Nagendra Madan Singh

Dose-Related Modulation of Event-Related Potentials to Novel and Target Stimuli by Intravenous Δ9-THC in Humans

Cannabinoids induce a host of perceptual alterations and cognitive deficits in humans. However, the neural correlates of these deficits have remained elusive. The current study examined the acute, dose-related effects of delta-9-tetrahydrocannabinol (Δ9-THC) on psychophysiological indices of information processing in humans. Healthy subjects (n=26) completed three test days during which they received intravenous Δ9-THC (placebo, 0.015 and 0.03 mg/kg) in a within-subject, double-blind, randomized, cross-over, and counterbalanced design. Psychophysiological data (electroencephalography) were collected before and after drug administration while subjects engaged in an event-related potential (ERP) task known to be a valid index of attention and cognition (a three-stimulus auditory ‘oddball’ P300 task). Δ9-THC dose-dependently reduced the amplitude of both the target P300b and the novelty P300a. Δ9-THC did not have any effect on the latency of either the P300a or P300b, or on early sensory-evoked ERP components preceding the P300 (the N100). Concomitantly, Δ9-THC induced psychotomimetic effects, perceptual alterations, and subjective ‘high’ in a dose-dependent manner. Δ9-THC -induced reductions in P3b amplitude correlated with Δ9-THC-induced perceptual alterations. Lastly, exploratory analyses examining cannabis use status showed that whereas recent cannabis users had blunted behavioral effects to Δ9-THC, there were no dose-related effects of Δ9-THC on P300a/b amplitude between cannabis-free and recent cannabis users. Overall, these data suggest that at doses that produce behavioral and subjective effects consistent with the known properties of cannabis, Δ9-THC reduced P300a and P300b amplitudes without altering the latency of these ERPs. Cannabinoid agonists may therefore disrupt cortical processes responsible for context updating and the automatic orientation of attention, while leaving processing speed and earlier sensory ERP components intact. Collectively, the findings suggest that CB1R systems modulate top-down and bottom-up processing.

Glycine transporter inhibitor attenuates the psychotomimetic effects of ketamine in healthy males: preliminary evidence.

Enhancing glutamate function by stimulating the glycine site of the NMDA receptor with glycine, D-serine, or with drugs that inhibit glycine reuptake may have therapeutic potential in schizophrenia. The effects of a single oral dose of cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl) amino-methylcarboxylic acid hydrochloride (Org 25935), a glycine transporter-1 (GlyT1) inhibitor, and placebo pretreatment on ketamine-induced schizophrenia-like psychotic symptoms, perceptual alterations, and subjective effects were evaluated in 12 healthy male subjects in a randomized, counter-balanced, within-subjects, crossover design. At 2.5 h after administration of the Org 25935 or placebo, subjects received a ketamine bolus and constant infusion lasting 100 min. Psychotic symptoms, perceptual, and a number of subjective effects were assessed repeatedly before, several times during, and after completion of ketamine administration. A cognitive battery was administered once per test day. Ketamine produced behavioral, subjective, and cognitive effects consistent with its known effects. Org 25935 reduced the ketamine-induced increases in measures of psychosis (Positive and Negative Syndrome Scale (PANSS)) and perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)). The magnitude of the effect of Org 25935 on ketamine-induced increases in Total PANSS and CADSS Clinician-rated scores was 0.71 and 0.98 (SD units), respectively. None of the behavioral effects of ketamine were increased by Org 25935 pretreatment. Org 25935 worsened some aspects of learning and delayed recall, and trended to improve choice reaction time. This study demonstrates for the first time in humans that a GlyT1 inhibitor reduces the effects induced by NMDA receptor antagonism. These findings provide preliminary support for further study of the antipsychotic potential of GlyT1 inhibitors.

Feasibility, Safety, and Efficacy of the Combination of D -Serine and Computerized Cognitive Retraining in Schizophrenia: An International Collaborative Pilot Study

The combination of pharmacotherapy and cognitive retraining (CRT) for the cognitive deficits of schizophrenia may be more efficacious than either approach alone, but this has not yet been tested. This study evaluated the feasibility, safety, tolerability, and efficacy of 12 weeks of D-serine, combined with CRT in the treatment of cognitive deficits in schizophrenia at two academic sites in parallel, in India and the United States. In a randomized, partial double-blind, placebo-controlled, parallel-group design, 104 schizophrenia subjects (US site=22, Indian site=82) were randomized to: (1) D-serine (30 mg/kg)+CRT (5 h/week), (2) D-serine+control CRT, (3) CRT+placebo D-serine, and (4) placebo+control CRT. Completion rates were 84 and 100% in the Indian and US samples, respectively. On various outcome measures of safety and tolerability, the interventions were well tolerated. D-Serine and CRT did not show any significant effect on the Global Cognitive Index, although both interventions showed differential site effects on individual test performance. CRT resulted in a significant improvement in Verbal Working Memory, and a trend toward improvement in Attention/Vigilance. This is the first study to demonstrating the feasibility, safety, and tolerability of combination pharmacotherapy and CRT in a multicenter international clinical trial. These preliminary findings provide support for future studies using higher doses of D-serine that have been shown to be efficacious or other pharmacotherapies, along with the newer cognitive remediation strategies that are individualized and that target basic information processing.

Nicotine Fails to Attenuate Ketamine-Induced Cognitive Deficits and Negative and Positive Symptoms in Humans: Implications for Schizophrenia

BACKGROUND The uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, ketamine, induces a range of symptoms resembling those seen in schizophrenia. Enhancement of nicotinic acetylcholine receptor (nAChR) function may have potential as a treatment for the cognitive deficits and negative symptoms of schizophrenia. Accordingly, we examined the modulatory effects of brain nAChR systems on NMDAR antagonist-induced effects. METHODS The interactive effects of ketamine and nicotine were evaluated in 37 healthy subjects in a randomized, placebo-controlled, double-blind, crossover counterbalanced, 2 (intravenous ketamine or placebo) × 2 (intravenous nicotine or placebo) design. Verbal and visual memory, sustained attention, working memory, response inhibition, emotion recognition, executive function, reaction time, motor function, and speed of processing were assessed once per test day, while negative and positive symptoms, perceptual alterations, and a number of feeling states were measured several times before and after administration of drugs. RESULTS Ketamine induced cognitive deficits and negative and positive symptoms. Nicotine worsened immediate recall, auditory working memory, response inhibition, and executive function and serial processing. Nicotine decreased (improved) reaction time on the sustained attention and choice reaction time tasks. Nicotine did not reduce ketamine-induced cognitive deficits or negative and positive symptoms. CONCLUSIONS At blood levels comparable with tobacco smoking, nicotine infusion does not appear to alleviate the ketamine-induced transient cognitive and behavioral effects in healthy subjects that resemble those seen in schizophrenia. The lack of an effect of nicotine on a spectrum of ketamine effects suggests that the consequences of NMDAR antagonism are not likely under the direct influence of nAChR.

Controversy revisited: selective serotonin reuptake inhibitors in paediatric depression

Articles published in the Viewpoint section of this Journal may not meet the strict editorial and scientific standards that are applied to major articles in The World Journal of Biological Psychiatry. In addition, the viewpoints expressed in these articles do not necessarily represent those of the Editors or the Editorial Board. Background: Selective serotonin reuptake inhibitors (SSRIs) are currently controversial treatments for paediatric depression. There have been several publications on the subject during recent years. This article summarizes their findings and provides some original thoughts, suggestions, and perspectives. Methods: Important and relevant articles presenting original data and published in leading journals during 2003–2005 were identified through a PubMed search. Articles instructive in content were selected. A narrative sequence is used to review the field, build arguments, and propound views. Results: Ten principal and several other auxiliary studies were identified for scrutiny. The findings of these studies suggest that published clinical trials of SSRIs in paediatric depression have overstated the antidepressant benefits and understated the risks of suicidal ideation and behaviour arising with treatment; the unpublished clinical trial data are even more unfavourable. Nevertheless, the clinical, epidemiological, and forensic data do suggest overall safety and efficacy of the SSRIs, amongst which fluoxetine may have the best risk–benefit profile. Conclusions: Psychotherapeutic interventions may not always be feasible or effective, especially when depression is more severe. The failure to prescribe a drug may, at the very least, lead to the loss of the placebo effect. It is therefore suggested that, if the diagnosis of unipolar depression is confident, appropriate doses of fluoxetine may be prescribed to depressed children and adolescents; the use of rescue medication to treat emergent agitation is important, and augmentation with psychotherapy may further improve outcomes. The monitoring of indices of growth may also be necessary.

Impact of an Educational Module in Antidepressant-Naive Patients Prescribed Antidepressants for Depression: Pilot, Proof-of-Concept, Randomized Controlled Trial

Background: Patients are educated about their illness and its treatment at the time of diagnosis. However, little is known about how much of this education is retained and how it influences knowledge about, attitudes toward, and experiences with medication in antidepressant-naive patients with depression. Methods: Antidepressant-naive outpatients with International Classification of Diseases-10 dysthymia or mild to moderate depression, who were advised antidepressant monotherapy, were randomized to control (n = 22) or intervention (n = 17) groups. Control patients received treatment as usual, and intervention patients received, in addition, a face-to-face, individualized, 10-min education session about the nature of depression, antidepressant treatment, efficacy and adverse effects of the prescribed drug, and plan of management. Knowledge about the illness and its treatment were assessed at baseline (before the educational intervention) and 6 weeks later. At follow-up, experiences with treatment were also evaluated. The study was double-blind. Results: At baseline, patients had poor knowledge about their illness and its treatment (most patients could not even name their diagnosis); however, few held unfavorable attitudes toward their prescribed medicines. At follow-up, there were modest improvements in both sets of outcomes. There were no differences between intervention and control groups in knowledge and attitude outcomes at baseline and end-point. Drug compliance did not differ between groups. However, importantly, intervention patients experienced a significantly larger number of adverse events than controls (mean, 3.5 vs. 1.7, respectively). Conclusions: For ethical reasons, patients need to be educated about their illness and its treatment. However, such education may be a two-edged sword, with an increased nocebo effect as the most salient consequence. Failure to identify benefits in our study may have been the result of a Type 2 error. This study provides a wealth of information on a large number of issues related to knowledge, attitudes, and experiences of depressed, mostly low-income outpatients in relation to education about depression and its treatment, and future research can build on the findings of this study. We also provide an extensive discussion on directions for further research.

Systematic Enhancement of Functioning as a Therapeutic Technique in Conversion Disorder

To explicitly outline a therapeutic technique for symptom removal in conversion disorder. We describe one patient with conversion dumbness and another with conversion paraplegia. The first patient was successfully treated in a single session, and the second was successfully treated across two weeks, both using systematic enhancement of functioning as a technique for symptom removal. This technique encourages the patient to express the desired behavior to whatever extent possible; subsequently, the patient is encouraged to gradually amplify the response until normal levels of functioning are achieved. The technique outlined is simple and practical but nevertheless receives no mention in conversion disorder literature. The technique can be applied to any situation in which behavioral amplification is desired.

Effects of electrical stimulus composition on cardiac electrophysiology in a rodent model of electroconvulsive therapy

Background: No electroconvulsive therapy (ECT) study on humans or in animal models has so far examined whether differently composed electrical stimuli exert different cardiac electrophysiological effects at constant electrical dose. The subject is important because cardiac electrophysiological changes may provide indirect information about ECT seizure quality as modulated by stimulus composition. Materials and Methods: Adult female Wistar rats (n = 20/group) received fixed, moderately suprathreshold (18 mC) electrical stimuli. This stimulus in each of eight groups was formed by varying pulse amplitude, pulse width, pulse frequency, and stimulus duration. The electrocardiogram was recorded, and time and frequency domain variables were examined in 30 s epochs in preictal (30 s before electroconvulsive shock [ECS]), early postictal (starting 15 s after stimulation), and late postictal (5 h after ECS) periods. Alpha for statistical significance was set at P < 0.01 to adjust for multiple hypothesis testing. Results: Cardiac electrophysiological indices in the eight groups did not differ significantly at baseline. At both early and late postictal time points, almost no analysis yielded statistically significant differences between groups for four time domain variables, including heart rate and standard deviation of R-R intervals, and for six frequency domain variables, including low-frequency power, high-frequency power, and total power. Conclusions: Cardiac electrophysiological measures may not be helpful to identify differences in seizure quality that are driven by differences in the composition of electrical stimuli at constant, moderately suprathreshold electrical dose. The generalization of this conclusion to threshold electrical doses and to human contexts requires a study.

Early and late postictal cardiac electrophysiological changes associated with low, moderate, and high dose electroconvulsive shocks

BACKGROUND Studies have examined the effects of electroconvulsive therapy (ECT) on human cardiac electrophysiology. However, no study has so far examined whether these effects vary with the magnitude of the electrical dose used to elicit the seizure. Because the benefits and adverse effects of the ECT seizure are dose-dependent, we examined the effects of different electrical doses of electroconvulsive shocks (ECS) on cardiac electrophysiology in an animal model with a view to determine whether cardiac electrophysiology could be a useful proxy to evaluate the quality of the ECT seizure. METHODS Adult female Wistar rats (n = 20/group) received sham, low dose (10 mC), moderate dose (18 mC), or high dose (25 mC) ECS. The electrocardiogram (ECG) was recorded and was analyzed for time and frequency domain variables in 30 s epochs in preictal (30 s before ECS), early postictal (starting 15 s after stimulation) and late postictal (5 h after ECS) periods. RESULTS ECS was associated with substantial changes in most time and frequency domain measures during the early postictal period; a strong parasympathetic effect was observed. However, the effects of different ECS doses did not differ for any variable. All changes returned to levels that were similar to those of the sham controls in the late postictal period. CONCLUSIONS The effect of ECS on time and frequency domain cardiac electrophysiological measures was not dose-dependent. This suggests that if higher electrical doses are associated with stronger central seizures, ECG-derived variables may not be useful proxies for the quality of the central seizure. The generalization of this conclusion from animal to clinical contexts requires study.