Behavioural Bra#l Research.

59 (1993) 1-9
1993 Elsevier Science B.V. All rights reserved. 0166-4328/93/$06.00

BBR 01501

Review article

The pharmacology of the nootropics; new insights and new questions

Cesare Mondadori*
CIBA-GEIGY Limited, Pharmaceutical Research DivMon, Basel (Switzerland)

(Received 7 May 1993)

(Revised version received 29 July 1993)
(Accepted 30 July 1993)

K<v words: Nootropics; Review; Memory: Mechanism of action; Steroid; Clinical implication

Up to now, the memory-enhancing effect of the nootropics has chiefly been investigated in the context of effects on energy metabolism and
on cholinergic and glutamatergic neurotransmission. Recent studies have also shown that the effect on memory is steroid-sensitive. The present
review article summarizes the available results and discusses them in the context of a new hypothesis on the mechanism of action and with respect
to clinical implications.

INTRODUCTION 17), by manipulations of D N A / R N A metabolism (cf.

Well to the fore among the objectives of modern
brain research is the elucidation of the mechanisms
underlying memory. Spurred on by the desire to under-
stand these processes and so discover ways of enhanc-
ing memory and treating disturbances, researchers have
studied countless series of psychoactive and neuro-
active substances for signs of potential pharmacologi-
cal effects or therapeutic properties. Surprisingly
enough, impartial observers browsing through the
reams of published findings hardly get the impression
that each new experiment marks one step closer to the
substrate of memory. All that can safely be said is that
practically every pharmacological intervention in the
workings of the brain affects some form or other of
learning and memory. Interactions with cholinergic<>,
dopaminergic TM, noradrenergic 4'84, and serotonergic4
neurotransmission modify the retention performance of
man and laboratory animals, as also do pharmacologi-
cal modulation of peptide-sensitive neurons (see e.g.
refs. 48, 94) and interactions with excitatory and in-
hibitory amino acids 6'62'8s. Nor does influencing neu-
rotransmission by any means exhaust the possibilities
of modulating memory: there are studies showing that
interventions in other physiological processes and in-
terference with other biochemical parameters can also
affect memory storage: retention performance is altered
by inhibitors of protein synthesis (for a review, see ref.
*For all correspondence.
ref. 47), by administration of steroids 32'49'67, and by
modulation of enzyme functions 3'55~8, etc.
One still almost untapped source of possibly impor-
tant information on the physiological bases of memory
or the control of memory processing is provided by the
nootropics of the piracetam type. In some respects,
these preparations occupy a special position in the
pharmacology of the central nervous system. They have
definitely positive effects on the retention performance
of laboratory animals in various experimental situa-
tions (see below), and they have some positive effects
in patients with memory problems 2"~2"13, or other cog-
nitive disturbances 37"76"s7. On the other hand, in all
tests belonging to the standard armamentarium of the
psychopharmacological laboratory they are practically
inert, and in both humans and animals practically free
of toxic effects. Opinions about these preparations are
highly divergent. For some, the absence of toxicity in-
dicates a lack of any pharmacological action; others see
it as pointing to a new therapeutic approach. Depend-
ing on the observer's standpoint, either the non-
responders in clinical trials testify to the inefficacy of
these agents, or the responders bear out their activity.
The highly reproducible memory-enhancing effects
demonstrable in our experiments in animals made it
possible to perform interaction studies, which opened
up new prospects of gaining insights into the mode of
action of the nootropics and perhaps also the memory-
storage processes involved. Another, more remote ob-
jective of our work was to find an explanation for the
fact mentioned above, that in clinical studies there is
always only a limited proportion of the patients that
respond well to treatment (see e.g. ref. 16).
This review presents the results of our research over
the past six years and discusses them in the general
context of the findings so far available.
THE B E H A V I O U R A L EFFECTS OF T H E N O O T R O P I C S
Although the first observed effect of piracetam on the
CNS was inhibition of central nystagmus in the rab-
bit 34, the further findings made during the last 25 years
showed that its main action consists in the improve-
ment of cognitive functions. The earliest studies were
concerned with pharmacological modulation of the am-
nesiogenic effects of cerebral electroshock. Giurgea and
Mouravieff Lesuisse ss demonstrated that piracetam re-
duced the disturbing influence of an electroshock on the
orientation of rats in a water maze. Many other authors
also reported similar anti-amnesic effects of both pi-
racetam and various chemically related compounds.
Studies by Cumin et al. ~5 with aniracetam and pirac-
etam, by Mondadori et al. 5~ with oxiracetam and pi-
racetam, and by Sara TM with etiracetam all showed a
distinct protective action against the effect of elec-
troshock. Butler et al. ~~ also described anti-amnesic ef-
fects of a whole series of piracetam analogues, includ-
ing pramiracetam. There have been numerous reports
of direct positive effects of nootropics on learning and
memory: thus, aniracetam and piracetam 9'92, etirac-
etam TM, and oxiracetam 5~'53 were found to exert direct
effects on the acquisition and retention performance of
rats and mice in both passive- and active-avoidance
paradigms. Pramiracetam improved the acquisition rate
in a 16-arm radial maze 6s and in a place-navigation
task TM, and aniracetam likewise displayed positive ef-
fects in a radial m a z e 46 and a matching-to-sample test v3.
Ennaceur found that piracetam and pramiracetam im-
proved performance in an object-recognition test 3,
while Perio e t al. 69 observed positive effects of anirac-
etam in a social-recognition test.
E F F E C T S ON E N E R G Y METABOLISM'?
The available findings on the mode of action of the
preparations can be grouped in four categories: (1) ef-
fects on energy metabolism; (2) effects on cholinergic
mechanisms; (3) effects on excitatory amino-acid-
receptor-mediated functions; (4) steroid sensitivity. The
absence of effects in traditional (transmitter-sensitive)
psychopharmacological tests caused the search for the
underlying mechanism to be shifted primarily in the
direction of energy metabolism. For a long time. the
increase in adenylate kinase acuvtty induced by plrac-
etam that had been observed by Nickolson and Wolth-
u i s '4 remained the only biochentical effect detected.
Woelk 89 then showed that piracetam augmented the
uptake of ~2p in phosphatidyl inositol and phosphati-
dyl chloride in glial cells and neurons. Grau et al.'"
found an increase in glucose utilization under hypoxlc
conditions and accelerated recovery in the EEG.
Piercey et al. TM observed no increase in glucose utiliza-
tion in response to piracetam, but a reversa[ of the
scopolamine-induced depression of glucose utilization.
The lack of psychopharmacological effects in the above
sense was then apparently substantiated, insofar as a
series of biochemical investigations of effects on trans-
mitters gave negative or contradictory results. Thus.
Poschel at a l 7 4 showed that neither piracetam nor
pramiracetam binds to the muscarinic cholinerg~c re-
ceptors, and no binding was detectable either in a
dopamine assay with haloperidol. Both piracetam and
pramiracetam were devoid of effects on the uptake of
GABA and serotonln. Pugsley et al. v-s found no ew-
dence of any effect in traditional pharmacological as-
says, Besides that. no effects could be found on nora-
drenaline, dopamine. 5-HT or 5-HIAA concentrations
in the rat cortex or midbrain. At very high doses (2000
mg/kg i.p.), piracetam raised striatal HVA without a f
fecting DA levels, indicating increased DA turnover.
No comparable increase in DA turnover was seen in
response to preumracetam. Receptor assays showed
that neither piracetam nor pramiracetam displayed any
affinity for DA. muscarinic, alpha 1.2-, and beta-l.2-
adrenergic, 5-ItT~, 5-HT2, GABA, adenosine, and ben-
zodiazepine receptors.
DO N O O T R O P I C S ACT VIA C H O L I N E R G I C MECHANISMS'?
The second category of findings derived from stud-
ies based on the hypothesis that the memory-enhancing
action of the nootropics could be mediated by cholin-
ergic effects. The intensive search for some connection
with cholinergic mechanisms was evidently prompted
by the findings of Deutsch ~2-~~, Bartus 7, and Drach-
man 2~'26, who showed that chotinergic mechanisms
were involved in learning and memory processes, and
by the reports of a cholinergic lesion in Atzheimer pa-
tients ~9,7o. The discovery that pramiracetam increases
high-affinity choline uptake 75 came as a relief and
sparked off a whole series of similar investigations with
other nootropics 6s'82"s3"ss that produced similar results.
Schindler 7'~ gives a table showing effects of nootropics
on high-affinity choline uptake. Further indications of
cholinergic effects emerged from the observations by
Spignoli and Pepeu 86, who showed that oxiracetam
prevented the decrease in the acetylcholine content of
the cortex and hippocampus resulting from cerebral
electroshock treatment. Pilch and Muller's findings 72
that piracetam increases the density of the muscarinic
cholinergic receptor in the frontal cortex of aged rats
also pointed to the involvement of cholinergic effects.
A long succession of studies was devoted to the effects
of nootropics on scopolamine-induced amnesia. It was
found that both pre-trial and post-trial administration
of nootropics in this model elicited anti-amnesic effects
(see ref. 79 for a tabulated overview). When this selec-
tion of findings on the effects of piracetam-like sub-
stances is viewed against the background of the already
available evidence for the involvement of cholinergic
mechanisms in learning and memory, the obvious con-
clusion is that these substances act by way of cholin-
ergic mechanisms. Seen in the context of the existing
information, however, this revelation could hardly be
described as a milestone in the progress of memory
research.
Upon closer scrutiny of the available results, how-
ever, it can be noted that there is hardly a single study
in which several piracetam-like nootropics actually dis-
played similar effects in parallel tests. Pugsley et a175
and Shih and Pugsley s3 observed effects on high-affinity
choline uptake into hippocampal synaptosomes after
administration of pramiracetam in doses of 44 and 88
mg/kg i.p. Neither higher nor lower doses were effec-
tive. Surprisingly, piracetam in doses of 100 and 300
mg/kg, and aniracetam in the range from 10 to 200
mg/kg were inactive. The discrepancy by comparison
with the positive influence on memory is astonishing:
first, pramiracetam also exerts memory-enhancing ef-
fects at doses over 88 mg/kg or under 44 mg/kg, and
secondly, piracetam and aniracetam likewise improve
the memory at the "inactive" doses. Then again, the
absence of effects of piracetam on choline uptake noted
by Pugsley et al. contradicts the observations reported
by Pedata et al/'~, showing that both piracetam and
oxiracetam had positive effects on high-affinity choline
uptake in rat cortex and hippocampus. Spignoli and
Pepeu's finding s6 that oxiracetam prevents the decrease
in the cortical and hippocampal acetylcholine contents
caused by a cerebral electroshock treatment is possibly
invalidated by the fact that piracetam was inactive
under the same conditions. Moreover, it would be un-
scientific to conclude that the compounds must act via
cholinergic mechanisms because they diminish scopo-
lamine-induced amnesia. All in all, the evidence so far
adduced in favour of a cholinergic effect of the noot-
ropics is feeble. By contrast, there is abundant evidence
suggesting that any plausible explanantion indicating
some tenuous concordance between Alzheimer pathol-
ogy, the therapeutic concept, and the theoretical mode
of action, tends to dim the perception of contradictions
and unanswered questions.
EFFECTS ON G L U T A M A T E RECEPTORS?
In the recent publications, a new line of research
appears to be blossoming forth. The sudden deluge of
literature on a possible common basis of long-term po-
tentiation (LTP) and memory 1'9 has set off a growing
trend to associate the effects of nootropics with some
interaction or other involving glutamate and aspartate
transmission. Paoli et al. 66 showed that oxiracetam can
partially antagonize the behavioural disturbance in-
duced by AP5. Belfiore et al. a reported similar obser-
vations. Marchi et al. 44 showed that oxiracetam in-
creases glutamate release in hippocampal slices. In an
oocyte expression system it has been shown that anirac-
etam amplifies currents mediated by the AMPA recep-
tors 39. Xiao et al. 91 confirmed this observation at hip-
pocampal AMPA receptors. The modulation of AMPA
receptors by aniracetam was of interest above all in
view of the fact that LTP also amplifies receptor-
mediated currents. In the meantime, however, doubts
have arisen about the validity of the assumption that the
receptor changes induced by LTP and aniracetam are
the same 5. Regardless of how the controversy may ul-
timately be settled, it seems probable that, for a variety
of reasons, the results now available will be of very little
help in clarifying the central problem of the mode of
action of the nootropics: (1) there is still too much
uncertainty about the connection between ETP and
learning1; (2)considering one single receptor in isola-
tion places various aspects of the action of a substance
in a highly artificial light. It is therefore quite possible
that the changes observed have nothing whatever to do
with the envisaged effect on memory. (3) As yet, no
comparative studies with different nootropics have been
published. Since Xiao etal. 91 point out that the
response-enhancing properties of aniracetam are not
common to all nootropics, because other drugs in this
class exert either weaker effects or none at all, it is
highly improbable that these experiments could help to
clarify the mechanisms underlying the memory-improv-
ing effects of the nootropics. The similarity of the effects
of the piracetam-like nootropics on memory and their
very close structural relationship nevertheless strongly
suggest that they all improve the memory by way of the
same mechanism. There is consequently ample reason
to continue searching for a mechanism shared by all the
representatives of this class of substances.
DO STEROIDS PLAY A ROLE IN MEDIATING THE
EFFECTS OF NOOTROPICS'?
Two aspects in particular led us to consider the pos-
sibility that steroids might somehow be involved in the
effects of the nootropics. One was the possible exist-
ence of internal memory-boosting mechanisms, which,
usually in conjunction with highly emotional states, can
evoke "flashbulb memories ''~ i.e. unusually vivid rec-
ollections. The other was the observation that autora-
diographs taken after the administration of radiola-
belled oxiracetam showed practically no activity in the
brain sg. The fact that emotional states, ACTH 2~, and
steroids 49 can augment memory storage prompted us
look for indications linking the effects of nootropics to
adrenal function. Surprisingly, it turned out that ox-
iracetam, piracetam, pramiracetam and aniracetam no
longer exerted any memory-enhancing effects in adrena-
lectomized animals s9, although the animals' general
learning capacity was not impaired by adrenalectomy.
A further series of experiments revealed that the loss of
effect was not simply a matter of the dosage of the
nootropics; even much higher doses were likewise in-
active after adrenalectomy54.
The next question was whether it was medullary or
cortical products of the adrenals that were critically
involved in the effects of the nootropics. To clarify this
point, the animals were pretreated with aminoglute-
thimide, which, in effect, produces a chemical blockade
of the adrenal cortex. Aminoglutethimide is an inhibi-
tor of several cytochrome-P450-mediated hydroxyla-
tion steps involved in steroid biosynthesis: e.g., 18-
hydroxylation of corticosterone (i.e. aldosterone
biosynthesis), side-chain cleavage (i.e. conversion of
cholesterol to pregnenolone), and ll-hydroxilation (i.e.
glucocorticoid biosynthesis, for a review see ref. 77).
Exactly like adrenalectomy, this pretreatment rendered
the four piracetam-type nootropics inactive s. Amino-
glutethimide itself had no effects on the retention per-
formance of the mice at the dose used. These findings
were the first indication that adrenocorticat products
played a part in mediating the effects of the piracetam-
like nootropics. In this context it must be conceded that
aminoglutethimide is not entirely devoid of effects on
the adrenal medulla: some elevations of catecholamine
levels have been observed 29.
In a second series of experiments, we studied the
influence of a mineralocorticoid antagonist on the
memory-enhancing effect of the nootropics. Pretreat-
ment with epoxymexrenon, a potent mineralocorticoid
antagonist TM produced a similar result: the memory-
enhancing effect of the noou'opics was completely
blocked. Again, the steroid blocker per se had no effect
on learning capacity 5. This was a first indication that
the mineralocorticoid receptors (Type I) were somehow
involved in bringing about the nootropic effect. A fur-
ther series of experiments then furnished first of all
proof that substitution therapy with aldosterone or cor-
ticosterone in adrenalectomized animals can restore
sensitivity to the effect of the nootropics, and secondly
a further indication that the mineTalocorticoid recep-
tors play an important part in mediating the effects of
nootropics: substitution with corticosterone or aldos-
terone was ineffective in adrenatectomized animals if at
the same time the Type-I receptors were blocked by
epoxymexrenon57. The results of these substitution ex-
periments additionally suggested that higher doses of
the hormone produced weaker effects. Logically, that
posed the question whether elevated plasma concen-
trations of steroids could likewise suppress the
memory-enhancing effects of the nootropics. The ex-
periments carried out to explore this possibility showed
that pretreatment with corncosterone or aldosterone
not only raised the hormone levels but also suppressed
the memory-improving effects of all the nootropics 5-~.
The parallel control expenments with arecoline, phys-
ostigmine, and tacrin (THAI yielded the totally unex-
pected finding that an increase in the steroid levels
likewise suppressed the memory-enhancing effect of
these cholinomimetics This opened up the possibility
that any form of pharmacologically induced memory
improvement might be blocked by steroids In the
course of another study 56 it was demonstrated that the
memory-enhancing effects of the gtycine antagonist
strychnine, the ACE inhibitor captopril, the Ca antago-
nist nimodopine, and the N M D A receptor blocker
CGP 37 849 can. in fact. also be completely suppressed
by pretreatment with corticosterone and aldosterone.
An overall evaluation of the findings made with the
four nootroplcs, the three cholinomimetics, and the
other four memory-enhancing substances strengthened
the hypothesis that every ph arnlacological improvement
of memory is mediated by some steroid-sensitive path-
way. Although this conclusion strictly speaking ortlv
holds for the passive-avoidance situation tested, initial
experiments have already shown that blockade of al-
dosterone biosynthesis by a specific inhibitor. CGS 20
287. suppresses the memory-enhancing effect normally
induced by oxiracetam in a social recognition test in
rats. Moreover. an extensive series of control experi-
ments had revealed that the memory-disturbing effects
of scopolamine, phenobarbitone, diazepam, and CGP
37 849 were not impaired by steroidal pretreatment 5~'.
Particularly interesting results were obtained with the
N M D A receptor blocker C G P 37 849: the same dose
of 3 mg/kg improved retention performance in the step-
down passive-avoidance test and impaired it in the
step-through passive-avoidance test. Whereas pretreat-
ment with aldosterone or corticosterone completely
suppressed the memory-improving effect in the step-
down situation, the memory-disturbing effect in the
step-through test situation was insensitive to the ste-
roids 56x'1. The results accunmlated so far do in fact
appear to favour the hypothesis that steroids selectively
block pharmacologically induced improvements of me-
mory.
NEW INSIGHTS AND A NEW HYPOTHESIS
The fact that drugs belonging to such diverse catego-
ries as nootropics, cholinomimetics, Ca-channel block-
ers, glycine-antagonists, ACE-inhibitors, and N M D A
receptor blockers were all capable of improving reten-
tion performance in our series of experiments clearly
illustrates that the mere categorization of a substance
as, say, cholinergic cannot be taken to mean that its
mode of action on memory is any nearer to being fully
understood. The finding that the memory-enhancing
effects of all these agents can be blocked by a slight
increase in corticosterone or aldosterone levels signifies
that somewhere in the chain of events ultimately lead-
ing to improvement of retention there are intermediate
links susceptible to the influence of steroids. It was
therefore conceivable that our results contained indi-
cations pointing to events that happen after neurotrans-
mission. This possibility served as a beacon for our
further studies. We had already demonstrated that all
the tested substances were also active when adminis-
tered after the learning trial 5-~. That these drugs still
improve memory even if they are given several hours
after the learning trial can only be interpreted in terms
of some modulatory influence on processes still ongo-
ing for some considerable time after the end of the
learning trial. Since steroids are potent modulators of
gene transcription s~'93, and the the nootropics appar-
ently interact with a process long outlasting the dura-
tion of the experiment, it would be unreasonable to
reject the hypothesis that the effect of the latter com-
pounds on memory might be brought about by modu-
lation of gene transcription or protein synthesis 52.
Granting the possibility that a learning experience may
lead to the activation of genes, it is obvious that such
processes take time. If the nootropics do, in fact, exert
an influence on sequential processes of this nature, it
follows that the memory-enhancing effect will only come
into evidence after a certain time-lag. Differences be-
tween treated and untreated animals would only be-
come manifest from that moment on when memory is
based on the products of the processes modulated by
the nootropics.
In a large series of experiments, we found that the
effects of nootropics only became measurable about
16-20 h after the learning trial, regardless of whether
the drugs were given before it or afterwards; not until
then was the retention performance of the treated ani-
mals appreciably better than the controls 'Ss. Since a
stable drug effect is still in evidence at all later intervals
investigated {up to 16 days), it seems reasonable to
suppose that the memory emanates from the same
source throughout the entire recorded retention interval
of 16 days. Oxiracetam must therefore have reinforced
the formation of a substrate necessary for the formation
of the long-term memory. The fact that the animals also
show some retention after shorter intervals is a clear
indication that recollection during these intervals oc-
curs by way of different mechanisms.
If the action of the nootropics facilitates the forma-
tion of the long-term memory trace, and if this effect
actually does come about through a modulation ofgene
transcription, then there is hope that insights into the
time-course of protein synthesis could well also furnish
indications of the level at which nootropics might in-
tervene. Current views postulate that the neuronal sig-
nals can activate immediate early genes (IEG's) and
thus lead to the formation of proteins with signal-
transduction functions. These proteins can then act as
regulators for late, or effector, genes (see e.g. refs. 35,
38). It is known that immediate early genes (e.g. c-los)
can be activated readily, in a matter of minutes, by
neuronal activity 14y'2s, or by lesions ~s. The activation
of late response genes, e.g. the N G F gene, on the other
hand, takes several h o u r s 3s. Since the effects of the
nootropics are known to be steroid-sensitive, the N G F
gene may be a particularly apt example, because its
transcription is likewise steroid-sensitive 4142. Theoreti-
cally, substances selectively affecting the transcription
of immediate early genes would only need to remain
capable of exerting a "retroactive" influence on the
storage of a previously experienced situation over the
time period during which elevated mRNA levels indi-
cate gene activation. In lesion-induced elevations of
c-fi)s, m R N A level is already past its peak effect after
two hours, but even after 12 h it remains elevated~s. In
the N G F gene, a cqos controlled late response gene, an
elevation of m R N A becomes detectable 3 h after the
lesion and reaches its maximum in about 12 h, but even
after 24 h it has not reverted to the initial levels 3'~. We
have already shown that the nootropics can improve
retention performance if they are administered within
up to 12 h after the learning process s2. Accordingly, on
the basis of the time-course of protein synthesis in
known genes no inferences can be drawn regarding the
levels at which the nootropics might intervene; the in-
formation so far available indicates that both the IEG's
and the late genes are activated within that space of
time.
What already seems quite certain is that the retarded
appearance of the drug-induced effect on memory ap-
plies only to memory improvement: our control experi-
ments with memory-impairing substances showed
clearly that negative effects are immediately perceptible,
i.e., after a retention interval of only one hour. That
makes it extremely unlikely that memory facilitation
and memory impairment are both induced by modula-
tion of the same process.
No matter whether this whole series of experiments
does or does not really open up intriguing new perspec-
tives in the above sense, it should not be forgotten that
despite all the experimental evidence it is still just a
theory. Recent findings concerning membrane-bound
steroid receptors in the brain 43"6S, including some as-
sociated with the GABA/benzodiazepine/ chloride-
channel complex43, admit of totally different interpre-
tations of how steroids might modulate the effects of
nootropics (or vice versa). The palette of possibilities
stretches from total peripheral to exclusively central
sites of action, and from modulations of brain com-
partmentation to modulation of protein phosphoryla-
tion. Many of these aspects still remain to be explored
experimentally before any conclusions can be drawn
about the mode of action.
CLINICAL I M P L I C A T I O N S
Given the available literature on the clinical effects of
the nootropics, there can be no doubt whatever that
there are patients with a form of dementia that re-
sponds very well to treatment with nootropics (see In-
troduction). A census across all the published reports
would put the proportion of such cases somewhere
between 10 and 30~/o. The response rate applies not
only to the nootropics, but also to all other preparations
tested in the symptomatic therapy of dementia, such as
tacrin, etc. (e.g. ref. 31). In view of these figures it is
obvious that investigations in a population of 6-15 pa-
tients can never afford a sound basis for any appraisal
of clinical efficacy; the likelihood of there being any
responders at all is far too small. Debate over the ef-
ficacy or inefficacy of these preparations resting on the
results of such inadequate studies is consequently futile,
above all while many really relevant problems of clini-
cal research still remain unresolved: e.g,, whether pa-
tients responding to cholinomimetics also respond to
nimodipine, plracetam, etc.. or which special physi-
ological or pathological characteristics separate re-
sponders from non-responders, Our experimental find-
ings concerning the association between effects on
memory and endogenous steroid levels could provide a
first clinically verifiable approach in the right direction.
Several studies have already shown that a large pre-
centage of Alzheimer patients have very significantly
elevated plasma cortisol levels (see e.g. ref. 45). Should
it prove that treatment with nootropics or cholinomi-
metics is less effective in patients with very high or very
low plasma concentrations of cortisol (or aldosterone),
then there might be possibilities of identifying potential
responders in advance and improving the therapeutic
prospects by treating them with inhibitors of steroido-
genesis or steroid antagontsts.
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