Wednesday, December 31, 2014

Internet Addiction

Most of us can understand the phenomenon of "internet addiction."    We can easily end up spending too much time on the internet, or on other electronic gadgets.  An interesting documentary called "Web Junkie," which is set in Shanghai, is a good introduction to the subject.  This documentary also illustrates some interesting elements of therapeutic care in China:  on the one hand, there is sort of an authoritarian, militaristic boot-camp style (epitomized by the doctor who runs the clinic).  Yet on other hand, there are some calm, gentle, patient, quiet therapists shown (such as the one female doctor). 

A recent meta-analysis by Cheng and Lee (*) showed that rates of internet addiction in different countries ranged between 2% and 10%.  Interestingly, rates were lower in countries with a higher quality of life, such as in Western Europe, and rates were much higher in countries with lower quality of life. 

Restriction of children's internet use by parents is associated with lower risks of internet addiction (**).    Low satisfaction with family relationships is a strong risk factor. (***).

Children with ADHD are at particularly high risk for internet addiction, with a strong association between addiction scale scores and ADHD severity scores. (****).  Depression, anxiety, and introversion are also risk factors.    Internet addiction is further associated with other addictive problems, including alcohol dependence and smoking. 

Another study looked at a rating scale called the IMQ-A,****** which assesses motives for using the internet.  The scale is based on the DMQ-R , which looks at a person's motives for drinking.   The highest risk for addiction is for those who are using the internet as a coping device (e.g. "to forget your worries"), while using it for social reasons or for education is less risky.

A recent review by Spada (******) suggests that the treatments thus far are quite straightforward:
 1) management of anxiety, depression, and ADHD symptoms
2) addressing family relationships if necessary
3) simply keeping track of internet use, and limiting it strictly
4) medication trials including antidepressants or stimulants if indicated.  Naltrexone 150 mg/d plus sertraline 100 mg/d was used effectively in one case. (*******).

I would add that basic lifestyle habits, including daily exercise, healthy diet, and a deliberate daily activity schedule (including social visits, work, and leisure), are essential, particularly since compulsive internet use leads to a lot of time spent alone in a sedentary posture. Postures in front of a device are also usually slumped, in a head-forward position, looking downwards.  Aside from physical health problems, this type of posture probably has negative psychological effects.  Standing and walking around regularly, with simple posture exercises, stretching in an extension position, etc. are bound to be useful.  Amy Cuddy's work on posture would be worth checking out--a good place to start would be her TED lectures. 

A few other points:
1) a bright screen should not be used near bedtime, since it will interfere with melatonin secretion, and cause sleep disruption.   An alternative for bedtime reading can be to use a device in which the font is reversed, with dim white letters on a black background. 
2) ironically, the internet can also be a valuable aid to treating psychological symptoms.  Web-based CBT can be nearly as effective as seeing a one-on-one counselor for some problems, and at the very least could be a valuable adjunct.   But the problems lie with spending too much time on-line, such that other aspects of life suffer.    Reward circuits in the brain may be fired up by numerous internet activities, in an exaggerated way, causing a distortion of judgment about the merits of continuing the activity. 

Ketamine for PTSD

Feder et al. (2014) published one of the first studies looking at possible use of ketamine to treat PTSD. * In this study, ketamine (0.5 mg/kg IV over 40 minutes) was compared with midazolam, on a randomized, double-blind basis, to treat PTSD patients.   In a crossover design, each patient was scheduled to receive a second infusion, 2 weeks later, of the drug they had not received the first time. 

I think a particular strength of this study was the use of midazolam as an active placebo.  The study would have been strengthened even further if they asked subjects afterwards to guess which medication they had received (most patients would have been familiar with benzodiazepines, and would have known that they did not lead to lasting improvements in their symptoms--presumably most of the patients would have wanted to receive the ketamine, as a novel, hopeful treatment).

The results appear similar to other studies of using ketamine to treat depression:  significant improvement in the week following the infusion.  The acute dissociative effects of the drug wear off completely within a few hours, as ketamine levels go down to zero during this time, yet the symptom improvements are maximal after 24 hours, and continue to be significant over a one-week period. 

The overall effect was to reduce PTSD and depression symptom scores at least by half, with improvements in all PTSD domains.

Side effects were not a major problem; in the 24 hours following the infusion, ketamine patients reported more blurry vision, restlessness, and nausea, compared to the midazolam patients.  Only one ketamine patient dropped out during the infusion, because he felt uncomfortable with it. 

For the patients who had received ketamine first, 7 of 22 were still responders after 2 weeks, compared to only 1 of the midazolam group. 

Once again, I think it would be useful for more studies to explore oral or sublingual ketamine dosing, since this would be much more convenient and practical for a larger number of patients.  A gradual intravenous infusion over 40 minutes leads to a fairly similar change in serum levels compared to GI absorption.  Rapid bolus dosing is an advantage of using IV, but this has not been used for administering ketamine to psychiatric patients.   There are differences in the ratio of ketamine vs. metabolites with the oral vs. IV routes, but I do not see that the differences are so great as to obstruct the benefits.   Dose finding is less precise with oral dosing, but this is a technical matter which can be simply resolved through careful titration.    In any case, science may answer this question for us, through well-designed trials.  A study design I would suggest for this would be a double-blind crossover study comparing oral ketamine + IV saline infusion   vs. IV ketamine + oral placebo, with one treatment per week for 4 weeks.  Doses could be adjusted according to response and side effects on treatments 2, 3, and 4.

Tuesday, December 30, 2014

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 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. 

Wednesday, December 17, 2014

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.   

Evolution & Psychiatry

It is richly interesting to consider the impact of evolutionary processes as they pertain to human behaviour and psychiatric phenomena.

This is an area which is, of course, laden with controversy.  Yet I find the controversy quite unnecessary, perhaps a reflexive reaction which itself could be understood in evolutionary terms.

Despite having several science degrees, including many courses in biology (including genetics and molecular genetics) I am embarrassed to admit that, during my undergraduate years, I never read major popular books by evolutionary theorists.  It is only recently that I have read The Selfish Gene by Richard Dawkins.   I was well-versed in textbook science, and even laboratory-based genetics, yet the joy of learning about genetics can be savoured much more deeply by taking a look at some of these popular works on the subject.

I do not find the subject matter of The Selfish Gene the slightest bit controversial.  I understand why some find it controversial, but I see this as mainly a product of simple human resistance to adapting entrenched beliefs (some of which have been around for millenia, and considered sacred) in the face of strong contrary evidence.  In this case, some of these entrenched beliefs touch on themes relating to religion and ethics.  It is similar to renaissance astronomers being met with disbelief or condemnation, following discoveries about planetary motions which were quite different from previous views.

Actually, as with most science, I find the subject of evolution to be delightfully, joyously interesting, and certainly not a threat to the culture's moral fabric, etc.     Understanding processes of nature need only increase one's sense of wonder and awe, not somehow render it more "spiritless."   My only objection to The Selfish Gene and other similar books is the use of the term "Darwinism."  While I admire the work of Darwin very much, I don't find that it is necessary or useful to attach his name to a system of understanding nature.  Attaching his name makes the subject sound like some kind of philosophical or political opinion (such as  "Calvinism" or "Marxism"), or a type of esthetic or artistic style.    The science of evolution is similar to the science of arithmetic, geometry, or physics.   We would not call a mathematician or physicist a "Pythagorean" or a "Newtonian."  

Evolutionary theory is a simple application of clear logic to a system in which phenomena are replicated.  Those phenomena which replicate more abundantly become more widespread in the population.  This is a self-evident truth, which leads in more complicated systems to some very interesting mathematics.   As Dawkins points out, this type of replication occurs in genes, but also in culture as "memes."   The application of game theory analysis to such replicating systems leads to an understanding of equilibria between competing strategies, which can persist in any population or culture.  Fluency in mathematics makes an insightful understanding of evolutionary science much more clear. 

How is this relevant to psychiatry?    An evolutionary analysis of behaviour reminds me a little of a psychoanalytic exploration of "the unconscious" -- it can bring to awareness behavioural tendencies that are favoured "as if" the genes themselves had a selfish motive.  Genes, being chemical entities, do not literally have motives, but the fact that they replicate leads to gene frequencies and genetically-based behaviours occurring as if they had motives.  Similarly, the "unconscious" could be understood as silent forces within the mind which guide action, outside of awareness.  Therapeutically, according to psychoanalytic theory, insight about one's unconscious motives can lead to a greater freedom of will, and to an escape from recurrent traps of symptoms.  Similarly, awareness of the "forces" caused by natural selection of genes can help us decide whether to culturally over-ride these forces, for the betterment of ourselves or of society.    For example, as Dawkins pointed out, biology itself cannot be relied upon to produce widespread altruism, and to produce an end to warlike or aggressive behaviour;  such a state can be shown mathematically not be an "ESS" (evolutionarily stable state).  So if we are to aim for widespread peace and altruism, we must culturally over-ride innate biological tendencies, on a personal and population level, and work to teach peace very actively.

For such a project to work, we would have to anticipate its meme-like properties, and be prepared to deal with ensuing problems.  For example, in religious cultures, the meme-like nature of associated beliefs and behaviours can cause deleterious cultural changes as a result of "natural selection."  While many religious beliefs are characterized by a deep sense of fairness, justice, peacefulness, and altruism, the memetic properties needed for beliefs to "propagate" lead to a high likelihood of negative elements, such as magical thinking, instilling fear of hell, suppressing contrary views despite strong evidence, espousing violent actions as sacred elements of following or defending one's faith, etc.   Religious memes can become "symbiotic" with memes for political power or influence, leading as we have often seen to religions and governments combining their influences to dominate a nation's political affairs. 

Tuesday, December 16, 2014

CBT vs psychodynamic therapy for Social Anxiety Disorder

In the October 2014 issue of The American Journal of Psychiatry we see an article by Leichsenring et al (18 authors!) comparing the outcome of social anxiety patients who had received either CBT or psychodynamic therapy.  The patients had about 25 sessions of either therapy, over about 9 months time.  They were followed up over the following 2 years after treatment ended.

The study shows that both groups improved similarly over 2 years:  about a 70% response rate, and a 40% remission rate.

But, huge weaknesses in the study here!

1) No placebo group!  
2) No documentation of the homework done in CBT.
3) No detailed description of how the psychodynamic therapy differed from the CBT, other than a passive reference to the technique or manuals used.

I feel that psychodynamic theory is similar to religious belief or theology:  it is finally a set of cultural practices, couched in a therapeutic milieu.  The actual beliefs are substantially fictional, but are grounded in basic ethical principles expressed in scholarly or literary language.    Similar to a great cathedral, a poetic section of a religious text, or a beautiful hymn, the therapeutic impact comes from the esthetics and earnestness of the fellow practitioners, mixed together with the style being a largely accepted cultural norm.  Fragments of accurate science are blended with fictional but culturally vivid therapeutic dogma (e.g. references to Greek mythology), a product of the testimonial accounts and opinions of strong-minded and literary thinkers, who yet are often poor scientists.  In some ways, it is akin to a medieval alchemist or astrologer, whose theories are mostly fictional, but who may still have a loving and intimate appreciation of their subject matter.  In psychodynamic therapy, there would clearly be a sense of attachment, security, a type of friendship or mentorship (even though these qualities would be normally never be admitted, except as "transference"), and an earnest focus on improvement.

In CBT, many of these same factors would be present, though in a more "coachlike" form.  One of the problems with CBT is that the cultural esthetics of the therapy is largely absent, compared to psychodynamic therapy.   If we compare CBT and psychodynamic therapy to religious denominations, it would be as if CBT would have its meetings in an accountant's office, while the psychodynamic sessions would take place in an environment laden with cultural symbolism, such as a church or cathedral, with musical or poetic accompaniment.  

So one of the strong therapeutic elements of psychodynamic therapy (the "cathedral-like" intellectual esthetics) is compellingly absent in most CBT.  I suspect some of the newer forms of CBT, such as mindfulness-based CBT, are introducing some more of this esthetic element, leading to improved effectiveness.

In treating anxiety of any sort, it appears obviously true to me that the therapy must involve the patient having many hours of practice facing anxious situations.  It is limited how much of this practice can actually take place during a CBT session.  Most of the practice would have to take place as homework.  As I have said elsewhere, psychotherapeutic change in many ways is akin to language learning, or to learning a physical skill or sport.  You can have your weekly lessons with the coach, but most of your improvement will take place if you diligently practice every day.

In this study, there was no mention of this most essential therapeutic agent of all:  the practice done, to face social anxiety situations!  Even in psychodynamic therapy,  I would expect that the therapist would facilitate exposure practice between sessions, even if this was not deliberately prescribed.  In some ways, with a resistant patient, a sensitive psychodynamic therapist could be more effective than a CBT therapist to do such encouragement effectively, just as a good priest may simply have a more effective interpersonal manner to encourage someone in a time of distress, compared to a good accountant.  

But no mention was made of how much the patients actually practiced their skills to manage social anxiety.

I find it quite incredible that 18 scholars, all touting their doctoral degrees in the author list, were required to produce such a trivial paper. 

Varenicline plus Bupropion for smoking cessation

Rose and Behm have shown in their November 2014 article in The American Journal of Psychiatry that 12 weeks of a combination of varenicline 1 mg twice daily combined with bupropion 150 mg twice daily, led to substantially improved abstinence rates for highly nicotine-dependent smokers. 

Most smoking cessation strategies have led to quite low abstinence rates.  A typical outcome would be a 25% probability of quitting after a determined attempt.  This is the first study I've seen that shows a strategy that leads to a 50% abstinence rate.  In fact, they found that the combination works best for the heaviest smokers who were most addicted. 

With smoking cessation, as with many other problems, I think that if a pharmacological strategy is considered, why not try the most effective strategy first? Why not try this combination first, rather than trying one much less effective treatment at a time?

Some remaining questions I have about ongoing management would be to question whether long-term varenicline could be necessary (e.g. for a year or more). 

And, with smoking, a big question now concerns the potential benefits and risks of e-cigarettes.  These are probably good harm reduction aids for many smokers, but on the other hand are addicting on their own, and could initiate dependency problems in young people who try them before smoking at all.   Overall, I think e-cigarettes are an important positive development to help people quit smoking, and also to help deplete the tobacco industry further. 

Quetiapine for borderline personality -- journal article review

This is the first in a planned series of posts to summarize a few interesting articles from psychiatry journals published in 2014.

We begin with an article by Donald Black et al.from The American Journal of Psychiatry 171:1174-82.

It's a very simple 8-week randomized controlled study of treating borderline personality patients with either quetiapine XR 150 mg daily, quetiapine XR 300 mg daily, or placebo.  There were about 100 participants in all.   DSM-IV criteria were used for the diagnosis, and the participants could not have active substance abuse, or be in the midst of a major mood or anxiety episode, etc. 

The "Zanarini scale" was used to track symptom changes.  As I look up this scale, I find it appears to be a simple distillation of DSM-IV criteria, with raters giving each item a numerical score.   Unbelievably, I find that I cannot actually look at the questions directly (a fee of over $40 is requested!), which is quite surprising for what amounts to a small collection of very simple questions.

Nevertheless, the quetiapine groups did better than the placebo group on the borderline symptom scales.  But they did not do compellingly better on broader scales including the Sheehan Disability Scale or the GAF.    There was no advantage of the 300 mg dose over the 150 mg dose.

A few criticisms:

 1) I see the placebo group actually had lower baseline symptom scores, which could have biased the placebo group to show less improvement (e.g. through regression to the mean contributing to the larger symptom changes in the other two groups).     The fact that the graph given in the article showed only symptom change, rather than total symptom score, would have further hidden this bias from the reader.  The error bars were not shown in the graph of symptom change.   I see that the total symptom scores are not shown anywhere in the paper! I'm surprised this got past peer review in a major journal!

2) While 150 mg is considered "low dose" here, it would be useful to see what the effect of 25 mg or 50 mg would be. 

3)  As usual with studies of this sort, it is only 8 weeks in duration.  I would be interested in seeing a duration of at least a year.  This would be relevant not only for evaluating effectiveness (including symptom improvements and dropout rates), but also for evaluating side-effect risks (such as weight gain and metabolic changes).

4) The question is not addressed as to whether the more expensive quetiapine XR preparation is actually needed, compared to the less expensive regular quetiapine.  

In summary, a simple, mediocre study, which lends modest support for a practice that most practitioners probably already have done for years anyway -- which is to offer borderline patients treatment with low-dose atypical antipsychotic medications.