Ismene Petrakis, MD

1. Finding effective pharmacotherapies for individuals with alcohol dependence and comorbid psychiatric disorders. Although there is a large body of literature evaluating medications for the treatment of alcoholism and other substance use disorders, there are no established pharmacotherapies for individuals with comorbid psychiatric illnesses. Nevertheless, patients with substance dependence and comorbid mental disorders constitute the majority of patients in clinical settings, and the presence of comorbid mental disorders confers a poorer prognosis. Further, individuals with comorbid mental diseases have been systematically excluded from most efficacy studies of potential pharmacotherapies and more research is needed in this patient population. In fact, there is some evidence that patients with comorbid disorders may be less likely to get the treatment they need, particularly in mental health clinics. This research attempts to answer clinically relevant questions about efficacy, effectiveness and pharmacologic use in dually diagnosed individuals in order to better inform the development of treatments. This work has included a utilization studies about the use of naltrexone in alcohol dependent veterans; effectiveness studies such as a large effectiveness study with 254 veterans across 3 VA sites evaluating the use of naltrexone and disulfiram alone and in combination in a “real world” clinical setting. The results suggested that medications to treat alcoholism are safe and effective in these patients and more effective than no medication. Interestingly, there was no advantage to combination treatment. Individuals with Post Traumatic Stress Disorder (PTSD) and those with psychosis did particularly well with medications to treat alcoholism.

In one of the first controlled studies to evaluate naltrexone for individuals with alcohol dependence and serious psychiatric disorder, patients with schizophrenia and alcohol dependence were randomized to naltrexone or placebo for a 12-week clinical trial. Naltrexone-treated patients had better alcohol related outcomes than placebo-treated patients. However, since naltrexone did not improve symptoms of psychosis or cognitive effects, further studies focused on treatments that might effectively treat symptoms of both disorders. Using administrative data, one study found that atypical neuroleptics are associated with no better outcomes than typical neuroleptics for substance misuse in schizophrenic patients. In a “proof of concept” treatment study evaluating a glutamatergic agent, a Stanley foundation-funded clinical trial was conducted using glycine as a treatment of both alcohol misuse and symptoms of schizophrenia. Preliminary results support previous research that glycine is effective for the negative symptoms of schizophrenia, but not alcohol consumption. It should be noted that the final data analysis is not yet complete. More recently and after the FDA approved acamprosate for the treatment of alcoholism, a study was funded and is ongoing evaluating acamprosate’s efficacy in patients with comorbid schizophrenia.

Individuals with PTSD have some of the highest rates of comorbid alcohol dependence and this is an important clinical issue,particularly at the VA. A recently completed study was conducted comparing 2antidepressants (a noradrenergic agent versus a serotonergic agent) in treating symptoms of both PTSD and alcoholism. Preliminary results suggest there were no differences between the groups; the equivalent efficacy of a noradrenergic agent with the more standard serotonergic agent is a promising finding. Building on these results I have obtained grant funding from the Department of Defense to evaluate a novel noradrenergic agent in the treatment of PTSD and comorbid alcohol dependence. The study was funded in September of ’08.

2. Evaluating the underlying neurobiology of these disorders and the behaviors that go with them, including craving,self-administration and a familial vulnerability. Advances in the understanding of alcohol’s effects on the brain and the associated behavioral effects have contributed to our knowledge of alcohol abuse and dependence and have led the way to the development of new treatments. Alcohol is now known to have multiple specific actions in the brain. Alcohol’s acute and chronic effects on specific targets in the brain may in part explain ethanol reward, dependence and the vulnerability to alcoholism.

Dr. Petrakis' research has focused on the serotonergic and glutamatergic systems and how these neurotransmitters affect craving, self-administration of alcohol and the vulnerability to develop alcoholism. Contrary to what might be expected from preclinical studies, 2 NIAAA-funded studies found there was no significant correlation of serotonin function with the magnitude of cue-induced craving and that cue included craving and alcohol self-administration were not dependent on ongoing synthesis of serotonin.

Much evidence supports the role of the n-methyl-d-aspartate (NMDA) glutamate receptor in the pathophysiology of alcoholism. Another NIAAA-funded study evaluated whether healthy individuals at increased familial risk to develop alcohol dependence exhibit alterations in NMDA receptor function. This objective was evaluated by comparing the dose-related effects of the NMDA receptor antagonist, ketamine, in healthy individuals with a strong family history of ethanol dependence compared to healthy individuals without a family history. Interestingly, individuals with a family history were found to be less sensitive to the subjective effects of ketamine than those without a family history. These results are being followed up and in order to both replicate the findings and to determine whether certain genotypes predict outcome in a second-round of NIAAA funded studies. In a collaboration with Dr. Albert Perrino of the Department of Anesthesiology we are also evaluating whether altered pain sensitivity is also a marker for the vulnerability to develop alcoholism.

Two new areas of study include the examination of gamma-aminobutyric acid (GABA) mechanisms underlying both the subjective effects of alcohol and the vulnerability to develop alcoholism using a barbiturate probe, and the role of nicotinic acetylcholine receptors in alcoholism. For the latter, a newly funded NIAAA grant (Sept 08) is examining the potential for the nicotinic receptor antagonist mecamylamine to attenuate alcohol use in alcohol dependent individuals.

• The Use of Prazosin for Treatment of Patients with Alcohol Dependence (AD) and Post-Traumatic Stress Disorder (PTSD)
• Treatment with Mecamylamine in Smoking and Non-Smoking Alcohol Dependent Patients
• Acamprosate for patients with Schizophrenia and Alcohol Dependence
• IV Alcohol Administration using a BrAC Method in Healthy Subjects with and without a Family History
• NMDA Dysregulation in Individuals with Family Vulnerability to Alcoholism