Burt Angrist

Early pharmacokinetics and clinical effects of oral d-amphetamine in normal subjects

Seven normal subjects received 0.25 mg/kg D-amphetamine orally, both after an overnight fast and again after a standard breakfast. Plasma levels, subjective and cardiovascular effects, and observer-rated activation were assessed hourly for 5 hr. Food did not affect amphetamine levels. Plasma levels peaked at 2-3 hr. Maximum cardiovascular effects generally occurred at 1 hr, whereas maximum behavioral and subjective effects occurred at 2 hr. Subjective and behavioral effects declined thereafter, in spite of substantial amphetamine levels. A separate group of 8 subjects received 0.5 mg/kg D-amphetamine orally. Plasma levels, subjective and cardiovascular effects, and activation ratings were assessed hourly for 4 hr. Maximum plasma levels were approximately twice those seen in the first group. In this case, plasma levels peaked at 3-4 hr; blood pressure and subjective and behavioral effects were all maximal at 2-3 hr and were declining by 4 hr, in spite of stable or rising plasma levels.

Clinical and Sensorimotor Gating Effects of Ketamine in Normals

The clinical similarities between PCP psychosis and schizophrenia have contributed importantly to the development of the glutamate hypothesis of schizophrenia. Sensory gating, as measured by prepulse inhibition of the acoustic startle reflex (PPI), is impaired in patients with schizophrenia. In animals, the noncompetitive NMDA antagonists PCP and ketamine disrupt PPI in a way that resembles the defect seen in schizophrenia. The purpose of this work is to investigate the modulation of sensory gating in humans by subanaesthetic doses of ketamine. 16 healthy male subjects received a 60-min infusion of ketamine (0.5 mg/kg) or normal saline on two separate days in a randomized double-blind crossover design. Clinical ratings and PPI were done during the infusion on both days. Ketamine produced robust clinical effects. Dissociative symptoms as measured by the CADSS increased from 0 ± 0.0 to 29.3 ± 14.3; negative symptoms (Affect Rating Scale) increased from 17.2 ± 0.8 to 24.8 ± 3.1; and total BPRS scores increased from 18.3 ± 0.8 to 26.4 ± 5.1. ANOVAs for these ratings were all significant at the p < .000 level, although BPRS increases were not in the range seen in decompensated schizophrenic patients. The amplitudes of the startle responses to pulse-alone stimuli were not significantly different on ketamine and placebo days. Ketamine did not cause disruption in PPI as expected. On the contrary, in the first block of the PPI session ketamine significantly enhanced PPI (ANOVA; F=6.15, p = .026). These results indicate that the clinical effects of ketamine are not coupled with schizophrenic-like disruption of PPI in normal controls.

Neuroleptic-induced akathisia: a review

Neuroleptic-induced akathisia (NIA) is a relatively common side effect of neuroleptics, in which patients complain of a subjective sense of restlessness usually referable to the legs and have characteristic motor movements. This paper will review: 1) history of spontaneously occurring syndromes of pathologic restlessness and NIA, 2) the clinical significance of NIA, 3) issues concerning the diagnosis and quantification of NIA, 4) treatments of NIA and 5) possible future directions for research in this area. Special attention will be paid to newer treatments for this syndrome, specifically beta-blockers.

Selective sensitization to the psychosis-inducing effects of cocaine: A possible marker for addiction relapse vulnerability?

Patients in inpatient rehabilitation for uncomplicated cocaine dependence were asked whether, compared with the time of their first regular use, they could now identify changes in the effects of similar doses of cocaine. We asked about a spectrum of cocaine effects “then” and “now” and whether the same amount of drug caused effects to occur to about the same degree, less intensely (tolerance), or more intensely (sensitization). Nearly half our sample developed predominantly paranoid psychoses in the context of cocaine use. Sensitization was consistently linked only to psychosis-related cocaine effects.It has been proposed that mesolimbic dopaminergic sensitization might contribute to addiction severity. A preliminary followup of patients who were sensitized or nonsensitized to psychosis development suggests that rehospitalization for treatment of addiction may be more frequent in the sensitized group.

Effects of d-cycloserine on negative symptoms in schizophrenia

INTRODUCTION The negative and cognitive symptoms of schizophrenia are poorly responsive to neuroleptic treatment. Glutamatergic dysfunction may mediate some of these symptoms. Low dose D-cycloserine (DCS) is a partial agonist at the glycine site of the NMDA-associated receptor complex, noncompetitively enhancing NMDA neurotransmission. Prior studies suggest a beneficial effect of DCS on negative symptoms and cognition. This treatment trial was initiated to confirm and extend these findings. METHODS Twenty-two male schizophrenic subjects displaying prominent negative symptoms who were stabilized on typical neuroleptics completed the study. A randomized double-blind parallel group design was used to compare the effects of 50 mg p.o. QD of DCS to placebo over 4 weeks. The two subject groups did not differ significantly in age, age of onset of illness or time on current neuroleptic treatment. Symptoms were rated by means of the SANS, BPRS and Abrams and Taylor rating scale. Cognition was assessed with the Sternberg Memory Test and the Continuous Performance Test. RESULTS Both medication groups improved over the 4 weeks of treatment. However, there were no significant differences between the DCS and placebo group on any symptom rating. DCS effects on cognition did not differ from placebo. DISCUSSION This study did not detect improvement in negative symptoms or cognitive performance with DCS treatment that has been found in some prior studies. This negative finding may be attributed to small sample size, relatively short duration of treatment and the overall modest effect of DCS. Future studies of DCS should be adequately powered to detect a small to medium effect size and should provide for a longer treatment phase than was used in this study in order to avoid a type II error.

Effect of treatment status on prepulse inhibition of acoustic startle in schizophrenia.

RationaleThe acoustic startle response is inhibited when the startling stimulus is preceded by a weaker non-startling acoustic stimulus. This phenomenon, termed prepulse inhibition of acoustic startle (PPI), is impaired in schizophrenics compared to normal controls. To date, there is conflicting evidence regarding whether PPI impairments improve with antipsychotic treatment.ObjectivesTo examine the effect of medication status on PPI in schizophrenic subjects.MethodsFirst, we performed acoustic startle testing on 16 schizophrenic subjects when they were acutely decompensated off medication and later after they were stabilized on antipsychotic treatment. Second, in a between-group design, we tested 21 schizophrenic subjects off medication, 16 subjects on atypical neuroleptics, and 27 subjects on typical neuroleptics.ResultsIn both the test-retest study and the between-group study, ANOVAs revealed no significant changes in startle to pulse alone stimuli, habituation of startle to pulse alone stimuli, PPI, latency to response onset, or latency to response peak between the treatment conditions.ConclusionsOur results do not support the hypothesis that impaired sensorimotor gating in schizophrenia improves with antipsychotic treatment. Rather, impaired gating persists despite symptomatic improvement on medication.

Stability of resting deoxyglucose metabolic values in PET studies of schizophrenia

Positron emission tomography (PET) and the deoxyglucose method were used to determine the test-retest stability of regional cerebral glucose metabolism in 8 male schizophrenic patients and 11 normal control subjects, scanned twice under baseline (resting) conditions. Normal and schizophrenic subjects showed comparable stability of regional metabolism. When the regional values were scaled to compensate for the effects of changes in whole brain metabolism, the resulting mean regional changes were reduced to about 1-2% in both groups. This study demonstrates that the baseline resting state is an appropriate reference state for schizophrenic subjects in deoxyglucose PET experiments.

Efficacy of propranolol in neuroleptic-induced akathesia.

The effects of propranolol, 20 to 30 mg/day, on neuroleptic-induced akathesia were compared with those of lorazepam, 2 mg/day, and periods of no treatment. Raters were blind to treatment condition. As reported in prior open studies, propranolol was found to be dramatically effective in reducing akathesia induced by neuroleptic treatment.

Nifedipine in the treatment of tardive dyskinesia

There have been several case reports of improvement in tardive dyskinesia (TD) after treatment with calcium-blocking agents. We have conducted prior single-blind (rater-blind) studies of verapamil and diltiazem and found a statistically significant improvement in TD with verapamil, and a small improvement that did not reach statistical improvement after diltiazem treatment. We now report a single-blind (rater-blind) study of a third calcium antagonist, nifedipine, in the treatment of TD. Nifedipine (30-60 mg/day) was administered to eight schizophrenic patients with TD. Mean AIMS scores on items 1-7 decreased from 12.9 +/- 2.0 (SD) at baseline to 10.8 +/- 2.7 after treatment (t = 3.66, p = 0.01). All subjects were able to tolerate the maximal dose of nifedipine without significant side effects. TD is known to be affected by drugs that affect dopamine neurotransmission. Several lines of pre-clinical and clinical evidence suggest interactions between the calcium antagonists and the CNS dopamine system and provide a possible explanation for the effects on TD seen with calcium antagonists.

Diminished Acoustic Startle in Chronic Cocaine Users

Chronic cocaine use has been shown to produce neurochemical alterations which persist after acute withdrawal. This study assessed the effects of cocaine use on the acoustic startle response and sensorimotor gating using prepulse inhibition (PPI) of startle. Nine male control subjects (mean age = 41.6) and 15 male cocaine users (mean age = 43.2) were tested, the latter after heavy cocaine use ranging from 4 to 27 years (mean age = 16.7). Cocaine users had been cocaine free for four days to six months (mean = 17 days) at testing. Cocaine users exhibited a 68% reduction in startle amplitudes (F = 7.4; df = 1,22; p < .01) compared to controls. There were trends towards increased PPI in cocaine users under certain conditions; however, there were no significant main effects. These results indicate that chronic cocaine use produces impairment of the startle response which persists after cessation of cocaine use. These findings may reflect changes in the dopaminergic system resulting from chronic cocaine use.