-
1.
Ketamine-facilitated behavioral treatment for cannabis use disorder: A proof of concept study.
Azhari, N, Hu, H, O'Malley, KY, Blocker, ME, Levin, FR, Dakwar, E
The American journal of drug and alcohol abuse. 2021;(1):92-97
Abstract
BACKGROUND Sub-anesthetic ketamine infusions may benefit a range of psychiatric conditions, including alcohol and cocaine use disorders. Currently, there are no effective pharmacological treatments for cannabis use disorder. OBJECTIVES The objective of this uncontrolled proof of concept trial was to test the feasibility, tolerability, and potential therapeutic effects of integrating ketamine infusions with a behavioral platform of motivational enhancement therapy and mindfulness-based relapse prevention in treating cannabis use disorder (CUD). METHODS Eight cannabis-dependent individuals (four female, four male) receiving motivational enhancement therapy and mindfulness-based relapse prevention behavioral treatments completed this single-blind outpatient 6-week study. Participants received either one or two infusions of ketamine (0.71 mg/kg [infusion 1]; 1.41 mg/kg [infusion 2] for non-responders) during the study. Participants self-reported cannabis use (Timeline Follow-Back) and underwent an assessment of confidence in abstaining from using cannabis (Drug-Taking Confidence Questionnaire) at predetermined time points throughout the study. RESULTS Ketamine infusions were well-tolerated and there were no adverse events. Frequency of cannabis use decreased significantly from baseline (B = 5.1, s.e = 0.7) to the week following the first infusion (B = 0.8, s.e = 0.412), and remained reduced at the end of the study (B = 0.5, s.e = 0.3). Participants' confidence in their ability to abstain from cannabis in potentially triggering situations increased significantly from baseline to the end of study. CONCLUSIONS These findings suggest that combining ketamine with behavioral therapy is feasible,tolerable, and potentially helpful, in treating cannabis-dependent individuals.
-
2.
Rating depression over brief time intervals with the Hamilton Depression Rating Scale: standard vs. abbreviated scales.
Luckenbaugh, DA, Ameli, R, Brutsche, NE, Zarate, CA
Journal of psychiatric research. 2015;:40-5
-
-
Free full text
-
Abstract
Although antidepressant trials typically use weekly ratings to examine changes in symptoms over six to 12 weeks, antidepressant treatments may improve symptoms more quickly. Thus, rating scales must be adapted to capture changes over shorter intervals. We examined the use of the 17-item Hamilton Depression Rating Scale (HDRS) to evaluate more rapid changes. Data were examined from 58 patients with major depressive disorder or bipolar disorder enrolled in double-blind, placebo-controlled, crossover studies who received a single infusion of ketamine (0.5 mg/kg) or placebo over 40 min then crossed over to the other condition. HDRS subscales, a single HDRS Depressed mood item, and a visual analogue scale were used at baseline, after a brief interval (230 min), and one week post-infusion. Effect sizes for the ketamine-placebo difference were moderate (d > 0.50), but one and two-item HDRS subscales had the smallest effects. Response rates on active drug were lowest for the complete HDRS (43%); the remaining scales had higher response rates to active drug, but the shortest subscales had higher response rates to placebo. Correlations between the changes from baseline to 230 min post-ketamine across scores were similar for most subscales (r = 0.82-0.97), but correlations using the single items were lower (r < 0.74). Overall, effect sizes for drug-placebo differences and correlations between changes were lower for one- and two-item measures. Response rates were lower with the full HDRS scale. The data suggest that, to best identify rapid antidepressant effects, a scale should have more than two items, but fewer items than a full scale.
-
3.
Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder.
DiazGranados, N, Ibrahim, LA, Brutsche, NE, Ameli, R, Henter, ID, Luckenbaugh, DA, Machado-Vieira, R, Zarate, CA
The Journal of clinical psychiatry. 2010;(12):1605-11
-
-
Free full text
-
Abstract
OBJECTIVE Suicidal ideation is a medical emergency, especially when severe. Little research has been done on pharmacologic interventions that could address this problem. Ketamine, an N-methyl-D-asparate antagonist, has been reported to have antidepressant effects within hours. We examined the effects of a single dose of ketamine on suicidal ideation in subjects with treatment-resistant major depressive disorder (MDD). METHOD Thirty-three subjects with DSM-IV-diagnosed MDD received a single open-label infusion of ketamine (0.5 mg/kg) and were rated at baseline and at 40, 80, 120, and 230 minutes postinfusion with the Scale for Suicide Ideation (SSI), the Montgomery-Åsberg Depression Rating Scale, the Hamilton Depression Rating Scale, and the Beck Depression Inventory. The study was conducted between October 2006 and January 2009. RESULTS Suicidal ideation scores decreased significantly on the SSI as well as on the suicide subscales of other rating instruments within 40 minutes; these decreases remained significant through the first 4 hours postinfusion (P < .001). Ten subjects (30%) had an SSI score ≥ 4 at baseline; all these scores dropped below 4 (9 dropped by 40 minutes and 1 by 80 minutes). For those patients with a starting score below 4 on the SSI, only 1 reached a score of 4. Depression, anxiety, and hopelessness were significantly improved at all time points (P < .001). CONCLUSIONS Suicidal ideation in the context of MDD improved within 40 minutes of a ketamine infusion and remained improved for up to 4 hours postinfusion. Future studies with ketamine in suicidal ideation are warranted due to the potential impact on public health. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00088699.
-
4.
Efficacy of ketamine in anesthetic dosage for the treatment of refractory complex regional pain syndrome: an open-label phase II study.
Kiefer, RT, Rohr, P, Ploppa, A, Dieterich, HJ, Grothusen, J, Koffler, S, Altemeyer, KH, Unertl, K, Schwartzman, RJ
Pain medicine (Malden, Mass.). 2008;(8):1173-201
Abstract
OBJECTIVE Advanced complex regional pain syndrome (CRPS) remains very difficult to treat. While subanesthetic low-dose ketamine has shown promise in early localized CRPS, its use in advanced CRPS has not been as effective. Since ketamine's analgesic potency and duration of effect in neuropathic pain are directly dose-dependant, we investigated the efficacy of ketamine in anesthetic dosage in refractory CRPS patients that had failed available standard therapies. METHODS Twenty ASA I-III patients suffering from refractory CRPS received ketamine in anesthetic dosage over 5 days. Outcome criteria were pain relief, effect on the movement disorder, quality of life, and ability to work at baseline and up to 6 months following treatment. RESULTS Significant pain relief was observed at 1, 3, and 6 months following treatment (93.5 +/- 11.1%, 89.4 +/- 17.0%, 79.3 +/- 25.3%; P < 0.001). Complete remission from CRPS was observed at 1 month in all patients, at 3 months in 17, and at 6 months in 16 patients. If relapse occurred, significant pain relief was still attained at 3 and 6 months (59.0 +/- 14.7%, P < 0.004; 50.2 +/- 10.6%, P < 0.002). Quality of life, the associated movement disorder, and the ability to work significantly improved in the majority of patients at 3 and 6 months. CONCLUSIONS This open-label trial suggests benefit in pain reduction, associated CRPS symptoms, improved quality of life and ability to work following anesthetic ketamine in previously refractory CRPS patients. However, a randomized controlled trial will be necessary to prove its efficacy.
-
5.
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.
-
6.
Ketamine attenuates glutamate-induced mechanical sensitization of the masseter muscle in human males.
Cairns, BE, Svensson, P, Wang, K, Castrillon, E, Hupfeld, S, Sessle, BJ, Arendt-Nielsen, L
Experimental brain research. 2006;(4):467-72
Abstract
The purpose of the present study was to determine whether glutamate-induced mechanical sensitization of the masseter muscle in human volunteers involves activation of peripheral N-methyl-D-aspartate (NMDA) receptors. Healthy male volunteers (n=18) participated in this randomized, two-session study. During each session, the volunteers received two injections into the right masseter muscle. An initial injection of glutamate (1 M, 0.2 ml) alone was followed 30 min later by a second injection of glutamate alone or glutamate combined with ketamine (10 mM). Pressure pain threshold (PPT) was assessed over the right masseter muscle at and 2 cm above the injection site, as well as over the right temporalis muscle and left masseter muscle prior to the first injection. The PPT was reassessed at all four sites every 5 min from 10 to 30 min after the second injection and once again 60 min after the second injection. Glutamate-evoked muscle pain, pain area and the sensory pain response index of the McGill pain questionnaire were all significantly reduced by co-injection of ketamine. The mean PPT values were significantly decreased by approximately 10%, 10, 15 and 25 min after injection of glutamate, but only over the site of injection. Co-injection of ketamine with glutamate also completely blocked the glutamate-induced mechanical sensitization 15 min post-injection as compared with glutamate alone. The lack of spread of mechanical sensitization outside the area of glutamate injection is consistent with the view that glutamate-induced mechanical sensitization results from a peripheral mechanism. The attenuation of glutamate-induced mechanical sensitization by ketamine suggests that this effect is mediated, in part, through activation of peripheral NMDA receptors.
-
7.
The intravenous ketamine test predicts subsequent response to an oral dextromethorphan treatment regimen in fibromyalgia patients.
Cohen, SP, Verdolin, MH, Chang, AS, Kurihara, C, Morlando, BJ, Mao, J
The journal of pain. 2006;(6):391-8
Abstract
UNLABELLED Fibromyalgia (FM) is a challenging pain syndrome for which no reliable pharmacologic treatment exists. Recent clinical studies suggest that N-methyl-D-aspartate receptors might play a role in the pathogenesis of this disorder. To determine whether an intravenous (IV) ketamine test predicts the response to a therapeutic trial with an oral N-methyl-D-aspartate receptor antagonist, we performed a low-dose (0.1 mg/kg) IV ketamine infusion on 34 consecutive patients with FM, which was subsequently followed by an oral dextromethorphan (DX) treatment regimen. As per previous guidelines, the cutoff value for a positive response to the IV ketamine test was designated to be 67% pain relief, and a positive response to DX treatment was 50% pain reduction at 4- to 6-week follow-up visits. The degree of correlation between pain relief with ketamine and DX was highly significant (Pearson correlation coefficient, 0.66; P < .001). Ten patients responded positively to both ketamine and DX, 19 responded to neither drug, 3 had a positive response to ketamine but not DX, and 2 obtained good pain relief with DX but not ketamine. The sensitivity of the IV ketamine test was 83%, the specificity was 86%, the positive predictive value was 77%, and the negative predictive value was 91%. An association was also found between the development of side effects to the two treatments. PERSPECTIVE The response to an IV ketamine infusion was found to predict the subsequent response to an oral dextromethorphan treatment regimen in fibromyalgia patients, with an observed agreement of 83%. Considering the refractory nature of fibromyalgia to conventional pain treatments, the IV ketamine test might enhance patient care by saving time and reducing unnecessary treatment trials.
-
8.
Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects.
Krystal, JH, Abi-Saab, W, Perry, E, D'Souza, DC, Liu, N, Gueorguieva, R, McDougall, L, Hunsberger, T, Belger, A, Levine, L, et al
Psychopharmacology. 2005;(1):303-9
Abstract
RATIONALE Some of the behavioral consequences of deficits in N-methyl-D-aspartate (NMDA) glutamate receptor function are thought to arise from the disinhibition of cortical glutamatergic circuitry. OBJECTIVE This study evaluated whether pretreatment with a drug that reduces glutamatergic activation, the group II metabotropic glutamate receptor (mGluR) agonist, LY354740, reduced the cognitive effects of the NMDA glutamate receptor antagonist, ketamine, in healthy human subjects. METHODS Nineteen healthy human subjects completed 3 test days during which LY354740 (matched placebo, 100 mg, 400 mg) was administered under double-blind conditions 4 h prior to the single-blind intravenous administration of saline and 5.7 h prior to ketamine administration (bolus of 0.26 mg/kg over 1 min, infusion of 0.65 mg/kg per hour for 100 min). Thus on each test day each subject received a single dose of LY354740 (or its matched placebo) and both saline and ketamine infusions. RESULTS Ketamine impaired attention, working memory, and delayed recall. It also produced positive and negative symptoms, perceptual changes, and dysphoric mood. LY354740 did not have a significant effect on working memory on the placebo day; however, it produced a significant dose-related improvement in working memory during ketamine infusion. CONCLUSIONS These data provide preliminary and suggestive evidence that LY354740 or other group II mGluR agonists might play a role in treating working memory impairment related to deficits in NMDA receptor function.
-
9.
A study of a topiramate pre-treatment on the effects induced by a subanaesthetic dose of ketamine on human reaction time.
Micallef, J, Gavaudan, G, Burle, B, Blin, O, Hasbroucq, T
Neuroscience letters. 2004;(2):99-103
Abstract
Ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, impairs reaction time performance and interacts with foreperiod duration, thereby suggesting that ketamine alters motor preparation. These effects can be attributed either to the blockade of NMDA receptors or to the stimulation of alpha-amino-3-hydroxy-5-methylisoxasole-4-proprionic acid (AMPA) and kainate receptors. The purpose of the present study was: (i) to replicate previous findings and (ii) to study the effect of a pre-treatment with topiramate, an AMPA/kainate antagonist, on the impairments induced by ketamine on RT. Thirty six healthy subjects (3 groups of 12) performed a two-choice RT task in which the foreperiod was manipulated. All subjects performed the task under perfusion of ketamine (intravenous bolus of 0.12 mg followed by a perfusion of 0.5 mg/kg over 60 mn) or placebo (saline). Depending on the group, an oral dose of topiramate (50 mg) or placebo (lactose) was administered 2 h before ketamine infusion (randomised, double-blind, double-dummy, parallel-group design). At the dose studied, topiramate exerted no detectable effect on RT. The results relative to ketamine corroborate previous findings and suggest that this molecule affects motor preparation through the blockade of NMDA receptors.
-
10.
Ketamine and fMRI BOLD signal: distinguishing between effects mediated by change in blood flow versus change in cognitive state.
Abel, KM, Allin, MP, Kucharska-Pietura, K, Andrew, C, Williams, S, David, AS, Phillips, ML
Human brain mapping. 2003;(2):135-45
-
-
Free full text
-
Abstract
No human fMRI studies have examined ketamine effects on the BOLD signal change associated with cognitive task performance. We wished to distinguish between effects on 1) cerebral blood flow, with resultant change in BOLD signal; and 2) cognition and neural mechanisms underlying BOLD signal change associated with task performance. Eight right-handed men (mean age 28.75 years) received ketamine or saline i.v. in a randomized, double-blind manner (bolus 0.23 mg/kg; 0.5 mg/kg over 45 min to a maximum 1 hr). Subjects viewed 10 alternating 30-sec blocks of faces with neutral expressions and a fixation cross and discriminated gender of faces. Gradient echo echoplanar images were acquired on a GE Signa 1.5 T Neurovascular system. One hundred T2-weighted images depicting BOLD contrast were acquired over 5 min (for each task) at each of 14 near-axial noncontiguous 7-mm thick planes. Ketamine significantly increased dissociative phenomena and negative symptoms, but did not affect performance of the gender discrimination task. Significant BOLD signal change was demonstrated predominantly in occipitotemporal cortex with both ketamine and placebo. Only two clusters in middle occipital gyrus (BA 18) and precentral gyrus (BA 4) showed significantly decreased BOLD signal change during ketamine compared to placebo. BOLD signal change was not significantly greater in any region during ketamine. Our findings demonstrate subtle rather than major differences between the effects of ketamine and placebo upon the BOLD signal change during perception of face-non face contrast. We suggest that they represent task-dependent effects of the drug/placebo, rather than task-independent effects of the drug per se, and indicate that the effects of ketamine on cerebral blood flow are predominantly focal and task-dependent, rather than global and task-independent.