Laili Soleimani

A randomized controlled trial of intranasal ketamine in major depressive disorder.

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial

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.

Novel glutamatergic drugs for the treatment of mood disorders

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.

Diagnosis and Treatment of Major Depressive Disorder

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.

Dextromethorphan/quinidine pharmacotherapy in patients with treatment resistant depression: A proof of concept clinical trial

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 45/10mg by mouth administered every 12h 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<0.001), as was QIDS-SR score (mean change: -5.9±6.6, t19=4.0, p<0.001). The response and remission rates in the ITT sample were 45% and 35%, respectively. LIMITATIONS Open-label, proof-of-concept design. CONCLUSIONS Herein we report acceptable tolerability and preliminary efficacy of DM/Q up to 45/10mg administered every 12h in patients with TRD. Future larger placebo controlled randomized trials in this population are warranted.

Prazosin during threat discrimination boosts memory of the safe stimulus

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.

Hemoglobin A1c Variability Predicts Symptoms of Depression in Elderly Individuals With Type 2 Diabetes

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.

Does Ketamine Have Rapid Anti-Suicidal Ideation Effects?

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.

Depressive Symptoms Are Associated with Cognitive Function in the Elderly with Type 2 Diabetes

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 < 0.001), and Overall Cognition (p < 0.002), but not Episodic Memory (p = 0.643) or Attention/Working Memory (p = 0.488). Secondary analyses using GDS as a continuous variable did not substantially change the results. Adjusting also for a history of antidepressant medication use slightly weakened the findings. Conclusion: Significant associations of depression with several cognitive domains and Overall Cognition even in cognitively normal elderly with T2D, suggest that depression may have a role in impaired cognitive function in T2D, which may be attenuated by antidepressants.

THE HAPTOGLOBIN 1-1 GENOTYPE IS ASSOCIATED WITH COGNITIVE FUNCTION AND DECLINE IN AFRICAN AMERICAN PERSONS WITH TYPE 2 DIABETES: THE ACCORD-MIND STUDY

patients of the Health Promotion Center in Samsung Medical Center who underwent pulmonary function test and Three-dimensional brain MRI. The pulmonary function was analyzed according to the quintiles of FVC or FEV1 (% pred). We used multivariate logistic regression model, for estimating the association of pulmonary function and CSVD markers (moderate to severe WMH, lacunes and microbleeds). Using linear regression model, we estimated the association of pulmonary function and cortical thickness across the quintiles of FEV1 (% pred) and FVC (% pred). We adjusted years of education, presence of hypertension, diabetes, hyperlipidemia, and smoking status. Results:Compared with the highest quintile of FVC, the odds ratios (ORs) for WMH in the lowest quintile was 2.58 (95% CI, 1.60-4.16). The ORs for the presence of microbleeds and lacunes were 1.78 (95% CI, 1.12-2.85) and 2.13 (95% CI, 1.293.50), respectively. Compared with the highest quintile of FVC (% pred), the lowest group showed cortical thinning in the frontal, parietal, and occipital lobe except temporal lobe. There was no relationship of quintiles of FEV1 % of predicted value with CSVD markers or cortical thickness. Path analyses showed that CSVD markers completely mediated the relationship between FVC and cortical thinning.Conclusions:Our findings therefore suggested that decreased pulmonary function, especially FVC (% pred) was associated with increased CSVD burdenwhich lead to cortical thinning even in cognitively normal subjects. This finding could be the cause of cognitive decline associated with decreased pulmonary function.