Assessment of Objective and Subjective Cognitive Function in Patients With Treatment-Resistant Depression Undergoing Repeated Ketamine Infusions.

BACKGROUND: Subanesthetic ketamine infusions can elicit rapid and sustained antidepressant effects, yet the potential cognitive impact of ketamine has not been thoroughly examined. This study measured changes in objective and subjective cognitive function following repeated ketamine treatment. METHODS: Thirty-eight patients with treatment-resistant depression were administered cognitive assessments before and after undergoing 7 i.v. ketamine infusions (0.5 mg/kg over 40 minutes) within a clinical trial examining the efficacy of single and repeated administrations. Depression severity and perceived concentration were evaluated with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptoms Self-Report. RESULTS: Twenty-three participants (60.5%) responded after repeated infusions (≥50% decrease in MADRS total scores). We measured significant improvements in several cognitive domains, including attention, working memory, verbal, and visuospatial memory (effect sizes ranging from Cohen d = 0.37-0.79). Cognitive changes were attributed to reduction in depressive symptoms except for improvement in verbal memory, which remained significant after adjustment for change in MADRS total score (P = .029, η p2 = 0.13). Only responders reported improvement in subjective cognitive function with repeated ketamine administration (MADRS item 6, P < .001, d = 2.00; Quick Inventory of Depressive Symptoms Self-Report item 10, P < .001, d = 1.36). CONCLUSION: A short course of repeated ketamine infusions did not impair neurocognitive function in patients with treatment-resistant depression. Further research is required to understand the potential mediating role of response and remission on improved cognitive function accompanying ketamine treatment as well as to examine longer-term safety outcomes. ClinicalTrials.gov identifier NCT01945047.

Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial.

(Reprinted with permission from The American Journal of Psychiatry 2019; 176:401-409).

Single and repeated ketamine infusions for reduction of suicidal ideation in treatment-resistant depression.

Repeated administration of subanesthetic intravenous ketamine may prolong the rapid decrease in suicidal ideation (SI) elicited by single infusions. The purpose of this secondary analysis was to evaluate reduction in SI with a single ketamine infusion compared with an active control, and prolonged suppression of SI with repeated and maintenance infusions. Thirty-seven participants with treatment-resistant depression (TRD) and baseline SI first received a single ketamine infusion during a randomized, double-blind crossover with midazolam. Following relapse of depressive symptoms, participants received six open-label ketamine infusions administered thrice-weekly over 2 weeks. Antidepressant responders (≥50% decrease in Montgomery-Åsberg Depression Rating Scale [MADRS] scores) received four further open-label infusions administered once-weekly. Changes in SI were assessed with the suicide items on the MADRS (item 10, MADRS-SI) and the Quick Inventory of Depressive Symptomatology-Self Report (item 12, QIDS-SI). Linear mixed models revealed that compared with midazolam, a single ketamine infusion elicited larger reduction in SI (P = 0.01), with maximal effects measured at 7 days postinfusion (P < 0.001, Cohen's d = 0.83). Participants had cumulative reductions in MADRS-SI scores with repeated infusions (P < 0.001), and no further change with maintenance infusions (P = 0.94). QIDS-SI results were consistent with MADRS-SI. Overall, 69% of participants had a complete alleviation of SI following repeated infusions. In TRD, single and repeated ketamine infusions resulted in decreases in SI which were maintained with once-weekly maintenance infusions. This study adds to the growing body of research suggesting ketamine as a possible novel treatment strategy for SI in mood disorders.

Ketamine for chronic depression: two cautionary tales

A growing body of literature has shown the effectiveness of ketamine for treating chronic depression. How long the beneficial effects of repeated ketamine last once infusions are stopped, however, remains largely unknown. Understanding the challenges that ensue after ketamine cessation can help clinicians optimally guide patients who opt for ketamine treatment and minimize the associated risks. In this commentary, we discuss some unexpected data gathered from participants of a pilot study on the effects of adjunctive ketamine infusion for resistant depression.

Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial.

OBJECTIVE: Subanesthetic ketamine doses have been shown to have rapid yet transient antidepressant effects in patients with treatment-resistant depression, which may be prolonged by repeated administration. The purpose of this study was to evaluate the antidepressant effects of a single ketamine infusion, a series of repeated ketamine infusions, and prolongation of response with maintenance infusions. METHODS: Forty-one participants with treatment-resistant depression completed a single-site randomized double-blind crossover comparison of single infusions of ketamine and midazolam (an active placebo control). After relapse of depressive symptoms, participants received a course of six open-label ketamine infusions administered thrice weekly over 2 weeks. Responders, classified as those participants who had a ≥50% decrease in their scores on the Montgomery-Åsberg Depression Rating Scale (MADRS), received four additional infusions administered once weekly (maintenance phase). RESULTS: Compared with midazolam, a single ketamine infusion elicited a significantly greater reduction in depressive symptoms at the primary efficacy endpoint (24 hours postinfusion). Linear mixed models revealed cumulative antidepressant effects with repeated infusions and doubling of the antidepressant response rate. Fifty-nine percent of participants met response criteria after repeated infusions, with a median of three infusions required before achieving response. Participants had no further change in MADRS scores during weekly maintenance infusions. CONCLUSIONS: Repeated ketamine infusions have cumulative and sustained antidepressant effects. Reductions in depressive symptoms were maintained among responders through once-weekly infusions. These findings provide novel data on efficacious administration strategies for ketamine in patients with treatment-resistant depression. Future studies should further expand on optimizing administration to better translate the use of ketamine into clinical settings.

What clinicians want: findings from a psychotherapy practice research network survey.

Practice research networks may be one way of advancing knowledge translation and exchange (KTE) in psychotherapy. In this study, we document this process by first asking clinicians what they want from psychotherapy research. Eighty-two psychotherapists in 10 focus groups identified and discussed psychotherapy research topics relevant to their practices. An analysis of these discussions led to the development of 41 survey items. In an online survey, 1,019 participants, mostly practicing clinicians, rated the importance to their clinical work of these 41 psychotherapy research topics. Ratings were reduced using a principal components analysis in which 9 psychotherapy research themes emerged, accounting for 60.66% of the variance. Two postsurvey focus groups of clinicians (N = 22) aided in interpreting the findings. The ranking of research themes from most to least important were-Therapeutic Relationship/Mechanisms of Change, Therapist Factors, Training and Professional Development, Client Factors, Barriers and Stigma, Technology and Adjunctive Interventions, Progress Monitoring, Matching Clients to Therapist or Therapy, and Treatment Manuals. Few differences were noted in rankings based on participant age or primary therapeutic orientation. Postsurvey focus group participants were not surprised by the top-rated items, as they were considered most proximal and relevant to therapists and their work with clients during therapy sessions. Lower ranked items may be perceived as externally imposed agendas on the therapist and therapy. We discuss practice research networks as a means of creating new collaborations consistent with KTE goals. Findings of this study can help to direct practitioner-researcher collaborations.

Presence is just an illusion: using fMRI to locate the brain area responsible to the meaning given to places.

Researchers have suggested different models to describe the feeling of presence. Most of them imply that presence is some kind of alternate state. Research conducted in our research team lead us to consider presence simply like a very powerful perceptual illusion, with the addition of challenging the meaning given to the place where the user actually is (i.e., being "there"). The aim of this study is to investigate the neural correlates of the illusion of presence in VR. Five right-handed adults were scanned in the fMRI and were immersed in two conditions: high and low presence, where the exact same stimulus was presented to participants during each condition but the context (narrative) provided differed significantly. Results show a clear, specific and statistically significant involvement of the parahippocampal area, the brain responsible for giving contextual meaning of places.

Effects of diffuse noxious inhibitory controls (DNICs) on the sensory-discriminative dimension of pain perception.

We have recently demonstrated that humans report heat stimuli as less painful when presented concurrently with a second noxious stimulus applied to another part of the body. Previous neurophysiological studies have shown that similar heterotopically applied noxious stimuli selectively and completely inhibit the activity of wide-dynamic-range (WDR) neurons in the dorsal horn - a phenomenon termed diffuse noxious inhibitory controls (DNICs). Taken together, these 2 lines of evidence suggest that activation of WDR cells may be necessary for normal perception of pain. Recent studies in the behaving monkey have additionally shown that WDR neurons respond to small changes in noxious heat stimuli better than do high threshold neurons, thus indicating a more specific role for WDR neurons in sensory-discriminative aspects of pain perception. If DNICs do indeed selectively and completely inhibit the activity of WDR neurons, then a heterotopically applied noxious stimulus should selectively interfere with a subject's ability to discriminate noxious stimuli. This hypothesis was tested using a noxious heat discrimination task and a cold water (5 degrees C) diffuse noxious stimulus. We found that the ability to detect small changes (0.4-0.8 degrees C) in painful heat stimuli applied to the face decreases when the person's hand is submerged in painfully cold water (P = 0.005) and that this effect persists, to a lesser extent, after the hand is removed from water. Control tasks, using visual stimuli, demonstrated that the modulation of nociceptive discrimination was not a generalized effect on sensory perception; other control measures indicated that the results could not be attributed to distraction, fatigue or changes in response bias.(ABSTRACT TRUNCATED AT 250 WORDS)

Diffuse noxious inhibitory controls (DNICs): psychophysical evidence in man for intersegmental suppression of noxious heat perception by cold pressor pain.

Counterirritation, the phenomenon of one painful stimulus reducing pain caused by a second noxious stimulus, has been recognized clinically for decades. Recently a physiological mechanism to explain counterirritation was described and termed diffuse noxious inhibitory controls (DNICs). Nevertheless, few psychophysical studies have examined systematically the effects of a noxious conditioning stimulus on pain perception. The present study examined the perception of painful heat stimuli on the face before, during and after the subject submerged a hand in painfully cold water (5 degrees C) for 5 min (cold pressor pain). We found that the subjects' ratings of the heat stimuli were significantly, although not completely, reduced during the cold pressor pain; this attenuation of pain perception continued after the noxious conditioning stimulus was withdrawn. Similarly, the pain threshold was significantly increased from 45.7 degrees C to 47.3 degrees C while the hand was in cold water and this threshold remained elevated after the cold water was terminated. Since DNICs have been found to completely and selectively inhibit the activity of only one type of pain transmission neuron (wide dynamic range), our data suggest that these neurons are involved in the perception of pain intensity. However, the persistence of residual pain perception in the presence of noxious conditioning stimuli indicates the importance of other nociceptive pathways.