Addiction Psychiatry: Clinical Insights

The purpose of this brief communication is to highlight clinically applicable information presented at the American Academy of Addiction Psychiatry Annual Meeting for our Psychiatric Times readers who were unable to attend.

Treatment for drug and alcohol depencencies
One of the highlights of the conference was an excellent symposium on “Pharmacogenetically Driven Treatment for Drug and Alcohol Dependencies” by luminaries in the addiction psychiatry field, including Henry Kranzler, MD, Thomas Kosten, MD, and Dave Oslin, MD. Take home points included:

Topiramate for alcohol use disorder
This medication has emerged as an evidence-based pharmacotherapy for the treatment of alcohol use disorder. A recent meta-analysis¹ of seven controlled trials demonstrate a pooled effect size of 0.46 on days abstinent from alcohol, with similar effect sizes observed for heavy drinking days per week, gamma glutamyl transpeptidase (GGT) levels, and reductions in craving.

The effect size observed are more than twice that seen by naltrexone and acamprosate; two FDA approved medications for the treatment of alcohol use disorder. Note: an application for FDA approval for topiramate is unlikely to occur since the original patent has expired and the compound can now be sold as a generic. Also, tolerability remains an issue with this medication (eg, cognitive slowing, paresthesias, glaucoma, kidney stones). Slow titration schedules, combined with thoughtful patient selection, can help increase adherence and the overall utility of this medication.

A recent study has also identified a genetic variant [single nucleotide polymorphism (SNP) rs2832407] in the AMPA/Kainate GRIK1 gene where homozygous carriers demonstrated a larger decrease in heavy drinking days per week (estimated NNT ~2-3) at a dose of 200 mg/daily² compared with non-carriers.² Of note, this is a preliminary finding and requires replication in additional controlled studies before genetic testing can be recommended for clinical practice.

Disulfiram for cocaine use disorder
Multiple lines of evidence suggest that chronic cocaine use leads to a hypodopaminergic state. Dopamine beta hydroxylase (DBH) is an enzyme involved in the conversion of dopamine (DA) to norepinephrine (NE) and it has been hypothesized that inhibition of DBH may help correct the hypodopaminergic state identified in individuals with cocaine use disorder. Disulfiram is an inhibitor of DBH, in addition to its role as an acetaldehyde dehydrogenase inhibitor in the treatment of alcohol use disorders.

Previous controlled trials have demonstrated a modest effect of disulfiram on increasing cocaine-free urines.³ Although, disulfiram appears to have a small effect size on cocaine use, with the absence of any current FDA approved medications for cocaine use disorder many addiction psychiatrists have elected to prescribe this medication, especially to individuals with comorbid alcohol and cocaine use disorder.

In an effort to identify a subpopulation of cocaine users that may have a more robust response to disulfiram a recent controlled trial evaluated a genetic variant in the DBH gene (SNP rs1611115) where homozogyous carriers have tonic low DBH levels and decreased cocaine free urines on disulfiram compared to non-carriers.⁴ Of note, this finding also requires replication prior to recommendations for changes in genetic testing in current clinical practice.

Future directions
In a keynote address, George Koob, PhD, current Director of the National Institute of Alcohol Abuse and Alcoholism (NIAAA), presented a summary of our current knowledge of the neurocircuitry involved in substance use disorder (for an excellent review see Koob and Volkow, 2010⁵). He discussed his vision for the future direction of the NIAAA and here are several highlights:

• Evidence have demonstrated that stress pathways including the anatomy of the bed nucleus stria terminalis, amygdala, and hypothalamic-pituitary access and also, neuropeptide systems including neuropeptide-Y, corticotropin releasing factor, and hypocretin/orexin become significantly dysregulated in chronic substance use. A priority of the NIAAA is developing compounds which interact with these stress neuropeptides to as they have been implicated in the pathophysiology of withdrawal and also, stress induced relapse.
• There are currently multiple FDA improved medications to treat individuals with alcohol use disorders, including naltrexone and acamprosate. A recent meta-analysis in JAMA⁶ provided further evidence for the efficacy of these medications with an estimated effect size similar to selective serotonin reuptake inhibitors. However, there remains limited utilization of these pharmacologic treatments in clinical practice likely due to both patient and physician related factors.
• Mounting evidence has demonstrated the efficacy of gabapentin to treat alcohol use disorders with recent publication of a 12-week RCT which demonstrated increased abstinence in 150 individual with alcohol use disorder treated with gabapentin compared to placebo.⁷ NIAAA is about to begin a multisite trial of the prodrug gabapentin enacarbil to assess its ability to decrease drinking in individuals with alcohol use disorder. If the trial is positive, Horizant may submit an application to the FDA for approval for the treatment of alcohol use disorder.
• Finally, NIAAA is about to begin the Adolescent Brain Cognitive Development (ABCD) study. ABCD is a national longitudinal study following 10,000 adolescents from the ages of 10 to 12 years, for a time period of 10 years, collecting brain imaging, neurocognitive, impulsivity, mental health, and substance use data. The goal of the study is to help differentiate the effects of premorbid structure and function (ie, prior to drug exposure) from the direct effects of substance use on the developing adolescent brain.

If you are interested in learning more about up-to-date treatment strategies for substance use disorders please consider joining the American Academy of Addiction Psychiatry as a member and/or attending the Annual Meeting next December in Huntington Beach, California. In addition, one-on-one mentoring on the use of the above medications and other clinical strategies for the treatment of substance use disorders are available through the Provider's Clinical Support System for Medication Assisted Treatment (PCSS-MAT) website: http://pcssmat.org.

Disclosures:

Dr Hoefer is Director of the Opiate Treatment Program at the San Francisco VA Medical Center and Associate Director of the UCSF Addiction Psychiatry Fellowship.

References:

1. Blodgett JC, Del Re AC, Maisel NC, Finney JW. A meta-analysis of topiramate’s effects for individuals with alcohol use disorders. Alcohol Clin Exp Res. 2014.38:1481-1488.
2. Kranzler HR, Covault JC, Feinn R, et al. Topiramate treatment for heavy drinkers: moderation by a GRIK1 polymorphism. Am J Psychiatry. 2014.171:445-452.
3. Carroll KM, Fenton LR, Ball SA, et al. Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients. Arch Gen Psychiatry. 2004;61:264-272
4. Koston TR, Wu G, Huang W, et al. Pharmacogenetic randomized trial for cocaine abuse: disulfiram and dopamin beta-hydroxylase. Biol Pyschiatry. 2013;73:219-224.
5. Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010;35:217-238.
6. Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient setting: a systematic review and meta-analysis. JAMA. 2014;311:1889-1900.
7. Mason BJ, Queelo S, Goodell V, et al. Gabapentin treatment for alcohol dependence: a randomized clinical trial. JAMA Intern Med. 2014;174:70-77.