Topiramate for Alcohol Use Disorders

Topiramate is an anticonvulsant which has shown some promise for treating a variety of psychiatric problems, including alcohol use disorders, binge eating, compulsive behaviour, and mood instability.  

One recent study, by Knapp et al, published in the February 2015 edition of The Journal of Clinical Psychopharmacology, compared topiramate with several other medications, and with placebo, for treating 85 heavy drinkers ("heavy" meaning over 35 drinks per week, for men).  * The study duration was 12 weeks.  The target dose of topiramate was 300 mg/day. 

Those in the topiramate group ended up having markedly fewer days of heavy drinking, markedly less total alcohol consumption, and reduced measures of craving, compared to placebo. In general, the topiramate group had at least twice as much improvement in these measures, compared to placebo, which was clinically very significant.  

This study was consistent with others, showing that topiramate can be an effective treatment for alcoholism.  **  

Cognitive-side effects (e.g. memory impairment)  are the main problem with topiramate.  So it is interesting to consider whether lower doses could be useful.  Martinotti et al (2014) did a small study showing topiramate 100 mg per day was useful for treating alcohol dependent patients, with a comparable effect size as the study quoted above.    ***

I am interested in topiramate for other problems which feature compulsive behaviour.  There is some promise in OCD, the studies showing mixed results.  In a genetic disorder called Prader-Willi syndrome, which is characterized by obesity, compulsive self-injury, and intellectual handicap, a trial of topiramate led to significant improvements in the compulsive self-injury.  ****   There have been several studies (e.g. *****) showing that topiramate can be of use in treating binge eating or bulimia, at doses similar to those described above.  Topiramate is also a leading preventative treatment for recurrent or chronic migraines, at a dose of 100 mg daily (******).  It is reasonable, then to think of topiramate in the many cases where there are a combination of these problems, for example a patient with recurrent migraines, who also may have binge eating symptoms, alcohol abuse symptoms, or compulsive self-injury. 

Meta-analysis

Meta-analysis is a powerful technique for summarizing data across many research studies.  For example, to understand the role of psychotherapy or antidepressants to treat depression, a meta-analytic study could give us our best starting point to estimate the effect size.

But the meta-analytic method has a prominent weakness, what I would call dilution:

Suppose that one is doing a meta-analysis of the effectiveness of surgery vs. supportive care for treating abdominal pain.   Many studies might show that surgery is remarkably effective, yet others would show no difference, or even a negative effect, compared to supportive care.  The meta-analysis could average these out, and conclude that there was little difference.    The reason for the dilution is that there are some specific types of abdominal pain, with specific causes, which are best treated surgically (e.g. appendicitis).    Many other types of abdominal pain settle down on their own, or require simple supportive measures.  In the past, it was often difficult to determine whether a patient definitely had appendicitis or not, in the early stages of the illness.   Therefore there would have been many unnecessary appendectomies, and many other cases of ruptured appendicitis operated on too late.

Similarly, in psychiatry, I think it is probably true that there are particular subtypes of depression (or other diagnoses), which respond much better to psychotherapy, or much better to a particular medication, or which might settle down completely on their own with no help at all.   At present, our diagnostic schemes do not help us very much to differentiate between these groups.  We often assume that mild depressions are best treated with psychotherapy, and severe depressions are more likely to need medication treatments.  While there is evidence that supports this assumption, it is not invariably true:  some cases of mild depression persist for long periods of time, do not improve with psychotherapy, but may improve dramatically with a medication trial.  Conversely, some severe cases of depression may not respond well to medications, but improve dramatically with psychotherapy (sometimes a very particular type of psychotherapy).

An ongoing area of research must be to improve our ability to predict the optimal treatment strategy.  I suspect that in most cases, this strategy will involve some combination of psychotherapy, medication, and practical social support.    I think that the science to help us in this task is more likely to come from genetics, and less likely to come from more sophisticated questionnaires or symptom scales.

The search for these answers is confounded, in psychiatry, by a very high risk of placebo-like psychological effects, which must be addressed by studies which have very careful placebo controls and active placebo controls.


For example, many patients are understandably attracted by a very "high-tech" or "advanced science" approach to treating their illness.  So we have some clinics which offer sophisticated technology, such as neurofeedback, PET imaging, genomic analysis, etc.  While these technologies are interesting, and possibly very useful, they also carry a sort of "guru effect."  A PET scan yielding exciting images showing metabolic changes in the brain, accompanied by a detailed diagnostic report, could be much more persuasive than reading the exact same report without the images.    Therefore the PET imaging could act as a marketing tool, to cause the person to take the report more seriously, irrespective of whether the imaging actually shows something of true scientific relevance.  It would be like visiting a fortune-teller, but receiving actual images of your brain which are referred to in the fortune-teller's predictions about you.   It would be especially convincing!    Similarly, with neurofeedback, the dazzle of the technology could cause people to take the therapeutic tasks more seriously, causing improvement separate from the independent benefit of the technique.   I am particularly concerned about the risk of bias with these techniques, because some clinics or private practitioners are charging very high fees for patients to have them.  This is an environment in which selective glowing testimonial accounts could distort a reasonable summary of the data.

In order to conduct research properly with these new modalities, we must have very careful active placebo groups.  In a neurofeedback study, for example, there should be sham neurofeedback which generates a similar type of interactive therapeutic task, with a similar degree of technological dazzle. 

Intensive vs. Regular CBT for PTSD

Ehlers et al. published a good study in the March 2014 edition of The American Journal of Psychiatry in which they compared the following treatments for PTSD:
1) 3 months of regular weekly CBT
2) 7 days in a row of intensive CBT (up to 2 hours daily)
3) 3 months of weekly supportive therapy
4)  waiting list control
 

They found similar good treatment results, after 40 weeks of follow-up, in the regular CBT and the intensive CBT groups, with a slight edge for better response in the regular CBT group.  Total remission in symptoms occurred in 50-70% of these groups, compared to only 30% in the supportive therapy group, and no change in the waiting list group.

Once again, a weakness in these CBT studies is a failure to account for the amount and quality of homework done.  Possibly the regular CBT group had more frequent reminders to keep up with homework tasks and exposure activities, which is a reason why they did slightly better than the intensive CBT subjects. 

What I take from this study is, first of all, CBT techniques (or related techniques which involve similar practice and exposure) are imperative, regardless of other supportive techniques also used. 

Second, I think there is a role for both intensive CBT and longer-term weekly CBT.  It could be useful to have a regular course of CBT with at least one week of intense weekly sessions as well.  It reminds me of any other skill to learn, such as learning a foreign language, learning to swim, learning a musical instrument, etc. :  regular lessons are great, but an intensive week-long program could give you a huge boost, in terms of skills, habit-building, and interested devotion to the work.  In both of these cases, much of the progress will be a result of diligent daily practice and homework, over a period of months. 

Topiramate treats alcoholism in those with a particular genotype

Kranzler et al, in the April 2014 edition of The American Journal of Psychiatry, show that topiramate 200 mg daily led to very substantial reduction in alcohol use in heavy drinkers, compared to placebo.  But this effect was dramatically present only for a subgroup of drinkers who have the  CC genotype of the rs2832407 gene.  This genotype is carried by about 42% of people having European ancestry. 

Topiramate stands out as a very reasonable, safe, and relatively well-tolerated adjunct in the treatment of alcoholism.  I don't think it is necessary to test for the genotype--it would be reasonable to offer an empirical trial, and to predict with the patient that there will be about a 40% chance of the medication having a dramatic effect.  If it doesn't help, the risks would be minimal.  Since topiramate is an anticonvulsant, it could theoretically treat or prevent withdrawal symptoms, even if it doesn't independently reduce the urge to drink. 

Marijuana: effects on memory

In order to show the effects of cannabis clearly in a research study, it is of course best to have a prospective, randomized, controlled experiment, conducted over a long period of time.

This would not be ethical in humans.  In fact, I don't see that it was particularly ethical in monkeys either.  But Verrico, Gu, et al. did such a study, published in the April 2014 edition of The American Journal of Psychiatry,  giving adolescent rhesus monkeys daily IV doses of THC  5 days per week for 6 months.  A control group, matched for baseline cognitive performance, received IV infusions with no THC.

They found significant impairments in spatial working memory in the THC group.

This is strong evidence that marijuana has negative effects on cognition in adolescents.  It did not prove that there are lasting cognitive deficits after the THC has been metabolized out of the body.

We can conclude from this study that daily heavy THC use in otherwise healthy adolescents is likely to interfere with optimal cognitive performance, which could impair schoolwork and possibly contribute to cumulative risk of various other developmental deficits. 

The study does not address risk to cognitive function in adults.    And it does not address the possibility that THC may be useful for managing other symptoms for some individuals, despite the side-effect of spatial memory impairment.