Attenuation of ketamine effects by nimodipine pretreatment in recovering ethanol dependent men: psychopharmacologic implications of the interaction of NMDA and L-type calcium channel antagonists.

Ketamine blocks the calcium channel associated with N-methyl-D-aspartate (NMDA) glutamate receptors. It has transient behavioral effects in healthy humans that resemble aspects of schizophrenia, dissociative disorders, and ethanol intoxication. Ethanol is an antagonist of both NMDA receptors and L-type voltage-sensitive calcium channels (VSCC) and it has minimal psychotogenic activity in humans. A double-blind placebo-controlled study was conducted that evaluated whether pretreatment with the L-type VSCC antagonist, nimodipine, 90 mg D, modulated ketamine response (bolus 0.26 mg/kg, infusion of 0.65 mg/kg/hr) in 26 ethanol-dependent inpatients who were sober for at least one month prior to testing. This study found that nimodipine reduced the capacity of ketamine to induce psychosis, negative symptoms, altered perception, dysphoria, verbal fluency impairment, and learning deficits. Nimodipine improved memory function, but had no other intrinsic behavioral activity in this patient group. Nimodipine pretreatment attenuated the perceived similarity of ketamine effects to ethanol as well as ketamine-induced euphoria and sedation. However, nimodipine did not reduce the stimulant effects of ketamine. These data suggest that antagonism of L-type VSCCs attenuates the behavioral effects of NMDA antagonists in humans. They support the continued evaluation of nimodipine in the treatment of neuropsychiatric disorders. They also suggest that drugs, such as ethanol, that combine NMDA and L-type VSCC antagonism may have enhanced tolerability without attenuation of their stimulant effects.

Effect of tryptophan depletion on alcohol cue-induced craving in abstinent alcoholic patients.

BACKGROUND: The capacity of alcohol cues to precipitate the desire to drink may be an important determinant of relapse to alcohol use in recovering alcohol-dependent patients. This study evaluated whether attenuation of serotonin synthesis via depletion of its precursor tryptophan reduces the magnitude of cue-induced craving for alcohol in recently abstinent alcoholic individuals. METHODS: Alcohol-dependent patients (n = 16), 1 to 3 months after detoxification, who exhibited a 20% or greater increase in reported craving when presented with an alcoholic beverage, completed two additional alcohol cue-exposure test days, 1 week apart. Each cue exposure was preceded by administration of a concentrated amino acid drink that resulted in a rapid and significant decline in plasma free tryptophan (active depletion, no tryptophan supplementation) or a similar drink containing tryptophan (placebo depletion). Tests were conducted in a randomized, double-blind fashion. RESULTS: There were no significant changes in the magnitude of cue-induced craving with active tryptophan depletion compared with placebo. CONCLUSIONS: These data question the dependence of alcohol cue-induced craving in sober alcoholics on the ongoing synthesis of serotonin.

Disulfiram treatment for cocaine dependence in methadone-maintained opioid addicts.

AIMS: Cocaine use by patients on methadone maintenance treatment is a widespread problem and is associated with a poorer prognosis. Recent studies have evaluated disulfiram as a treatment for individuals with comorbid alcohol and cocaine abuse. We evaluated the efficacy of disulfiram for cocaine dependence, both with and without co-morbid alcohol abuse, in a group of methadone-maintained opioid addicts. DESIGN: Randomized double-blind, placebo-controlled trial. SETTING: Urban methadone maintenance clinic. PARTICIPANTS: Sixty-seven cocaine-dependent, methadone-maintained, opioid-dependent subjects (52% female; 51% Caucasian). INTERVENTION: Study medication, either disulfiram or placebo, was placed directly in the methadone to ensure compliance for 12 weeks. MEASUREMENTS: Primary outcome measures included weekly assessments of the frequency and quantity of drug and alcohol use, weekly urine toxicology screens and breathalyzer readings. FINDINGS: Disulfiram treated subjects decreased the quantity and frequency of cocaine use significantly more than those treated with placebo. Alcohol use was minimal for all subjects regardless of the medication. CONCLUSIONS: Disulfiram may be an effective pharmacotherapy for cocaine abuse among methadone-maintained opioid addicts, even in those individuals without co-morbid alcohol abuse. Disulfiram inhibits dopamine beta-hydroxylase resulting in an excess of dopamine and decreased synthesis of norepinephrine. Since cocaine is a potent catecholamine re-uptake inhibitor, disulfiram may blunt cocaine craving or alter the "high", resulting in a decreased desire to use cocaine.

CSF monoamine metabolite and beta endorphin levels in recently detoxified alcoholics and healthy controls: prediction of alcohol cue-induced craving?

BACKGROUND: Abnormalities in central neurotransmitter systems have been described in alcohol-dependent individuals and may contribute to alcohol craving. This study compared cerebrospinal fluid (CSF) levels of monoamine metabolites and beta endorphin levels in samples from early-onset alcohol-dependent patients (n = 20), late-onset alcohol-dependent patients (n = 14), and healthy controls (n = 23). It also evaluated whether these CSF measures levels predicted the degree of craving experienced in response to an alcohol cue. METHODS: Individuals meeting DSM-III and -IV R-criteria for alcohol dependence, 1 to 3 months postdetoxification, and healthy controls underwent a lumbar puncture. Patients also completed a cue exposure test day between 3 and 15 days later. RESULTS: Alcohol-dependent patients had lower CSF levels of the norepinephrine metabolite MHPG compared with the healthy subjects, but this difference disappeared when differences in age between the groups were accounted for. No other group comparisons between patients and healthy subjects reached significance. CSF levels of the dopamine metabolite HVA were significantly higher in the early-onset patients compared with the late-onset patients and controls. The CSF measures did not predict the precue levels of craving, or the increase in craving after alcohol cue exposure. CONCLUSIONS: These results are inconclusive about the role of monoaminergic dysregulation in recovering alcoholics. They also question the utility of these CSF measures to predict alcohol cue reactivity in patients who have been sober at least 1 month.

NMDA agonists and antagonists as probes of glutamatergic dysfunction and pharmacotherapies in neuropsychiatric disorders.

Antagonists of the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors and agonists of the glycine-B coagonist site of these receptors have been important tools for characterizing the contributions of NMDA receptor pathophysiology to a large number of neuropsychiatric conditions and for treating these conditions. Among these disorders are Alzheimer's disease, chronic pain syndromes, epilepsy, schizophrenia, Parkinson's disease, Huntington's disease, addiction disorders, major depression, and anxiety disorders. This review will examine pathophysiological and therapeutic hypotheses generated or supported by clinical studies employing NMDA antagonists and glycine-B agonists and partial agonists. It will also consider ethical issues related to human psychopharmacological studies employing glutamatergic probes.

Preliminary evidence of low cortical GABA levels in localized 1H-MR spectra of alcohol-dependent and hepatic encephalopathy patients.

OBJECTIVE: The aim of the study was to compare levels of neuroactive amino acids in the cerebral cortex of healthy subjects, recently detoxified alcohol-dependent patients, and patients with hepatic encephalopathy. METHOD: Metabolite levels were measured in the occipital cortex by using spatially localized 1H-MRS. Five recently detoxified alcohol-dependent and five hepatic encephalopathy patients with alcohol and non-alcohol-related disease were compared with 10 healthy subjects. RESULTS: The combined level of gamma-aminobutyric acid (GABA) plus homocarnosine was lower in the alcohol-dependent and hepatic encephalopathy patients than in the healthy subjects. CONCLUSIONS: The findings suggest that GABA-ergic systems are altered in both alcohol-dependent and hepatic encephalopathy patients.

Toward a rational pharmacotherapy of comorbid substance abuse in schizophrenic patients.

The prevalence of substance abuse is elevated among schizophrenic patients. When free of illicit substances and sober, substance-abusing schizophrenic patients may have a better prognosis than other frequently hospitalized schizophrenic patients. However, the cost of substance abuse is great in terms of rehospitalization, homelessness, risk of other medical illness, disruption of social and vocational function, exacerbation of symptoms, suicide, and increased health care expenses. Important recent developments in medications for reducing substance abuse in nonschizophrenic populations make it timely to consider factors that might contribute to substance abuse among schizophrenic patients. This review will focus on substances most frequently abused by schizophrenic patients: nicotine, alcohol, cannabis, and psychostimulants. It concentrates on two conceptual foci: "self-medication hypotheses" and "comorbid addiction vulnerability hypotheses". The relationship between these hypotheses and possible pharmacotherapeutic approaches for substance-abusing schizophrenic patients will be considered.

Alterations of benzodiazepine receptors in type II alcoholic subjects measured with SPECT and [123I]iomazenil.

OBJECTIVE: Alterations in cortical benzodiazepine receptor density have been described in postmortem and in vivo studies of alcoholic subjects. The authors attempted to replicate these findings using single photon emission computed tomography and the benzodiazepine receptor radiotracer [123I]iomazenil. METHOD: They measured the distribution volume of benzodiazepine receptors in 11 recently detoxified patients with type II alcoholism and 11 healthy comparison subjects. The tracer was given as a bolus followed by a continuous infusion to achieve sustained binding equilibrium at the benzodiazepine receptors. Data were analyzed by using a region of interest method (regions of interest were identified on coregistered magnetic resonance imaging scans) and by a pixel-by-pixel method (distribution volume maps were analyzed with statistical parametric mapping for between-group differences). RESULTS: The region of interest analysis revealed that alcoholic patients had significantly lower benzodiazepine distribution volume than comparison subjects in the frontal, anterior cingulate, and cerebellar cortices. Statistical parametric mapping revealed two large excursions in which the distribution volume in alcoholic patients was significantly lower than in comparison subjects: the anterior cingulate, extending into the right middle frontal gyrus, and the left occipital cortex. CONCLUSIONS: Benzodiazepine receptor distribution volume is significantly lower in several cortical regions and the cerebellum in alcoholic subjects than in healthy comparison subjects. These results are consistent with previous reports and might indicate either a toxic effect of alcoholism on benzodiazepine receptors or a vulnerability factor for developing alcoholism.

Naltrexone augmentation of neuroleptics in schizophrenia.

This study was conducted to determine whether the addition of naltrexone to ongoing neuroleptic treatment would facilitate the reduction in positive or negative symptoms in patients with schizophrenia. Twenty-one patients meeting DSM-III criteria for schizophrenia were enrolled; all patients had been stabilized for at least 2 weeks on their dosage of neuroleptic medicine before entering the study. Patients were randomized to receive either placebo or naltrexone 200 mg/day for 3 weeks in addition to their neuroleptic. Patients randomized initially into the placebo arm were crossed over to receive naltrexone in a single-blind fashion for 3 additional weeks. All patients were rated weekly with the Brief Psychiatric Rating Scale (BPRS). Fifteen patients received placebo and six received naltrexone in the first 3 weeks. No significant effects of naltrexone on total BPRS scores or BPRS subscale scores were observed. Patients who received naltrexone on a single-blind basis at the end of the placebo-controlled trial demonstrated a transient exacerbation in negative symptoms as reflected by the total BPRS score and the BPRS Withdrawal-Retardation subscale score. Repeated-measures analysis of variance (ANOVA) on the BPRS total score of the subsequent treatment with naltrexone showed a trend for a significance in the drug by time effect. Repeated-measures ANOVA on the BPRS Withdrawal-Retardation subscale of the subsequent treatment with naltrexone showed a significant drug by time effect. The current data failed to indicate a clinical benefit when naltrexone was added to the neuroleptic regimen. Other potential applications of naltrexone in schizophrenia are addressed.

Dose-related ethanol-like effects of the NMDA antagonist, ketamine, in recently detoxified alcoholics.

BACKGROUND: This study evaluated the dose-related ethanol-like subjective effects of the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine hydrochloride in recently detoxified alcoholics. METHODS: Twenty male inpatients meeting DSM-III-R criteria for alcohol dependence and who had not consumed alcohol for 10 to 27 days prior to the study completed 3 test days that involved the intravenous infusion of ketamine hydrochloride (0.1 mg/kg or 0.5 mg/kg) or saline solution under randomized double-blind conditions. Ethanol-like subjective effects were assessed using the Sensation Scale; the Biphasic Alcohol Effects Scale; visual analog scales to measure "high" and degree of similarity to ethanol, cocaine, and marijuana; a scale assessing the number of standard alcohol drinks producing similar subjective effects; and visual analog scales measuring ethanol craving. RESULTS: Ketamine produced dose-related ethanol-like effects on each scale measuring its similarity to ethanol. Its effects were more similar to the sedative or descending limb effects of ethanol than to the stimulant or ascending limb effects. Ketamine effects also were more like ethanol than marijuana or cocaine. Ethanol-like effects were more prominent at the higher ketamine dose, a dose rated as similar to greater levels of ethanol intoxication. However, ketamine did not increase craving for ethanol. CONCLUSION: The production of ethanol-like subjective effects by ketamine supports the potential clinical importance of NMDA receptor antagonism among the mechanisms underlying the subjective effects of ethanol in humans.

Complications of alcohol withdrawal: pathophysiological insights.

Disease processes or events that accompany acute alcohol withdrawal (AW) can cause significant illness and death. Some patients experience seizures, which may increase in severity with subsequent AW episodes. Another potential AW complication is delirium tremens, characterized by hallucinations, mental confusion, and disorientation. Cognitive impairment and delirium may lead to a chronic memory disorder (i.e., Wernicke-Korsakoff syndrome). Psychiatric problems associated with withdrawal include anxiety, depression, and sleep disturbance. In addition, alterations in physiology, mood, and behavior may persist after acute withdrawal has subsided, motivating relapse to heavy drinking. Recent advances in neurobiology may support the development of improved medications to decrease the risk of AW complications and support long-term sobriety.

Effect of alpha-methyl-para-tyrosine on response to cocaine challenge.

This study evaluated the effect of an acute reduction in catecholamine synthesis produced by alpha-methyl-para-tyrosine (AMPT), a tyrosine hydroxylase inhibitor, on cocaine-induced euphoria. In a blinded, placebo-controlled study, AMPT (1 g p.o. T.I.D.) was given to 10 non-treatment-seeking cocaine abusers prior to intranasal administration of 2 mg/kg cocaine. AMPT, but not placebo, reduced plasma levels of the dopamine metabolite homovanillic acid and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol. AMPT also elevated prolactin levels, indicating inhibition of the tuberoinfundibular dopamine system. AMPT pretreatment produced a trend toward diminished cocaine "high" AMPT also tended to lower heart rate and blood pressure responses to cocaine, but had no effect on serum cocaine levels. Although we cannot rule out the therapeutic potential of the depletion strategy, our results with AMPT alone, at this dose, do not strongly support it.