Drug Development Research 2:433-439 (1982)

Nootropics: Myth or Reality?

S. Kanowski
Department for Gerontopsychiatry, Free University, West Berlin

ABSTRACT

Kanowski, S.: Nootropics: Myth or reality? Drug Dev. Res. 2:433439,1982.

Through the ages there have been two strong human motivations: to remain on this earth as long as possible, and to maintain or regain ones youth and activities in ones old age. The fountain of youth is an ancient mythologicalversion of this strong desire. The question arises, whether nootropics is a modern one. For a clear understanding it is necessary to distinguish between geroprophylactica and gerotherapeutica. The extent to which promising models for the development of gerotherapeutica do exist and the value of currently existing gerotherapeuticawill be points of discussion. Strong emphasis will be given to the difference between statistical significance and clinical relevance in the clinical evaluation of the latter.
Key words: nootropica, CBS, gerontology, geroprophylactics, gerotherapeutics

INTRODUCTION
For centuries the main view of old age seems to have been a pessimistic one. In accordance with that view the last or preterminal phase of our life has been described in such terms as illness, weakness, and immobility, loss of social relationship, and feedback. Disengagement from reality and activity is considered to be a function of all these impairments, and, in turn, has the function of preparation for ones own dying. No wonder that individuals at any time looked at the last phase of their lives with great fear and searched around for remedies, like the fountain of youth. But obviously every remedy recommended so far has failed to satisfy the dream of immortality and eternal youth. In our era, pharmaceutical industry has taken on this dream and is making attempts to develop a, should we say, dry fountain of youth in form of tablets, capsules, and powders. The question arises: Are we still in a state of mythology or can these drugs change reality as we have so far known it?

Received April 22, 1982; accepted June 12, 1982. Address reprint requests to Prof. Dr. S . Kanowski, Department for Gerontopsychiatry, Reichsstrasse 15, 1000 Berlin 19, Federal Republic of Germany.

0272-4391/82/0205-0433$02.500 1982 Alan R. Liss, Inc.

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I shall try to answer three questions: Why do people ask for drugs preventing them from or alleviating the burdens of aging and what are the impairments they feel or fear? Do we have theories of the normal or the pathological aging processes which would allow for the development of pharmacological models? How effective are the pharmacological agents currently on the market under the name nootropics ? QUESTION ONE To answer the first question one can begin by analyzing the indications given by the blurbs and advertisements, because it seems reasonable to assume that pharmaceutical sales promotion tries to meet peoples complaints and expectations of miraculous cures. Here are some examples of the indications in some of these ads: premature or early fatigue; somatic and psychic decline of performance; loss of memory and lack of concentration; depression; prolonged convalescence; disturbances of cerebral metabolism, improvements of disturbed cerebral blood flow; prevention of signs of degeneration and symptoms of old age; lack of drive, etc. All these indications correspond to a model of a general decline of functions particularly in the CNS during the aging process. In gerontology this model is well known as the deficit model of old age. On the basis of recent results of psychological research in gerontology the generality of this model has been questioned. There is no clear evidence of mental decline as an effect of simple biological aging; the evidence indicates an impairment of psychomotoric performance which can be the result of many different factors [Thomae, 19761. What instead transpires from ongoing research in this field is a great potential of plasticity among the normal older population [Baltes and Baltes, 19801; that is, given different conditions and situations, the older person may show quite different performances. Based on both mere retest effects as well as training effects in intellectual performance (Fig. 1) Baltes and co-workers conclude: we believe that older individuals generally live in a context of cognitive deprivation. Consequently, when it comes to psychometric intelligence test, older persons are likely to function below their optimal level of performance. It follows that relatively short-term behavioral interventions (such as retesting and cognitive training) result in significant improvement [Baltes and Baltes, 19801. What we might conclude from these research results is that complaints of older people about a mental decline may be due to a lack of training and stimulation rather than to an assumed biophysiological aging process. Older people might inadvertently contribute to this deprivation. Since they share the common stereotypes on aging with younger people, they run, all too easily, into the trap of the self-fullfilling prophecy. QUESTION TWO Biological research as yet has not been too successful in finding or describing significant changes in the CNS which could be attributed to a pure physiological aging process. The rates of neuronal cell loss and diminution of energy and of transmitter, and nucleic acid metabolism during the aging process are neither as consistent nor do they reach such an extent as to explain an unavoidable decline of mental functions. Thus, it does not seem reasonable to expect specific drug effects on mental performance via changes in neuronal processes. Furthermore, there do not exist reliable and clinically relevant models of aging related to changes in the human brain. The latter, if existing, could provide a solid basis of pharmacological research in this field. Currently there are no drugs available, however, with the geroprophylactic effects as defined by Coper and Kanowski [1976]. The scene changes when we enter the field of pathological aging, which is the field of gerontopsychiatry. There is no doubt at all about macro- and microscopical atrophy of brain parenchym indicating the biological basis of this kind of mental impairment in old age. The chronic organic brain syndrome (CBS) represents the core symptomatology of pathologically induced mental decline in old age. It can be measured along two dimensions (Fig. 2): (1) impairment of intellectual

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functions, and (2) personality changes. The former are more easily accessible to quantitative measurement than the latter. Disturbances of memory, lack of concentration, disturbances of thinking and comprehension, of orientation and control of emotion are the main signs of intellectual dysfunction within the context of CBS. It is very well known that the CBS is largely independent of the underlying pathologic process. This very unspecifity poses important problems concerning theory and construction of models of the CBS. We have to consider multiple etiology and pathogenesis of the CBS. At present the assumption that disturbances of vigilance regulation might represent a final common pathogenetic course (Fig. 2) remains speculative. This ambiguous situation has some consequences for pharmacological research as well. For experimental as well as for clinical evaluation of drug effects it

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Fig. 1. Mean percentage of correct solutions across retest trials of fluid intelligence (figural relations, induction) as a function of retests in elderly subjects [Bakes and Bakes, 19801.

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will be necessary to decide on the criterion level. That is, decisions need to be made whether a given drug acts on symptom level, syndrome level, or influences pathogenetic mechanisms or even etiology. The construction of models of the CBS have to be related to this decision. We have to realize that there are various subsets of the CBS in terms of etiology and pathogenesis with more or less broad intersections (Fig. 3). Unless a given drug does not influence the final common pathogenetic pathway-for instance, vigilance regulation-we cannot expect that one drug improves all subsets of CBS. As far as our present knowledge extends, energy, transmitter, and nucleid acid .metabolism are primarily involved albeit to a different degree, in the different structures of CBS or dementia [Hoyer, 19801 and most likely are also differentially linked to the different symptoms. Apparently, energy metabolism is primarily associated with the case of cerebrovascular dementia, whereas in the case of senile dementia dopaminergic transmitter systems seem to be primarily involved. In addition, we must acknowledge interactions between different metabolic systems-for instance, between energy and transmitter metabolism, as Bowen and Davison [ 19781 demonstrated. From a clinical and neurophysiological viewpoint there is, indeed, evidence that vigilance regulation plays an important part in chronic organic brain disease. The spectrum of disturbances of vigilance reaches from random fluctuations of wakefulness over states of drowsiness to complete inversions of the sleep-wake cycle. Lack of concentration and reduced perception and comprehension are further indicators of lowered vigilance. Thus, we have at least some hypothetical suppositions about which neurophysiological and neurochemical systems might be involved in the development of CBS. It seems to be reasonable, therefore, to use such systems as targets for pharmacological intervention.

Fig. 3 . Total set and some subsets of CBS. Pathogenetic subsets, narrow hatching; etiologic subsets, wide hatching.

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QUESTION THREE
How effective are the nootropic drugs currently on the market? There is no doubt that drugs like hydergine, pyrithioxine, piracetam, and pyritinol influence cerebral functions. Drug influences on EEG changes and behavioral changes have been demonstrated in placebo-controlled, doubleblind studies. EEG changes all tend toward improvement in vigilance [Bente, 1979, 19801. Behavioral changes, assessed on the basis of clinical rating scales scored by physicians or nurses, show improvement of patients with chronic organic brain lesions. Thus drug effects can be taken for granted although the mode of pharmacodynamic action of these drugs remains as yet widely unknown. For instance, McDonald [1979], when reviewing 26 clinical studies, comes to the conclusion that Hydergine does produce some global improvement . . . and . . . favorably influences certain aspects of cognitive functioning, e. g., confusion, mental alertness, impairment of recent memory, disorientation, in elderly institutionalized patients as assessed by subjective clinical rating scales. The same could be said for piracetam [Bente et al., 19781 or the other drugs just mentioned. Why, then, are we dissatisfied with the clinical efficacy of nootropics? Let me mention three points that seem critical to me. (1) All drugs available do not have a reliable effect. Some patients do respond favorably and others not at all. The lack of reliability is demonstrated also by the fact that the differences between verum and placebo effects vary between 15 and 20% for all drugs. Furthermore, as of now, a clear correlation between the different test or behavior parameters influenced by the drugs has not been established. (2) Presently it is not possible to delineate clear-cut differential indications in terms of functional disabilities or nosologic entities or metabolic syndromes for any of the drugs. (3) There is an important difference between statistical significance and clinical relevance. It may well be that a given drug improves the patients ab es in the digit span test by 1 to 2 points in 70% of the cases, whereas a placebo effect is present only in 50% of the control group. This difference may be statistically significant. However, this result tells us nothing or little about the patient himself or those who care for him see any reliable and relevant s in dealing with daily life situations. Coming back to our general question of whether nootropics are myth or reality, what conclusions might be drawn? Nootropics are gerotherapeutics but not geroprophylactics. CBS can be considered the main indication of nootropics since impairment of vigilance seems to be a general factor in the pathogenesis of CBS and most of the drugs dealt with here exert a vigilance stimulating effect. Other symptoms also show improvement but less consistently. At the present nootropics must be regarded as drugs with established action upon cerebral functions but rather weak and instable improvement in psychometric and behavioral parameters. These drug effects seem to be weak particularly when compared with the severe and frequently progressive course of chronic organic brain diseases. In cases of dementia, particularly in those of primary or secondary degenerative origin, where we have no efficient therapeutic principles besides cardiovascular therapy, nootropics can be regarded and used as a supplementary therapy. Their application, however, should not prevent extensive differential diagnostics. The latter assists in the search for treatable etiologies in the cases of secondary dementias and will yield a basis for a fundamental therapy ruled by principles of internal medicine. The use of nootropics, furthermore, will not replace or substitute for good psychosocial guidance of the patient and his often severely burdened family.

REFERENCES
Baltes, P.B. and Baltes, M. : Plasticity and variability in psychosocial aging: Methodological and theoretical issues. In G.E. Gurski (ed): Determining the Effects of Aging on the Central Nervous System. Berlin: Schering AG, 1980, pp. 41-66. Bente, D., Glatthaar, G., Ulrich, G and Lewinsky, M.: Piracetam and Vigilanz. Arzneim.-ForschJDrug Res. 28: 1529-1530, 1978.

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Bente D.: Vigilance and evaluation of psychotropic drug effects on EEG. Pharmakopsychiatr. Neuropsychopharmakol. 12: 137-14, 1979. Bente, D. : Moglichkeiten und Grenzen der Elektroenzephalographie in der geriatrisch-pharmakotherapeutischen Forschung. Vortrag aus dem 7. Rothenburger Gesprach vom 7./8. 11. 1980. F. K. Schattauer-Verlap, in press. Bowen, D.M. and Davison, A.N.: Biochemical changes in the normal ageing brain and in dementia. In Isaacs, B. (ed): Recent Advances in Geriatric Medicine. Edinburgh, London, New York: Churchill Livingstone, 1978. Coper, H. and Kanowski, S.: Geriatrika: Theoretische Grundlagen, Envartungen, Priifung, Kritik. Hippokrates 47: 303-319, 1976. Hoyer, S .: Pathophysiologische Muster der zerebralen Insuffizienz im Alter. Vortrag aus dem 7. Rothenburger Gesprach vom 7.03. 11. 1980. F. K. Schattauer-Verlag, in press. McDonald, R.J.: Hydergine: A review of 26 clinical studies. Pharmakopsychiatr. Neuropsychopharmakol. 12: 407422, 1979. Thomae, H.: Patterns of Aging. Findings from the Bonn Longitudinal Study of Aging. Basel: S. Karger Verlag, 1976.