Comprehensive Psychiatry

(Official Journal of the American Psychopathological Association)

V O L . 40, N O . 6 NOVEMBER/DECEMBER1999

A History of Antipsychotic Drug Development

Winston W. Shen

The history of antipsychotic drug development has States and about 40 throughout the world. Thereafter,
had a long and torturous course, often based on there was a hiatus in the development of antipsychot-
chance findings that bear little relationship to the ics until the introduction of clozapine treatment in the
intellectual background driving observations. In 1891, United States in 1990 opened the era of "atypical"
Paul Ehrlich observed the antimalarial effects of meth- antipsychotic drugs, which show a reduced potential
ylene blue, a phenothiazine derivative. Later, the phen- to induce extrapyramidal symptoms (EPS), an in-
othiazines were developed for their antihistaminergic creased efficacy for the negative symptoms of schizo-
properties. In 1951, Laborit and Huguenard adminis- phrenia, no elevation of prolactin after chronic use
tered the aliphatic phenothiazine, chlorpromazine, to (except risperidone), and, at least for clozapine, effec-
patients for its potential anesthetic effects during tiveness in some patients previously regarded as
surgery. Shortly thereafter, Hamon et al. and Delay et treatment-refractory. This review describes the avail-
al. extended the use of this treatment in psychiatric able atypical antipsychotic drugs and their characteris-
patients and serendipitously uncovered its antipsy- tics, and concludes by highlighting those in the phar-
chotic activity. Between 1954 and 1975, about 15 maceutical "pipeline."
antipsychotic drugs were introduced in the United Copyright© 1999 by W.B. Saunders Company

IN SEARCH OF AN ANTIMALARIAL DRUG these was a diethylaminoethyl derivative of methy-

HE CHEMICAL CLASS of phenothiazines lene blue. This derivative, which proved to have
T had its origin in the latter half of the 19th more active antimalarial activity than methylene
blue, was too toxic to be clinically useful. Later,
century and was associated with the flourishing dye
industry in England. In 1856, W.H. Perkin pro- Schulemann and other German chemists discov-
duced an exquisite purple dye called mauve by ered quinacrine, which together with quinine long
oxidizing aniline, and due to its potential commer- provided the primary therapy for malaria around
cial value, various compounds related to aniline the world.1
were quickly subjected to numerous types of chemi- During World War II, early Japanese victories in
cal reactions.~ As an outcome of this activity in Southeast Asia again denied the Allies access to the
1876, Caro synthesized methylene blue, a phenothi- quinine-producing area of the world. This time, as
azine derivative, and a few years later Bernthesen part of a program to find a synthetic antimalarial
synthesized phenothiazine. agent for the Allies, Gilman et al. 2 synthesized a
For centuries, quinine--a constituent of the bark group of compounds in which the aminoalkyl
of the cinchona tree that grows in the tropics--was chains were attached to the central nitrogen atom of
used to treat malaria throughout the world. 1 But the phenothiazine ring. Unlike quinacrine, Gil-
during World War I, the Germans found themselves man's phenothiazine derivatives were inactive as
cut off from the world's primary supplies of an antimalarial drug.I
quinine. Consequently, they had to look for a
synthetic substitute. During their search, they uncov-
ered the work by the German bacteriologist, Paul From the Department of Psychiatry, Saint Louis University
Ehrlich, who observed in 1891 that methylene blue School of Medicine, St Louis, MO.
was effective in treating the symptoms of malaria. Address reprint requests to Winston W. Shen, M.D., Depart-
ment of Psychiatry, Saint Louis University School of Medicine,
Building on Ehrlich's earlier observations, W. Sch-
1221 S Grand Blvd, St Louis, MO 63104-1016.
ulemann and his coworkers synthesized additional Copyright © 1999 by W.B. Saunders Company
compounds related to methylene blue. 1 One of O010-440X/99/4006-0009510. 00/0

Comprehensive Psychiatry,Vol. 40, No. 6 (November/December), 1999: pp 407-414 407

408 WINSTON W. SHEN

IN SEARCH OF BETTER ANTIHISTAMINES CLINICAL TRIALS WITH CHLORPROMAZINE

Unaware of Gilman's work, 2 French researchers Based on their fortuitous observations of the
at the Socirt6 des Usines cliniques at Rhrne- CNS effects of chlorpromazine, Laborit and Hugue-
Poulenc Laboratories (Paris, France) studied pheno- nard supplied chlorpromazine to two groups of
thiazine derivatives identical to those developed by psychiatrists: Hamon, Paraire, and Velluz at the
Gilman.1 They confirmed that aminoalkyl phenothi- Central Military Hospital--the Val de Grflce--in
azines do not possess significant antimalarial activ- Paris 5 and Delay, Deniker, and Harl at the psychiat-
ity. 1,2 But these Rh6ne-Poulenc scientists did not ric clinic of Sainte-Anne Hospital in Paris. 3,6,7The
give up, and they continued to evaluate these first reported chlorpromazine-treated case was a
compounds for antihistamine effects.1 57-year-old laborer who was admitted to the Val de
Before World War II, the best antihistamine Grace because of erratic, uncontrollable behav-
agent was phenbenzamine (2339 RP [Rhrne- ior. 1,5 Prior to hospitalization, the patient made
Poulenc]). 1 During the War, as part of the further impassioned political speeches in cafes, pro-
research to find antimalarial agents in the United claimed a love of liberty while walking down the
States and France, numerous antihistamines were street with a flower pot, and intermittently as-
produced that were superior to phenbenzamine, one saulted strangers. 5 Within 1 day of receiving chlor-
of which was chlorpheniramine. Later, scientists at promazine, he was noted to be calmer, and 1 week
Rhrne-Poulenc Specia Laboratories found that one later he was joking with the medical staff. 1,5After 3
of the aminoalkyl phenothiazines, promethazine weeks, the patient appeared nearly normal and was
(3277 RP), which shares a common chemical discharged. 5 Other patients treated with chlorproma-
structure with phenbenzamine, is a more potent zine for agitated and hyperactive behavior showed
antihistamine with a longer duration of action.1 similar benefit. 1.6,7
The identity of the first psychiatrists to adminis-
AN AGENT TO POTENTIATE ANESTHESIA ter chlorpromazine to patients remains a matter of
Pharmacologic characterization of promethazine dispute. 3,8,9 In 1957, three parties--Laborit,
showed that it is associated with more pronounced Lehmann, and Deniker--were awarded the Lasker
sedation than any other antihistamine. 1 In 1950, H. Prize for their work with chlorpromazine, l° but
Laborit, the French Navy anesthesiologist, found other awards in 1993 have recognized Laborit,
that promethazine potentiates the activity of other Hamon, Paraire, and Velluz for their role in identi-
anesthetic agents, leading rapidly to its use in fying chlorpromazine's therapeutic effects.3,9Appar-
clinical anesthesia. 3 ently, Hamon et al. used chlorpromazine in conjunc-
Excitement over promethazine's anesthetic- tion with barbiturates in their patients on January
potentiating effects led Rhrne-Poulenc scientists 19, 1952, for the first time and then abandoned the
on a search for other phenothiazine derivatives with field of chlorpromazine pharmacotherapy. 3 On the
similar activity. 1 In 1950, S. Courvoisier and her other hand, Delay et al. treated patients with
associates tested a new compound, chlorpromazine chlorpromazine alone, reported their findings after
(4560 RP), which was previously synthesized by E Hamon et al., but remained interested in chlorproma-
Charpentier. 1,3 Courvoisier et al. found that chlor- zinc pharmacotherapy for some time. 3,6,7This con-
promazine prolongs sleep induced by barbiturates fusion and dispute may account for the fact that the
in rodents, prevents apomorphine-induced emesis Nobel Prize Committee never recognized any of
in dogs, and also inhibits the conditioned avoidance- the discoverers of chlorpromazine despite its revo-
escape response in mice. 3 In 1951, Laborit and lutionary clinical significance. 3
Huguenard reported that patients who are induced In 1952 Rh6ne-Poulenc released chlorpromazine
to a state of "artificial hibernation" by a "lytic under the trade name of Largactil, meaning "large
cocktail" of chlorpromazine, promethazine, and an CNS effect, ''11 and in 1954 Smith, Kline and
analgesic require lower doses of anesthetic agents French (Philadelphia, PA) marketed it under the
and better withstand the stress of surgical trauma. 1,3,4 trade name of Thorazine. This made chlorproma-
They also observed that chlorpromazine-medicated zine available to investigators around the world,
patients do not lose consciousness but do become and the clinical findings of Hamon's and Delay's
sleepy and show a lack of interest in what occurs teams were promptly confirmed by Stahelin and
around them. 4 Kielholz 12 in Germany, Lehmann and Hanra-
ANTIPSYCHOTIC DRUG HISTORY 409

ham 13,14in Canada, and Winkelman in the United and pharmacologists became convinced of an abso-
States. 15 Findings from the United States and lute connection between EPS and the clinical
Canada were the first to be published in English. effectiveness of antipsychotic drugs. 24,25 This atti-
With the exception of one study in which the tude was reinforced with the introduction of halo-
patients served as their own control, 16 these were peridol in 1958 by Haase and Janssen. 24,25Tardive
all open-label studies. The therapeutic effect of dyskinesia induced by chlorpromazine and its re-
chlorpromazine was not definitively established lated antipsychotic drugs has been recognized as a
until the completion of a study by the US Veterans concern since 1959 after the first report from
Administration Collaborative Study Group in the France.26, 27
late 1950s. 17,18However, long before the study was
published, large decreases in psychiatric inpatient INTRODUCTION OF CLOZAPINE
populations were witnessed around the world be-
cause of the widespread use of chlorpromazine or German psychiatrists working with G. Stille at
its related drugs. 8 Wander Pharmaceuticals in Bern, Switzerland, in
the early 1960s worked to refute the concept that
INTRODUCTION OF ANTIPSYCHOTIC AGENTS EPS and antipsychotic efficacy were linked. 25Their
work led to the introduction of clozapine, an
The incredible clinical success of chlorproma-
antipsychotic with no EPS or minimally associated
zine stimulated a widespread search for other
EPS. lk26 Clinical confirmation of this profile for
antipsychotic drugs at Rh6ne-Poulenc, where Char-
clozapine was provided in open studies by Aus-
pentier and Courvoisier had previously identified
trian 28 and German 29 investigators in 1966, and
the structural features necessary for potent biologi-
later by Swiss researchers 3° in a double-blind study
cal activity, and thousands of additional phenothi-
in 1971. The Wander Company, the manufacturer
azine derivatives were synthesized and tested. 19
of clozapine at that time, found itself in a bizarre
Although chlorpromazine remained the most pre-
situation. 26 Clozapine was briefly marketed and
scribed antipsychotic agent throughout the 1960s
quickly withdrawn. 26Besides the embarrassment of
and early 1970s, a many drugs with similar antipsy-
lacking of EPS, the initial enthusiasm for clozapine
chotic efficacy but different chemistry, potency, and
was further dampened by (1) the purchase of
side-effect profiles were introduced to the market. 11
Wander Pharmaceuticals Corp by Sandoz Pharma-
Among the 40 or more antipsychotic drugs intro-
ceuticals Corp 31 and, most significantly, (2) reports
duced to the world by 19902° (about 15 in the
from Finland that life-threatening incidents of
United States H) were trifluoperazine, thioridazine,
agranulocytosis were associated with clozapine
chlorprothixene, thiothixene, haloperidol, etc. The
treatment. 32 However, enthusiasm for the drug was
last of this series to be approved by the US Food
maintained by a small cadre of clinical investigators
and Drug Administration (FDA) was loxapine, a
and G. Honigfeld at Sandoz, who observed that cloza-
dibenzodiazepine, in 1975.11 Despite this prolifera-
pine was remarkably effective in treatment-resistant
tion of antipsychotic drugs, only 11 depot prepara-
patients. This led to a landmark double-blind study of
tions of eight different compounds were marketed
clozapine in a well-defined group of treatment-resistant
in the world by 19902°,2~; of these, only two
patients whose blood cell counts were closely moni-
(fluphenazine and haloperidol) were available in
tored during treatment, 33 and ultimately to its
the US market. 1!
introduction to the US market in 1990.
DESCRIPTION OF EXTRAPYRAMIDAL
SYMPTOMS ADVENT OF ATYPICAL
In 1954, 2 years after chlorpromazine first came ANTIPSYCHOTIC DRUGS
into clinical use, acute extrapyramidal symptoms Clozapine was first marketed in association with
(EPS) including parkinsonism, dystonias, and aka- an intimately linked system of blood monitoring
thisia began to be described and recognized as side and drug availability in patients previously demon-
effects associated with the use of chlorpromazine strated to be treatment-resistant. Its initial use in
and reserpine. 22 In a 1961 report, 23 the prevalence studies and clinics established that it was useful not
of EPS in patients treated with antipsychotic drugs only for treating positive symptoms (such as hallu-
was estimated as 38.9%. The majority of clinicians cinations, delusions, disorganized behavior, and
410 WINSTON W. SHEN

disorganized speech) associated with schizophrenia pine analog antagonists, and risperidone, sertin-
but also for treating negative symptoms (such as dole, and ziprasidone can be grouped together as
severe social withdrawal, inactivity, apathy, affec- serotonin/dopamine antagonists (written personal
tive flattening, and poverty of thought).34 This communication with John G. Csernansky, M.D.,
activity rapidly destroyed the general conviction January 27, 1999). The chemical structures of
that the efficacy and EPS profile were linked, and typical antipsychotic drugs in the former class have
led to an emerging concept of "atypical" antipsy- a three-ring nucleus, but those in the latter class do
chotic drugs. Although no precise definition of this not.
concept has ever been established, a drug with the As a group, all of these marketed atypical
property of "atypicality" shows a clinical profile antipsychotic drags have been demonstrated in
with a low propensity to induce EPS (or EPS- double-blind clinical trials to have reduced or
sparing35) and with efficacy for the negative symp- minimal EPS at clinically effective doses and some
toms of schizophrenia. Other characteristics com- efficacy in treating the negative symptoms of
monly identified as atypicality are an efficacy in schizophrenia.33,36-39 However, only clozapine has
treatment-refractory patients and, sometimes, a been demonstrated to provide efficacy in treatment-
failure to induce a serum prolactin elevation. refractory schizophrenic patients. 33 In addition,
Clozapine's success quickly led to the develop- none of these drugs except risperidonea3 show
ment of other atypical antipsychotic drugs. The first elevated serum prolactin levels after chronic admin-
of these, risperidone, was approved in 1994, 36 istration. Table l, which is expanded from a recent
olanzapine in 1996, 37 sertindole in 1997 (in some practice guideline for the treatment of patients with
countries outside of the United States),38 and queti- schizophrenia of the American Psychiatric Associa-
apine in 1997. 39 Due to cardiac safety concerns tion, summarizes clinical characteristics of atypical
raised by the FDA, 4° the manufacturer of sertindole antipsychotic drugs. ~
has abandoned an effort to seek a US marketing Detailed receptor-binding profiles of atypical
license. Ziprasidone41 was still under regulatory antipsychotic drugs have been generated in an
review as of February 1999. attempt to understand their differences in phannaco-
dynamics and clinical activity. The attempt to
CLINICAL CHARACTERISTICS OF ATYPICAL explain how atypical antipsychotic drugs work and
ANTIPSYCHOTIC DRUGS how they differ among themselves has caught the
All atypical antipsychotic drugs currently mar- imagination of many basic scientists and clinicians.
keted in the United States belong to the group of The comparison of the ratio of plasma Ki (pKi)
mixed receptor antagonists.42 Risperidone is an values for serotonin 2A (5-HTzA) and dopamine 2
improvement from the chemical structure of halo- (D:) binding activity has been most strongly pro-
peridol; olanzapine and quetiapine are derived posed as providing the potential pharmacological
from that of clozapine. Among the mixed receptor basis of the unique clinical effects of atypical
antagonists, clozapine, olanzapine, and quetiapine antipsychotic drags, a5 but relationships between D2
can be logically categorized as multireceptor cloza- and D3, Da, and (x2 have also been proposed. ~,47

Table 1. Brief Summary of Clinical Characteristics of Atypical Antipsychotic Available in the United States
(haloperidol included for reference)
Yearof US Clinical Equivalent Degree ProvenEnhanced ElevatedProlactin for
Effectiveness
Antipsychotic Introduction Oral Dose (rag/d) of EPS Efficacy After Chronic Use NegativeSymptoms

Clozapine 1990 50 0? Yes No Yes

Risperidone 1994 1-2 + No Yes Yes
Olanzapine 1996 2-3? 0-+? No No Yes
Quetiapine 1997 50-100 0-+? No No Yes
Sertindole* -- 2-3? 0-+? No No Yes
Ziprasidonet -- ? ? No ? Yes
Haloperidol 1958 2 +++ No Yes No

Data are from Kane et al., 33 Marder and Meibach, 3s Beasley et al.,37VanKammen et al., 3a Arvantis et al., 39 Prakash et al., 41 and the
American Psychiatric Association. ~
*Licensing for the US market not currently pursued.
tUnder application for release to the US market.
ANTIPSYCHOTIC DRUG HISTORY 411

Researchers are still trying to interpret the informa- Table 2. Chronology of Antipsychotic Drug Development
tion for the receptor profiles of atypical antipsy- Year Development
chotic drugs. 48,49 However, pKi values involving 1956 Perkin synthesized mauve ~
variable neurotransmission of the drugs are still 1896 Caro synthesized methylene blue, a phenothiazine
useful to predict side effects, as shown elsewhere. 5° derivative 1
1878 Berthsen synthesized phenothiazine 1
1891 Paul Ehrlich observed that methylene blue helped
DRUGS IN THE PIPELINE OR NOT AVAILABLE
patients with malaria 1
IN THE UNITED STATES 1944 Gilman et ai. found a lack of antimalarial effect for
Pharmaceutical companies have numerous candi- phenothiazines 2
1950 Laborit and Huguenard used promethazine in anesthe-
date antipsychotic compounds in various stages of sia3,4
the pharmaceutical pipeline. 42 Besides the previ- 1951 Laborit and Huguenard produced artificial hibernation
ously described six atypical antipsychotic drugs, with chlorpromazine 4
the mixed receptor antagonists also include zot- 1952 Hamon et al. and Delay et al. showed chlorpromazine's
antipsychotic effect 5.6,9
epine, savoxepine, and amperozide. Zotepine is
1953 St~ihelin and Kielholz confirmed chlorpromazine's anti-
available in Europe 5L52 and Asia, 53 but not in the
psychotic efficacy in Germany 12
United States. It has three-ring structure51,53 and 1954 Chlorpromazine marketed in the US by Smith, Kline
should belong to the class of multireceptor cloza- and French Laboratories as an antivomiting agent ~5
pine analog atypical antipsychotic drugs. Ampero- Lehmann and Hanrahan confirmed chlorpromazine's
zide is under development in Europe. 54 antipsychotic efficacy in MontreaP T M
Winkelman confirmed chlorpromazine's antipsychotic
Apart from the mixed receptor antagonist strat-
efficacy in the US ~s
egy, other mechanisms are also used in the current Steck described EPS induced by chlorpromazine and
or recent development of antipsychotic drugs: (1) reserpine 20
specific DI/D 2 antagonists: amisulpride (D2), raclo- 1958 Haloperidol introduced to the market22
pride (O2), NNC 01-0687 (D1), and NNC 01-0756; 1959 Sigwald et al. described tardive dyskinesia 27
1960 Veterans Administration Collaborative Study reported
(2) partial D2 agonists: SDZ HDC 912, MAR 327,
its double-blind results for antipsychotic agents 17,~8
pramipexode (SND 929), roxindole, talipexole 1961 Ayd reported EPS incidence of -38.9% 23
(BHT 920), and terguride; (3) 5-HT antagonists: 1962 Carlsson and Lindquist demonstrated dopaminergic-
ondansetron (5-HT3), zacopride (5-HT3), and rita- blocking effect of antipsychotic drugs 57
serin (5-HT2); and (4) miscellaneous mechanisms: 1975 Molindone introduced to the US market 11
1990 Clozapine approved bythe FDA ~1,33
bretazenil, milacemide, and peptides. 42 Some of
1994 Risperidone approved by the FDA 11.36
these have been marketed for other indications. For 1996 Olanzapine approved by the FDA37
example, the 5-HT3 antagonist odansetron is used 1997 Quetiapine approved by the FDA39
as an antiemetic drug.
Based on the concept that N-methyl-D-aspartate
(NMDA) receptor hypofunction is the neuropharma- chlorpromazine since Ehrlich's clinical observation
cologic basis for schizophrenia, 55 D-serine is used of methylene blue in 1891 from an antimalarial, to
as an add-on to an antipsychotic drug and is found an antihistamine, to an anesthetic, and eventually to
to be effective in improving the negative symptoms an antipsychotic medication. Because Ehrlich had a
of schizophrenia. 56 However, the development of working relationship with Hoechst Pharmaceuti-
D-serine as an add-on rather than a first-line antipsy- cals, 59 he could afford to use a systematic "brute-
chotic drug is yet to be seen. force" approach to make things happen. 59,6° For
example, there is the story of the famous discovery
DISCUSSION of arsphenamine (or salvarsan, the 606th com-
Table 2 summarizes the chronology of antipsy- pound) in a series of chemicals that Ehrlich and his
chotic drug development and contains some events 57 Japanese collaborator Hata studied as possible
that are not mentioned in the text of this article. treatments for syphilis .59Without the support of the
Antipsychotic drug development has come a long pharmaceutical company, Ehrlich could not afford
way, from the serendipitous discoveries of chemi- to have his relentless pursuit and to fail his
cals by trial and error. Chlorpromazine came to the screenings 605 times. Based on this historical
attention of psychiatry through a convoluted his- review, all activities of antipsychotic drug develop-
tory.58 It had taken almost 60 years to develop ment have been closely financed by pharmaceutical
412 WINSTON W. SHEN

houses. Even today, the resources for antipsychotic The newly released atypical antipsychotic drugs
drug development still originate from private indus- have yet to prove that they are as efficacious as
trial support rather than from public research clozapine, which is still considered the "gold
organizations such as the National Institute of standard." 26For these reasons, research to alleviate
Mental Health. clozapine-induced side effects6e may be more cost-
It is unthinkable that chlorpromazine and other effective than developing brand-new atypical anti-
related compounds were released by the regulatory psychotic drugs. More studies on the treatment and
agents to the market before demonstrating efficacy prevention of clozapine-induced agranulocytosis32
with the clinical data from double-blind and pla- might be a better and cheaper answer than the
cebo-controlled studies in 1960.1618 The thalid- development of a brand-new substitute drug, espe-
omine tragedy led to the passage of the Kefauver- cially since granulocyte colony-stimulating factors
Harris amendments to the Pure Food and Drug Act have been used effectively to reverse this hemato-
in 1962. 60 This legislation required that new drugs logic side effect.63
be shown to be efficacious and safe.6° Since then, Noncompliance is an issue in the treatment of
all marketed antipsychotic drugs have been sub- schizophrenia, and the formulation of depot prepa-
jected to this FDA standard for licensing. rations of atypical antipsychotic drugs is an urgent
From 1975 to 1990, there was a hiatus in need if treatments with these new agents for
antipsychotic drug development, during which no schizophrenic patients are used more extensively.11
activities for developing new antipsychotic agents Hopefully, a long-acting form of an atypical antipsy-
were seen. Based on the data of controlled compara- chotic drug will be available soon.21
tive studies, 17,18all typical antipsychotic drugs are The experiences of atypical antipsychotic drug
equal in efficacy but their side effects are different. development have moved drug design from a pure
Thus, during that period, the manufacturers stressed dopamine antagonist strategy to other neurotrans-
the side effects of competitors' drugs to promote mission strategies with serotonin, glutamate (includ-
their o w n drugs. 61 For example, the manufacturers of ing NMDA), cholinergic,or even neuropeptide receptor-
low-potency antipsychotic drugs stressed the EPS side targeting. The involvement of other neurotransmitters
effects to promote their drugs, whereas the makers of in the activity of atypical antipsychotic drugs may
high-potency antipsychotic drugs emphasized the car- make EPS less possible and an improvement of nega-
diovascular side effects of low-potency antipsychotics. tive symptoms more possible. Recent activities in
The lack of activity in antipsychotic drug development antipsychotic drug development not only have changed
in those 15 years might be due to the dogmatic the pharmacologic concept of schizophrenia but also
restraints of the dopamine hypothesis of schizophre- have fueled the enthusiasm in schizophrenia re-
nia57and Haase's concept of "no antipsychotic efficacy search, which in the past decade, after a 15-year
if no EPS. ''24 When clozapine was developed, its hiatus, has been unprecedentedly active.
manufacturer was hesitant to introduce it to the market,
not due to the issue of its efficacy but to its absence of
the EPS side effect.26 CONCLUSION
At present, the new antipsychotic drugs are The history of antipsychotic drug development
synthesized with more precise receptor targeting started with the serendipitous discovery of chlor-
according to the guidelines of psychopharmaco- promazine in 1952. Most of the typical antipsy-
logic principles, although the exact neurobiology chotic drugs were introduced between 1954 and
and etiology of schizophrenia are still unknown. 1975. The introduction of clozapine to the US
There is not a systematic guideline for antipsy- market in 1990 heralded the new era of pharmaco-
chotic drug development because the exact psycho- therapy for schizophrenia with atypical antipsy-
pathology of schizophrenia is still unknown. Only chotic drugs. As of February 1999, four atypical
after sufficient clinical experience will clinicians be antipsychotic drugs (clozapine, risperidone, olanza-
able to determine whether an individual atypical pine, and quetiapine) are available in the United
antipsychotic drug represents, as promised, a unique States. They are at least as effective as typical
compound or just another "me-too" drug, as in the antipsychotic drugs in treating the positive symp-
case of typical antipsychotic drugs, tricyclic antide- toms of schizophrenia while causing fewer EPS
pressants, or serotonin-specific reuptake inhibitors. side effects. They also show superiority over typi-
ANTIPSYCHOTIC DRUG HISTORY 413

cal antipsychotic drugs in improving the negative basis to identify antipsychotic drugs with minimal
symptoms of schizophrenia. side effects and a broader spectrum of efficacy.
The advent of atypical antipsychotic drugs has
brought unprecedented excitement to the research
of schizophrenia. Hopefully, the pharmacological ACKNOWLEDGMENT

basis for atypicality will be identified and used as a Larry D. Alphs, M.D., Ph.D., helped to prepare this article.

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