Garth Kroeker

Monday, October 5, 2009

Pregnancy & Depressive Relapse

I was looking at an article in JAMA from 2006, which was about pregnant women taking antidepressants. They were followed through pregnancy, and depressive relapses were related to changes in antidepressant dose. Here's a link to the abstract:

http://www.ncbi.nlm.nih.gov/pubmed/16449615

The study is too weakly designed to allow strong conclusions. Yet the abstract makes a statement about "pregnancy not being protective" which--while possibly true--is not directly related to the findings from the study. This criticism was wisely conceived by the author of "The Last Psychiatrist" blog:
http://thelastpsychiatrist.com/2006/10/jama_deludes.html

Yet the JAMA study is not uninformative.

And the criticism mentioned above goes a bit too far, in my opinion. The critique itself makes overly strong statements in its own title & abstract.

It appears quite clear that pregnant women with a history of depressive illness, who are taking antidepressants, but decrease or discontinue their medication during the pregnancy, have a substantially higher risk of depressive relapse.

Because the study was not randomized, we cannot know for sure that this association is causal. But causation would be reasonably suggested. It does not seem likely that this large effect would have been caused by women whose "unstable" depressive symptoms led them to discontinue their antidepressants (i.e. it does not seem likely to me that "reverse causation" would be a prominent cause for this finding). I think this could happen in some cases, but not frequently. Nor does it seem likely to me that a woman already taking an antidepressant, who becomes more depressed during the pregnancy, would therefore stop taking her medication. This, too, could happen (I can think of clinical examples), but I don't think it would be common. It seems most likely to me that the causation is quite simple: stabilized depressive illness during pregnancy is likely to become less stable, and more prone to relapse, if antidepressant medication is discontinued.

The critique of this article also discusses the fact that women in the study who increased their doses of medication also had higher rates of depressive relapse, yet this fact is not mentioned very much in the abstract or conclusion. This finding is also not surprising--what other reason would a pregnant woman have to increase a dose of medication which she was already taking during her pregnancy, other than an escalation of symptoms? In this case, depressive relapse (which can happen despite medication treatment) is likely the cause of the increased dose--the increased dose is unlikely to have caused the depressive relapse.

Yet, as I said above, the study only allows us to infer these conclusions, as it was not randomized. And I agree that the authors overstate their conclusions in the abstract. In order to more definitively answer these questions, a randomized prospective study would need to be done.

Tuesday, September 29, 2009

Astronomical Photographs

N-Acetylcysteine for treatment of compulsive disorders

N-acetylcysteine is an antioxidant which modulates the glutamate system in the brain. Glutamate is actually the most prevalent neurotransmitter in the brain, and generally has strongly activating effects on nerve cells.

A recent study in Archives of General Psychiatry described groups of individuals with compulsive hair-pulling behavior (trichotillomania), randomized to receive either placebo, or N-acetylcysteine 1200 mg/day, then up to 2400 mg/day, over 12 weeks:
http://www.ncbi.nlm.nih.gov/pubmed/19581567

The N-acetylcysteine group had about 50% reduction in hair-pulling behaviour, with no change in the placebo group. Those in the N-acetylcysteine group did not report any side effects. In fact, the only side effects were among those in the placebo group.

The same author published a study in 2008 showing a substantial improvement in compulsive gambling behavior in a group given NAC at an average dose of about 1500 mg/d:
http://www.ncbi.nlm.nih.gov/pubmed/17445781

A very preliminary study showed that NAC may have some promise in treating cocaine addiction:
http://www.ncbi.nlm.nih.gov/pubmed/17113207

NAC has shown some promise as an adjunctive treatment for chronic schizophrenia; in this study the dose was 1000 mg twice daily, over 24 weeks. Once again, there were no side-effects. As I look at the body of the paper, I see that there was a definite favorable effect from the NAC compared to placebo, in several domains, but the size of the effect seemed clinically modest:
http://www.ncbi.nlm.nih.gov/pubmed/18436195

So NAC appears to be an appealing therapy for a variety of frequent, and often difficult-to-treat psychiatric symptoms. There do not appear to be side effect problems.

At this point, NAC can be obtained from health food stores in Canada, as a nutritional supplement. It is also on the prescription formulary in an injectable form for treating acetaminophen toxicity.

Friday, September 25, 2009

Randomized Controlled Trials in psychiatry

There is a good debate presented in the September 2009 issue of the Canadian Journal of Psychiatry (pp. 637-643), about the importance of randomized controlled trials in psychiatric research and clinical practice.

Steven Hollon presents a strong case supporting the philosophical foundations of RCT research, while Bruce Wampold presents many good points about the present limitations and weaknesses prevalent in current psychiatric RCT research studies. In particular, Wampold points out that much evidence exists regarding the relevance of the individual therapist (and, I might add, of the individual sense of patient-therapist alliance or connection) in determining therapeutic outcomes, and that this very individual factor may have a stronger influence on outcome than the particular "treatment" being offered (whether it be CBT, psychoanalysis, a medication combination, etc.).

My own view of a lot of the evidence resonates with these ideas. I strongly support the importance of randomized controlled trials in medicine and psychiatry. Yet it often seems to me that many variables are not accounted for. The impact of the individual therapist is one specific factor. If the patient is more comfortable with one therapist than another, than this factor alone may greatly outweigh the effect of the particular style of therapy being offered. Interestingly, this factor may not necessarily depend on the length of experience of the therapist -- sometimes a trainee may have a more positive therapeutic impact than a therapist who has decades of experience. This fact is not surprising to me: a lot of psychotherapy can have a lot to do with the capacity for the therapeutic relationship to grow and be healthy, which may depend substantially on very personal factors in the therapist. This may be humbling to those of us who revere the notion of psychotherapeutic theory being of paramount importance.

The whole of psychiatric theory may, at least in some cases, be less important than the goodness of a single interpersonal connection.

But I do also believe that certain therapeutic techniques are more effective than others. I think that strategies which promote daily long-term psychological work just have to be more effective (along the lines of language learning again). Also I think that strategies which encourage and help a person to face their fears or to move away from destructive habits are more likely to be helpful than strategies which do not look at these issues.

Many other factors are often not controlled (or examined at all) in present psychiatric RCTs, including nutrition, exercise, other self-care activities, supportive relationship involvement, community involvement, altruistic activity, etc.

Another factor that I have considered is the heterogeneity of many studied psychiatric populations. Different individuals with so-called "major depressive disorder" may in fact have different underlying causes for their symptoms; some of these individuals may respond well to one type of treatment, others may respond to something else. I suppose the RCT design remains appropriate in this situation, yet a powerful focus in research, in my opinion, needs to be to examine why some people respond to something, while others don't.

This erratic pattern of response doesn't just happen with individuals in a particular study. There are whole studies in which a well-proven psychiatric treatment (such as an antidepressant) doesn't end up differing from placebo. I don't think such studies show that antidepressants (or other treatments) are ineffective, but I do think it strongly suggests that the current criteria for psychiatric diagnoses are insufficient to predict treatment response as consistently as we need.
Often times, these negative studies are dismissed automatically. In many cases, such studies have been poorly designed, and that is the main problem. But in other cases, I think we need to very carefully examine such negative studies, to understand why they were negative.

This is consistent with another type of scientific rigor (different from the RCT empirical approach): in mathematics, a single counterexample is sufficient to disprove a theorem. If such a counterexample is found, it can be extremely fruitful to examine why it occurred--in this way a new and more valuable theorem can be conceived. The process of generating the disproven theorem was not a waste of time, but could be understood as part of a process to find the accurate theorem. Such examples abound in other fields, such as computer programming--a program or algorithm may work quite well, but generate errors or break down in certain situations. Careful examination of why the errors are taking place is the only way to improve the program, and perhaps also to more deeply understand the problem the program was supposed to solve.

Wednesday, September 16, 2009

Perils of Positive Thinking?

Joanne Wood et al. had an article published in Psychological Science in June 2009. It was a study in which subjects with low self-esteem felt worse after doing various "positive thinking" exercises. Subjects with higher self-esteem felt better with self-affirming statements.

Here is a link to the abstract: http://www.ncbi.nlm.nih.gov/pubmed/19493324

So the study seems to suggest that it could be detrimental to engage in "positive thinking" if you are already having depressive thoughts, or negative thoughts about yourself or your situation. The authors theorize that if you if have a negative view of yourself, then it may simply draw more attention in your mind to your own negative self-view, if you force yourself to make a positive statement about yourself. The positive statement may simply seem ridiculous, unrealistic, unattainable, perhaps a reminder of something you don't have or feel that you cannot ever have.

However, the study is weak, and demonstrates something that most of us could see to be obviously true. The study is cross-sectional, and looks at the effect of a single episode of forced "positive thinking." This is like measuring the effect of marathon training after one single workout, and finding that those already in good shape really enjoyed their workout, while those who hadn't run before felt awful afterward.

Any exercise to change one's mind has to be practiced and repeated over a period of months or years. A single bout of exercise will usually accomplish very little. In fact, it will probably lead to soreness or injury, especially if the exercise is too far away from your current fitness level. I suppose if the initial "exercise" is a gentle and encouraging introduction, without overdoing it, then much more could be accomplished, as it could get one started into a new habit, and encourage hope.

"Positive thinking" exercises would, in my opinion, have to feel realistic and honest in order to be helpful. They may feel somewhat contrived, but I think this is also normal, just as phrases in a new language may initially feel contrived as you practice them.

And, following a sort of language-learning or athletic metaphor again, I think that "positive thinking" exercises cannot simply be repeating trite phrases such as "I am a good person!" Rather, they need to be dialogs in your mind, or with other people -- in which you challenge yourself to generate self-affirming statements, perhaps then listen to your mind rail against them, then generate a new affirming response. It becomes an active conversation in your mind rather than bland repetition of statements you don't find meaningful. This is just like how learning a language requires active conversation.

Self-affirmation may initially be yet another tool which at times helps you get through the hour or the day. But I believe that self-affirming language will gradually become incorporated deeply into your identity, as you practice daily, over a period of years. Actually, I think the "language" itself is not entirely the source of identity change; I think such language acts as a catalyst which resonates with a core of positive identity which already exists within you, and allows it to develop and grow with greater ease. This core of positivity may have been suppressed due to years of depression, environmental adversity, or other stresses.