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Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression.

BACKGROUND A single subanesthetic (intravenous) IV dose of ketamine might have rapid but transient antidepressant effects in patients with treatment-resistant depression (TRD). Here we tested the tolerability, safety, and efficacy of repeated-dose open-label IV ketamine (six infusions over 12 days) in 10 medication-free symptomatic patients with TRD who had previously shown a meaningful antidepressant response to a single dose. METHODS On day 1, patients received a 40-min IV infusion of ketamine (.5 mg/kg) in an inpatient setting with continuous vital-sign monitoring. Psychotomimetic effects and adverse events were recorded repeatedly. The primary efficacy measure was change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) score. If patients showed a > or =50% reduction in MADRS scores on day 2, they received five additional infusions on an outpatient basis (days 3, 5, 8, 10, and 12). Follow-up visits were conducted twice-weekly for > or =4 weeks or until relapse. RESULTS Ketamine elicited minimal positive psychotic symptoms. Three patients experienced significant but transient dissociative symptoms. Side effects during and after each ketamine infusion were generally mild. The response criterion was met by nine patients after the first infusion as well as after the sixth infusion. The mean (SD) reduction in MADRS scores after the sixth infusion was 85% (12%). Postketamine, eight of nine patients relapsed, on average, 19 days after the sixth infusion (range 6 days-45 days). One patient remained antidepressant-free with minimal depressive symptoms for >3 months. CONCLUSIONS These pilot findings suggest feasibility of repeated-dose IV ketamine for the acute treatment of TRD.

Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression

BACKGROUND Ketamine is reported to have rapid antidepressant effects; however, there is limited understanding of the time-course of ketamine effects beyond a single infusion. A previous report including 10 participants with treatment-resistant major depression (TRD) found that six ketamine infusions resulted in a sustained antidepressant effect. In the current report, we examined the pattern and durability of antidepressant effects of repeated ketamine infusions in a larger sample, inclusive of the original. METHODS Participants with TRD (n = 24) underwent a washout of antidepressant medication followed by a series of up to six IV infusions of ketamine (.5 mg/kg) administered open-label three times weekly over a 12-day period. Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion. RESULTS The overall response rate at study end was 70.8%. There was a large mean decrease in Montgomery-Åsberg Depression Rating Scale score at 2 hours after the first ketamine infusion (18.9 ± 6.6, p < .001), and this decrease was largely sustained for the duration of the infusion period. Response at study end was strongly predicted by response at 4 hours (94% sensitive, 71% specific). Among responders, median time to relapse after the last ketamine infusion was 18 days. CONCLUSIONS Ketamine was associated with a rapid antidepressant effect in TRD that was predictive of a sustained effect. Future controlled studies will be required to identify strategies to maintain an antidepressant response among patients who benefit from a course of ketamine.

Neurobiological mechanisms in major depressive disorder

Nearly 1 in 5 people will experience a major depressive episode at some point in their lives.[1][1] In this review, we discuss data describing how genes, psychosocial adversity in childhood, and ongoing or recent psychosocial stress may impact multiple neurobiological systems relevant to major

Ketamine for depression: Where do we go from here?

Since publication of the first randomized controlled trial describing rapid antidepressant effects of ketamine, several reports have confirmed the potential utility of this dissociative anesthetic medication for treatment of major depressive episodes, including those associated with bipolar disorder and resistant to other medications and electroconvulsive therapy. These reports have generated several questions with respect to who might respond to ketamine, how, and for how long. To start answering these questions. We used PubMed.gov and ClinicalTrials.gov to perform a systematic review of all available published data on the antidepressant effects of ketamine and of all recently completed, ongoing, and planned studies. To date, 163 patients, primarily with treatment-resistant depression, have participated in case studies, open-label investigations, or controlled trials. All controlled trials have used a within-subject, crossover design with an inactive placebo as the control. Ketamine administration has usually involved an anaesthesiologist infusing a single, subanesthetic, intravenous dose, and required hospitalization for at least 24 hours postinfusion. Response rates in the open-label investigations and controlled trials have ranged from 25% to 85% at 24 hours postinfusion and from 14% to 70% at 72 hours postinfusion. Although adverse effects have generally been mild, some patients have experienced brief changes in blood pressure, heart rate, or respiratory rate. Risk-benefit analyses support further research of ketamine for individuals with severe mood disorders. However, given the paucity of randomized controlled trials, lack of an active placebo, limited data on long-term outcomes, and potential risks, ketamine administration is not recommended outside of the hospital setting.

Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial.

The N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine may have rapid, albeit transient, antidepressant properties. This study in patients with treatment-resistant major depression (TRD) aimed to (1) replicate the acute efficacy of single-dose intravenous (i.v.) ketamine; (2) test the efficacy of the glutamate-modulating agent riluzole in preventing post-ketamine relapse; and (3) examine whether pretreatment with lamotrigine would attenuate ketamines psychotomimetic effects and enhance its antidepressant activity. Twenty-six medication-free patients received open-label i.v. ketamine (0.5 mg/kg over 40 min). Two hours prior to infusion, patients were randomized to lamotrigine (300 mg) or placebo. Seventeen patients (65%) met response criterion (50% reduction from baseline on the Montgomery-Asberg Depression Rating Scale) 24 h following ketamine. Lamotrigine failed to attenuate the mild, transient side-effects associated with ketamine and did not enhance its antidepressant effects. Fourteen patients (54%) met response criterion 72 h following ketamine and proceeded to participate in a 32-d, randomized, double-blind, placebo-controlled, flexible-dose continuation trial of riluzole (100-200 mg/d). The main outcome measure was time-to-relapse. An interim analysis found no significant differences in time-to-relapse between riluzole and placebo groups [log-rank chi(2) = 0.17, d.f. = 1, p = 0.68], with 80% of patients relapsing on riluzole vs. 50% on placebo. The trial was thus stopped for futility. This pilot study showed that a sub-anaesthetic dose of i.v. ketamine is well-tolerated in TRD, and may have rapid and sustained antidepressant properties. Riluzole did not prevent relapse in the first month following ketamine. Further investigation of relapse prevention strategies post-ketamine is necessary.

Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial.

IMPORTANCE Few pharmacotherapies have demonstrated sufficient efficacy in the treatment of posttraumatic stress disorder (PTSD), a chronic and disabling condition. OBJECTIVE To test the efficacy and safety of a single intravenous subanesthetic dose of ketamine for the treatment of PTSD and associated depressive symptoms in patients with chronic PTSD. DESIGN, SETTING, AND PARTICIPANTS Proof-of-concept, randomized, double-blind, crossover trial comparing ketamine with an active placebo control, midazolam, conducted at a single site (Icahn School of Medicine at Mount Sinai, New York, New York). Forty-one patients with chronic PTSD related to a range of trauma exposures were recruited via advertisements. INTERVENTIONS Intravenous infusion of ketamine hydrochloride (0.5 mg/kg) and midazolam (0.045 mg/kg). MAIN OUTCOMES AND MEASURES The primary outcome measure was change in PTSD symptom severity, measured using the Impact of Event Scale-Revised. Secondary outcome measures included the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impression-Severity and -Improvement scales, and adverse effect measures, including the Clinician-Administered Dissociative States Scale, the Brief Psychiatric Rating Scale, and the Young Mania Rating Scale. RESULTS Ketamine infusion was associated with significant and rapid reduction in PTSD symptom severity, compared with midazolam, when assessed 24 hours after infusion (mean difference in Impact of Event Scale-Revised score, 12.7 [95% CI, 2.5-22.8]; P = .02). Greater reduction of PTSD symptoms following treatment with ketamine was evident in both crossover and first-period analyses, and remained significant after adjusting for baseline and 24-hour depressive symptom severity. Ketamine was also associated with reduction in comorbid depressive symptoms and with improvement in overall clinical presentation. Ketamine was generally well tolerated without clinically significant persistent dissociative symptoms. CONCLUSIONS AND RELEVANCE This study provides the first evidence for rapid reduction in symptom severity following ketamine infusion in patients with chronic PTSD. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with this disabling condition. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00749203.

Physical exercise and depression

Recently, the US Department of Health and Human Services issued its first ever physical activity guidelines, which were developed because ‘‘we clearly know enough now to recommend that all Americans . . . engage in regular physical activity to improve overall health and to reduce risk of many health problems.’’1 The current weekly recommendation (2.5 hours of moderate aerobic physical activity, 1.25 hours of vigorous aerobic physical activity, or an equivalent combination of moderate and vigorous aerobic physical activity plus additional muscle strengthening activities on 2 or more days) has increased from the 1995 recommendation issued by the American College of Sports Medicine and the Centers for Disease Control and Prevention of at least 30 minutes of moderate physical activity on most days of the week. The Mayo Clinic lists several medical benefits of regular physical activity on its Web site, including weight management, increased cardiovascular function, prevention and control of chronic diseases, and improvement in sleep.2 Number 1 on its list is the positive effect of physical activity on psychological well-being. Major depressive disorder (MDD) is characterized by periods of depressed mood and/or anhedonia (ie, loss of interest or pleasure) that last at least 2 weeks in combination with several somatic symptoms (changes in appetite, sleep, energy level, and psychomotor function) and cognitive disturbances (feelings of worthlessness or inappropriate

Experience sampling and ecological momentary assessment for studying the daily lives of patients with anxiety disorders: A systematic review

Anxiety disorders are highly prevalent. Symptoms may occur unpredictably (e.g., panic attacks) or predictably in specific situations (e.g., social phobia). Consequently, it may be difficult to assess anxiety and related constructs realistically in the laboratory or by traditional retrospective questionnaires. Experience sampling methods (ESM) and ecological momentary assessment (EMA) can deepen the understanding of the course of anxiety disorders by frequently assessing symptoms and other variables in the natural environment. We review 34 ESM/EMA studies on adult panic disorder, generalized anxiety disorder, social phobia, post-traumatic stress disorder, and obsessive-compulsive disorder, as well as anxiety disorders in youth. Benefits of ESM/EMA for the study of anxiety disorders include generating insight into the temporal variability of symptoms and into the associations among daily affect, behaviors, and situational cues. Further, ESM/EMA has been successfully combined with ambulatory assessment of physiological variables and with treatment evaluations. We provide suggestions for future research, as well as for clinical applications.

Bright light exposure during acute tryptophan depletion prevents a lowering of mood in mildly seasonal women

We investigated the influence of bright light exposure on the mood-lowering effect of acute tryptophan depletion (ATD). Mildly seasonal healthy young women without a personal or family history of psychiatric disorders remained in either dim or bright light during two test days. Tryptophan-deficient and nutritionally balanced amino acid mixtures were administered in counterbalanced order. Mood state was assessed using the Profile of Mood States (POMS) and Visual Analogue Scales (VAS). In dim light, ATD decreased POMS scores across most subscales, indicating a worsening of mood. In bright light, mood was unaffected by ATD. Thus, bright light blocked the worsening of mood caused by ATD. This was also observed on the positive mood VAS. These results indicate a direct, immediate interaction between bright light and serotonin function. Bright light might help protect against ATD-induced mood change by increasing serotonin above the threshold level below which there is a lowering of mood.

Alcohol in a social context: Findings from event-contingent recording studies of everyday social interactions

BACKGROUND Data concerning the effects of alcohol on social interaction in everyday life are limited. METHODS Healthy volunteers in 4 studies of social behaviors and mood were instructed to complete record forms immediately after a social interaction had occurred, a method known as event-contingent recording. Record forms asked questions about quarrelsome, agreeable, dominant, and submissive behaviors; about aspects of mood; and, in 3 studies, about perceptions of others. Each form also contained a question about alcohol consumption prior to a social interaction. For the present report, only social interactions taking place in the evening and outside the work setting were included. Only individuals who consumed alcohol at least once in these circumstances were included (n = 171). RESULTS Social interactions involving alcohol were primarily characterized by higher levels of agreeable behaviors, by perceptions of greater agreeableness in others, and by more positive mood. Alcohol consumption was not associated with higher levels of quarrelsomeness. CONCLUSIONS Alcohol consumption in a social context may have predominantly positive effects, an observation which is at odds with most alcohol-induced aggression experiments performed in laboratory settings. Drinking in everyday life may be less likely to result in aggression because, unlike in most laboratory experiments, individuals can choose among a variety of behaviors in response to social cues and the alcohol dose consumed is usually lower. Event-contingent recording provides a new approach for the study of alcohols effects in everyday life and the conditions in which alcohol might result in interpersonal aggression.