Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial.

BACKGROUND: Suicide is a devastating public health problem and very few biological treatments have been found to be effective for quickly reducing the intensity of suicidal ideation (SI). We have previously shown that a single dose of ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, is associated with a rapid reduction in depressive symptom severity and SI in patients with treatment-resistant depression. METHOD: We conducted a randomized, controlled trial of ketamine in patients with mood and anxiety spectrum disorders who presented with clinically significant SI (n = 24). Patients received a single infusion of ketamine or midazolam (as an active placebo) in addition to standard of care. SI measured using the Beck Scale for Suicidal Ideation (BSI) 24 h post-treatment represented the primary outcome. Secondary outcomes included the Montgomery-Asberg Depression Rating Scale--Suicidal Ideation (MADRS-SI) score at 24 h and additional measures beyond the 24-h time-point. RESULTS: The intervention was well tolerated and no dropouts occurred during the primary 7-day assessment period. BSI score was not different between the treatment groups at 24 h (p = 0.32); however, a significant difference emerged at 48 h (p = 0.047). MADRS-SI score was lower in the ketamine group compared to midazolam group at 24 h (p = 0.05). The treatment effect was no longer significant at the end of the 7-day assessment period. CONCLUSIONS: The current findings provide initial support for the safety and tolerability of ketamine as an intervention for SI in patients who are at elevated risk for suicidal behavior. Larger, well-powered studies are warranted.

Effects of triazolam on drinking in baboons with and without an oral self-administration history: a reinstatement phenomenon.

In a test of the reinforcing efficacy of triazolam under an oral drug self-administration procedure, three baboons consumed higher volumes of triazolam than of vehicle. Although these results suggested that triazolam was serving as a reinforcer, the unconditioned effect of triazolam itself on drinking remained unclear. Therefore, the effect of pretreatment with triazolam on consumption of a nondrug fluid was assessed in sessions that were otherwise identical to oral drug self-administration sessions. Following oral pretreatment with triazolam (0.6-19.2 mg total dose), there was a dose-dependent increase in drinking, suggesting that triazolam increased fluid consumption per se. However, subsequent manipulations showed that following pretreatment with triazolam, there was no systematic change in tap water consumption from the regular drinking spout and that the dipsogenic effect of pretreatment with triazolam was not specific to a particular fluid; however, the effect was specific to prior experience with the oral self-administration procedure. Thus, the dose-related increase in consumption from the drinkometer spout following triazolam pretreatment most likely is explained as the "priming" or "reinstatement" of an operant that previously had produced drug reinforcement, even though extinction (i.e., substitution of the drug vehicle) was in effect.

Zaleplon and triazolam physical dependence assessed across increasing doses under a once-daily dosing regimen in baboons.

The ability of the GABA(A)-receptor-subtype-selective hypnotic zaleplon to produce physical dependence was compared to the nonselective benzodiazepine triazolam. Progressively increasing doses of zaleplon and triazolam were given to baboons by intragastric infusion once each day, with doses increasing every 17 days. Next, the highest dose was given for 10-34 additional days by continuous infusion. Both drugs produced increases in food-maintained lever pressing, ataxia, and time to complete a fine motor task. Plasma levels increased dose-dependently; drug was detectable 24 h after higher doses. Flumazenil produced a mild or intermediate precipitated-withdrawal syndrome on day 14 of all dosing conditions. When drug delivery ended after 85-100 days, a benzodiazepine-type withdrawal syndrome occurred. Physical dependence potential of zaleplon and triazolam appear similar.

Reinforcement loss and behavioral tolerance to d-amphetamine: using percentile schedules to control reinforcement density.

Two procedures were used to examine the impact of reinforcement loss on the development of behavioral tolerance to the effects of d-amphetamine on control over response number in rats. Under both procedures, trials consisted of at least one left-lever press followed by a single right-lever press. Consecutive left-lever presses on each trial comprised a "run". A targeted percentile schedule provided reinforcement if the current run length was closer to the target length (12) than two-thirds of the most recent 24 runs. This procedure differentially reinforced runs around 12 while holding reinforcement probability constant at 0.333. A second group acquired the differentiation under the percentile schedule, but was then shifted to a procedure which yoked reinforcement probability by subject and run length to that obtained under asymptotic percentile schedule performance. The two procedures generated roughly comparable, but not identical, control run lengths, response rates, reinforcement probabilities and reinforcement rates. Only under the yoked procedure, however, did drug-induced disruptions in run length produce decreases in reinforcement density. Acute administration of amphetamine produced dose-related decreases in run length and overall response rate under both procedures. Daily pre-session administration of 1.7mg/kg amphetamine persistently suppressed run length under the percentile procedure, but not under the yoked procedure. Run lengths under the latter gradually increased with repeated amphetamine to a level equal to or slightly below baseline levels. Response rate was suppressed initially, and tolerance developed inconsistently to this effect in both groups. Dose-effect curves obtained when doses of amphetamine were substituted for the chronic dose showed a larger shift to the right with the yoked than percentile group for run length, and a similar but smaller effect for overall response rate. These results indicate that reinforcement loss substantially contributes to the development of tolerance to the behavioral effects of amphetamine, even when the comparison behaviors are generated by reinforcement contingencies that under non-drug conditions control very similar rates and patterns of behavior and reinforcement. Future comparison of acute and chronic drug effects on behaviors maintained by the percentile and yoked procedures may prove very helpful in illuminating drug-behavior interactions and the dynamic interrelations typically engendered by more traditional reinforcement schedules.

A demonstration of the graded nature of the generalization function of drug discrimination learning within the conditioned taste aversion procedure.

Although control of discriminative performance will often generalize to different doses of the training drug or to drugs from the same class as the training drug, the nature of this generalization is unknown. Prior work has suggested that the generalization is primarily quantal in nature with animals displaying either vehicle-appropriate or drug-appropriate responding, depending upon their detection of the drug stimulus. It has been questioned whether this quantal nature of generalization reflects a characteristic response to drug stimuli or whether such responding is a function of the specific training and testing procedures used to establish and measure drug discrimination learning. The present paper evaluated this issue by analyzing the generalization functions of individual subjects trained and tested within one specific drug discrimination procedure, i.e. the conditioned taste aversion design. Responding within this design was generally graded. It is clear that quantal responding is not a necessary outcome of drug generalization assessments and that the nature of generalization in drug discrimination learning is a function of the specific procedure utilized in training and testing the discrimination. The results of the present analysis are discussed in terms of other recent work reporting graded functions.

Color affects perceived odor intensity.

In Experiment 1, some odorous solutions (e.g., strawberry) were rated as smelling stronger when colored (e.g., red) than when colorless. Experiment 2 showed this effect to be due to a perceptual change rather than a response to experimental demand characteristics. Experiment 3 showed that the color-induced increase in odor intensity is not due to subjects' preexperimental experience with particular color-odor combinations, because the increase occurred with novel ones. We conclude that color induces a weak olfactory percept that combines with odorant-induced percepts. The effect may be due to conditioning or may be the result of residual intersensory neural connections left over from infancy.

Behavioral effects of enantiomers of dizocilpine under two "counting" procedures in rats.

Stereoisomers of the N-methyl-D-aspartate antagonist dizocilpine (MK-801) were studied to determine whether behavioral effects on complex operants depend on reinforcement loss accompanying behavioral disruption. Rats earned food pellets if the run of consecutive left-lever presses preceding a trial-terminating right-lever press approximated a target of 12. A percentile schedule reinforced any run closer to the target than two-thirds of the runs on the most recent 24 trials. Once the sequence was learned, half the subjects were shifted to a procedure that yoked reinforcement for each length run to the probability that length generated pellets during asymptototic percentile performance. Although these two procedures generate similar control run and reinforcement distributions, disrupting behavior reduced reinforcement probability far more under the yoked than the percentile procedure. Despite this difference in drug-induced reinforcement loss, both enantiomers produced similar dose-related decreases in run length and response rate under both procedures, with the (-) isomer approximately one log unit less potent than the (+) isomer. The absence of differential effects under these procedures diminishes the likelihood that reinforcement loss contributes to dizocilpine's effects, indirectly bolstering claims that dizocilpine directly affects learning.

Naloxone as a stimulus in drug discrimination learning: generalization to other opiate antagonists.

Nonopiate dependent animals were trained to discriminate the opiate antagonist naloxone (1 mg/kg) from distilled water within the conditioned taste aversion baseline of drug discrimination learning. Specifically, rats injected with naloxone prior to a saccharin-LiCl pairing, and with its vehicle prior to saccharin alone, rapidly acquired the drug discrimination, avoiding saccharin following the administration of naloxone and consuming saccharin following its vehicle after only three conditioning trials. Once the discrimination was acquired, generalization tests revealed that the opiate antagonists diprenorphine and naltrexone and the mixed opiate agonist/antagonist nalorphine completely generalized to the naloxone cue at doses of 1.8, 5.6 and 18 mg/kg, respectively. That discriminative control was established with a low dose of naloxone (i.e., 1 mg/kg) and other compounds with opiate antagonist activity generalized to the naloxone cue suggest that the stimulus effects of naloxone were likely mediated through the opiate receptor. Because each of these compounds are reported to bind to the mu receptor (with varying affinities and varying degrees of selectivity), the stimulus properties of naloxone are likely mediated at this specific receptor subtype.

The effects of food schedule adaptation on the ability of naloxone to suppress the acquisition of schedule-induced polydipsia.

Naloxone suppressed the acquisition of schedule-induced polydipsia (SIP) in rats given no previous exposure to the feeding schedule. Adaptation to the feeding schedule prior to SIP acquisition attenuated this suppression. Specifically, water consumption, bout probability, licks/bout and maximum lick rates during the interpellet interval (IPI) were significantly increased by adaptation. Although adaptation attenuated the suppressive effects of naloxone on SIP, this attenuation was not complete. Adapted, naloxone-treated subjects displayed both decreased water consumption and bout probability as compared to distilled water-treated controls. Unlike the effects of adaptation on naloxone's suppression of SIP, adaptation completely eliminated naloxone's suppression of feeding. That adapted subjects ate at control levels while still displaying a lower level of SIP suggests that the suppressive effect of naloxone on the acquisition of SIP is not an indirect effect of naloxone on feeding, but rather a direct effect of naloxone on developing SIP. Given that naloxone has a general suppressive effect on drinking (including SIP), what remains to be determined is why naloxone has no effect on established SIP. Possible explanations for this are discussed.

Response acquisition under targeted percentile schedules: a continuing quandary for molar models of operant behavior.

The number of responses rats made in a "run" of consecutive left-lever presses, prior to a trial-ending right-lever press, was differentiated using a targeted percentile procedure. Under the nondifferential baseline, reinforcement was provided with a probability of .33 at the end of a trial, irrespective of the run on that trial. Most of the 30 subjects made short runs under these conditions, with the mean for the group around three. A targeted percentile schedule was next used to differentiate run length around the target value of 12. The current run was reinforced if it was nearer the target than 67% of those runs in the last 24 trials that were on the same side of the target as the current run. Programming reinforcement in this way held overall reinforcement probability per trial constant at .33 while providing reinforcement differentially with respect to runs more closely approximating the target of 12. The mean run for the group under this procedure increased to approximately 10. Runs approaching the target length were acquired even though differentiated responding produced the same probability of reinforcement per trial, decreased the probability of reinforcement per response, did not increase overall reinforcement rate, and generally substantially reduced it (i.e., in only a few instances did response rate increase sufficiently to compensate for the increase in the number of responses per trial). Models of behavior predicated solely on molar reinforcement contingencies all predict that runs should remain short throughout this experiment, because such runs promote both the most frequent reinforcement and the greatest reinforcement per press. To the contrary, 29 of 30 subjects emitted runs in the vicinity of the target, driving down reinforcement rate while greatly increasing the number of presses per pellet. These results illustrate the powerful effects of local reinforcement contingencies in changing behavior, and in doing so underscore a need for more dynamic quantitative formulations of operant behavior to supplement or supplant the currently prevalent static ones.

Differentiating benzodiazepine- and barbiturate-like discriminative stimulus effects of lorazepam, diazepam, pentobarbital, imidazenil and zaleplon in two- versus three-lever procedures.

Previous studies found that animals trained to discriminate pentobarbital show a relatively inclusive generalization profile. They generalize to sedative-hypnotics and anxiolytics, regardless of differences among such drugs in molecular mechanism of action. In contrast, animals trained to discriminate lorazepam have shown a generalization profile that appears selective for compounds with in-vitro profiles as full agonists at the benzodiazepine modulatory site. The present study investigated whether benzodiazepine receptor ligands, to which pentobarbital-trained rats had generalized under a two-lever procedure, would occasion pentobarbital- or lorazepam-appropriate responding when the rats were retrained to discriminate among pentobarbital, lorazepam and the no-drug condition under a three-lever procedure. A second group of rats was trained first to discriminate lorazepam and then retrained under the same three-lever procedure. Under the two-lever procedure, all pentobarbital-trained rats showed dose-dependent generalization to lorazepam, but not all lorazepam-trained rats showed full generalization to pentobarbital. Both groups showed full generalization to diazepam and zaleplon, a novel hypnotic that is selective for alpha, 1-subunit-containing subtypes of the gamma-aminobutyric acid (GABA)A receptor. Pentobarbital-trained rats, but not all lorazepam-trained rats, generalized to imidazenil. Under the three-lever procedure, dose-dependent generalization to lorazepam and pentobarbital was demonstrated on the appropriate levers. Diazepam shared discriminative effects with pentobarbital, zaleplon shared discriminative effects with lorazepam, and imidazenil shared discriminative effects with lorazepam and pentobarbital. These results show that when the opportunity for finer differentiation of discriminative effects of GABAergic drugs is provided, a generalization profile more in line with differential in-vitro profiles can be revealed.

Comparison of ethanol metabolism in male and female cynomolgus macaques (Macaca fascicularis).

The physiological consequences of drinking ethanol differ among men and women; however, the biological basis of this gender difference is unknown. Our study characterized sex-related blood ethanol concentration (BEC) 60 min postethanol administration and ethanol elimination rates in male and female monkeys and across the phases of the menstrual cycle. Subjects were male (n = 4) and female (n = 4) cynomolgus monkeys (Macaca fascicularis) with a history of ethanol exposure and maintained at a lean body weight by food restriction. On three separate occasions, each monkey was administered 1.0 g/kg ethanol intragastrically and blood samples (20 microl) were collected every 60 min over a 5-hr period. For females, three phases of the menstrual cycle were determined by the presence of menses and plasma progesterone levels. There was no effect of menstrual cycle on mean 60 min BECs or mean rates of elimination. Mean BECs 60 min after 1.0 g/kg ethanol were: males = 86 mg/dl (+/- 2; n = 4) and females = 82 mg/dl (+/- 5; n = 4). There was no effect of sex on the highest BEC measured, which occurred at the 60 min time point in all subjects. Female monkeys did have faster average rates of ethanol elimination [34 +/- 2 (mg/dl)/hr] compared with males [23 +/- 1 (mg/dl)/hr]. The sex differences in metabolism of ethanol found with the macaque monkey model correlates well with human subject studies and suggests this is an appropriate model to further explore gender differences in response to ethanol.