For me, the theme that connects these diseases is that they’re both diseases of cognitive dysfunction. The nature of the dysfunction differs, the onset of the dysfunction differs, but the consequence of the cognitive dysfunction is devastating in both conditions. We now know, and clinicians have been aware for some time, that the cognitive dysfunction in schizophrenia is the greatest single hindrance to rehabilitation. It’s not the severity of the hallucinations or delusions, not even the degree of asociality. What keeps people from relearning social and vocational skills and having successful rehabilitation is the cognitive dysfunction in schizophrenia.

Few people outside our group are really committed to both diseases. In the U.S., and less so in Europe, the notion that psychiatrists should have a primary interest in what is often regarded as a neurological disease—that is, Alzheimer’s—has been somewhat of a difficulty. But our interest has always extended beyond what traditional psychiatrists do in Alzheimer’s, which is treat just behavioral problems. That interest stems from our original work at really a very basic level, on the neurotransmitter basis of learning and memory. That work brought our attention to acetylcholine and that in turn brought attention to Alzheimer’s when acetylcholine was shown to be an important defect, which in turn led to our involvement in the treatment of Alzheimer’s by reversing the deficit in cholinergic neurotransmission. Those drugs are called acetylcholinesterase inhibitors.

That was the first one. There have been a number more now that are better tolerated. But of course the scientific basis of this started in the late 70s and early 80s and has long been superceded by much more sophisticated science. No one today viewing drug discovery or development in Alzheimer’s disease would contemplate therapies that are solely cholinergic any longer.

That’s a very hard question. Sometimes you would like to think that what you’re doing now is having the biggest impact. I think clearly the development of the whole group of cholinesterase inhibitors—including the mechanism to assess the effect on the patients and some of the methodology used in the studies, and even the choice of agents that have been studied—is an important legacy of the Alzheimer’s work. And most recently, that work had an important codicil to it: a paper we published last year in JAMA (K.L. Davis, R.C. Mohs, D. Marin, D.P. Purohit, D.P. Perl, M. Lantz, G. Austin, and V. Haroutunian, "Cholinergic markers in elderly patient with early signs of Alzheimer disease," JAMA, 281[15]: 1401-6, 21 April 1999) that has been very widely cited, pointing out that the cholinergic defect which we all thought was so pervasive was actually not a very early abnormality in the disease. The patients with the earliest symptoms of the disease, who went to autopsy having died of something else, didn’t show a very profound acetylcholinergic defect. It only becomes obvious in the middle stages of the disease. We regard that as interesting because it fits so well with observations made in large study after large study that the patients who have the most dramatic responses to cholinesterase inhibitors are patients in the middle stages of the disease.

I think the most important thing we’ve done in schizophrenia has been done since that review article. It addresses the question of whether the cognitive component of schizophrenia, particularly in very bad outcome cases, is a progressive disease or not. We have been prospectively studying a large series of patients who are quite elderly and have substantial cognitive impairment. What we found and recently published is that after age 65 there is a precipitous drop in cognitive capacities of these patients and that the dementia they have is not a consequence of any known central nervous system co-morbidity. We have done 100 consecutive autopsies and found no reason to explain this profound dementia. The best reference for that work is a 1 January 1999 article in Biological Psychiatry, (P.D. Harvey, J.M. Silverman, R.C. Mohs, M. Parella, L. White, P. Powchik, M. Davidson, and K.L. Davis, "Cognitive decline in late-life schizophrenia: a longitudinal study of geriatric chronically hospitalized patients," Biological Psychiatry, 45[1]: 32-40, 1 January 1999). The other paper that’s very important is on these 100 consecutive autopsies we did. That’s in Archives of General Psychiatry, 1998, volume 55 (D.P. Purohit, D.P. Perl, V. Haroutunian, P. Powchik, M. Davidson, and K.L. Davis, "Alzheimer disease and related neurodegenerative diseases in elderly patients with schizophrenia: a postmortem neuropathologic study of 100 cases," Archives of General Psychiatry, 55[3]: 205-11, March 1998).

We are trying to find what in fact is the neurochemical basis of that dementia or at least what are the best guesses as to what they might be. We found that when we compared demented with non-demented schizophrenics who are over 65, one of the biggest differences is in noradrenergic activity. We are trying to treat that deficit with a drug that increases norepinephrine. That’s one implication. The second implication relates to the cognitive decline in schizophrenia before age 65. That is much, much less severe and much more subtle, but cognitive problems are still quite important and still a rate-limiting step in rehabilitation. The question is whether there’s a similarity between what is exacerbating past age 65 and what was more subtly occurring in younger schizophrenics. Maybe by studying older people with such a profound deficit, we will be able to find cellular and molecular characteristics of the defect more readily, do something about it, and then extend that work to younger people. In other words we can study the problem in its most exacerbated form. That also raises the following very important issue: if this is not a static lesion, then there may very well be a degenerative component. The question becomes, are cells dying in schizophrenia? Is there a neurotoxicity associated with the disease? We really need to know that.

I’m relatively optimistic. I think there is a powerful genetic component to this disease. Even though it’s quite likely to be a consequence of multiple genes, I would be surprised if we don’t begin to tease apart what some of those genes are in the next decade. Even if we only have four or five genes out of maybe 15 involved, if we can trace those four or five genes to their cellular consequences, it may help us really unravel at least where we should be looking. Even if it’s only in a few families. What we’ve learned about Alzheimer’s from a few families with unusual mutations—families that constitute less than one percent of all Alzheimer’s families—has taught us so much about the disease that we can now make very rational suggestions about therapeutics. I think we may be able to do the same thing if we can find a few genes and few families in schizophrenia.

The most important lead appears to be in ways to alter the processing of the amyloid precursor protein. It’s becoming increasingly clear that one of the initiating steps in Alzheimer’s pathology is the deposition of these amyloid plaques, and it is becoming possible to conceptualize ways that we can either alter the way the amyloid precursor protein is processed to become plaques, or even to clear the amyloid more effectively once it’s there. A very critical line of inquiry leading to therapeutics is all about amyloid, altering it, and its consequences.

At the moment there is a distant number two, which would actually be numbers two, three, four, and five. Those are other ways to keep nerve cells from dying. That may be through diminution of free radical production, or through altering the development of neurofibrillary tangles by changing the hyperphosphorylation of the tau protein that forms those tangles. Or it may be through diminishing excitotoxicity, and that may mean altering glutamate transmission in particular brain regions. And lastly it may be through altering inflammatory processes. Because there appear to be a number of inflammatory mechanisms that seem to be substantially enhanced and that could be neurotoxic in Alzheimer’s disease. It may be, however, and we just don’t know if some of these inflammatory mechanisms may be preserving cells. Those are all areas people are very interested in.

There are promising approaches to finding out what’s going on in the disease. I think two are really very important. One is to use more powerful imaging techniques to image both functionally and through spectroscopy the abnormalities that exist in the brain of schizophrenic patients. The second is to tease apart the phenotype of schizophrenia into things we call endophenotypes, or small symptoms of the disease that many people have, and try to find genetic correlates of these endophenotypes and extend those correlates into family members who don’t have the full spectrum of schizophrenia but still share that endophenotype. There may be people, for example, who process stimuli abnormally. There may be people who can’t attend very well to tasks. Or there may be people who are a little bit asocial in their interactions, or a little bit illogical. These are all small parts of the schizophrenia phenotype. If we just focus on those small endophenotypes, seek them in close relatives and family members and attempt to find genetic correlates, we may be able to tease apart the whole syndrome. Those are two approaches I think will be ultimately most useful.

I think to be a psychiatrist and to take care of diseases that are as disabling as schizophrenia and Alzheimer’s is to give you a slightly different perspective on medicine and therapeutics. That perspective is that it’s very hard to look patients in the eye with the current armamentarium of drugs and to be satisfied with what we have to offer. A consequence of dealing with patients who are so unfortunate all the time, I think, is that you develop a moral imperative to do research. If you didn’t think there was hope at the end of the tunnel, that there was going to be something better to offer, you’d just close up shop because at the moment nobody is getting cured.

As I look back on what I’ve done I feel good about the following accomplishments. When I began to work in Alzheimer’s disease, treatments for the condition were completely irrational and the drugs had no efficacy. Now, in part because of work I and many other people did, there are a number of compounds out there that have a strong scientific rationale and are actually efficacious, and it’s likely in the next decade and certainly the next two decades we will have much better drugs. I can see that as very rewarding, and even though my own role may not be all that large I can see that I have played some part in it. In schizophrenia, I’m very much enthused by the sea change that has happened in the way the disease has been conceptualized over only the last five years. It has gone from a perception when I started in this business that we would have to deal with hallucinations and delusions, to the view that there are hallucinations and delusions and also negative symptoms, to the view that we are missing the whole story and it’s really about cognition. Unless we start to develop treatments for that cognitive deficit, we’re not really going to do a whole lot to normalize these unfortunate people. To the degree that I have been part of adding to the weight of evidence that cognition is very important in schizophrenia, I’m pleased with what I’ve accomplished.

Dr. Kenneth L. Davis
Mount Sinai School of Medicine
Department of Psychiatry
New York, NY, USA