BREAKDOWN IN GUT BARRIERS TO BACTERIA MAY PROMOTE INFLAMMATION AND CRAVING IN ALCOHOLICS


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Bacteria in the gastrointestinal tract fulfill many vital functions and are critical for digestion. Yet, these same bacteria can induce strong inflammatory responses by the immune system if they penetrate the gut and enter the bloodstream.

Although acute inflammation is a natural response to protect the body, chronic or systemic inflammation is linked to numerous disorders and diseases. Prior research has established the involvement of inflammatory processes in the development of psychiatric disorders, including major depression and alcohol dependence, but the origins of such inflammation have remained unclear.

Now, researchers at Université Catholique de Louvain in Belgium, led by senior authors Dr. Philippe de Timary and Dr. Peter Stärkel, have found that inflammatory pathways are stimulated in alcohol-dependent patients by bacteria that escape the gut barrier, which correlated with alcohol craving. They report their findings in the current issue of Biological Psychiatry.

“In this study, we established a link between alcohol consumption, craving and activation of pro-inflammatory cytokines which contribute to a systemic inflammatory status in alcohol-dependent patients,” said Stärkel.

To conduct this work, they recruited 63 actively-drinking alcohol-dependent patients who underwent testing both before and after alcohol detoxification. That data was compared with testing from 14 healthy volunteers.

When patients were exposed to alcohol, the researchers found that the inflammatory response originated from gut-derived bacterial products that crossed the gut barrier, which in turn, activated specific inflammatory pathways in blood mononuclear cells.

Prior to undergoing detoxification, the observed inflammation correlated with both alcohol consumption and alcohol craving among the alcohol-dependent patients. Following detoxification, some, but not all, of the altered inflammatory processes were either partially or fully recovered.

“This establishes a new concept where events having their origin at peripheral sites in the body could modify central brain mechanisms that ultimately influence behaviour in alcohol dependence,” Stärkel explained.

Dr. John Krystal, Editor of Biological Psychiatry, commented, “This study suggests that there may be a link between inflammatory processes that develop when gut barriers to bacteria break down and risk for continued heavy drinking among people with alcohol use disorders. The findings suggest that it might be helpful to protect and restore gut integrity and to reduce inflammation when helping patients recover from alcohol use disorders.”

Stärkel agreed, adding, “The study does not only open new areas for research but also identifies new targets for developing novel treatment and management approaches for alcohol dependence. Targeting the gut-brain axis either at the level of the gut itself or at the level of effector cells such as blood mononuclear cells in order to influence behaviour could become a potential option in the care of alcohol-dependent patients.”

Gabapentin Treatment for Alcohol Dependence.


A Randomized Clinical Trial

Importance  Approved medications for alcohol dependence are prescribed for less than 9% of US alcoholics.

Objective  To determine if gabapentin, a widely prescribed generic calcium channel/γ-aminobutyric acid–modulating medication, increases rates of sustained abstinence and no heavy drinking and decreases alcohol-related insomnia, dysphoria, and craving, in a dose-dependent manner.

Design, Participants and Setting  A 12-week, double-blind, placebo-controlled, randomized dose-ranging trial of 150 men and women older than 18 years with current alcohol dependence, conducted from 2004 through 2010 at a single-site, outpatient clinical research facility adjoining a general medical hospital.

Interventions  Oral gabapentin (dosages of 0 [placebo], 900 mg, or 1800 mg/d) and concomitant manual-guided counseling.

Main Outcomes and Measures  Rates of complete abstinence and no heavy drinking (coprimary) and changes in mood, sleep, and craving (secondary) over the 12-week study.

Results  Gabapentin significantly improved the rates of abstinence and no heavy drinking. The abstinence rate was 4.1% (95% CI, 1.1%-13.7%) in the placebo group, 11.1% (95% CI, 5.2%-22.2%) in the 900-mg group, and 17.0% (95% CI, 8.9%-30.1%) in the 1800-mg group (P = .04 for linear dose effect; number needed to treat [NNT] = 8 for 1800 mg). The no heavy drinking rate was 22.5% (95% CI, 13.6%-37.2%) in the placebo group, 29.6% (95% CI, 19.1%-42.8%) in the 900-mg group, and 44.7% (95% CI, 31.4%-58.8%) in the 1800-mg group (P = .02 for linear dose effect; NNT = 5 for 1800 mg). Similar linear dose effects were obtained with measures of mood (F2 = 7.37; P = .001), sleep (F2 = 136; P < .001), and craving (F2 = 3.56; P = .03). There were no serious drug-related adverse events, and terminations owing to adverse events (9 of 150 participants), time in the study (mean [SD], 9.1 [3.8] weeks), and rate of study completion (85 of 150 participants) did not differ among groups.

Conclusions and Relevance  Gabapentin (particularly the 1800-mg dosage) was effective in treating alcohol dependence and relapse-related symptoms of insomnia, dysphoria, and craving, with a favorable safety profile. Increased implementation of pharmacological treatment of alcohol dependence in primary care may be a major benefit of gabapentin as a treatment option for alcohol dependence.

Soure: JAMA

Anticonvulsant Promising for Alcohol Dependence.


The anticonvulsant gabapentin, a widely prescribed anticonvulsant used to treat epilepsy and neuropathic pain, is showing promise in the treatment of alcohol dependence, new research suggests.

Results from a 12-week, randomized, placebo-controlled trial show that participants taking 1800 mg of gabapentin were twice as likely to refrain from heavy drinking and 4 times as likely to stop drinking altogether compared with participants taking placebo.

“Gabapentin’s effect on drinking outcomes is at least as large or greater than those of existing FDA-approved treatments,” lead researcher Barbara Mason, PhD, Scripps Research Institute, La Jolla, California, said in a statement.

The study was published online November 4 in JAMA Internal Medicine.

Filling a Treatment Gap

According to investigators, gabapentin has the potential to fill a large gap in the treatment of alcohol dependence. They note that of the estimated 8.5 million alcohol-dependent Americans, statistics show that only 720,000 prescriptions were filled for US Food and Drug Administration (FDA)–approved medications for alcohol dependence in 2007, most of them prescribed by psychiatrists.

Previous studies of gabapentin for alcohol-dependent persons have suggested that the drug may be safe and effective, but conclusive results have been hampered by small sample size and methodologic or dosing issues.

To provide a more definitive evaluation of the drug for alcohol dependence, the researchers conducted a 12-week, double-blind, placebo-controlled, randomized, dose-ranging trial of 150 adults with current alcohol dependence who were attending a single outpatient center.

Participants were randomly assigned to receive 900 mg/day, 1800 mg/day, or placebo. All patients received concomitant counseling.

The study’s primary outcomes included sustained abstinence and no heavy drinking, and decreases in alcohol-related insomnia, dysphoria, and craving in a dose-dependent manner.

Results showed that gabapentin significantly improved the rates of abstinence and no heavy drinking with rates of 4.1% (95% confidence interval [CI], 1.1% – 13.7%) in the placebo group, 11.1% (85% CI, 5.2% – 22.2%) in the 900-mg group, and 17.0% (95% CI, 8.9% – 30.1%) in the 1800-mg group.

Further, the investigators report that the no-heavy-drinking rate was 22.5% (95% CI, 13.6% – 37.2%) in the placebo group, 29.6% (95% CI, 19.1% – 42.8%) in the 900-mg group, and 44.7% (95% CI, 31.4% – 58.8%) in the 1800-mg group.

In addition, the results showed that the drug significantly reduced cravings, depression, and sleeplessness. The researchers report that gabapentin had a favorable safety profile with no reports of serious adverse events.

According to Dr. Mason, gabapentin offers several potential advantages over the 3 other FDA-approved medications for alcohol dependence. It is “the only medication shown to improve sleep and mood in people who are quitting or reducing their drinking, and it’s already widely used in primary care ― that’s an appealing combination,” she said.

Broader Access to Treatment

In an accompanying editorial,Edward V. Nunes, MD, writes that the finding that gabapentin prevents relapse in alcohol-dependent patients is “an important development.”

“This well-designed and well-powered trial replicates the positive findings of several previous smaller trials,” Dr. Nunes writes.

He notes that a large proportion of alcohol-dependent patients presenting to family physicians fall into the mild to moderate range of alcohol dependence, which further suggests “the strong potential for gabapentin in the treatment of alcohol dependence in primary care.”

Acting director of the National Institute on Alcohol Abuse and Alcoholism, Kenneth R. Warren, PhD, said, “Gabapentin adds to the list of existing medications that have shown promise in treating alcohol dependence. We will continue to pursue research to expand the menu of treatment options available for alcoholism in the hopes of reaching more people.”

Concurrent Naltrexone and Prolonged Exposure Therapy for Patients With Comorbid Alcohol Dependence and PTSDA Randomized Clinical Trial.


Importance   Alcohol dependence comorbid with posttraumatic stress disorder (PTSD) has been found to be resistant to treatment. In addition, there is a concern that prolonged exposure therapy for PTSD may exacerbate alcohol use.

Objective   To compare the efficacy of an evidence-based treatment for alcohol dependence (naltrexone) plus an evidence-based treatment for PTSD (prolonged exposure therapy), their combination, and supportive counseling.

Design, Setting, and Participants   A single-blind, randomized clinical trial of 165 participants with PTSD and alcohol dependence conducted at the University of Pennsylvania and the Philadelphia Veterans Administration. Participant enrollment began on February 8, 2001, and ended on June 25, 2009. Data collection was completed on August 12, 2010.

Interventions   Participants were randomly assigned to (1) prolonged exposure therapy plus naltrexone (100 mg/d), (2) prolonged exposure therapy plus pill placebo, (3) supportive counseling plus naltrexone (100 mg/d), or (4) supportive counseling plus pill placebo. Prolonged exposure therapy was composed of 12 weekly 90-minute sessions followed by 6 biweekly sessions. All participants received supportive counseling.

Main Outcomes and Measures   The Timeline Follow-Back Interview and the PTSD Symptom Severity Interview were used to assess the percentage of days drinking alcohol and PTSD severity, respectively, and the Penn Alcohol Craving Scale was used to assess alcohol craving. Independent evaluations occurred prior to treatment (week 0), at posttreatment (week 24), and at 6 months after treatment discontinuation (week 52).

Results   Participants in all 4 treatment groups had large reductions in the percentage of days drinking (mean change, −63.9% [95% CI, −73.6% to −54.2%] for prolonged exposure therapy plus naltrexone; −63.9% [95% CI, −73.9% to −53.8%] for prolonged exposure therapy plus placebo; −69.9% [95% CI, −78.7% to −61.2%] for supportive counseling plus naltrexone; and −61.0% [95% CI, −68.9% to −53.0%] for supportive counseling plus placebo). However, those who received naltrexone had lower percentages of days drinking than those who received placebo (mean difference, 7.93%; P = .008). There was also a reduction in PTSD symptoms in all 4 groups, but the main effect of prolonged exposure therapy was not statistically significant. Six months after the end of treatment, participants in all 4 groups had increases in percentage of days drinking. However, those in the prolonged exposure therapy plus naltrexone group had the smallest increases.

Conclusions and Relevance   In this study of patients with alcohol dependence and PTSD, naltrexone treatment resulted in a decrease in the percentage of days drinking. Prolonged exposure therapy was not associated with an exacerbation of alcohol use disorder.

Source: JAMA

Disconnecting Neural Networks May Improve Psychopathology.


Three studies look at functional connectivity with and without treatment in patients with dysthymia, alcohol dependence, and obsessive-compulsive disorder.

 

Cognitive control, the use of contextual information to guide behavior in a flexible and goal-directed manner, depends on suppression of the default mode network (DMN) that mediates internal focus (e.g., thinking about oneself) and activation of the externally focused, task-positive salience network (SN) and central executive network (CEN). Three research groups used magnetic resonance imaging (MRI) to investigate how effective psychiatric treatments affect these networks.

A double-blind, placebo-controlled, manufacturer-supported study of duloxetine involved 32 patients with dysthymic disorder and functional-connectivity MRIs. Analyses controlled for relevant variables (e.g., psychiatric comorbidities). Patients had greater baseline DMN connectivity (i.e., more activity) than 25 normal controls. Duloxetine normalized connectivity by week 10, similar to results in major depression.

Other investigators correlated resting-state connectivity with cognitive control over automatic reactions to visual stimuli in 15 severely alcohol-dependent patients and 16 healthy controls. All received 200-mg modafinil and placebo in crossover fashion. In both groups, cognitive control improved with modafinil. However, in only the alcohol-dependence group, connectivity with modafinil decreased between the DMN and the task-positive SN and CEN. Patients’ decreased DMN-SN connectivity was correlated with improved cognitive control.

Another group examined connectivity in 9 patients with obsessive-compulsive disorder (OCD) receiving active or sham deep brain stimulation (DBS) to the nucleus accumbens (NAc). Patients had stronger connectivity than 13 healthy controls between the NAc and the lateral and medial prefrontal cortex. With active DBS, patients’ connectivity was reduced to the controls’ level. Reduction in this frontostriatal connectivity was correlated with reduction in OCD symptoms.

Comment: Preference for internally generated over situationally relevant information characterize all three conditions — rumination on negative-mood–congruent themes in depression, obtaining reward from alcohol in alcohol dependence, and obsessions and drive for rituals in OCD. Medications, deep brain stimulation, and, possibly, effective psychotherapy might disconnect excessive, internally focused information flow from externally responsive behavioral and cognitive systems, restoring adaptive and goal-directed behavior. Further studies of neural networks may identify new therapies.

 

Source: Journal Watch Psychiatry