Ketamine-enhanced prolonged exposure therapy in veterans with PTSD: A randomized controlled trial protocol.

BACKGROUND: The 2023 VA/DoD Clinical Practice Guideline for the Management of PTSD recommends individual, manualized trauma-focused such as Prolonged Exposure (PE) over pharmacologic interventions for the primary treatment of PTSD. Unfortunately, clinical trials of trauma-based therapies in the military and veteran population showed that 30% to 50% of patients did not demonstrate clinically meaningful symptom change. Ketamine, an FDA-approved anesthetic with potent non-competitive glutamatergic N-methyl-d-aspartate antagonistic properties, has demonstrated to enhance the recall of extinction learning and decrease fear renewal without interference of extinction training in preclinical studies. METHODS: We plan to conduct a single site RCT comparing three ketamine treatment vs. active placebo (midazolam) adjunct to PE therapy among Veterans with PTSD. Pharmacological phase will start simultaneously with PE session 1. Infusions will be administered 24 h. prior to PE session for the first 3 weeks. After PE is completed (session 10), patients will be assessed during a 3-month follow-up period at various time points. We estimate that out of 100 veterans, 80 will reach time point for primary outcome measure and will be considered for primary analysis. Secondary outcomes include severity of depression and anxiety scores, safety and tolerability of ketamine-enhanced PE therapy, cognitive performance during treatment and early improvement during PE related to the rate of dropouts during PE therapy. DISCUSSION: Results of the proposed RCT could provide scientific foundation to distinguish the essential components of this approach, enhance the methodology, elucidate the mechanisms involved, and identify sub-PTSD populations that most likely benefit from this intervention.

A Systematic Review of the Neurocognitive Effects of Psychedelics in Healthy Populations: Implications for Depressive Disorders and Post-Traumatic Stress Disorder.

OBJECTIVE: This study aims to provide an overview of pharmacological trials that examine the neurocognitive effects of psychedelics among healthy individuals and patients with post-traumatic stress disorder (PTSD) or major depressive disorder (MDD). METHODS: The Preferred Reporting Items for Systematic Reviews (PRISMA) was used as a guide to structure and report the findings for this review. A literature search included the MEDLINE database up until December 2022. We included randomized or open-label human studies of MDMA, psilocybin, mescaline, LSD, DMT, or cannabis reporting non-emotionally charged neurocognitive outcomes ("cold cognition") measured through validated neuropsychological tests. RESULTS: A total of 43 full-text papers on MDMA (15), cannabis (12), LSD (6), psilocybin (9), DMT/ayahuasca (1), and mescaline (0) were included, mostly on healthy subjects. A single article on MDMA's effects on cognition in subjects with PTSD was included; there were no studies on psychedelics and neurocognition in MDD. Most of the studies on healthy subjects reported detrimental or neutral effects on cognition during the peak effect of psychedelics with a few exceptions (e.g., MDMA improved psychomotor function). Performance on the type of neurocognitive dimension (e.g., attention, memory, executive function, psychomotor) varies by type of psychedelic, dosage, and cognitive testing. CONCLUSIONS: Small samples and a lack of uniformed methods across studies preclude unequivocal conclusions on whether psychedelics enhance, decrease, or have no significant effect on cognitive performance. It is foreseen that psychedelics will soon become an available treatment for various psychiatric disorders. The acute and long-term effects on cognition caused by psychedelics should be assessed in future studies.

Antidepressant Strategies for Treatment of Acute Depressive Episodes Among Veterans.

OBJECTIVE: The 2016 VA/DoD Clinical Practice Guideline for Management of Major Depressive Disorder offers consensus-based recommendations when response to the initial antidepressant medication is suboptimal; however, little is known about "real-world" pharmacological strategies used by providers treating depression in the Veterans Affairs Health Care System (VAHCS). METHODS: We extracted pharmacy and administrative records of patients diagnosed with a depressive disorder and treated at the Minneapolis VAHCS between January 1, 2010 and May 11, 2021. Patients with bipolar disorder, psychosis-spectrum, or dementia diagnoses were excluded. An algorithm was developed to identify antidepressant strategies: monotherapy (MONO); optimization (OPM); switching (SWT); combination (COM); and augmentation (AUG). Additional data extracted included demographics, service utilization, other psychiatric diagnoses, and clinical risk for hospitalization and mortality. RESULTS: The sample consisted of 1298 patients, 11.3% of whom were female. The mean age of the sample was 51 years. Half of the patients received MONO, with 40% of those patients receiving inadequate doses. OPM was the most common next-step strategy. SWT and COM/AUG were used for 15.9% and 2.6% of patients, respectively. Overall, patients who received COM/AUG were younger. OPM, SWT, and COM/AUG occurred more frequently in psychiatric services settings and required a greater number of outpatient visits. The association between antidepressant strategies and risk of mortality became nonsignificant after accounting for age. CONCLUSIONS: Most of the veterans with acute depression were treated with a single antidepressant, while COM and AUG were rarely used. The age of the patient, and not necessarily greater medical risks, appeared to be a major factor in decisions about antidepressant strategies. Future studies should evaluate whether implementation of underutilized COM and AUG strategies early in the course of depression treatment are feasible.

A Systematic Review of Neurocognitive Effects of Subanesthetic Doses of Intravenous Ketamine in Major Depressive Disorder, Post-Traumatic Stress Disorder, and Healthy Population.

BACKGROUND AND OBJECTIVE: Ketamine, a noncompetitive, high-affinity antagonist of the N-methyl-D-aspartate type glutamate receptor, has been investigated for its high efficacy and rapid antidepressant effect and, more recently, for its potential utility in post-traumatic stress disorder (PTSD). The proposal that ketamine's antidepressant and anti-suicidal mechanism may be in part due to its procognitive effect contrasts with the well-established decreased performance on spatial working memory and pattern recognition memory among long-term frequent users. We aimed to review the neurocognitive effects of subanesthetic doses of intravenous ketamine in pharmacological studies among healthy subjects and patients with PTSD or depression. METHODS: We included studies in English, among healthy adults, or with PTSD or unipolar or bipolar depression where the primary or secondary cognitive outcomes were measured by means of validated neuropsychological test. We excluded studies that reported the use of ketamine only in combination with other drugs or psychotherapy, or studies investigating emotion-laden cognitive functions. RESULTS: Ketamine administration among patients with depression and possibly with PTSD does not show significant impairment of cognitive functions in the short-term, in contrast with the immediate altered cognitive dysfunction found in healthy subjects. The potential procognitive effects of ketamine seem more pronounced in cognitive domains of executive function, which is in line with the putative molecular, cellular, and synaptic mechanisms of ketamine's therapeutic action. CONCLUSIONS: The potential procognitive effect of ketamine deserves further exploration. Whether ketamine has transient or sustained neurocognitive benefits beyond its antidepressant effects is unknown. Improved cognition by ketamine might be used to facilitate psychotherapy interventions for PTSD and depression.

Neurocognitive effects of repeated ketamine infusions in comorbid posttraumatic stress disorder and major depressive disorder.

BACKGROUND: The glutamate N-methyl-d-aspartate (NMDA) receptor antagonist ketamine rapidly ameliorates posttraumatic stress disorder (PTSD) and depression symptoms in individuals with comorbid PTSD and major depressive disorder (MDD). However, concerns over ketamine's potential neurocognitive side effects have yet to be assessed in this population. The current study investigated 1) changes in neurocognitive performance after a repeated ketamine dosing regimen and 2) baseline neurocognitive performance as a predictor of ketamine treatment effect. METHOD: Veterans with comorbid PTSD and MDD (N = 15) received six infusions of 0.5 mg/kg ketamine over a 12-day period. Neurocognitive and clinical outcomes assessments occurred at baseline and within 7 days of infusion-series completion using the CogState battery. RESULTS: Repeated ketamine infusions did not significantly worsen any measures of cognition. Rather, significant improvement was observed in working memory following completion of the infusion series. In addition, greater improvements in PTSD and MDD symptoms were associated with lower working memory, slower processing speed and faster set shifting at baseline. Lower verbal learning was also predictive of improvement in depression. LIMITATIONS: This study applied an open-label design without a placebo control. As such, it is not known to what extent the correlations or improvement in neurocognitive performance may have occurred under placebo conditions. CONCLUSION: This is the first study to examine the neurocognitive effects of repeated ketamine in participants with comorbid PTSD and MDD. Our findings suggest potential baseline neurocognitive predictors of ketamine response for comorbid PTSD and MDD symptoms.

Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial.

This study tested the efficacy of repeated intravenous ketamine doses to reduce symptoms of posttraumatic stress disorder (PTSD). Veterans and service members with PTSD (n = 158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n = 54), low dose (0.2 mg/kg; n = 53) or standard dose (0.5 mg/kg; n = 51) ketamine. Participants were assessed at baseline, during treatment, and for 4 weeks after their last infusion. Primary analyses used mixed effects models. The primary outcome measure was the self-report PTSD Checklist for DSM-5 (PCL-5), and secondary outcome measures were the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and the Montgomery Åsberg Depression Rating Scale (MADRS). There were no significant group-by-time interactions for PTSD symptoms measured by the PCL-5 or CAPS-5. The standard ketamine dose ameliorated depression measured by the MADRS significantly more than placebo. Ketamine produced dose-related dissociative and psychotomimetic effects, which returned to baseline within 2 h and were less pronounced with repeated administration. There was no evidence of differential treatment discontinuation by ketamine dose, consistent with good tolerability. This clinical trial failed to find a significant dose-related effect of ketamine on PTSD symptoms. Secondary analyses suggested that the standard dose exerted rapid antidepressant effects. Further studies are needed to determine the role of ketamine in PTSD treatment. ClinicalTrials.gov identifier: NCT02655692.

Neurocognitive performance of repeated versus single intravenous subanesthetic ketamine in treatment resistant depression.

BACKGROUND: Ketamine demonstrated rapid antidepressant effects in treatment-resistant depression (TRD). However, evaluation of ketamine's neurocognitive effect in TRD is unclear. We aim to (1) characterize baseline neurocognitive performance as a predictor of the change in severity of depressive symptoms over time, and (2) investigate the association of six versus single intravenous (IV) ketamine and neurocognitive changes from baseline to the end of treatment. METHODS: Subjects with TRD were randomized to receive either five IV midazolam followed by a single IV ketamine or six IV ketamine during a 12-day period. Depression symptom assessments occurred prior and 24 h after infusion days using the Montgomery-Åsberg Depression Rating Scale. Neurocognitive tasks were designed to test attention, memory, speed of processing, and set shifting using the CogState battery at baseline and at the end of treatment. RESULTS: Better complex working memory at baseline predicted improvement in MADRS scores of ketamine (vs midazolam) after 5 infusions. Most, but not all, neurocognitive functions remained stable or improved after repeated or single ketamine. There was a greater differential effect of treatment on speed of processing, set shifting, and spatial working memory that favors subjects in the six ketamine group. These cognitive improvements from baseline to the end of treatment were robust when controlling for age and changes in depression severity. CONCLUSION: The study suggests that six IV ketamine compared to single IV ketamine has a mood independent procognitive effect among TRD patients. Large scale studies are needed to confirm whether ketamine enhances cognitive function in TRD.

A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression.

The strategy of repeated ketamine in open-label and saline-control studies of treatment-resistant depression suggested greater antidepressant response beyond a single ketamine. However, consensus guideline stated the lack of evidence to support frequent ketamine administration. We compared the efficacy and safety of single vs. six repeated ketamine using midazolam as active placebo. Subjects received either six ketamine or five midazolam followed by a single ketamine during 12 days followed by up to 6-month post-treatment period. The primary end point was the change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) score at 24 h after the last infusion. Fifty-four subjects completed all six infusions. For the primary outcome measure, there was no significant difference in change of MADRS scores between six ketamine group and single ketamine group at 24 h post-last infusion. Repeated ketamine showed greater antidepressant efficacy compared to midazolam after five infusions before receiving single ketamine infusion. Remission and response favored the six ketamine after infusion 4 and 5, respectively, compared to midazolam before receiving single ketamine infusion. For those who responded, the median time-to-relapse was nominally but not statistically different (2 and 6 weeks for the single and six ketamine group, respectively). Repeated infusions were relatively well-tolerated. Repeated ketamine showed greater antidepressant efficacy to midazolam after five infusions but fell short of significance when compared to add-on single ketamine to midazolam at the end of 2 weeks. Increasing knowledge on the mechanism of ketamine should drive future studies on the optimal balance of dosing ketamine for maximum antidepressant efficacy with minimum exposure.

Antidepressant Effect of the VA Weight Management Program (MOVE) Among Veterans With Severe Obesity.

INTRODUCTION: Obesity is prevalent among users of Veteran's Health Administration services, where it is comorbid with depression, post-traumatic stress disorder, type 2 diabetes, cardiovascular disease, colon, and breast cancer. Among obese subjects, severe obesity represents a subpopulation with the highest risk of depression. We investigate the antidepressant effect of a local VA weight management program (Managing Overweight Veterans Everywhere - MOVE) among depressed veterans with severe obesity. MATERIAL AND METHODS: In a 10-week prospective pilot study, 14 clinically depressed veterans with severe obesity were recruited from: (1) the 2-week residential based intense MOVE program (IMP) (N = 7) and (2) the 10-week educational module of self-management MOVE program (SMP) (N = 7). Subjects had a Beck Depression Inventory, 2nd edition (BDI-II) score > 12 and BMI > 40 or BMI > 35 with associated to comorbid conditions. Concurrent treatment for depression such as medications or psychotherapy was excluded. The primary efficacy endpoint was the change in BDI-II score form baseline to week 10. Analysis consisted of linear mixed model with baseline BDI-II score as a covariate, and level of MOVE intervention (IMP vs. SMP), time, and time by treatment interaction as fixed effects, and random patient effect. Pearson's correlation examined the relationships between clinical and demographic variables and change in severity of depression by BDI-II scores. Secondary outcomes include weight loss and energy expenditure. RESULTS: The sample was composed by 14 subjects (IMP = 7; SMP = 7) mostly unemployed (N = 9), married (N = 10), mid-aged (mean = 58.2, SD = 8.4), Caucasian (N = 13), male (N = 12), with recurrent depression (N = 11), and a mean overall duration of current depressive episode of 13.5 months (SD = 10.2). Out of 14 participants; seven had a family history of mood disorder, two had previous psychiatric hospitalization, three had a previous suicidal attempt, and eight had a history of substance use disorder. There was a significant decrease in severity of depression among all 14 (F3,36.77 = 5.28; P < 0.01); antidepressant effect favored the IMP compared to SMP at day 12 (F1,15.10 = 9.37, P = 0.01) and week 6 (F2,27.34 = 4.26, P = 0.03), but effect fell short of significance at week 10. The change in severity of depression measured by BDI-II score significantly correlated with total weight loss (r = -0.60; P = 0.04) and daily energy expenditure at 12 days (r = -0.67; P = 0.01), week 6 (r = -0.59; P = 0.03), and week 10 (r = -0.71; P = 0.01). CONCLUSIONS: Depressed veterans with severe obesity improved their depressive symptoms by participating in the MOVE program. Veterans in the IMP had greater but short-term antidepressant effect as compared to educational intervention for obesity. Future studies with larger sample size may elucidate the underlying mechanisms of weight reduction to improve depression and, more importantly, sustain response among veterans with severe obesity.

Mental Health Diagnoses in Veterans Referred for Outpatient Geriatric Psychiatric Care at a Veterans Affairs Medical Center.

INTRODUCTION: Nearly half of the U.S. veterans are over 65 years of age. Older veterans are at higher risk for mental health (MH) conditions, which are associated with increased mortality and health care costs. Given the deficit of specialty-trained geriatric providers, we are conducting a Quality Improvement initiative to improve MH services for older veterans at Minneapolis Veterans Affairs Health Care System. Our first step is to understand the demographic and diagnostic characteristics of veterans referred for geriatric MH specialty treatment. MATERIALS AND METHOD: We conducted a retrospective chart review of demographics and psychiatric diagnoses in veterans seen for outpatient geriatric MH intake between May 1, 2011 and April 30, 2016. We used chi-square and Spearman's rho tests to examine age, diagnoses, and service-time era variables. RESULTS: 1,059 veterans were evaluated, average age of 73.5 years. Depressive (47%), neurocognitive (42%), and anxiety disorders (22%) were the most common MH conditions. Vietnam veterans showed higher prevalence of depressive (56%), post-traumatic stress (11%), and alcohol use (10%) disorders. World War II veterans showed higher prevalence of neurocognitive disorders (71%). Neurocognitive disorder prevalence was significantly correlated with age. CONCLUSIONS: Prevalence and comorbidity of major MH conditions is high in veterans referred for geriatric MH services. Future work will examine challenges faced by non-specialty providers in caring for older veterans, with the goal of developing targeted educational and clinical interventions to better address aging veterans' MH needs.

Efficacy, Safety, and Durability of Repeated Ketamine Infusions for Comorbid Posttraumatic Stress Disorder and Treatment-Resistant Depression.

OBJECTIVE: The present study examined the efficacy, safety, and durability of repeated ketamine infusions for the treatment of comorbid posttraumatic stress disorder (PTSD) and treatment-resistant depression (TRD) in a sample of veterans. METHODS: Individuals with comorbid DSM-5-defined PTSD and DSM-IV-defined major depressive disorder (N = 15) received 6 intravenous ketamine infusions (0.5 mg/kg) on a Monday-Wednesday-Friday schedule over a 12-day period from May 2015 to June 2016. Data from outcome measures were collected before and 24 hours after each infusion and weekly for 8 weeks following the final infusion. RESULTS: Continuous measures of symptom change were significant for both disorders and were associated with large effect sizes (mean decrease in PTSD Checklist for DSM-5 score = 33.3 points [95% CI, 23.0-43.5 points], P < .0005, sample size-adjusted Cohen d [d'] = 2.17; mean decrease in Montgomery-Asberg Depression Rating Scale score = 26.6 points [95% CI, 23.0-30.2 points], P < .0005, d' = 4.64). The remission rate for PTSD was 80.0%, and the response rate for TRD was 93.3%. Participants in remission from PTSD after the infusion series (n = 12) had a median time to relapse of 41 days. Similarly, participants whose depression symptoms responded to the infusion series (n = 14) had a median time to relapse of 20 days. Repeated ketamine infusions were associated with transient increases in dissociative symptoms. No participant reported worsening of PTSD symptoms over the study duration. CONCLUSIONS: This study, the first open-label study of repeated ketamine infusions in a comorbid population, found rapid and sustained improvement in PTSD and depression symptoms. This report suggests that repeated ketamine treatments are safe and may represent an efficacious treatment for individuals with comorbid PTSD and TRD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02577250.

Examining Burnout, Depression, and Self-Compassion in Veterans Affairs Mental Health Staff.

OBJECTIVES: Burnout, a state of emotional exhaustion associated with negative personal and occupational outcomes, is prevalent among healthcare providers. A better understanding of the psychological factors that may be associated with resilience to burnout is essential to develop effective interventions. Self-compassion, which includes kindness toward oneself, recognition of suffering as part of shared human experience, mindfulness, and nonjudgment toward inadequacies and failures, may be one such factor. The purpose of this study was to examine the relationships between burnout, depression, and self-compassion in Veterans Affairs (VA) mental health staff. DESIGN: Cross-sectional study. SETTING: VA medical center and affiliated community-based clinics. PARTICIPANTS: VA mental health staff. OUTCOME MEASURES: The 19-item Copenhagen Burnout Inventory, the 26-item Self-Compassion Scale, and the Patient Health Questionnaire 2-item depression screen. Demographic information included age, sex, years worked in current position, and number of staff supervised. RESULTS: One hundred and twenty-eight of a potential 379 individuals (33.8%) responded. Clerical support, nursing, social work, psychology, and psychiatry were the major professions represented. Self-compassion was inversely correlated with burnout (r = -0.41, p < 0.001), and inversely correlated with depression (rpb = -0.39, p < 0.001). The inverse relationship between self-compassion and burnout remained significant even after accounting for depressive symptoms and demographic variables in a multiple linear regression model. Of all the variables examined, self-compassion was the strongest predictor of burnout. CONCLUSIONS: The results of this study support the hypothesis that self-compassion may be associated with resilience to burnout. Alternatively, decreased self-compassion may be a downstream effect of increased burnout. Prospective, longitudinal studies are needed to determine the directional relationship between these factors, and whether interventions that cultivate self-compassion may decrease burnout and/or protect against its negative personal and professional outcomes.

Facial recognition of happiness among older adults with active and remitted major depression.

Biased emotion processing in depression might be a trait characteristic independent of mood improvement and a vulnerable factor to develop further depressive episodes. This phenomenon of among older adults with depression has not been adequately examined. In a 2-year cross-sectional study, 59 older patients with either active or remitted major depression, or never-depressed, completed a facial emotion recognition task (FERT) to probe perceptual bias of happiness. The results showed that depressed patients, compared with never depressed subjects, had a significant lower sensitivity to identify happiness particularly at moderate intensity of facial stimuli. Patients in remission from a previous major depressive episode but with none or minimal symptoms had similar sensitivity rate to identify happy facial expressions as compared to patients with an active depressive episode. Further studies would be necessary to confirm whether recognition of happy expression reflects a persistent perceptual bias of major depression in older adults.

The Effect of Repeated Ketamine Infusion Over Facial Emotion Recognition in Treatment-Resistant Depression: A Preliminary Report.

In contrast to improvement in emotion recognition bias by traditional antidepressants, the authors report preliminary findings that changes in facial emotion recognition are not associated with response of depressive symptoms after repeated ketamine infusions or relapse during follow-up in treatment-resistant depression.

Neurocognitive performance and serial intravenous subanesthetic ketamine in treatment-resistant depression.

The N-methyl-D-aspartate glutamate receptor antagonist ketamine has demonstrated rapid antidepressant effects in treatment-resistant depression (TRD). However, evaluation of ketamine's neurocognitive aspects in TRD has started to be explored. This study aims to (1) examine baseline neurocognitive performance and change in severity of depressive symptoms through six ketamine infusions, (2) examine the neurocognitive effects after completion of serial infusions and whether changes were associated to relapse to depression. Six IV infusions of 0.5 mg/Kg ketamine over 40 min were conducted on a Monday-Wednesday-Friday schedule during a 12-d period on 15 patients with TRD followed by a 4-wk observational period. Neurocognitive functioning was assessed using the CogState battery at baseline and at each follow-up visit. Tasks were designed to test attention, memory (working, visual, and verbal), speed of processing, and set shifting. The likelihood of response through six infusions was greater among depressed subjects with lower attention at baseline (F(1,13)=5.59, p=0.034). Significant improvement was found in scores of visual memory (F(4,33.82)=5.12, p=0.002), simple working memory (F(4, 24.85)=3.29, p=0.027) and complex working memory (F(4, 32.76)=4.18, p=0.008) after the last ketamine infusion. However, neurocognitive changes were accounted for by improvement in the severity of depressive symptom. The acute neurocognitive effect after completion of repeated infusions was not associated with the likelihood of subsequent relapse during follow-up. Our findings suggest a potential baseline neurocognitive predictor of ketamine response and the apparently lack of short-term neurocognitive impairment after completion of six ketamine infusions in TRD.

Emotion recognition processing as early predictor of response to 8-week citalopram treatment in late-life depression.

BACKGROUND: In subjects with depression, exposure to antidepressants improves recognition of positive emotions. This phenomenon, which occurs early in the course of treatment, has been proposed as the initial step in the mechanism of action to subsequent therapeutic effects of antidepressants. To this date, it has not been well examined among older depressed patients. METHOD: Older subjects with non-psychotic major depressive disorder were treated with citalopram in an 8-week open-label study. The main predictor of response and remission was the change in emotion recognition between baseline and day 7. Covariates included executive functions, baseline anxiety level, medical comorbidity, level of subjective stress, serum citalopram level, and level of social support. RESULTS: Twenty-seven patients were considered for final analysis. Overall, accuracy of emotion recognition significantly improved between baseline (75%) and day 7 (83%) (X(2) = 34.50, df = 1, p < 0.001). Improvement to identify happy expressions occurred at 25% and 50% intensity with ceiling effect at 0%, 75%, and 100%. Change in emotion processing was marginally significant in predicting antidepressant response at day 56. Multivariate analysis showed that emotion processing is a significant predictor of response and remission when considered along with perceived level of social support. CONCLUSIONS: Recognition of mildly intense happy expression, which improved early in the course of citalopram treatment, predicts subsequent antidepressant response and remission when considered along with perception of social support. Further studies would be necessary to examine specific neural substrates in the affective network involved in the acute therapeutic action of antidepressant in late-life depression.

Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment resistant depression.

BACKGROUND: Ketamine has been showing high efficacy and rapid antidepressant effect. However, studies of ketamine infusion wash subjects out from prior antidepressants, which may be impractical in routine practice. In this study, we determined antidepressant response and remission to six consecutive ketamine infusions while maintaining stable doses of antidepressant regimen. We also examined the trajectory of response and remission, and the time to relapse among responders. METHODS: TRD subjects had at least 2-month period of stable dose of antidepressants. Subjects completed six IV infusions of 0.5mg/kg ketamine over 40min on a Monday-Wednesday-Friday schedule during a 12-day period participants meeting response criteria were monitored for relapse for 4 weeks. RESULTS: Fourteen subjects were enrolled. Out of twelve subjects who completed all six infusions, eleven (91.6%) achieved response criterion while eight (66.6%) remitted. After the first infusion, only three and one out of twelve subjects responded and remitted, respectively. Four achieved response and six remitted after 3 or more infusions. Five out of eleven subjects remain in response status throughout the 4 weeks of follow-up. The mean time for six subjects who relapsed was 16 days. LIMITATIONS: Small sample and lack of a placebo group limits the interpretation of efficacy. CONCLUSIONS: Safety and efficacy of repeated ketamine infusions were attained without medication-free state in patients with TRD. Repeated infusions achieved superior antidepressant outcomes as compared to a single infusion with different trajectories of response and remission. Future studies are needed to elucidate neural circuits involved in treatment response to ketamine.