Posted by Snowie on September 10, 2000, at 21:08:23
Medscape Psychopharmacology Today
Recovery vs ResponseThomas AM Kramer, MD
[Medscape Mental Health 5(4), 2000]
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Some years ago, I went jogging with a colleague friend of mine, and we were discussing various professional struggles we were having with institutions over the position and role of psychiatry. In the course of this conversation, my friend said to me, "The trouble that we have in psychiatry is that we treat disorders that have very high morbidity but very low mortality. As horrible as it sounds, we would get more respect if our patients died more often of their illnesses. As it is, they sit home, quietly hallucinating or profoundly depressed, but not really calling attention to themselves or bothering anyone. If incompetent or inadequate treatment is provided, nobody really notices."
The wisdom of this statement continues to give me pause. Its implications go well beyond the role of psychiatry in medical schools or general hospitals, and get into basic issues involving treatment planning and the clinicians' relationship to the scientific literature. Put simply, it means that psychiatric patients are more likely to remain with treatable symptoms than patients with virtually any other class of disorder. Recently, in psychopharmacology, this issue has been discussed in the context of the difference between response and recovery. More and more, we find ourselves discussing what we need to do to take a response to a medication and turn it into a recovery from a psychiatric illness.
The difference between "response" and "recovery" exists because the terms originate from very different areas of our field. The term "response" comes, for the most part, from the scientific literature. When a study is done with a potential or established psychopharmacological agent, the goal is to see if the medication causes a drug response. Although the definition of a drug response varies from study to study, some generalizations can be made. Most drug studies are done over a 6-week period, so response is established within that particular time frame. Most of the studies are done with either a placebo arm, so as to be able to compare placebo response to drug response, or a placebo washout, with the hope that all of the potential research subjects who would be prone to a placebo response will be eliminated from the study. Researchers do not like a placebo response. They work hard to either factor it out or eliminate it outright. Finally, most drug study response is defined as a 50% or greater reduction in symptoms.
The term "recovery" comes, for the most part, from clinicians. When patients go to see any kind of physician, the goal is to have them recover from the illness that is causing them to seek treatment. Patients do not seek treatment to get a little bit better; they seek treatment, ideally, to be cured. While the term "cure" applies to painfully few treatments for illnesses today, physicians practice medicine by using all of the tools they have to make the illness as absent and remote as possible. As a result, there is no time limit, nor is there any prescribed duration of treatment. If the patient gets better relatively quickly, so much the better, but if it takes sequential trials of treatment going on for a considerable length of time, recovery remains the goal. Examples of this include the treatment refractory depressed patient, requiring multiple trials of different antidepressants both singularly and in combination before he/she achieves a true recovery, and many of the newer pharmacological treatments for schizophrenia, which seem to continue to improve the patients the longer they are on the medication. Clinicians, unlike researchers, are thrilled with a placebo response. At the very least, it provides more time for the medication to actually take effect, if the placebo response is transient. If it is long lasting, then the patient has recovered, and whether it is a true drug response or not is irrelevant to both the patient and the clinician. Finally, although a 50% reduction in symptoms may give a researcher a sense of accomplishment, it would merely indicate to most clinicians that they were only half done with their work.
Examining the difference between the terms "response" and "recovery" reflects the enormous difference in the worlds of scientific literature and the clinical practice of psychopharmacology. On the basis of this, the relevance of scientific literature to clinical practice must be called into question. Psychopharmacologists generally treat refractory or seriously ill patients because, in the current climate, primary care physicians treat most of the other patients. Often, these patients require a level of creative thinking to clinical approach well beyond what could be found in the literature. We would all like the safety of prescribing only treatments that are "evidence based" but in this business, we rarely have that luxury. The scientific literature rarely tells us what to do when the established treatments for a particular disorder fail. Instead, a psychopharmacological mythology is developed in which practitioners hear about something that worked for a colleague on a difficult patient, and they try it themselves. This information can be disseminated through the literature in the form of case reports or letters to the editor, but occasionally it can be nothing more than rumor. Treatments that may have started out in this way can often develop into mainstream treatments, particularly if the drugs have already been developed for a different purpose and so are available for use.
For example, many of us were using valproate in the treatment of bipolar disorder for years before it was actually studied in a scientific and comprehensive way. By the time that valproate was approved by the Food and Drug Administration for the treatment of bipolar disorder, it was an established treatment among most clinicians. I found out that pindolol may be useful in treatment refractory depression in a casual conversation with a colleague, long before I saw any mention of it in the literature. Although its usefulness as an adjunctive treatment for depression is controversial, clinicians who initially used it with the hope that it would succeed where all else had failed inspired those studies that have been done with it. Lastly, there is some indication that very low-dose thioridazine (less than 50 mg/day) may be as effective an "atypical antipsychotic" as any of the more expensive atypical antipsychotics currently available on patent. This indication does not come from the literature, per se, but from conversations that I have had with clinicians who had used it successfully. I have no idea whether this is true or not, but I am quite certain, since thioridazine is no longer on patent, that no drug company will pay for a study to find out. Hopefully, government institutions such as the National Institute of Mental Health will look into this question. It is interesting to note, however, that these past, present, and possibly future scientific studies have been inspired and incited by clinicians and their struggles to get their patients into a complete recovery.
Since the primary goal of clinical science (as opposed to basic, laboratory bench science) is to improve clinical practice, it begs the question as to how these 2 worlds diverged to this extent. The major difference may still be that the practice of medicine in general and of psychopharmacology in particular remains an art and not a science. Although we continuously strive to make the practice of psychopharmacology more scientific, and we have been enormously successful in this regard, we still must prescribe a great deal of treatment that is not "evidence based." What may be more problematic for the future is the fact that much of the research being done currently in clinical psychopharmacology is initiated and funded by pharmaceutical companies. Their interests are closer to the researchers than to the clinicians because those are the interests of the Food and Drug Administration. Pharmaceutical companies are much more interested in bringing new products and indications for old products to market than simply advancing the science of psychopharmacology. For example, 2 competitive antidepressants may work better in combination than either product alone. Who would fund a study proving this scientifically? Neither drug company would have any incentive to do so; thus, it would fall upon government-funded research, which has been subject to both cutbacks and politics to such an extent that such a study would be unlikely.
Another major issue that diverges the worlds of clinical research and clinical practice is the issue of patient selection for studies. This is particularly problematic for studies that are sponsored by pharmaceutical companies, as these companies have an enormous financial investment in having the study come out with a positive result. As such, they want to be particularly careful as to who they admit as a research subject into their study. The subjects that finally make it into the studies are patients with no comorbid illnesses, no concurrent medical conditions, no substance abuse, and bear so little resemblance to the patients that most of us see in clinical practice that some might argue that the results are essentially meaningless to clinicians. Two recent articles have illustrated this point. One, by Humphries and Weisner, looked at studies of treatments for alcoholism and found that the exclusion criteria for the studies would have excluded most of the patients actually in treatment for alcoholism.[1] The other, by Mohr and Czobor, tracked inclusion and exclusion criteria for drug trials in schizophrenia over the period of time that such trials have been done and discovered that criteria are getting increasingly rigid and subjects are becoming far afield from the diverse presentation seen in most clinical practice.[2]
The ultimate divergence of the clinician and the scientist may boil down to one of philosophy. For the scientist, the primary goal is knowledge and understanding. It is important for the scientist to investigate and to prove or disprove any given hypothesis. Clinicians, on the other hand, use scientific reasoning, but their ultimate goal is to improve the life of their patients. If they understand the mechanisms by which their treatments work, or use treatments that are clearly proven to be effective, so much the better, but that is not their focus. It is a well-accepted fact that clinicians owe a great debt to the scientific community for providing them with many of the tools they use to help their patients. It should, perhaps, be equally accepted that it is the clinicians, in their efforts to do whatever they can to alleviate suffering, that often provide the investigators with the initial clue as to what to investigate. While many object to medical treatments, psychopharmacological or otherwise, that are not evidence based, they may be all that is available. No one would argue if our disorders had higher mortality; it is accepted practice in all of medicine to do whatever one can to prevent death. Given the nature of the disorders that we treat, we need to focus our energies on the high morbidity of psychiatric illness and not allow people to remain with symptoms that may be treatable.
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References
[1] Humphries K, Weisner C. Use of exclusion criteria in selecting research subjects and its effect on the generalizability of alcohol treatment outcome studies. Am J Psychiatry. 2000;157:588-594.
[2] Mohr P, Czobor P. Subject selection for the placebo and comparator controlled trials of neuroleptics in schizophrenia. J Clin Psychopharmacol. 2000;20:240-245.
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