-
1.
Mood and neuropsychological effects of different doses of ketamine in electroconvulsive therapy for treatment-resistant depression.
Zhong, X, He, H, Zhang, C, Wang, Z, Jiang, M, Li, Q, Zhang, M, Huang, X
Journal of affective disorders. 2016;:124-30
Abstract
BACKGROUND Treatment-resistant depression (TRD) is a growing clinical challenge. Electroconvulsive therapy (ECT) is an effective tool for TRD treatment. However, there remains a subset of patients who do not respond to this treatment with common anesthetic agent. Ketamine, a noteworthy anesthetic agent, has emerged as an augmentation to enhance the antidepressant efficacy of ECT. Trials of i.v. ketamine in TRD indicated dose-related mood enhancing efficacy. We aimed to explore anesthetic and subanesthetic concentrations of ketamine in ECT for TRD with respect to their impact on mood and neuropsychological effects. METHODS Ninety TRD patients (36 males, 54 females; average age, 30.6 years old) were randomly assigned to receive either ketamine (0.8mg/kg) (n=30), subanesthetic ketamine (0.5mg/kg) plus propofol (0.5mg/kg) (n=30) or propofol (0.8mg/kg) (n=30) as an anesthetic and underwent 8 ECT sessions. The primary outcome measures were the 17-item Hamilton Depression Rating Scale (HDRS-17), cognitive assessments and seizure parameters. RESULTS The ketamine group had an earlier improvement in HDRS-17, longer seizure duration, lower electric quantity, a higher remission rate, and a lower degree of executive cognitive impairment compared to the ketamine+propofol and propofol groups. The ketamine+propofol group showed earlier improvement in the HDRS-17, a longer seizure duration and a different seizure energy index when compared to the propofol group. LIMITATIONS The postoperative dissociative side effect was not assessed. CONCLUSIONS Both anesthetic and subanesthetic concentrations of ketamine have rapid mood enhancing actions in ECT for TRD, while anesthetic concentrations results in larger magnitudes of antidepression and cognitive protection. ECT with ketamine anesthesia might be an optimized therapy for patients with TRD.
-
2.
Rapid antidepressant effects of repeated doses of ketamine compared with electroconvulsive therapy in hospitalized patients with major depressive disorder.
Ghasemi, M, Kazemi, MH, Yoosefi, A, Ghasemi, A, Paragomi, P, Amini, H, Afzali, MH
Psychiatry research. 2014;(2):355-61
Abstract
Accumulating evidence suggests that N-methyl-d-aspartate receptor (NMDAR) antagonists (e.g. ketamine) may exert rapid antidepressant effects in MDD patients. In the present study, we evaluated the rapid antidepressant effects of ketamine compared with the electroconvulsive therapy (ECT) in hospitalized patients with MDD. In this blind, randomized study, 18 patients with DSM-IV MDD were divided into two groups which received either three intravenous infusions of ketamine hydrochloride (0.5 mg/kg over 45 min) or ECT on 3 test days (every 48 h). The primary outcome measure was the Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS), which was used to rate overall depressive symptoms at baseline, 24 h after each treatment, 72 h and one week after the last (third) ketamine or ECT. Within 24 h, depressive symptoms significantly improved in subjects receiving the first dose of ketamine compared with ECT group. Compared to baseline level, this improvement remained significant throughout the study. Depressive symptoms after the second dose ketamine was also lower than the second ECT. This study showed that ketamine is as effective as ECT in improving depressive symptoms in MDD patients and have more rapid antidepressant effects compared with the ECT.
-
3.
The NMDA antagonist ketamine and the 5-HT agonist psilocybin produce dissociable effects on structural encoding of emotional face expressions.
Schmidt, A, Kometer, M, Bachmann, R, Seifritz, E, Vollenweider, F
Psychopharmacology. 2013;(1):227-39
-
-
Free full text
-
Abstract
RATIONALE Both glutamate and serotonin (5-HT) play a key role in the pathophysiology of emotional biases. Recent studies indicate that the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine and the 5-HT receptor agonist psilocybin are implicated in emotion processing. However, as yet, no study has systematically compared their contribution to emotional biases. OBJECTIVES This study used event-related potentials (ERPs) and signal detection theory to compare the effects of the NMDA (via S-ketamine) and 5-HT (via psilocybin) receptor system on non-conscious or conscious emotional face processing biases. METHODS S-ketamine or psilocybin was administrated to two groups of healthy subjects in a double-blind within-subject placebo-controlled design. We behaviorally assessed objective thresholds for non-conscious discrimination in all drug conditions. Electrophysiological responses to fearful, happy, and neutral faces were subsequently recorded with the face-specific P100 and N170 ERP. RESULTS Both S-ketamine and psilocybin impaired the encoding of fearful faces as expressed by a reduced N170 over parieto-occipital brain regions. In contrast, while S-ketamine also impaired the encoding of happy facial expressions, psilocybin had no effect on the N170 in response to happy faces. CONCLUSION This study demonstrates that the NMDA and 5-HT receptor systems differentially contribute to the structural encoding of emotional face expressions as expressed by the N170. These findings suggest that the assessment of early visual evoked responses might allow detecting pharmacologically induced changes in emotional processing biases and thus provides a framework to study the pathophysiology of dysfunctional emotional biases.
-
4.
Mismatch negativity encoding of prediction errors predicts S-ketamine-induced cognitive impairments.
Schmidt, A, Bachmann, R, Kometer, M, Csomor, PA, Stephan, KE, Seifritz, E, Vollenweider, FX
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2012;(4):865-75
-
-
Free full text
-
Abstract
Psychotomimetics like the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine and the 5-hydroxytryptamine2A receptor (5-HT(2A)R) agonist psilocybin induce psychotic symptoms in healthy volunteers that resemble those of schizophrenia. Recent theories of psychosis posit that aberrant encoding of prediction errors (PE) may underlie the expression of psychotic symptoms. This study used a roving mismatch negativity (MMN) paradigm to investigate whether the encoding of PE is affected by pharmacological manipulation of NMDAR or 5-HT(2A)R, and whether the encoding of PE under placebo can be used to predict drug-induced symptoms. Using a double-blind within-subject placebo-controlled design, S-ketamine and psilocybin, respectively, were administrated to two groups of healthy subjects. Psychological alterations were assessed using a revised version of the Altered States of Consciousness (ASC-R) questionnaire. As an index of PE, we computed changes in MMN amplitudes as a function of the number of preceding standards (MMN memory trace effect) during a roving paradigm. S-ketamine, but not psilocybin, disrupted PE processing as expressed by a frontally disrupted MMN memory trace effect. Although both drugs produced positive-like symptoms, the extent of PE processing under placebo only correlated significantly with the severity of cognitive impairments induced by S-ketamine. Our results suggest that the NMDAR, but not the 5-HT(2A)R system, is implicated in PE processing during the MMN paradigm, and that aberrant PE signaling may contribute to the formation of cognitive impairments. The assessment of the MMN memory trace in schizophrenia may allow detecting early phases of the illness and might also serve to assess the efficacy of novel pharmacological treatments, in particular of cognitive impairments.
-
5.
A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression.
Diazgranados, N, Ibrahim, L, Brutsche, NE, Newberg, A, Kronstein, P, Khalife, S, Kammerer, WA, Quezado, Z, Luckenbaugh, DA, Salvadore, G, et al
Archives of general psychiatry. 2010;(8):793-802
-
-
Free full text
-
Abstract
CONTEXT Existing therapies for bipolar depression have a considerable lag of onset of action. Pharmacological strategies that produce rapid antidepressant effects-for instance, within a few hours or days-would have an enormous impact on patient care and public health. OBJECTIVE To determine whether an N-methyl-D-aspartate-receptor antagonist produces rapid antidepressant effects in subjects with bipolar depression. DESIGN A randomized, placebo-controlled, double-blind, crossover, add-on study conducted from October 2006 to June 2009. SETTING Mood Disorders Research Unit at the National Institute of Mental Health, Bethesda, Maryland. Patients Eighteen subjects with DSM-IV bipolar depression (treatment-resistant). INTERVENTIONS Subjects maintained at therapeutic levels of lithium or valproate received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days 2 weeks apart. The Montgomery-Asberg Depression Rating Scale was used to rate subjects at baseline and at 40, 80, 110, and 230 minutes and on days 1, 2, 3, 7, 10, and 14 postinfusion. MAIN OUTCOME MEASURES Change in Montgomery-Asberg Depression Rating Scale primary efficacy measure scores. RESULTS Within 40 minutes, depressive symptoms significantly improved in subjects receiving ketamine compared with placebo (d = 0.52, 95% confidence interval [CI], 0.28-0.76); this improvement remained significant through day 3. The drug difference effect size was largest at day 2 (d = 0.80, 95% CI, 0.55-1.04). Seventy-one percent of subjects responded to ketamine and 6% responded to placebo at some point during the trial. One subject receiving ketamine and 1 receiving placebo developed manic symptoms. Ketamine was generally well tolerated; the most common adverse effect was dissociative symptoms, only at the 40-minute point. CONCLUSION In patients with treatment-resistant bipolar depression, robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist.
-
6.
Ethanol-like effects of thiopental and ketamine in healthy humans.
Dickerson, D, Pittman, B, Ralevski, E, Perrino, A, Limoncelli, D, Edgecombe, J, Acampora, G, Krystal, JH, Petrakis, I
Journal of psychopharmacology (Oxford, England). 2010;(2):203-11
-
-
Free full text
-
Abstract
The gamma-aminobutyric acid-A (GABA(A)) and N-methyl-D-aspartate (NMDA) receptors mediate aspects of the behavioural effects of alcohol. Prior studies reported drugs that block NMDA receptors or facilitate GABA(A) receptor function produce ethanol-like effects in humans. The purpose of this study was to compare the ethanol-related effects of two pharmacological agents with known NMDA and GABA(A) receptor activity. As part of an ongoing, larger study, 28 subjects (age, 21-30) with no personal or family histories of alcoholism were administered subanesthetic doses of the GABA(A) receptor agonist thiopental, the NMDA receptor antagonist, ketamine and placebo on three separate test days. Various ethanol-related measures were administered. At doses of thiopental and ketamine that produced similar levels of sedation and cognitive effects, both agents produced significant ethanol-like effects and subjective intoxication. However, the intensity of the ethanol-like effects of ketamine was greater than that of thiopental. In addition, ketamine produced alterations in perception that were not produced by thiopental. These data provide further support for a model where GABA(A) receptor facilitation may contribute significantly to ethanol effects associated with social drinking, whereas NMDA receptor antagonism may contribute to relatively greater extent to features of ethanol 'intoxication'.
-
7.
Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist.
Phelps, LE, Brutsche, N, Moral, JR, Luckenbaugh, DA, Manji, HK, Zarate, CA
Biological psychiatry. 2009;(2):181-4
-
-
Free full text
-
Abstract
BACKGROUND A high rate of comorbidity exists between mood disorders and alcohol dependence. Furthermore, both ketamine, a dissociative anesthetic with a recently described rapid-onset antidepressant effect, and ethanol are N-methyl-D-aspartate (NMDA) receptor antagonists. Previous investigations of healthy individuals with a family history of alcohol dependence have found that these individuals have an attenuated response to ketamine's perceptual disturbance and dysphoric effects similar to that found in individuals with a self-reported history of alcohol dependence. This study investigated whether a family history of alcohol dependence influences ketamine's initial antidepressant effect. METHODS Twenty-six subjects with DSM-IV treatment-resistant major depression were given an open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg) and rated using various depression scales at baseline, 40, 80, 120, and 230 min postinfusion. The primary outcome measure was Montgomery-Asberg Depression Rating Scale (MADRS) scores. RESULTS Subjects with a family history of alcohol dependence showed significantly greater improvement in MADRS scores compared with subjects who had no family history of alcohol dependence. CONCLUSIONS A family history of alcohol dependence appears to predict a rapid initial antidepressant response to an NMDA receptor antagonist.
-
8.
Ketamine aggravates symptoms of acute stress disorder in a naturalistic sample of accident victims.
Schönenberg, M, Reichwald, U, Domes, G, Badke, A, Hautzinger, M
Journal of psychopharmacology (Oxford, England). 2008;(5):493-7
Abstract
The glutamatergic N-methyl-D-aspartate receptor antagonist ketamine produces transient dissociative states and alters cognitive functioning in healthy humans, thus resembling the core symptoms of acute and chronic post-traumatic stress disorder (PTSD). First evidence exists that the common use of the analgesic and sedative properties of ketamine during emergency care correlates with sustained symptoms of PTSD in accident victims. The aim of the present study was to examine whether ketamine administration after moderate accidental trauma modulates dissociation and other symptoms of acute stress disorder (ASD) in the direct aftermath of the event. Accident victims were screened within the third day after admission to hospital for symptoms of ASD (Peritraumatic Dissociative Experiences Questionnaire, ASD Scale) and prior stressful life events (Traumatic Life Events Questionnaire). Subjects had received a single or fractionated dose of either racemic ketamine (n=13), opioids (n=24) or non-opioid analgesics (n=13) during initial emergency treatment. There were no significant differences between medication groups in demographic and clinical characteristics such as injury severity or prior traumatization. With respect to ASD symptomatology three days post-event there were significant associations between ketamine analgosedation and increased symptoms of dissociation, reexperiencing, hyperarousal and avoidance relative to the comparison groups.Growing evidence exists that ketamine might modulate or aggravate early post-traumatic stress reactions when given in the acute trauma phase, which in turn might contribute to long-lasting symptomatology.
-
9.
Effects of the NMDA-receptor antagonist ketamine on perceptual correlates of long-term potentiation within the nociceptive system.
Klein, T, Magerl, W, Nickel, U, Hopf, HC, Sandkühler, J, Treede, RD
Neuropharmacology. 2007;(2):655-61
Abstract
We recently reported perceptual correlates of long-term potentiation (LTP) of synaptic strength within the nociceptive system demonstrating the functional relevance of LTP for human pain sensation. LTP is generally classified as NMDA-receptor dependent or independent. Here we show that low doses of the NMDA-receptor antagonist ketamine (0.25 mg/kg) prevented the long-term increase in perceived pain to electrical test stimuli, which was induced by high-frequency electrical stimulation (HFS) of nociceptive afferents. Whereas in a control experiment HFS led to a stable increase in perceived pain by 51% for the entire observation period of 1h HFS given 4 min after i.v. ketamine was ineffective. In contrast, HFS induced a two-fold increase of pinprick-evoked pain surrounding the HFS site (secondary neurogenic hyperalgesia) in both experiments. Pain evoked by light tactile stimuli (allodynia) was also unaffected by ketamine. These data support the concept that homotopic hyperalgesia to electrical stimulation of the conditioned pathway is a perceptual correlate of NMDA-receptor sensitive homosynaptic LTP in the nociceptive system, e.g. in the spinal cord. Although secondary neurogenic hyperalgesia and allodynia are induced by the same HFS protocol, they involve additional NMDA-receptor insensitive mechanisms of heterosynaptic facilitation.
-
10.
Effects of ketamine on serum and tracheobronchial aspirate interleukin-6 levels in infants undergoing cardiac surgery.
Zeyneloglu, P, Donmez, A, Bilezikci, B, Mercan, S
Journal of cardiothoracic and vascular anesthesia. 2005;(3):329-33
Abstract
OBJECTIVE Corrective surgery for congenital heart defects in children frequently requires cardiopulmonary bypass (CPB). Serum and bronchoalveolar levels of interleukin-6 (IL-6) may be useful in assessing the severity of the systemic inflammatory response after CPB. In the present study, the authors aimed to compare the effects of ketamine anesthesia and isoflurane anesthesia with respect to serum and tracheobronchial aspirate (TBA) IL-6 levels in infants undergoing CPB for cardiac surgery. DESIGN Prospective and randomized controlled study. SETTING University-based teaching hospital. PARTICIPANTS Thirty-four infants aged 2 to 24 months were randomized into 2 groups. INTERVENTIONS In group K (n = 17), anesthesia was induced with intravenous (IV) ketamine, 1 to 2 mg/kg, and fentanyl, 1 to 2 microg/kg, and was maintained with infusions of ketamine, 25 to 75 microg/kg/min, and fentanyl, 10 microg/kg/h. In group I (n = 17), induction was achieved with IV thiopental sodium, 3 to 5 mg/kg, and fentanyl, 1 to 2 microg/kg, and was maintained with 1% isoflurane and fentanyl, 10 mug/kg/h. Blood and TBA samples were obtained at 6 and 4 stages, respectively. MEASUREMENTS AND MAIN RESULTS Serum IL-6 and TBA IL-6 levels were similar in the 2 groups at all stages (p > 0.05). CONCLUSION The present results show that ketamine anesthesia does not provide superiority over isoflurane anesthesia with respect to serum and TBA IL-6 levels.