PERSPECTIVES
state-dependence of memory5. This refers to
TIMELINE
Discovering risperidone:
the LSD model of psychopathology
Francis C. Colpaert
In the 1970s and 1980s, Janssen
Pharmaceutica Research, which had a
broad interest in central nervous system
disorders and nurtured intellectual freedom,
developed original, and at times heretical,
concepts. It took decades for the scientific
community to endorse some of these
concepts. Among them were such notions
as an elementary particle of behaviour, the
introduction of response quality in receptor
theory, and the idea that tolerance does not
develop to opioids. These concepts
enabled the discovery of the antipsychotic
risperidone, a unique full antagonist of the
interoceptive effects of LSD.
In the early 1970s, the Janssen Pharmaceutica
company had behind it the successful discov-
ery of such central nervous system (CNS)
agents as fentanyl and haloperidol, and a host
of further opioid analgesic and antipsychotic
agents1. Joining Janssen Pharmaceutica at the
time as a young CNS pharmacologist meant
becoming immersed in Dr Paul Janssen-the-
physician’s (known in the laboratory as ‘Dr
Paul’) unrelenting desire to further the treat-
ment of disease through a research pro-
gramme that, among other peculiarities, exer-
cised its very own study design and data
analysis2,3 that reduced awesome biological
complexity to elegant, starkly effective sim-
plicity. It also meant benefiting from Dr
Janssen-the-chemist’s seemingly unlimited
resourcefulness in providing pharmacological
tools and research compounds. To the novice
and innocent it was a brave world of bound-
less intellectual freedom and naively
NATURE REVIEWS | DRUG DISCOVERY
© 2003 Nature Publishing Group
undaunted courage. So much so that we
undertook the study of subjective experi-
ences, or interoception, in laboratory animals.
The pharmacology of interoception
By the 1970s, opioids such as fentanyl had
become indispensable tools for achieving
deep, surgical analgesia, but these agents also
slowed gastrointestinal motility and were
thought to be useful for the treatment of diar-
rhoea, a disconcerting and at times life-threat-
ening condition. However, the use of opiods
to treat this condition was severely hampered
by their potential for abuse, which can eventu-
ally develop into dependence and addiction.
By that time, a number of American clinical
pharmacologists, including Isbell, Fraser,
Martin and Jasinski4, had developed remark-
ably objective and quantified — genuinely sci-
entific — procedures demonstrating that opi-
oids in humans produce opioid-specific
subjectively experienced effects, such as ‘feel-
ings of well-being’, that are crucial for the initi-
ation of the non-medical use of opioids.
Also by that time, behavioural pharmacol-
ogists had developed a model to study the
“In stark contrast to the
then-prevailing wisdom…
we suggested that this
technology no longer
measured the state-
dependence of memory.”
the observation that what an organism learns
while being in a given state (for example, an
alcohol-induced state) can be better remem-
bered in that same state as opposed to any
other state (for example, the sober state). The
model involves training laboratory animals to
execute a particular behavioural response fol-
lowing injections of, for instance, alcohol. In
tests of retrieval, the animals remember the
response better when they are again injected
with alcohol as opposed to saline (and vice
versa, which demonstrates that retrieval is
conditional upon the state that prevailed at
the time of learning). In a further develop-
ment of the model, however, animals were
trained to execute one response after having
received one pharmacological treatment, and
to execute a similar but alternative response
after having received another treatment. In
stark contrast to the then-prevailing wisdom,
and igniting a controversy that would simmer
for decades, we suggested that this technology
no longer measured the state-dependence of
memory. Instead, it provided a measurement
of the ability of animals to discriminate
between the subjective experiences induced
by one pharmacological treatment as
opposed to another6, and the new technology
was named Drug Discrimination (DD).
In a typical DD experiment (BOX 1), rats
are initially trained to press one of two levers
in order to obtain food. Thereafter, discrimi-
nation training is instituted; before the ses-
sion, the animal is injected with either drug
or saline. On drug days, pressing only the left
lever is rewarded; on saline days, pressing
only the right lever is rewarded. After a
number of discrimination training sessions,
rats learn to perceive the ‘subjective’ effects
of the drug, determine the difference from
(that is, discriminate those from) saline
injection, and choose the appropriate lever.
By this lever choice, the rats categorically
indicate whether they received the training
drug; in an analogy to quantum physics, this
categorical choice arguably constitutes an
elementary particle of behaviour7.
VOLUME 2 | APRIL 2003 | 3 1 5
PERSPECTIVES

A remarkable feature of the DD technol- those of the training drug. That is, will the rat number of rats choosing the drug lever
ogy is its pharmacological specificity. After choose the drug or the saline lever? It turns increases with higher test doses. Rats will also
discrimination training has been completed, out that rats trained in this manner exhibit a generalize to other benzodiazepines, but not
so-called generalization tests can be carried surprisingly accurate pharmacology. For to any of a vast array of non-benzodiazepine
out. In such a test, the rat is injected with a example, rats trained on a ‘training’ dose of a drugs and other pharmacological tools.
drug other than the training drug, and the benzodiazepine will generalize (that is, choose Furthermore, benzodiazepine antagonists,
experimenter can ask whether the drug being the drug lever with) lower doses of that ben- but not any other agents, antagonize the gen-
tested produces subjective effects that are like zodiazepine in a dose-dependent manner; the eralization that a benzodiazepine will other-
wise produce. Similarly specific patterns of
generalization are found with discriminations
Box 1 | The Drug Discrimination model of most CNS agents and receptor-subtype-
In this model of in vivo behavioural pharmacology, partially food-deprived, hungry animals (for selective neuropharmacological ligands8. As
example, rats) are initially trained, in daily 15-min sessions, to press one of two levers for food such, the DD technology possesses both a
(see figure). Eventually, the animals press the lever ten times in order to obtain the food pellet, specificity and breadth of applicability that
which they then receive in the receptacle from a more distantly located dispenser. Once this are comparable to that of its contemporary, in
capability is established, Drug Discrimination training is initiated. That is, at some time point vitro radioligand binding. As DD provides
before every session (for example, 15 mins beforehand), the rat is injected with either a drug (for experimental access to the animal homologue
example, 0.16 mg per kg of lysergic acid diethylamide (LSD)) or its vehicle (for example, of subjective drug effects, Dr Paul commented
physiological saline). On days when it receives LSD before the session, the rat is required to press that it constituted the first laboratory tech-
one of the levers (for example, the left-hand lever or ‘LSD lever’) for food; pressing the right-hand nique of true psychopharmacology.
lever yields no reward, and might even result in some punishment (for example, a startling noise).
On days when it receives saline, the rat is required to press the right-hand ‘saline’ lever; pressing An opioid interoceptiom
the LSD lever yields no reward. Drug and saline days occur in a quasi-random fashion; the only Rats trained to discriminate fentanyl from
indication the animal has in deciding which lever to choose in any given session is the drug or saline, again with a high degree of specificity,
saline injection that it received prior to the session. Many drugs, including LSD, produce will generalize to other opioids, such as mor-
subjective (interoceptive) effects that the saline injection does not mimic; it is the presence or
phine, heroin and codeine, but not to any
absence of these interoceptive effects that provides the indication as to which lever is appropriate,
non-opioid agents9. Opioids — ligands that
and should therefore be chosen, on any particular day. Implementing this scheme for a number of
selectively activate opioid receptors — also
sessions results in the animal successfully discriminating LSD from saline; eventually, the rat
slow gastrointestinal motility (for example, as
reliably chooses the LSD lever after LSD injection, and the saline lever after saline injection. This
is when the experimenter can begin to ask questions. measured by the inhibition of castor oil-
The reliable discriminative response is maintained by further training sessions, but on some induced diarrhoea in the rat), but do so with a
days (for example, once a week) a test is conducted. On these occaisions, some new potency that does not correlate with their
pharmacological agent is administered, and again the animal has to decide which lever to press. ability to make rats generalize to fentanyl after
This choice is measured as the first lever on which the rat completes ten presses. The evidence they have been trained to discriminate fen-
indicates that, in such test sessions, the animal will only chose the LSD lever with doses of LSD tanyl from saline10. Rats so trained were there-
itself or other agents that very closely mimic the neurobiological action of 0.16 mg per kg of LSD; fore a means of detecting opioids that were
as indicated in the text, with any other treatment the rat will choose the saline lever, even if that effective anti-diarrhoeals but which would
treatment does produce interoceptive, but not LSD-like, effects. not produce subjective opioid effects, and it
was by this route that loperamide was discov-
ered11,12. Presumably because of its poor pene-
tration of the blood–brain barrier, orally
administered loperamide counteracted castor
oil-induced diarrhoea at 0.15 mg per kg but,
at doses up to 40 mg per kg, failed to make the

? rats generalize with fentanyl. In the early

1980s, loperamide became the mainstay treat-
ment of diarrhoea and saved scores of
patients from fatal dehydration and ion loss; it
has not, however, been abused.

Opioid tolerance: only apparent?

The DD technology seemed to offer unique
experimental access to the analysis of subjec-
tivity, and its validity was reinforced by the
successful prediction it made for loperamide.
But there remained a fundamental concern,
with opioid DD in particular. In order for rats
to adequately master fentanyl–saline discrimi-
nation, some 50 training sessions are
required, half of which are preceded by the
injection of a substantial dose of the opioid.

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 PERSPECTIVES

curve did not move at all14. This rather stun-

Box 2 | Responses to receptor activation
ning finding put us at a decisive crossroads.
Receptor One option was to consider that textbook
II activation I III
pharmacology was not to be disputed; it
meant that tolerance did develop in the
experiment, but that for some unidentified
c reason it did not cause the gradient to shift
Rc
rightward. It also implied an even more severe
Response magnitude

criticism of a technology that not only was

b flawed because of an ever-changing sensitiv-
Rb
ity, but that also failed to provide any control
over this change. The second option, which
a we embraced, was to consider, simply, that the
Ra gradient did not shift and that, therefore, tol-
erance does not develop to opioid DD. And so
began an epic, excruciatingly long, and always
0
0 Concentration 0 Response magnitude solitary struggle on two fronts. The scientific
community that principally used DD held
Molecules that can bind to a given receptor (that is, receptor ligands) can differ from each other that tolerance does develop to opioid DD; it
in terms of their affinity, that is, the concentration at which binding occurs. Receptor ligands required some 20 years for this community to
can also differ in terms of efficacy; as shown in panel I of the figure (middle), ligands a, b and c reconsider this analysis15. The broader scien-
activate the receptor in a concentration-dependent manner, but do so to a maximal extent tific groups concerned with opioid pharma-
(or ceiling level) that differs between the ligands. Note that, for the sake of simplicity, the ligands cology and pain in general, however, were to
shown in panel I differ only in efficacy, not in affinity. Again for the sake of simplicity, all three focus on another question: if tolerance does
ligands shown are ‘positive’ agonists that produce a greater-than-zero activation of the receptor; not develop to opioid DD, how can this be
so-called inverse agonists that produce negative activation also exist, but are not shown. reconciled with the tolerance that is observed
Ideas about the mechanisms by which responses are elicited by receptor activation have evolved to develop as a matter of course to all other
considerably. In Ariëns’ classical concept (panel II), the quantitatively different magnitudes of opioid effects, most notably analgesia?
receptor activation that ligands a, b and c produce, elicit responses that differ in magnitude Implying that received wisdom had it wrong,
along a single response dimension (that is, that differ only in a quantitative manner). This is not and inviting the wrath of these communities
unlike the case in physics where a given quantity of action elicits a linearly related quantity of
for decades to come, I suggested that toler-
reaction. In a more recent conception (panel III), the different receptor activations elicit
ance does not develop to the molecular action
responses (Ra, Rb, Rc) that differ in a manner that is qualitative. The magnitude of these different
of opioids, and that the tolerance that is
responses (abscissa) does relate to that of the receptor activation, but does so along a bell-shaped
observed with opioid analgesia, for example,
function; thus, the response occurs only within a limited range of receptor activation. This is not
unlike the case of the perception of light, in which quantitatively different wavelengths is only apparent.
(analogous to quantitatively different receptor activations) elicit colours that vary qualitatively This suggestion was based on a theory of
(analogous to responses Ra, Rb and Rc). the formal mechanisms of signal transduc-
Ariëns’ concept has long been extremely successful for a vast array of receptor systems; the need tion in pain-processing systems16. The con-
for the more recent concept has arisen, in particular, from studies of (G protein-coupled) opioid cept specifies that any input to nociceptive
and 5-HT receptors. systems causes not one effect, but two effects
that are paradoxical, or opposite in sign.
Accordingly, opioid receptor activation pro-
For up to two years afterwards, the rats can to fentanyl in the DD technique presumably duces first analgesia as a so-called first-order
then be submitted to generalization tests, but implies that the rats became tolerant to the effect, but then also hyperalgesia as a second-
these are typically interspersed, once or twice opioid, and that any measurements obtained order effect. As opioid treatment is contin-
weekly, among training sessions that are con- in tests were flawed because of an ever-shift- ued, the second-order hyperalgesia grows
tinued in order to insure the long-term accu- ing sensitivity (such as that which accompa- and apparently neutralizes the first-order
racy of the discrimination. As such, over the nies receptor desensitization). This flaw, analgesia. This theory offered an account of
course of the training, and during the time which textbook pharmacology seemed to the apparent tolerance to opioid analgesia
that the tests are conducted, the rats receive make inevitable, would gravely detract from while preserving the notion that the initial
several hundred fentanyl injections. the usefulness of the DD technology. molecular action of opioids remains
Tolerance (that is, loss of effect) develops We trained rats and determined the fen- immutable. Pharmacological Reviews accep-
to opioid analgesia, to opioid respiratory tanyl dose–response curve (also called the ted a discussion of this concept17, but not
depression, and to all other opioid-receptor- stimulus generalization gradient) immedi- without the editor requiring18 for the first
mediated effects of opioid agonists. Indeed, ately after the rats were trained, as well as after time since the journal’s creation that a cri-
tolerance to opioids is so widely observed that repeated training sessions for up to four tique of the paper be published alongside
pharmacology textbooks, such as Principles of months. Despite continuing to expose the the review19. The concept discussed in
Drug Action: The Basis of Pharmacology13, animals to fentanyl in the meantime, the fen- Pharmacological Reviews received powerful
propose that the development of tolerance tanyl gradient did not shift, in contrast to validation recently, with the verification of a
constitutes no less than a defining feature of what the tolerance hypothesis would have set of highly peculiar predictions that only
specific opioid actions. The frequent exposure predicted. In fact, the fentanyl dose–response this theory makes16,17,20. Some molecular

NATURE REVIEWS | DRUG DISCOVERY VOLUME 2 | APRIL 2003 | 3 1 7

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PERSPECTIVES
a The quality beyond the quantity
In his wonderfully elegant and analytical the-
ory of the molecular pharmacology of recep-
tor-mediated drug actions, Ariëns22 defined
two parameters that were to exhaustively
account for ligand–receptor interactions. One
is that of affinity, that is, the readiness with
b which (or concentration at which) the ligand
binds to the receptor. The other is that of effi-
cacy (or intrinsic activity), that is, the maxi-
mal extent to which the ligand can activate
the receptor. The theory was all about quan-
tity: a given quantity of a ligand possessing a
Figure 1 | Structural formula of the pure LSD quantified efficacy predictably produced the
antagonists pirenperone and risperidone. quantified magnitude of response. The theory
a | Pirenperone, 3-[2-[4-(4-fluoro-benzoyl)- adequately explained the actions and interac-
piperidino]-ethyl]-2-methyl-4H-pyrido[1,2-a]- tions of what were then referred to as agonists
pyrimidine-4-one. b | Risperidone, 3-[2-[4-(6-
and antagonists, and also of ligands that pro-
fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]ethyl]-
2-methyl-6,7,8,9-tetrahydro-pyrido[1,2-a]-
duced more complex, partial and mixed ago-
pyrimidine-4-one. LSD, lysergic acid diethylamide. nist and antagonist effects.
In rats discriminating 0.04 mg per kg fen-
tanyl from saline, typical opioid agonists pro-
mechanism might exist that mimics the CNS duced dose-dependent and full (that is,
effects of nociceptive stimulation. Con- 100%) generalization, and no antagonist
sidered as the opposite of the action of mor- effects. Opioid antagonists, such as naloxone,
phine, nociception should produce pain as a
first-order effect, but then produce second-
order hypo-algesia. With chronicity, the sec- “The same intricate web of
ond-order hypo-algesia should grow at the
expense of the first-order pain. In laboratory developments that yielded
studies, the effects of the very-high-efficacy risperidone also led to drug
5-HT1A receptor agonist F 13640 seem to fit
these predictions21. In conditions under discoveries in seemingly
which tolerance to morphine develops, the unrelated areas.”
chronic infusion of F 13640 causes inverse
tolerance (that is, incremental as opposed to
decaying analgesia). In addition, F 13640 blocked fentanyl fully, and produced no ago-
cooperates with nociception in producing, nist effect. The partial and mixed opioid lig-
paradoxically, analgesia. So, F 13640 sets in and cyclazocine produced a partial general-
motion two unprecedented neuroadaptive ization (that is, 36%), and at the same doses
mechanisms that result in it achieving an antagonized fentanyl to an extent that was
unprecedented analgesia in models of nicely complementary (that is, about 64%).
chronic pain and neuropathic allodynia. A These data23,24 were precisely what Ariëns pre-
similar analgesia cannot be attained by opi- dicted, but there was a puzzle. If the lever-
oid or other agents that act through further choice response in the DD technology was of
molecular mechanisms of central analgesia21. a quantal nature, how could a partial response
Pending the results of ongoing clinical stud- occur? A closer analysis showed that it did
ies, these new mechanisms could revolution- not; some rats fully generalized cyclazocine,
ize the treatment and science of pain. and in these rats cyclazocine did not antago-
Although it took a long time to generate nize fentanyl, whereas in all other rats, cycla-
this degree of validation for the scientific zocine antagonized fentanyl but did not gen-
community, both our findings10 and the eralize with it. The explanation of these data
concepts16 developed in the 1970s convinced was that although all rats received the same
us, at least privately, that tolerance does not fentanyl training dose, they differed in the
develop to opioid DD in particular. This extent to which that dose activated opioid
reassurance regarding the technology’s sta- receptors. Where the magnitude of activation
bility, along with its specificity and lop- was low, cyclazocine should generalize, not
eramide-afforded validity, enticed us to con- antagonize; and where the activation was
duct DD studies of other intriguing high, cyclazocine should antagonise, but not
pharmacological phenomena, such as partial generalize. Importantly, this explanation
receptor agonism. implied that the discriminative stimulus
318 | APRIL 2003 | VOLUME 2
© 2003 Nature Publishing Group
effects of activating opioid receptors to a high,
as opposed to a low, magnitude differed in a
qualitative manner24–26. In other words, a par-
ticular quality of response to receptor activa-
tion occurs within a limited, perhaps narrow,
bandwidth of activation, and not with either
lower or higher levels of activation (BOX2 ).
Similarly, quantitatively different wavelengths
of light generate effects that vary qualitatively
as colours. This conclusion called for the
addition of a third parameter to Ariëns’ recep-
tor theory. As has happened before in the his-
tory of receptor theory27, it took some time to
begin to unravel the molecular mechanisms
of receptor properties that were postulated
from less direct observations made at higher
levels of integration. Today, Kenakin28 and
others29 recognize that at G protein-coupled
receptors, such as the µ-opioid receptors, G
proteins can be engaged to different extents
through a single receptor, depending on the
agonist (agonist-directed trafficking of the
receptor stimulus)28,29. The most directly anal-
ogous findings to our in vivo opioid DD
results are that some ligands at the (G pro-
tein-coupled) 5-HT1A receptor yield a concen-
tration-dependent bell-shaped curve in
directing receptor signalling to the Gαi3 pro-
tein subtype in vitro30. Equally in advance of
the physiological analysis of interoception31,32,
this exercise in receptor theory made us
realise that particular qualities of discrimina-
tive, or subjective effects, may arise from par-
ticular levels of receptor activation. With this
in mind, we began to study LSD.
From LSD to risperidone
In the 1960s and 1970s, at the Janssen labora-
tories as elsewhere, the stereotypical behav-
iours induced by amphetamine and other cat-
echolamine-releasing agents in rodents served
as a laboratory model of schizophrenia3. This
was because amphetamine in humans mimic-
ked some of the productive or positive symp-
toms (for example, psychomotor agitation) of
the disease, and the stereotypical behaviours it
produced in animals seemed to express these
effects. Lysergic acid diethylamide (LSD) also
had potential as a drug-model of schizophre-
nia; it was known to induce hallucinations
and had further effects (for example, ‘social
withdrawal’) that mimicked other symptoms.
However, LSD was not used as a model, as it
did not robustly induce any behaviour or
other readily accessible action in animals that
could be meaningfully related to its subjective
effects in humans. Until we conducted a DD
analysis of LSD in the rat, that is.
Evidence from the literature indicated
that LSD might act through both dopamin-
ergic (DA) and serotonergic (5-HT) systems
www.nature.com/reviews/drugdisc
 PERSPECTIVES

measured, in vivo, by the agents’ ability to

Concept
1950 Opioid tolerance
Drug discovery
Haloperidol
Technology
1960 State-dependence
Drug-model
LSD
1970
Technology, concept
Drug discrimination
1980 Concept
No opioid tolerance
Drug discovery
Risperidone
1990
2000
2010
Figure 2 | The risperidone drug-discovery process. Schematic representation of the concepts,
technologies, prior drug discoveries and the LSD drug-model of psychopathology, as they occurred over
time to eventually result in the discovery of risperidone. Note how the risperidone discovery is embedded in
a web of cause–effect developments that also resulted in the discovery of such seemingly unrelated agents
as the antidiarrhoeal loperamide and the recent analgesic F 13640. LSD, lysergic acid diethylamide.
in the brain, and the analysis focused on the
ability of antagonists at DA and 5-HT
receptors to block LSD discrimination. We
found that the antipsychotic DA antagonists
available at the time, such as haloperidol,
dose-dependently depressed rat behaviour
without counteracting LSD. This suggested
that either those agents were unable to
antagonize the LSD discrimination, or that
they might do so only, and to an unknown
extent, at doses that impair behaviour. 5-HT
receptor pharmacology of that time was,
rather crudely, one of agonists and antago-
nists, and we examined all of the putative
5-HT antagonists available. Remarkably, the
5-HT antagonists did antagonize LSD, indi-
cating the involvement of 5-HT receptors in
LSD’s discriminative effects. However, and
equally remarkably, all antagonists produced
only partial antagonism. Furthermore, when
Drug discovery
Opium, morphine
Concept
Ariens, receptor theory
Drug discovery
Fentanyl
Drug discovery
Loperamide
Concept
Quality in receptor theory
Drug discovery
F 13640
tested for their ability to mimic LSD,
the antagonists consistently partially gener-
alized with LSD, and this to an extent that
was complementary to their maximal antag-
onist effect33,34.
With the DD analysis of partial receptor
activation in mind, these data led us to the
hypothesis that the discriminative effects of
LSD arise from a low and narrow range of
5-HT receptor activation. The data also made
us realise that no available agent was capable of
adequately blocking LSD’s subjective effects,
and provided the impetus to devise a drug dis-
covery strategy that molecular pharmacology
also adopted decades later35.We and others had
long been aware of the 5-HT antagonist activ-
ity that DA-antagonist antipsychotic agents
also exert, but a “clinical correlate of this activ-
ity in schizophrenia [remained] unknown”36.
These 5-HT-antagonist properties were
counteract tryptamine-induced convulsions
in the rat36, as well as by their in vitro ability
to displace 3H-spiperone37 from a binding
site that had been identified38 as the 5-HT2
receptor. After initial screening of DA antag-
onists using these latter two assays as mea-
sures of the 5-HT antagonist activity of DA
antagonists, the hunt for a pure LSD antago-
nist yielded34 the first such compound,
pirenperone (FIG. 1). However, the kinetic
features of pirenperone in humans were
found to be inadequate, and in 1985 we dis-
covered risperidone, a longer-acting ben-
zisoxazole derivative 39. Risperidone also
antagonized LSD in a complete manner, and
without displaying any LSD-like agonist
activity. Risperidone was approved by the
US FDA in 1993, and was the first antipsy-
chotic in 15 years to achieve that status.
Presumably because of its peculiar profile of
activity, the agent seems safe and effective
for treating schizophrenia, and also the psy-
chotic, affective or behavioural symptoms
associated with other disorders40–42. After I
left the Janssen laboratories in 1986, my for-
mer colleagues reported on risperidone’s
long-lasting ability to antagonize LSD43 and,
befitting the nomenclature of the time,
labelled the compound ‘atypical’. Risperi-
done was also described as an antagonist at
both D2 and 5-HT2 (now 5-HT2A) receptors44.
However, several points suggest that 5-HT2
receptors are not the sole mediators of the
LSD-antagonist activity of risperidone. Both
pirenperone and risperidone, the only LSD
antagonists described to date that are both
pure and potent, exert DA-antagonist activity
in addition to their 5-HT receptor-mediated
actions. Also, the correlation with physio-
logical function that elevated a mere radioli-
gand-binding site to the status of 5-HT2
receptor38 is one that holds for ligands pos-
sessing both 5-HT and DA receptor affinity,
but does not hold for certain other agents45.
The selective 5-HT 2 antagonist ritanserin
fully antagonizes LSD, but only at huge
doses that are far in excess of those at which
it blocks 5-HT2 receptors46. Finally, new
molecular sites and modes of LSD action
continue to be uncovered47. More research is
needed to specify risperidone’s molecular
and cellular mechanisms. However, since
its introduction into medical practice,
the compound has proven beneficial
to schizophrenic and, interestingly, to
‘socially withdrawn’ autistic patients48. And
that, for the would-be doctors-of-disease
whom Dr Janssen-the-physician-cum-
chemist inspired us to become, was what
mattered most.

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PERSPECTIVES
Conclusion
How, then, was risperidone discovered? Not
merely as the outcome of a defined, precisely
targeted, linear drug-discovery project.
Rather, it occurred (FIG. 2) after a sinuous,
unpredictable route to which previous drug
discoveries (for example, those of haloperi-
dol and fentanyl) gave impetus, through
novel technologies (for example, DD) and
through fundamental research (for example,
in receptor theory and opioid tolerance),
which in some instances took decades for
the scientific community to at least tolerate,
if not endorse. In addition, clinical research
provided the LSD model of disease. The
same intricate web of developments that
yielded risperidone also led to drug discov-
eries in seemingly unrelated areas (for
example, loperamide and F 13640). Other
important factors in the development of
risperidone were a resourceful medicinal
chemistry group, and a climate of excep-
tional intellectual freedom and genuine
concern with medical progress, in which the
boundaries between the theoretical and the
applied, between the academic and the
industrial, and between the hypothesis and
the treatment were blurred. However,
despite the convoluted path to risperdione,
in another way the development of risperi-
done was straightforward: it was fuelled by
the desire to treat and understand, inspired
by intense fundamental research, and
enabled by technological developments,
which meant that we could seize opportuni-
ties to advance medicine where they seemed
within reach. Notably, the pathway to
risperidone chiefly cut across the field of
in vivo pharmacology, and in particular
behavioural pharmacology, underscoring
the unique contribution of this field 49 to
drug discovery.
Centre de Recherche Pierre Fabre, 17 avenue Jean
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e-mail: francis.colpaert@pierre-fabre.com
doi:10.1038/nrd1062
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Acknowledgement
The author is grateful to Drs M. Kleven, P. Pauwels and
A. Newman-Tancredi for their contribution on an earlier version
of this paper.
Online links
FURTHER INFORMATION
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