pursuit of glutamatergic agents as novel therapeutic agents. Here, we review preclinical and clinical investigations of glutamatergic agents in mood disorders with a focus on depression. We begin with discussion of evidence for the rapid antidepressant effects of ketamine, followed by studies of the antidepressant efficacy of the currently marketed drugs riluzole and lamotrigine. Promising novel agents currently in development, including N-methyl-D-aspartate (NMDA) receptor modulators, 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) receptor modulators, and drugs with activity at the metabotropic glutamate (mGlu) receptors are then reviewed. Taken together, both preclinical and clinical evidence exists to support the pursuit of small molecule modulators of the glutamate system as novel therapeutic agents in mood disorders. It is hoped that by targeting neural systems outside of the monoamine system, more effective and perhaps faster acting therapeutics can be developed for patients suffering from these disabling disorders.

CME Educational Objectives 1. Understand the overlapping and unique presentations of adult attention-deficit/hyperactivity disorder (ADHD) and bipolar disorders. 2. Understand the cognitive components of adult ADHD and bipolar disorder. 3. Recognize the applicability of various rating scales used in clinical work to distinguish adult ADHD from bipolar disorder. Case 1 Mr. A was a 40-year-old white man with a psychiatric history of bipolar disorder and adult attention-deficit/hyperactivity disorder, who presented to the clinic for treatment of a depressive episode characterized by his feeling depressed, isolated, and anhedonic, with significant neurovegetative symptoms and intermittent passive suicidal ideation.

Suicide is defined as an act of violence toward oneself with the intention to die. Suicide completion is a prominent cause of worldwide mortality and its prevention poses a major challenge to the psychiatric and world health communities. The Centers for Disease Control and Prevention (CDC) reported that as of 2013, suicide was the 10th major cause of death – totaling 41,149 deaths in the United States (US) (Centers for Disease Control and Prevention, CDC)[1]. Despite a growing armamentarium of the psychiatric medications to treat mood disorders, effective pharmacologic interventions for suicidality continue to elude us. Statistics demonstrate no meaningful decrease in the rate of suicide [2, 3]. In fact, within the US, there has been an alarming 28.4% increase in the age-adjusted suicide rates (from 13.7 to 17.6 per 100, 000) for adults aged 35–64 years between 1999 and 2010 (CDC [4]), as well as a 2.4% increase in the age-adjusted death rate due to suicide in 2012 compared to 2011[5]. Suicide is a multi-factorial phenomenon and our current nosology addresses it within symptom components of other psychiatric conditions exclusively. Almost 90% of suicide cases are associated with some form of psychiatric illness, chiefly Major Depressive Disorder (MDD), Psychotic Disorders, or Borderline Personality Disorder [2]. The new DSM-5 Task Force and work groups recognized an emerging need for the investigation of suicidality as an independent phenomenon. To stimulate thinking along these lines, a new category “suicidal behavior disorder” was added to the manual under “Conditions for Further Study”[6]. Recent guidelines from the National Alliance for Suicide Prevention Research Task Force outline priority questions to guide current and future research on suicide. Paramount among this research agenda is defining the etiology of suicide with the aim of increasing detection and accurately predicting suicide risk to provide effective preventive services and interventions. In this review, we will describe current treatment approaches to suicidality and summarize the existing literature on ketamine as a potential treatment candidate. We will consider clinical trial data concerning the rapid antidepressant effects of ketamine in mood disorders, as well as the strength of evidence for ketamine’s anti-suicidal effect beyond its antidepressant actions. The neurobiology of suicide, including the role of glutamate, will be discussed.

Major depressive disorder is a common illness, particularly in patients with medical and neurologic conditions. This article summarizes current data on the epidemiology, diagnosis, and treatment of major depression, with special emphasis on the diagnosis and treatment of depression in medical and neurologic patients. We reviewed the role of pharmacotherapies, psychotherapies, somatic treatments, and alternative remedies and we included practical advice for clinician regarding the timing and sequence of these treatments, the role of standardized depression scales, and the criteria for referrals to specialty consultants.

Background.Suicide is a devastating public health problem and very few biological treatments have been found to be effective for quickly reducing the intensity of suicidal ideation (SI). We have previously shown that a single dose of ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, is associated with a rapid reduction in depressive symptom severity and SI in patients with treatment-resistant depression.Method.We conducted a randomized, controlled trial of ketamine in patients with mood and anxiety spectrum disorders who presented with clinically significant SI (n = 24). Patients received a single infusion of ketamine or midazolam (as an active placebo) in addition to standard of care. SI measured using the Beck Scale for Suicidal Ideation (BSI) 24 h post-treatment represented the primary outcome. Secondary outcomes included the Montgomery–Asberg Depression Rating Scale – Suicidal Ideation (MADRS-SI) score at 24 h and additional measures beyond the 24-h time-point.Results.The intervention was well tolerated and no dropouts occurred during the primary 7-day assessment period. BSI score was not different between the treatment groups at 24 h (p = 0.32); however, a significant difference emerged at 48 h (p = 0.047). MADRS-SI score was lower in the ketamine group compared to midazolam group at 24 h (p = 0.05). The treatment effect was no longer significant at the end of the 7-day assessment period.Conclusions.The current findings provide initial support for the safety and tolerability of ketamine as an intervention for SI in patients who are at elevated risk for suicidal behavior. Larger, well-powered studies are warranted.

Background: Neuropeptide Y (NPY) may enhance resilience to chronic stress. Low brain NPY reported in major depression may normalize in response to antidepressants. Methods: In this study, we examined the relationship of reported childhood trauma to cerebrospinal fluid (CSF) NPY–like immunoreactivity (NPY-LI) in 61 medication-free major depressive disorder (MDD) patients and 20 matched healthy volunteers. Results: Higher CSF NPY-LI was found in MDD compared to the healthy volunteer group ( p = 0.01). A positive correlation of CSF NPY-LI with more adverse childhood trauma ( p = 0.001) may be indicative of an intact but insufficient NPY-related stress response. Conclusions: We hypothesize that differences in published results may be explained by the existence of two groups of MDD in terms of CSF NPY levels: MDD with low CSF NPY prior to stress or in response to stress, and those with robust NPY responses to stress. Future studies should confirm the two groups and seek the molecular mechanism for their differences.

The N-methyl-D-aspartate glutamate receptor antagonist ketamine, delivered via an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant depression. The current study was designed to test the safety, tolerability, and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial.In a randomized, double-blind, crossover study, 20 patients with major depression were randomly assigned, and 18 completed 2 treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution. The primary efficacy outcome measure was change in depression severity 24 hours after ketamine or placebo, measured using the Montgomery-Åsberg Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with ketamine were also measured.Patients showed significant improvement in depressive symptoms at 24 hours after ketamine compared to placebo (t = 4.39, p.001; estimated mean Montgomery-Åsberg Depression Rating Scale score difference of 7.6 ± 3.7; 95% confidence interval, 3.9-11.3). Response criteria were met by 8 of 18 patients (44%) 24 hours after ketamine administration compared with 1 of 18 (6%) after placebo (p = .033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters.This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression.

Most reviews of pharmacological strategies for delirium treatment evaluate the effectiveness of these interventions for delirium prevention, reduction in duration and severity of ongoing delirium, and other outcomes that extend beyond the recommendations of expert treatment guidelines. However, little if any attention is given to substantiating the potential benefits of such treatment or addressing the methodological weaknesses that, in part, limit the pharmacological recommendations made by expert treatment guidelines. Therefore, the authors conducted a systematic review to provide the most up-to-date and inclusive review of published prospective trials of potential pharmacological interventions for the prevention and treatment of delirium, and they discuss potential benefits of pharmacological prevention of delirium and/or reduction of ongoing delirium episode duration and severity.The analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, including prospective randomized and nonrandomized double-blind, single-blind, and open-label clinical trials of any pharmacological agent for the prevention or treatment of delirium and reviewing them systematically for effectiveness on several predefined outcomes.The pharmacological strategies reviewed showed greater success in preventing delirium than in treating it. Significant delirium prevention effects are associated with haloperidol, second-generation antipsychotics, iliac fascia block, gabapentin, melatonin, lower levels of intraoperative propofol sedation, and a single dose of ketamine during anesthetic induction and with dexmedetomidine compared with other sedation strategies for mechanically ventilated patients.These promising results warrant further study with consideration of the methodological weaknesses and inconsistencies of studies to date.

Preliminary evidence suggests intravenous ketamine has rapid effects on suicidal cognition, making it an attractive candidate for depressed patients at imminent risk of suicide. In the first randomized controlled trial of ketamine using an anesthetic control condition, we tested ketamine's acute effects on explicit suicidal cognition and a performance-based index of implicit suicidal cognition (Implicit Association Test; IAT) previously linked to suicidal behavior.Symptomatic patients with treatment-resistant unipolar major depression (inadequate response to ≥3 antidepressants) were assessed using a composite index of explicit suicidal ideation (Beck Scale for Suicidal Ideation, Montgomery-Asberg Rating Scale suicide item, Quick Inventory of Depressive Symptoms suicide item) and the IAT to assess suicidality implicitly. Measures were taken at baseline and 24 hr following a single subanesthetic dose of ketamine (n = 36) or midazolam (n = 21), a psychoactive placebo agent selected for its similar, rapid anesthetic effects. Twenty four hours postinfusion, explicit suicidal cognition was significantly reduced in the ketamine but not the midazolam group.Fifty three percent of ketamine-treated patients scored zero on all three explicit suicide measures at 24 hr, compared with 24% of the midazolam group (χ(2) = 4.6; P = .03). Implicit associations between self- and escape-related words were reduced following ketamine (P = .01; d = .58) but not midazolam (P = .68; d = .09). Ketamine-specific decreases in explicit suicidal cognition were largest in patients with elevated suicidal cognition at baseline, and were mediated by decreases in nonsuicide-related depressive symptoms.Intravenous ketamine produces rapid reductions in suicidal cognition over and above active placebo. Further study is warranted to test ketamine's antisuicidal effects in higher-risk samples.