Dr. Kramer – All Things They Taught Us That Were Wrong in Psychiatry

Dr. Kramer – All Things They Taught Us That Were Wrong in Psychiatry

Thu, 15 Sep 2005

In a 2004 column, a psychiatrist who engages in “myth busting” inadvertently confirms that psychiatry is given to prescribing mood swings.

He acknowledges that sometimes effective treatments are dropped (benzodiazepines) for new ones that are worse–he cites SSRI antidepressants.

He also acknowledges that psychiatry clung to the dopamine myth to justify the drugs prescribed, noting the truism: If all a psychiatrist has is a hammer–everything in sight looks like a nail!

The dopamine theory died with the advent of the new antipsychotics–but these ‘atypical’ antipsychotics are proving to be more harmful long-term than the old antipsychotic hammers.

Dr. Kramer also confirms the insidious influence drug companies have in determining a psychiatrist’s choice of treatment: “the treatment of anxiety symptomatology was considered one of the first great successes of psychopharmacology with the advent of benzodiazepines. Now, with the marketing push to find new indications for established blockbuster drugs, current thinking is that benzos are overly dangerous because of their abuse potential and as such should not be considered first-line agents. It seems to me that they were perfectly adequate first-line agents for years. We did not give them to drug abusers; we took careful substance-abuse histories before prescribing them, but they were safe and effective in most patients. This is a painful example of a truism of accepted practice being changed by marketing. Drug companies create a perceived “need.”

In Selling Sickness Ray Moynihan and Alan Cassels chart out precisely how Pharma creates that perceived need.

Contact: Vera Hassner Sharav
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http://www.medscape.com/px/viewindex/more?Bucket=columns&SectionId=1599

Medscape Psychopharmacology Today
All the Things They Taught Us That Were Wrong
Thomas A. M. Kramer, MD
Posted 05/03/2004

Introduction

One of the many wonderful things I learned in medical school is that my parents were probably wrong about not letting me go swimming after I ate. Actually, making me wait an hour probably made it more likely that I would have a cramp in the water. When it comes to debunking myths, I believe there are two kinds of people : those who think it is wonderful and those who think it is horrible My response is firmly in the former category. I see the dispelling of supposed truths as progress — as evidence that we are moving forward, constantly questioning and continuously learning. I very much enjoyed the recent programs by the television journalist John Stossel in which he demonstrated that many accepted truisms are false. With this column, I would like to indulge in some myth-busting for psychopharmacology, and hopefully my colleagues who also enjoy questioning authority will enjoy and perhaps even contribute to this discussion.

Depression

Antidepressants treat depression, right? Not when I was a resident in the 1980s (OK, in the early 1980s). I was taught that antidepressants were only effective for those depressions that had the physical symptoms associated with the diagnosis of major depression, such as a sleep disturbance, an eating disturbance, diurnal variation, etc. These were then referred to as endogenous depressions, and these were the only depressions that required medication Other depressions that were a result of some grief-provoking event or of coping with some form of tragedy were referred to as reactive depressions and could only be treated with psychotherapy. I have discussed the distinction between endogenous vs reactive depression in a previous column (“Endogenous Versus Exogenous: Still Not the Issue”), and although I have no desire to revisit that discussion here, I present this to you as the first in a series of truisms about the psychopharmacologic treatment of depression that our profession embraced and then discarded.

The Evolving Myth

By the time I finished my residency, it had been globally noticed that antidepressant medications generally helped depression, regardless of the presence of precipitating events or concurrent physical manifestations. Then we were taught that we should treat all depression that interfered with social or occupational functioning with antidepressants. The problem with this, of course, is that it made some people manic, but then we would start a mood stabilizer, so then we would be treating all aspects of the illness — depression and mania. This approach actually chugged along for quite some time, until some people began to notice that although antidepressants may make the depressive symptoms in bipolars go away, at least in the absence of a mood stabilizer they seemed to make them cycle more quickly and more coarsely. Now conventional wisdom has reversed itself again in the face of specific treatments for bipolar depression, such as lamotrigine, combination therapy with olanzapine and fluoxetine, and perhaps even second-generation antipsychotics as a group. There is even some debate among clinicians as to whether antidepressants, even given concurrently with a mood stabilizer (such as lithium or valproate), have a role at all in the treatment of bipolar depression. When all you had was a hammer, everything looked like a nail. It’s always wonderful to have new tools, but it is never a good idea to throw away the old ones. Although there is evidence that antidepressants can have a negative impact on the course of bipolar disorder, there is also evidence that patients treated only with mood stabilizers have considerably higher morbidity, particularly regarding depressive symptomatology.

Receptor Sites Revisited

We are in the process of moving from the model of continuing medical education to the model of lifelong learning. The major reason why this has become a core competency for medical practice is that all fields of medicine, including psychopharmacology, are advancing at a dramatic rate, and this not only involves new knowledge, techniques, treatments, and understanding, but it is challenging and rethinking old ideas and assumptions. Once again returning to what I was taught as a resident, in the 1980s there was no question about what caused psychosis — too much dopamine. The way to treat psychosis was blocking D2 receptors. Then, clozapine’s efficacy was tested and proven, and all of a sudden all bets were off. Here was a drug that appeared to be enormously effective but didn’t do what an antipsychotic was supposed to do ie, block D2 receptors.

Everything we were taught was wrong. This thinking began to refocus the discussion about schizophrenia away from treating positive symptoms (once again, all we have is a hammer, so all we will talk about are the nails) to the other aspects of the illness, such as negative symptoms and cognitive dysfunction, and people began to recall that one of the original terms for schizophrenia was dementia praecox. How did clozapine make patients better? One thing that it did was block a negative-feedback loop via serotonin antagonism so that patients were not quite so hypofrontal. We knew from the earliest, functional neuroimaging studies that schizophrenics had decreased activity in their frontal cortex, but up until this point, we did not have a hammer for that. Another idea that this began to challenge was that if blocking a D2 receptor was good, then blocking it more tightly or blocking more of them must be better. Can you block a receptor too much? There is now good evidence that you can, particularly D2 receptors. The higher the saturation of binding and the stronger the binding coefficient, the more likely side effects and secondary negative symptomatology are. Put simply, second-generation antipsychotics may have more effectiveness because they bind more loosely and less completely to the D2 receptors in the brain.

Another example is memantine, our newest tool in the struggle against Alzheimer’s disease. This drug appears to be effective because it has a low affinity for the N-methyl-D-aspartate (NMDA) glutamate receptor. Because it has only a low affinity, it only has an effect when the glutamate system is hyperactive and potentially neurotoxic, so it slows the progression of cell death in Alzheimer’s disease. This is in stark contrast to drugs that have a high affinity for the NMDA glutamate receptor, such as ketamine or dextromethorphan, which can interfere with the overall functioning of the glutamate system and in some cases mimic schizophrenia to the point of precipitating psychosis.

Fixing What Works

The issue of the treatment of anxiety symptoms and the use of benzodiazepines has also been addressed here in a previous column (“A Conversation With a Colleague”), but in the context of this discussion, I think it is important to note that benzodiazepines were the mainstay, at least in patients with no vulnerability toward substance abuse. No one seemed to have much of a problem with this. Indeed, the treatment of anxiety symptomatology was considered one of the first great successes of psychopharmacology with the advent of benzodiazepines. Now, with the marketing push to find new indications for established blockbuster drugs, current thinking is that benzos are overly dangerous because of their abuse potential and as such should not be considered first-line agents. It seems to me that they were perfectly adequate first-line agents for years. We did not give them to drug abusers; we took careful substance-abuse histories before prescribing them, but they were safe and effective in most patients. This is a painful example of a truism of accepted practice being changed by marketing. Drug companies create perceived “need.” Another example includes subtypes of antidepressants — many were marketed as first-line until the patents had run out. Then all of a sudden, they are held up as inadequate as compared with new subtypes, still on patent competition. In many cases, this may be an example of attempting to fix something that works just fine.

Accepted Practice Changes Over Time

Changes in what is considered truth or accepted practice are not limited to comparing different agents. Many of the agents we have used are now significantly different doses This is particularly true with antipsychotics. Once again, harking back to my residency, we used doses of haloperidol routinely that would be considered toxic today. We maintained lithium levels on our patients, particularly when using it for augmentation of an antidepressant in treatment-refractory patients, which were so low as to be considered ineffective today. As we began to use anticonvulsants as mood stabilizers, it took years for it to occur to us that perhaps the blood levels that prevent seizures and for mood stabilization may not be the same. Now it is relatively well accepted that the patients require higher levels for mood stabilization. These are more examples of things we said were true 10 or 15 years ago, but we have now changed our minds.

Psychopharmacology requires a sense of humor. Sometimes, the best use of evidence-based medicine is to remember how little evidence we have. To be an effective psychopharmacologist requires flexibility and open-mindedness. Old wisdom should never be overwritten by new science.

Thomas A. M. Kramer, MD, Associate Professor of Psychiatry, University of Chicago, Chicago, Illinois

Disclosure: Thomas A. M. Kramer, MD, has no significant interests to disclose.

Medscape General Medicine. 2004;6(2):e19. ©2004 Medscape

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