ClinicalTrials.gov identifier: NCT00088699.

Background The rapid clinical antidepressant effects of the glutamatergic modulator ketamine may be due to its ability to restore synaptic plasticity and related effects on sleep-wake and circadian systems. Preclinical studies indicate that ketamine alters expression of circadian clock-associated molecules, and clinical studies of ketamine on plasticity-related biomarkers further suggest an association with sleep slow waves and sleep homeostasis. Methods Wrist activity monitors were used to examine the pharmacologic and rapid antidepressant effects of ketamine on markers of circadian timekeeping (amplitude and timing) in mood disorders. Circadian amplitude and timing of activity at baseline, post-infusion Day1 (D1), and Day3 (D3) were measured in 51 patients with major depressive disorder (MDD) or bipolar disorder (BD). Results Compared with either placebo or baseline, a mood-independent decrease of the central circadian value (mesor) was present on D1 after ketamine treatment. Mood-associated circadian effects between rapid (D1) responders and non-responders were found at baseline, D1, and D3. At baseline, a phase-advanced activity pattern and lower mesor distinguished subsequent responders from non-responders. On D1, ketamine non-responders had a lower mesor and a blunted 24-hour amplitude relative to baseline. On D3, patients with a persisting clinical response exhibited a higher amplitude and mesor compared with non-responders. Conclusions The findings are the first to demonstrate an association between ketamine’s clinical antidepressant effects and circadian timekeeping. The results suggest that trait-like circadian activity patterns indicate rapid mood response to ketamine, and that mediators of continuing ketamine-induced mood changes include altered timing and amplitude of the circadian system.

Background Fatigue is a multidimensional condition that is difficult to treat with standard monoaminergic antidepressants. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist produces rapid and robust improvements in depressive symptoms in treatment-resistant depression. However, there is a dearth of literature examining the anti-fatigue effects of ketamine. We hypothesize that ketamine will rapidly improve fatigue symptoms in treatment-resistant depressed patients. Methods This is an exploratory analysis of data obtained from two double-blind, randomized, placebo-controlled, crossover trials. A total of 36 participants with treatment-resistant bipolar I or II disorder in a depressive episode (maintained on therapeutic levels of lithium or valproate) received a single infusion of ketamine hydrochloride intravenously (0.5mg/kg over 40 minutes) or placebo. A post-hoc analysis compared fatigue scores on ketamine vs. placebo at 10 time points from baseline through 14 days post-treatment using the National Institute of Health-Brief Fatigue Inventory. Results A linear mixed model showed that ketamine significantly lowered fatigue scores compared to placebo from 40 minutes post-treatment to Day 14 with the exception of Day 7. The largest difference in anti-fatigue effects between placebo and ketamine was at day 2 (d=.58, p < .05). The effect remained significant after controlling for changes in non-fatigue depressive symptoms. Limitation The retrospective nature and a small sample size are study limitations. Conclusions Ketamine rapidly improved fatigue relative to placebo in a group of individuals with treatment-resistant bipolar depression. NMDAR is a glutamate receptor; hence, glutamate may represent a valuable target to study the clinical efficacy of new anti-fatigue approaches in multiple disorders.

ObjectiveThis prospective investigation examined: 1) processing speed and working memory relative to other cognitive domains in non-demented medically managed idiopathic Parkinson’s disease, and 2) the predictive role of cortical/subcortical gray thickness/volume and white matter fractional anisotropy on processing speed and working memory.MethodsParticipants completed a neuropsychological protocol, Unified Parkinson’s Disease Rating Scale, brain MRI, and fasting blood draw to rule out vascular contributors. Within group a priori anatomical contributors included bilateral frontal thickness, caudate nuclei volume, and prefrontal white matter fractional anisotropy.ResultsIdiopathic Parkinson’s disease (n = 40; Hoehn & Yahr stages 1–3) and non-Parkinson’s disease ‘control’ peers (n = 40) matched on demographics, general cognition, comorbidity, and imaging/blood vascular metrics. Cognitively, individuals with Parkinson’s disease were significantly more impaired than controls on tests of processing speed, secondary deficits on working memory, with subtle impairments in memory, abstract reasoning, and visuoperceptual/spatial abilities. Anatomically, Parkinson’s disease individuals were not statistically different in cortical gray thickness or subcortical gray volumes with the exception of the putamen. Tract Based Spatial Statistics showed reduced prefrontal fractional anisotropy for Parkinson’s disease relative to controls. Within Parkinson’s disease, prefrontal fractional anisotropy and caudate nucleus volume partially explained processing speed. For controls, only prefrontal white matter was a significant contributor to processing speed. There were no significant anatomical predictors of working memory for either group.ConclusionsCaudate nuclei volume and prefrontal fractional anisotropy, not frontal gray matter thickness, showed unique and combined significance for processing speed in Parkinson’s disease. Findings underscore the relevance for examining gray-white matter interactions and also highlight clinical processing speed metrics as potential indicators of early cognitive impairment in PD.

Background Suicide is a common reason for psychiatric emergency and morbidity, with few effective treatments. Anxiety symptoms have emerged as potential modifiable risk factors in the time before a suicide attempt, but few studies have been conducted using laboratory measures of fear and anxiety. We operationally defined fear and anxiety as the increased in startle reactivity during anticipation of predictable (fear-potentiated startle) and unpredictable (anxiety-potentiated startle) shock. We hypothesized that a lifetime history of suicide attempt (as compared to history of no suicide attempt) would be associated with increased fear-potentiated startle. Methods A post-hoc analysis of fear- and anxiety-potentiated startle was conducted in 28 medication-free patients with Major Depressive Disorder (MDD) divided according to suicide attempt history. Results The magnitude of fear-potentiated startle was increased in depressed patients with lifetime suicide attempts compared to those without a lifetime history of suicide attempt (F(1,26) = 5.629, p = .025). There was no difference in anxiety-potentiated startle by suicide attempt history. Limitations This is a post-hoc analysis of previously analyzed patient data from a study of depressed inpatients. Further replication of the finding with a larger patient sample is indicated. Conclusions Increased fear-potentiated startle in suicide attempters suggests the role of amygdala in depressed patients with a suicide attempt history. Findings highlight the importance of anxiety symptoms in the treatment of patients at increased suicide risk.

OBJECTIVE Processing speed alters the traditional Stroop calculations of interference. Consequently, alternative algorithms for calculating Stroop interference have been introduced to control for processing speed, and have done so in a multiple sclerosis sample. This study examined how these processing speed correction algorithms change interference scores for individuals with idiopathic Parkinson’s Disease (PD, n= 58) and non-PD peers (n= 68). METHOD Linear regressions controlling for demographics predicted group (PD vs. non-PD) differences for Jensen’s, Golden’s, relative, ratio, and residualized interference scores. To examine convergent and divergent validity, interference scores were correlated to standardized measures of processing speed and executive function. RESULTS PD - non-PD differences were found for Jensen’s interference score, but not Golden’s score, or the relative, ratio, and residualized interference scores. Jensens’ score correlated significantly with standardized processing speed but not executive function measures. Relative, ratio and residualized scores correlated with executive function but not processing speed measures. Golden’s score did not correlate with any other standardized measures. CONCLUSIONS The relative, ratio, and residualized scores were comparable for measuring Stroop interference in processing speed-impaired populations. Overall, the ratio interference score may be the most useful calculation method to control for processing speed in this population.

PurposeThis study examined the links between 24-hour activity patterns (specifically, amplitude and timing of wrist activity) and the persisting qualities of clinical antidepressant response to the glutamatergic modulator ketamine.MethodsTwenty-four-hour activity patterns were compared across 5 days of 24-hour activity rhythms in patients with major depressive disorder who displayed either a brief antidepressant response (24–48 hours), a continued antidepressant response (>72 hours), or no antidepressant response to ketamine. These postinfusion-response profiles were then used retrospectively to examine cohort-specific fitted parameters at baseline, postinfusion day 1 (D1), and postinfusion D3.ResultsRelative to the nonresponders, the cohort experiencing a brief antidepressant response had blunted 24-hour amplitude that extended from baseline through D3 and postketamine phase advance of activity on D1 that reverted to baseline on D3. Relative to the nonresponders, the cohort experiencing a continued antidepressant response to ketamine had phase-advanced activity at both baseline and D1, as well as increased amplitude on D1 and D3.ConclusionTaken together, the results suggest that the time course of antidepressant response to ketamine is influenced by underlying biological differences in motor activity timekeeping. These differences may provide clues that link durable mood response with the molecular machinery of the circadian system, thus leading to more effective interventions. In addition, biomarkers of preinfusion motor activity (eg, amplitude, timing) may be useful for recommending future individualized treatment interventions, to the extent that they help identify patients who may relapse quickly after treatment.

The feasibility of mindful hypnotherapy (MH) intervention for stress reduction was investigated in a randomized trial. Forty-two collegeage participants with elevated stress were randomized into MH intervention or wait-list control condition. MH participants completed an 8-week intervention with 1-hour individual sessions and self-hypnosis audio recordings for daily mindfulness. Results indicated excellent feasibility, determined by participant satisfaction, treatment adherence (84% compliance rate), and low rate of adverse events (4.5%). There were significant differences between the MH and control groups postintervention, with the mindful hypnotherapy intervention resulting in significant and large decrease in perceived distress, p < .001, 15.35 (1.54), Hedge's g = − 1.14, and increase in mindfulness, p < .001, 50.07 (2.04), Hedge's g = 1.36. This study indicates that MH is a feasible intervention for stress reduction and increasing mindfulness.