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.
Tuesday, December 30, 2014
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.
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.
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.
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.
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.
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