Ismene L. Petrakis

Naltrexone augmentation of neuroleptic treatment in alcohol abusing patients with schizophrenia

ObjectiveAlcohol abuse in patients with schizophrenia is associated with psychiatric and social complications. While two medications have been approved by the Federal Drug Administration (FDA) for the treatment of alcoholism: disulfiram and naltrexone, no medications have been approved for individuals with alcohol dependence and comorbid schizophrenia. The purpose of this study was to evaluate the efficacy of naltrexone in alcohol-abusing schizophrenic patients.MethodThirty-one patients with schizophrenia and comorbid alcohol abuse or dependence were treated for 12 weeks in an outpatient study using naltrexone or placebo in a randomized, double-blind fashion in addition to their neuroleptic medication. Patients also participated in a weekly therapy using cognitive-behavioral drug relapse prevention strategies combined with skills training. Outcomes included drinking measured by the time line follow-back method, craving using the Tiffany Craving Questionnaire, psychotic symptoms using the Positive and Negative Symptoms Scale (PANSS), side effects and a measures of abnormal involuntary movements.ResultsThere were no significant differences in treatment exposure or medication compliance between groups. Naltrexone treated patients had significantly fewer drinking days, heavy drinking days (>5 drinks) and reported less craving compared to the placebo treated patients. Naltrexone did not affect symptoms of schizophrenia, such as psychosis. The medication was well tolerated and there were no group differences in side effects.ConclusionsThese data suggest that naltrexone may be an effective medication for individuals with comorbid alcohol dependence and schizophrenia. Given the widespread problems associated with alcohol misuse in this population, and the lack of effective pharmacotherapies, these findings represent an exciting clinical development.

Fluoxetine treatment of depressive disorders in methadone-maintained opioid addicts

This study tested the effectiveness of fluoxetine as a treatment for depression in a population of methadone-maintained opioid addicts. Methadone-maintained opioid addicts (44) with depression received fluoxetine or placebo in addition to their methadone, in a double-blind randomized trial, for 12 weeks. Depressive symptoms decreased significantly overall with no significant differences between the groups treated with fluoxetine versus placebo. In addition, drug use outcomes, including cocaine and heroin self-reported use and urine toxicology were measured. There was a significant decrease in heroin use in treatment, but no medication effect. Cocaine use, was unchanged from pre-treatment to endpoint. In separately analyzing data for the subsample of subjects with the most severe depression, there was a significant decrease in depression during treatment and a significant decrease in self-reported cocaine use, but no medication effect on either depressive symptoms or on cocaine use. This study suggests that fluoxetine is not an effective agent in treating depression or cocaine use in this population.

Preliminary analysis of positive and negative syndrome scale in ketamine-associated psychosis in comparison with schizophrenia.

OBJECTIVE Studies of the effects of the N-methyl-d-aspartate (NMDA) glutamate receptor antagonist, ketamine, have suggested similarities to the symptoms of schizophrenia. Our primary goal was to evaluate the dimensions of the Positive and Negative Syndrome Scale (PANSS) in ketamine users (acute and chronic) compared to schizophrenia patients (early and chronic stages). METHOD We conducted exploratory factor analysis for the PANSS from four groups: 135 healthy subject administrated ketamine or saline, 187 inpatients of ketamine abuse; 154 inpatients of early course schizophrenia and 522 inpatients of chronic schizophrenia. Principal component factor analyses were conducted to identify the factor structure of the PANSS. RESULTS Factor analysis yielded five factors for each group: positive, negative, cognitive, depressed, excitement or dissociation symptoms. The symptom dimensions in two schizophrenia groups were consistent with the established five-factor model (Wallwork et al., 2012). The factor structures across four groups were similar, with 19 of 30 symptoms loading on the same factor in at least 3 of 4 groups. The factors in the chronic ketamine group were more similar to the factors in the two schizophrenia groups rather than to the factors in the acute ketamine group. Symptom severities were significantly different across the groups (Kruskal-Wallis χ(2)(4) = 540.6, p < 0.0001). Symptoms in the two ketamine groups were milder than in the two schizophrenia groups (Cohens d = 0.7). CONCLUSION Our results provide the evidence of similarity in symptom dimensions between ketamine psychosis and schizophrenia psychosis. The interpretations should be cautious because of potential confounding factors.

Novel Pharmacological Approaches to Drug Abuse Treatment

The field of pharmacologic addiction treatment is expanding rapidly. While there are currently several FDA-approved medications for nicotine, alcohol, and opiate dependence, research into novel pharmacological approaches for these and additional substances is legion. Each drug of abuse, while sharing a common final neural pathway of increasing dopaminergic tone, has unique and individual characteristics that are important in developing improved and varied treatments. In this chapter, we discuss such research and present the neurobiological underpinnings of these explorations. In general, addiction treatment is focused on four areas: (1) reducing withdrawal discomfort, (2) diminishing cravings, (3) blocking rewarding effects of the drug, and (4) treating comorbidities, such as depression or ADHD. We present current ideas in pharmacologic research for nicotine, alcohol, cannabis, stimulants, and opiates.

Pharmacotherapeutic Effects of Opioid Antagonists in Alcohol-Abusing Patients with Schizophrenia

Schizophrenia is a devastating clinical disorder that affects ~1% of the general population. The prevalence of alcohol use disorders among schizophrenic patients is greater than the rate observed in the general population. While behavioral treatments have been developed to treat patients with comorbid schizophrenia and substance use, pharmacologic management may provide another therapeutic option for these patients. The opioid antagonist naltrexone was developed and approved by the Food and Drug Administration (FDA) to treat alcohol use disorders in noncomorbid patients. More recently, there has been interest in the use of opioid antagonist treatment for patients with schizophrenia and comorbid alcohol dependence. The evidence supporting the use of naltrexone in this group is from data from heterogeneous samples of dually diagnosed patients including those with schizophrenia and schizoaffective disorder and from one randomized trial in patients with schizophrenia and schizoaffective disorder. The controlled clinical trial in patients with schizophrenia and alcohol use/dependence compared naltrexone to placebo augmentation of neuroleptic in 31 outpatients. Outcomes focused on alcohol use and craving, but also rigorously evaluated symptoms of psychosis, cognitive symptoms and side effects. The results consistently suggest that naltrexone is both safe and effective in this group of patients. Taken together, the data suggest that the opioid antagonist naltrexone may be a good therapeutic option to treat alcohol use disorders in patients with schizophrenia.

Dyslipidemia associated with heavy alcohol use.

BACKGROUND AND OBJECTIVES Alcohol has many effects on lipid metabolism and has been associated with elevated triglycerides. The purpose of this paper is to report a case of globally dysregulated lipids secondary to alcohol use and to describe the natural history of this phenomenon after drinking cessation. METHODS We present a case of an otherwise healthy patient (N = 1) who was admitted to our facility for alcohol detoxification and found to have extreme lipid dysregulation. He was treated with benzodiazepines for alcohol withdrawal but no hypolipidemic agents were given. RESULTS Lipid indices self-corrected and were found to be normal following just several weeks of sobriety in the absence of treatment with any hypolipidemic agents. DISCUSSION The literature regarding the effects of alcohol on lipid metabolism is briefly reviewed followed by a discussion of how these findings might apply to this patient in particular as well as implications for broader clinical practice. CONCLUSION AND SCIENTIFIC SIGNIFICANCE Alcohol has the ability to dysregulate several lipid indices in addition to elevating triglycerides. The rapid resolution of dyslipidemia suggests that additional treatment may not be necessary for patients who are able to abstain from alcohol but that hypolipidemic agents may be indicated for those patients who continue to drink. Additionally, clinicians should consider checking lipid panels in patients who present with alcohol intoxication and are found to have other laboratory abnormalites or those who have risk factors for hyperlipidemia.

Alcohol and Glutamate Neurotransmission in Humans

Ethanol has multiple specific targets in the brain that combine to yield a complexly nuanced psychoactive agent (1). However, the study of glutamatergic targets of ethanol have been a recent development (2). The recency of these clinical studies may be surprising. Glutamate is the most prevalent excitatory neurotransmitter in the cerebral cortex and it mediates most output of the cortex and limbic system (3). Also, the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor is among the highest-affinity targets of ethanol inthe brain (4). This chapter will provide an introduction to studies indicating that NMDA receptor blockade contributes to the behavioral effects of ethanol in humans. In doing so, it will provide clinical insights into the neurobiology of the rewarding and dysphoric effects associated with the blockade of NMDA receptors by ethanol. This chapter will then describe evidence of glutamatergic dysregulation in ethanol-dependent patients. In doing so, it will emphasize the hypothesis that ethanol tolerance may be associated with alterations in the reward valence of the NMDA antagonist component of ethanol action. It will also describe evidence that the familial vulnerability to alcoholism may be associated with alterations in NMDA receptor function that promote its use.