Review

Cite This: ACS Chem. Neurosci. 2019, 10, 79−88 pubs.acs.org/chemneuro

Classics in Chemical Neuroscience: Chlorpromazine

Debra Boyd-Kimball,* Katelyn Gonczy, Benjamin Lewis, Thomas Mason, Nicole Siliko,
and Jacob Wolfe
Department of Chemistry and Biochemistry, University of Mount Union, Alliance, Ohio 44601, United States

ABSTRACT: The discovery of chlorpromazine in the early 1950s revolutionized the clinical
treatment of schizophrenia, galvanized the development of psychopharmacology, and standardized
protocols used for testing the clinical efficacy of antipsychotics. Furthermore, chlorpromazine
expanded our understanding of the role of chemical messaging in neurotransmission and reduced
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the stigma associated with mental illness, facilitating deinstitutionalization in the 1960s and 1970s.
In this review, we will discuss the synthesis, manufacturing, metabolism and pharmacokinetics,
pharmacology, structure−activity relationship, and adverse effects of chlorpromazine. In
Downloaded via LMU MUENCHEN on January 28, 2019 at 12:55:47 (UTC).

conclusion, we summarize the history and significant contributions of chlorpromazine that have
resulted in this potent first-generation antipsychotic maintaining its clinical relevance for nearly 70 years.
KEYWORDS: Chlorpromazine, antipsychotic, schizophrenia, psychopharmacology, dopamine, history

■ INTRODUCTION
Schizophrenia is a severe, chronic psychological disorder
characterized by the presence of positive, negative, and
cognitive symptoms.1−4 Until the mid-20th century a diagnosis
of schizophrenia historically meant a lifetime of confinement to
an asylum.5−7 Standard treatments of the time were electro-
convulsive therapy (ECT) and prolonged sleep therapy, which
were employed with agitated patients.5,7−10 The introduction
of chlorpromazine (CPZ) in the early 1950s catalyzed the
development of psychopharmacology11 and expanded our
understanding of chemical signaling in neurotransmission.12
Additionally, CPZ helped to reduce the public stigma
surrounding mental illness, leading to the deinstitutionalization
of those with schizophrenia.6,7,10,13 In this review, we attempt
to synthesize a portion of the literature on CPZ to describe the
synthesis and basic properties of this first-generation
antipsychotic that has persisted for almost 70 years as the
“gold standard” to which all other antipsychotics are compared.
notable modern synthetic routes to chlorpromazine hydro-
chloride was patented by Wang in 2012 under Patent
CN102617509 (A). This synthesis, which includes the
substitution of 2-chlorophenothiazine with N,N-dimethyl-3-
chloropropylamine followed by neutralization with hydro-
chloric acid, provides yields that are higher than those of
traditional methods (>90%). This higher yield is attributed to
the use of sodium hydroxide and tetrabutylammonium
bromide as the condensing agents, strict control of the raw
material ratio, and an indicator for the end point of the
salification reaction (Scheme 2).22
■ MANUFACTURING INFORMATION
CPZ, produced in the United States under the brand name
Thorazine, was approved by the Food and Drug Admin-
istration (FDA) for the treatment of schizophrenia in 1957.23

■
CHEMICAL SYNTHESIS
CPZ, 3-(2-chlorophenothiazin-10-yl)-N,N-dimethylpropan-1-
amine (CAS Registry No. 50-53-3), is a low-molecular weight
phenothiazine derivative (molecular weight of 318.1). The first
synthetic route to CPZ was reported from the laboratories of
Rhô ne-Poulenc by Paul Charpentier, and U.S. Patent
2,645,640 A was issued on July 14, 1953 (Scheme 1).14,15 In
the original synthesis, the chlorophenothiazine (2) was
prepared by the cyclization of 3-chlorodiphenylamine (1)
with sulfur in the presence of an iodine catalyst and heat. The
cyclization yielded the 2- and 4-chlorophenothiazine isomers
that were separated by fractional crystallization. Deprotonation
of 2 with sodium amide was then followed by addition of N,N-
dimethyl-3-chloropropylamine. Distillation of the ethereal
extract yielded CPZ (3), which was then recrystallized as the
hydrochloride.14,15
Since its first synthesis in 1951, various other routes to
produce CPZ have been recognized.16−21 One of the more
CPZ was primarily manufactured by GlaxoSmithKline under
the brand name Thorazine in tablet form, but its production
was discontinued in 2016.24 USL Pharma was granted FDA
approval for the production and sale of CPZ on July 9, 1974.
Two weeks later, West-Ward Pharmaceuticals was granted
FDA approval on July 25, 1974.25 Many other U.S.
manufacturers gained FDA approval for the sale of CPZ but
have since discontinued production of the drug. It is currently
manufactured by companies in the United States under the
generic name chlorpromazine hydrochloride, by USL Pharma
in tablet form, and by West-Ward Pharmaceuticals in
intravenous (iv) form. In tablet form, CPZ is available in
doses of 25, 50, 100, and 200 mg.26 In injection form, CPZ is
available at a strength of 25 mg/mL.27
Received: May 29, 2018
Accepted: June 21, 2018
Published: June 21, 2018

© 2018 American Chemical Society 79 DOI: 10.1021/acschemneuro.8b00258

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Scheme 1. Original Synthesis of Chlorpromazine (3) Reported by Charpentier14,15
Scheme 2. Recent Synthesis of Chlorpromazine Hydrochloride22
■ DRUG METABOLISM AND PHARMACOKINETICS
CPZ has no hydrogen bond donors, two hydrogen bond
acceptors, and a cLogP of 5.80.28 Together, these properties
conform to Lipinski’s rules and are consistent with the
acceptable drug metabolism and pharmacokinetic (DMPK)
parameters and central nervous system (CNS) penetration of
CPZ. The metabolism of CPZ varies based on its method of
administration. If administered orally, CPZ undergoes
extensive presystemic first-pass metabolism.29 This metabolism
can be quantified by the bioavailability of unchanged CPZ that
reaches circulation (F%). This value has been reported as low
and variable ranging from 4 to 38%.30 It has been seen that
orally administered CPZ begins to appear in systemic
circulation after a mean lag time of 0.4 h and is subsequently
absorbed for an average of 2.9 h. The average peak
concentration of unaltered CPZ after this absorption was
calculated to be 0.079 μg/mL, occurring 2−4 h after
ingestion.31
Alternatively, when CPZ is intravenously administered, the
drug avoids extensive first-pass metabolism and the average
clearance rate has been calculated to be 1.06 L h−1 kg−1.
Additionally, the average volume of distribution at a steady
state was found to be 8.88 L kg−1.30 As expected, upon
comparison of the oral and iv administration of CPZ, the data
gathered on its pharmacokinetics vary. The mean half-life and
AUC values are listed in Table 1. AUC, or area under the
plasma drug concentration versus time curve, indicates the
bodily exposure after administration of a drug.32
CPZ undergoes dramatic metabolism that ultimately results
in at least 17 recoverable metabolites from urine or plasma
samples.33 The five main metabolites of CPZ include
Table 1. Comparison of Mean Half-Lives and AUC Values
with Various Methods of Administration30
formulation mean half-lifea (h) AUCa (ng h−1 mL−1)
oral, 25 mg 5.48 (1.72) 27.80 (14.90)
oral, 50 mg 9.52 (4.55) 81.80 (79.20)
oral, 100 mg 11.05 (2.80) 247.00 (127.00)
iv, 10 mg 11.10 (4.33) 135.00 (24.50)
a
Numbers in parentheses indicate standard deviations.
80
Review
chlorpromazine 5-sulfoxide (A), mono-N-demethylchlorpro-
mazine (B), di-N-demethylchlorpromazine (C), 7-hydroxy-
chlorpromazine (D), and glucuronic acid conjugates (Figure
1).30,34−36 These metabolites are produced by specific hepatic
cytochrome P450 (CYP) isozymes. For example, CYP1A2 and
CYP3A4 have been found to catalyze the mono-N-
demethylation, di-N-demethylation, and 5-sulfoxidation of
CPZ. Additionally, CYP2D6, with the assistance of CYP1A2,
has been shown to be the primary isozyme that performs the 7-
hydroxylation of CPZ.29,35−37
A genetic component of pharmaceutical drug metabolism
has been reported as a factor contributing to the wide range of
pharmacokinetic values for CPZ. Genetic polymorphisms
among the P450 enzymes, specifically CYP2D6, have been
shown to lead to the emergence of two different phenotypes:
extensive metabolizers and poor metabolizers. More specifi-
cally, the CYP2D6 polymorphism is known as the
debrisoquine/sparteine polymorphism.29,38 Such polymor-
phisms could account for the variation in pharmacokinetic
values among experimental patients. Genetic testing can be
done before experimentation to eliminate this variable.29
Additionally, care must be taken when comparing reported
pharmacokinetic data, particularly with respect to historical
studies, in light of such subject specific metabolic variation.
■
PHARMACOLOGY
CPZ demonstrates a high affinity for dopamine (DA) receptors
and acts as a receptor antagonist by inhibiting adenylate
cyclase activity. The first in its class, CPZ became the “gold
standard” against which other first-generation, and even
second-generation, antipsychotics were compared.39,40 While
CPZ has several active metabolites that cross the blood−brain
barrier, including 7-hydroxychlorpromazine, it has been shown
that unaltered CPZ is primarily responsible for the CNS
response.41 The primary pharmaceutical activity of CPZ is
dopamine D2 receptor (D2R) antagonism with therapeutic
concentrations across a range of 60−80%. Therapeutic
concentrations resulting in levels of D2R occupancy of >78%
account for extrapyramidal symptoms (EPS) as explained by
the fast-off D2R theory of antipsychotic action. Positron
emission tomography (PET) imaging has shown that many
conventional antipsychotics, such as CPZ, occupy D2Rs for a
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Figure 1. Scheme of primary metabolites found in urine samples.34−37 Letters indicate the type of enzymatic reaction catalyzed by the designated
cytochrome P450 isozymes: (A) 5-sulfoxidation, (B) mono-N-demethylation, (C) di-N-demethylation, and (D) 7-hydroxylation.

period of time longer than those of many atypical question about the efficacy and blockage of the 5-HT neuronal
antipsychotics, which wear off quickly following an oral dose. system by CPZ remains. For most 5-HT receptors, a low
This increased duration of occupancy is due to the tighter binding affinity is reported.41,44 A notable exception to this is
binding of CPZ, and other typical antipsychotics, to D2Rs in the 5-HT2A receptor subtype that exhibits Ki values similar to
comparison to those of atypical antipsychotics. Such prolonged that of the D2R (Table 2).42−45 However, the high 5-HT2A
stimulation of D2Rs by CPZ contributes to the high rates of occupancy does not necessarily provide a unique clinical profile
EPS observed in patients.42 While the binding affinity of CPZ for CPZ because atypical antipsychotics, like clozapine, share a
for other dopamine receptors has been tested, the D1, D3, and similar blockage of this receptor, signifying that D2Rs most
D4 receptors show low affinity, designating the low likelihood likely play the largest role in the clinical profile of the
of these receptors playing a role in the antipsychotic activity antipsychotic activity of the drug. Therefore, at typical clinical
(Table 2).41−43 dosages, blockage of the 5-HT2A receptor by CPZ appears to
For a majority of its history, CPZ was mainly studied as a be just as likely as blockage by atypical antipsychotics.45
D2R antagonist. More recently, the study of the binding Additionally, contrasting studies report that while CPZ
interactions of CPZ has been expanded beyond the DA system demonstrates 5-HT2A receptor inhibition in vitro, this
to include other receptor sites. In particular, the serotonin (5- pharmacological profile is lost in vivo.46
HT) system has been extensively investigated; however, some CPZ is also a known adrenoceptor antagonist, which
contributes to its antipsychotic effect. CPZ has shown a high
Table 2. Summary of Select Inhibitor Constants Associated affinity for the α1A and α1B subtypes of this receptor, which is
with Chlorpromazine coexpressed in the frontal cortex and thalamus.47 Within rats,
CPZ has a 4-fold higher affinity for the α1A adrenoceptor
receptor Ki (nM) subtype, which is higher than that exhibited at D2Rs.47−49 The
serotonin44 inhibitor α1A adrenoceptor could account for the antipsychotic
5-HT1A 3115 activity of CPZ because psychosis is a symptom due to
5-HT1B 1489 hyperactivity of adrenergic receptors.49 Additionally, at high
5-HT1D 452 doses, CPZ has also been shown to increase hippocampal
5-HT1E 344 acetylcholine release. While several atypical antipsychotics can
5-HT2A 3.32 induce this response at a lower dose, it is suggested that CPZ
5-HT2C 15.55 increases acetylcholine release through inhibition of terminal
muscarinic M2 autoreceptors.50

■
5-HT3 977
5-HT5A 118
5-HT6 12 STRUCTURE−ACTIVITY RELATIONSHIP (SAR)
5-HT7 21 Although CPZ has been extensively characterized as binding to
dopamine44 a variety of targets (Table 2), relatively few structural binding
D1 112 mechanisms have been elucidated because of the age of CPZ.
D2 2 First crystallized from solution by McDowell in 1969, the
D3 5 functional propylamine moiety present on CPZ was found to
D4 10.8 be facing the A-ring with its chlorine substituent.51 This
D4.2 26.2 conformation was initially of some debate, but simple overlay
D4.4 15.9 studies of this A-ring-facing conformation with DA placed both
D5 133 the A-ring and protonatable tertiary amine in positions similar
adrenoceptor47 to those of DA (Figure 2).52 These observations were
α1A 1.5 eventually validated by potential energy calculations and
α1B 5.6 molecular dynamics simulations with phenothiazine, xanthine,
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Figure 2. Structural similarities between DA and CPZ. An early
overlay study by Horn and Snyder52 made the astute observation that
if the propylamine arm of CPZ faces the A-ring, this would cause the
A-ring and propylamine to line up with the aromatic ring and amine
found in DA. This was later confirmed as the biologically active form
of CPZ by further work.53,54
and thioxanthene derivatives that indicated critical van der
Waals interactions between the side chain and the chlorine A-
ring substituent existed. Increasing such van der Waals forces
was clinically associated with an increased level of D2R
binding, antipsychotic efficacy, and EPS.53,54
Although a co-crystal structure is sorely lacking, one fairly
well understood interaction is between CPZ and the D2R,
where the drug exerts its greatest clinical effects. Earlier work
suggested that CPZ must contain a protonatable amine to
effectively bind the D2R as both quaternary ammonium and
dimethylsulfonium derivatives showed substantially decreased
D2R affinity.55 Schetz and Floresca concluded that the cationic
amine group of CPZ bound to a highly conserved aspartate
residue on the third transmembrane helix of the D2R. This
SAR was most likely responsible for bringing CPZ into the
ligand binding site crevice of the D2R.56 A tryptophan residue
in the sixth transmembrane helix that sits on one side of the
binding crevice in a cluster of aromatic residues is considered a
molecular switch that is responsible for D2R activation. Binding
of DA to the D2R results in flipping of this molecular switch
and a conformational change, whereas CPZ binding does
not.56,57 This most likely can be attributed to a lack of or
improper steric clashing between the bulky aromatic residues
that are thought to cause D2R activation upon DA binding.56
Thus, in a primitive sense, CPZ does “blockade” the D2R to
exert its effects.
An additional area of which some characterization has
occurred is the binding of CPZ to cation-selective pentameric
ligand-gated ion channels (pLGICs), such as nAChRs and the
5-HT3R.58 These receptors allow for the fast conversion of a
chemical signal to an electrical signal at synapses, and CPZ
appears to modulate their activity in different ways. In
nAChRs, CPZ physically obstructs the ion channel.59 Photo-
affinity studies have indicated that CPZ can bind at sites near
both the cytoplasmic and extracellular portions of the
transmembrane pore.60 In contrast, CPZ binds directly to
the 5-HT3R ligand binding site and antagonizes serotonin
function.61,62
In addition to binding with multiple receptors, CPZ has
been shown to interact with lipid bilayers. Because of its bulk
phenothiazine ring structure, CPZ easily diffuses into
bilayers.63 This is stabilized by the hydrogen bonding of the
phosphate group from membrane phospholipids with the
propylamine moiety of CPZ.54 CPZ was found to be
preferentially sequestered on the inner leaflet of membranes
82
Review
because of its ionic interactions with the anionic phospholipids,
phosphatidylinositol (PI) and phosphatidylserine (PS);
however, it has been demonstrated that CPZ is preferentially
bound to phosphoinositides present on the inner leaflet when
compared to PS.63 This claim was supported by work that
determined polyphosphoinositide levels in erythrocytes were
upregulated in the presence of CPZ.64 This points to the
possible physical sequestration of CPZ by the these densely
charged phospholipids that could ultimately lead to the
disruption of intracellular signals by phospholipase C-
generated second messengers, inositol 1,4,5-trisphosphate
(IP3) and diacylglycerol (DAG).63,64 Although these studies
focused on erythrocytes because of their easily quantifiable
morphological index, this principle could be applied to other
lipid bilayers because of their universally anionic inner leaflets.
■
ADVERSE EFFECTS
CPZ is an antipsychotic medication that works at all levels of
the CNS, with subcortical levels being the primary target.8
CPZ was at one time the main drug for the treatment of
schizophrenia but has since been discontinued by many
pharmaceutical companies.23,24 Studies have shown that use of
CPZ can result in weight gain, sedation, movement disorders
(tremors and shaking), and orthostatic hypotension. Ortho-
static hypotension is usually observed when CPZ is
administered in higher doses.65 Some of these EPS side effects
are seen with many antipsychotic drugs and are the main
concern when prescribing CPZ.66 EPS most often occurs when
D2Rs are highly occupied, resulting most often in acute
dystonic reactions or tardive dyskinesia.42 These are usually
seen when the dosage of CPZ is changed, especially in children
and young adults.67 Additionally, CPZ can cause drug-induced
parkinsonism.68 This side effect is often seen in elderly patients
within the first few months of treatment.69 The presence of
EPS in schizophrenic patients using CPZ was initially thought
to be an indicator that proper dosages had been achieved.
Further evidence and research showed that EPS could worsen
psychotic symptoms to the point that they were irreversible
and lethal in some cases.70 Research has shown that decreasing
the dose of CPZ to <600 mg/day reduced the risk of the onset
of EPS to levels equivalent with those of second-generation
drugs for schizophrenia treatment.66 The most commonly
reported side effects of CPZ include drowsiness, sedation, dry
mouth, and nasal discomfort. CPZ negatively affects various
systems in the body, including the cardiovascular, respiratory,
endocrine, metabolic, and immune systems. It also commonly
has negative effects on many organs, such as the eyes,
intestines, liver, and skin.71 Many of these negative effects are
typical of first-generation antipsychotics and are the reason that
second-generation drugs were developed.72
■
HISTORY AND SIGNIFICANCE IN CHEMICAL
NEUROSCIENCE
The serendipitous discovery of the neuroleptic properties of
chlorpromazine grew out of the simultaneous investigation of
phenothiazine derivatives for a variety of clinical applications.
Phenothiazines make up a class of molecules that were
originally developed in the late 19th century in the dye and
textile industries; during the early 20th century, however,
phenothiazines were recognized for their antiseptic and
antiparasitic properties and explored for antihistaminic proper-
ties, but research on known phenothiazines was halted because
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of toxicity concerns. During World War II, the Allied forces in
southeast Asia experienced a restricted supply of quinine for
the treatment of malaria and researchers turned again to
phenothiazines.73 Aminoalkyl derivatives of phenothiazine
were synthesized74 but were devoid of antimalarial activity.73
The lack of antimalarial properties was confirmed by
researchers at Rhône-Poulenc Laboratories in France, who
continued to study these derivatives for their antihistaminic
properties, notably bringing promethazine (Phenergan) to the
market as a clinical allergy treatment in 1947.73,75 Con-
currently, other researchers, including Daniel Bovet and Henri-
Marie Laborit, were studying the ability of these antihistaminic
compounds to alleviate stress and shock reactions. Laborit, a
French army surgeon, was particularly interested in identifying
a pharmacologically active agent with hypothermic and
sedative effects to induce an artificial hibernation that could
prevent surgical shock.76 Laborit used promethazine in
combination with dolantine creating his “lytic cocktail” and
noted that anxious patients were relaxed and calm following
surgery,77 consistent with the reported use of promethazine as
a sedative to calm patients with manic depression.78
At Rhô ne-Poulenc, Simone Courvoisier analyzed the
sedative properties of all the antihistaminic agents Paul
Charpentier and his team had synthesized since 1944 and
determined promazine appeared to be a promising option;73
thus, Charpentier undertook the synthesis of promazine
derivatizes and, in December 1950, synthesized CPZ. On the
basis of the promising results of in vitro and in vivo laboratory
tests,79,80 Laborit tested the activity of CPZ in his lytic cocktail
and observed that patients were relaxed and calm not only after
surgery but also before surgery. On the basis of such
observations, Laborit predicted the implication of these agents
in treating psychiatric disorders.81 Pharmacodynamic and
pharmacokinetic studies showed that CPZ possessed a broad
range of pharmaceutical activities, including, but not limited to,
antipyretic, anticonvulsant, adrenolytic, antiemetic, and anti-
fibrillatory activities.80 On the basis of this wide range of
pharmacological activity, CPZ was commercialized in 1952 in
France by Rhô ne-Poulenc under the commercial name
Largactil meaning large in action.73,82,83
CPZ was first administered to a hospitalized manic patient in
January 1952 as an adjunct therapy. The patient rapidly calmed
and, as therapy continued over a period of 3 weeks, remained
calm, ultimately being discharged from the hospital.84 Jean
Delay and Pierre Deniker were the first to administer CPZ
alone as a pharmaceutical agent in psychiatric patients at
Hôpital Sainte-Anne in Paris. Delay and Deniker confirmed the
efficacy of the agent in calming agitated or psychotic patients
but noted that a dose significantly higher than that reported by
Laborit was necessary to achieve these effects when CPZ was
administered alone.85 On the basis of the observed effects,
Delay proposed the term neuroleptic to classify CPZ and any
agent producing a similar slowing of motor activity.86 The use
of CPZ in psychiatry spread quickly through Europe to the
Psychiatrische Universitätsklinik in Switzerland where Felix
Labhardt published work on the efficacy of CPZ in treating
schizophrenia87,88 and to the University of Birmingham in
England where Joel and Charmain Elkes conducted and
published the first controlled test of CPZ.89 Elkes’ study was
blind and self-controlled and notably introduced randomized
trials and placebo-controlled research methodology into
psychiatry.73,82,90
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While the use of CPZ spread quickly across Europe, Heinz
Lehmann (Montreal) and Smith Kline & French Laboratories
(Philadelphia), now GlaxoSmithKline, can be credited with
introducing CPZ to North America.73,91 Lehmann initially
tested the sedative effects of CPZ compared to those of
secobarbital in healthy volunteers, and concluding that CPZ
induced “selective inhibition”, or a sedation that did not impair
cognitive function, Lehmann set up a clinical trial of CPZ on
71 psychiatric patients that was the first published in North
America.8,92,93 Smith Kline & French Laboratories obtained
the license from Rhône-Poulenc to market CPZ in the United
States and brought CPZ to market in 1954 under the name
Thorazine. Originally approved by the FDA as an antiemetic,
CPZ was first used in the United States as a hypothermic agent
during surgery rather than in psychiatric use;73,91 however, in
1953, Frank Ayd (Baltimore) had become the first psychiatrist
authorized by the FDA to study CPZ. Nevertheless, in 1954,
N. William Winkelman (Philadelphia) and Willis H. Bower
(Boston) independently published work on the clinical use of
CPZ in a range of psychiatric disorders while Ayd published
his findings on CPZ in 1955. Collectively, these publications
prompted the general acceptance of CPZ in the management
of psychiatric illness in North America.73,94−97 It is estimated
that 2 million patients were prescribed CPZ in the first 8
months,5 resulting in $75 million in gross sales for Smith Kline
& French in 1955.73 Agranulocytosis,98 liver toxicity, and EPS
were observed and reported, but the neuroleptic effect of CPZ
was determined to outweigh the risks for most pa-
tients.8,68,92,99−106 Haase later suggested that a “neuroleptic
threshold” in which the dosage could be therapeutically useful
without producing EPS would be optimal;107 however,
therapeutic dosages of CPZ could not be disentangled from
EPS effects.108−110
The first meta-analysis on the clinical efficacy of
chlorpromazine in the treatment of schizophrenia was
published in 1960 and highlighted the need for standardized
methods of scientific inquiry to be used in the clinical study of
CPZ and any other such agent.111 Indeed, the first reports on
the use of CPZ were small in scale, and many lacked the use of
appropriate controls. This is an issue that Lehmann himself
highlights in retrospect,93 and while Elkes’ contribution to the
development of these methods was significant,73,82,90,112 Elkes’
study reported the effect of CPZ in a number of psychotic
conditions that included only 13 patients with schizophrenia.89
The first large-scale controlled studies of CPZ in schizophrenic
patients were conducted in numerous U.S. Veterans Admin-
istration (VA) neuropsychiatric hospitals113,114 and through
the National Institute of Mental Health Psychopharmacology
Service Center (NIMH-PSC).115 In the first VA study, CPZ
was tested against promazine, phenobarbital, and a lactose
placebo in a double-blind, crossover study that lasted 24 weeks
in total and found the efficacy of CPZ was significantly greater
than that of promazine and the two control agents.113 The
second VA study used CPZ as a positive control in a double-
blind, 12-week study to test therapeutic efficacy of other
phenothiazine derivatives.114 These studies focused solely on
the therapeutic efficacy of CPZ in men, with both studies
largely dominated by chronic schizophrenic patients.113,114
The NIMH-PSC study attempted to address these limitations
in the experimental design by limiting the patient pool to those
newly admitted with no hospitalization in the prior 12 months
and utilizing mixed-gender groups for each treatment at each
of the nine collaborating hospitals. The therapeutic efficacy of
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thioridazine and fluphenazine was tested against CPZ, and
while this study found no significant difference in the
therapeutic effects of the phenothiazines tested, it did begin
to cast doubt on the hypothesis that extrapyramidal symptoms
were necessary for clinical effectiveness.115
While CPZ was broadly prescribed worldwide by the 1960, a
mode of action was still unknown, and studies had failed to
reach a consensus about the recommended dosage. In 1962, it
was reported that discrepancies in earlier CPZ studies could
have been due to the hypothermic effect of the drug.116 When
the hypothermic effect of the drug was controlled, Carlsson
and Lindqvist reported that CPZ blocked dopamine receptors
in mice, resulting in a feedback mechanism that increased the
synthesis and metabolism of catecholamines,117 which was
further supported by reports of increased dopamine synthesis
and metabolism induced by CPZ118−122 and led to the
proposal of the dopamine hypothesis of schizophrenia.123
Evidence of the CPZ blockade of dopamine receptors was
reported in the mid-1970s,124−126 lending further support to
the mode of action of CPZ and the dopamine hypothesis of
schizophrenia.127−130
Prior to the introduction of CPZ, patients diagnosed with
schizophrenia may have been secluded from society living out
the remainder of their lives in the confines of a hospital;
however, CPZ made the symptoms of schizophrenia more
manageable, and more individuals with schizophrenia found a
life outside of the institutional care system. This helped to
break the stigma surrounding mental health as these patients
were integrated into society and normalized mental health care
within communities.6,7,10,131 In the United States, with the help
of federal funding of deinstitutionalization,132 it is estimated
that the number of institutionalized patients declined from
>500000 in the mid-1950s to 60000 by 2000.7
The clinical development of CPZ as a therapeutic agent for
schizophrenia was recognized in 1957 when Deniker, Laborit,
and Lehmann were recognized with the American Public
Health Association’s Albert Lasker Clinical Medical Research
Award.73,133,134 It should also be noted that Daniel Bovet was
also recognized in the same year with the Nobel Prize in
Medicine for his contributions to the synthesis of antihist-
amines,135 which subsequently led to the synthesis of
promazine and, ultimately, CPZ.134
Overall, the discovery of chlorpromazine revolutionized our
understanding of mental illness and introduced the field of
psychopharmacology,90,93,112,136,137 including the development
of standardized screening methods and protocols for large-
scale, multihospital double-blind controlled tests that brought
psychiatry into the medical mainstream.73,82,89,111,113−115,138
To facilitate communication, the study of CPZ led to the
founding of the Collegium Internationale Neuro-Psychophar-
macologicum (CINP) in 1957139 and the American College of
Neuropsychopharmacology (ACNP) in 1960.140 Studies of
CPZ provided evidence that neurons communicate by
chemical messengers, further contributing to our broader
understanding of neurochemistry.12,141,142 Additionally, chlor-
promazine changed the way that we think about and treat
mental illness, leading to deinstitutionalization around the
world.6,7,10,131 CPZ remains the “gold standard” positive
control for testing the clinical efficacy of new antipsychotic
agents,143 and while the introduction of second-generation
antipsychotics has diminished the clinical use of CPZ, it
remains reliable in clinical efficacy and on the World Health
Organization Model List of Essential Medicines.144 For almost
84
Review
70 years, CPZ has withstood the test of time, and it is only
fitting that CPZ holds a special place as a classic in chemical
neuroscience.
■
AUTHOR INFORMATION
Corresponding Author
*Department of Chemistry and Biochemistry, University of
Mount Union, Alliance, OH 44601. Phone: 330-823-3674.
Fax: 330-823-8531. E-mail: boydkidl@mountunion.edu.
ORCID
Debra Boyd-Kimball: 0000-0003-3059-0024
Author Contributions
K.G. wrote the section on drug metabolism and pharmacoki-
netics. B.L. wrote the section on chemical synthesis. T.M.
wrote the section on structure−activity relationships. N.S.
wrote the section on pharmacology. J.W. contributed sections
on manufacturing information and adverse effects. D.B.-K.
wrote the abstract, introduction, and history and significance in
chemical neuroscience sections. K.G., B.L., T.M., N.S., and
D.B.-K. prepared figures and tables. All authors contributed to
the editing of the final manuscript.
Notes
The authors declare no competing financial interest.
■
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88 DOI: 10.1021/acschemneuro.8b00258
ACS Chem. Neurosci. 2019, 10, 79−88