Classics in Chemical Neuroscience: Chlorpromazine - ACS Publications

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Classics in Chemical Neuroscience: Chlorpromazine Debra Boyd-Kimball, Katelyn Gonczy, Benjamin Lewis, Thomas Mason, Nicole Siliko, and Jacob Wolfe ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.8b00258 • Publication Date (Web): 21 Jun 2018 Downloaded from http://pubs.acs.org on June 22, 2018

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ACS Chemical Neuroscience

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, OH 44601, USA

*Address correspondence to: Debra Boyd-Kimball, Department of Chemistry and Biochemistry, University of Mount Union, Alliance, OH 44601, USA Phone: 330-823-3674; Fax: 330-823-8531; E-mail: [email protected]

Keywords: chlorpromazine, antipsychotic, schizophrenia, psychopharmacology, dopamine, history

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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 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 conclusion, we summarize the history and significant contributions of chlorpromazine which have resulted in this potent first-generation antipsychotic persisting in clinical relevance for nearly 70 years.

Introduction Schizophrenia is a severe, chronic psychological disorder characterized by the presence of positive, negative, and cognitive symptoms.1-4 Up until the mid-twentieth century a diagnosis of schizophrenia historically meant a lifetime of confinement to an asylum.5-7 Standard treatments of the time were electroconvulsive therapy (ECT) and prolonged sleep therapy which were employed with agitated patients.5,7,810

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.


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Chemical Synthesis CPZ, 3-(2-chlorophenothiazin-10-yl)-N, N-dimethylpropan-1-amine (CAS No. [50-53-3]), is a low molecular weight phenothiazine derivative (MW = 318.1). The first synthetic route to CPZ was reported from the laboratories of Rhône-Poulenc by Paul Charpentier and US patent number US 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 which 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 notable modern synthetic routes to chlorpromazine hydrochloride 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 hydrochloric acid, provides higher yields than traditional methods (above 90%). This higher yield is attributed to the use of sodium hydroxide and tetrabutyl ammonium bromide as the condensing agents, strict control of the raw material ratio, and an indicator for the end point of the salification reaction.22 Scheme 1: Original synthesis of chlorpromazine (3) reported by Charpentier.14,15



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Scheme 2: Recent synthesis of chlorpromazine hydrochloride.22

Manufacturing Information CPZ, produced in the United States under the brand name Thorazine®, was approved by the FDA for treatment of schizophrenia in 1957.23 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 production and sale of CPZ on July 9th, 1974. Two weeks later, West-Ward Pharmaceuticals was granted FDA approval on July 25th, 1974.25 Many other U.S. manufacturers had 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 West-Ward Pharmaceuticals in intravenous form. In tablet form, CPZ is available in dosages of 25 mg, 50 mg, 100 mg, and 200 mg.26 In injection form, CPZ is available at the strength of 25 mg/mL.27

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 4-38%.30 It has


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been seen that orally administered CPZ begins to appear in systemic circulation after a mean lag time of 0.4 hours and is subsequently absorbed for an average of 2.9 hours. The average peak concentration of unaltered CPZ after this absorption was calculated to be 0.079 µg/ml, occurring two to four hours 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·hr-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, when comparing the oral and IV administration of CPZ, the data gathered on its pharmacokinetics varies. The mean half-life and AUC values are shown in Table 1. AUC, or area under the plasma drug concentration versus time curve, indicates the bodily exposure after administration of a drug.32 Table 1: Comparison of mean half-life and AUC values (SD) between varying administration methods.30 Mean Half-Life

AUC

(hr)

(ng·hr-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)

Formulation

Numbers in parentheses indicate standard deviation values.

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 chlorpromazine 5-sulfoxide (A), monoN-demethylchlorpromazine (B), di-N-demethylchlorpromazine (C), 7-hydroxychlorpromazine (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-Ndemethylation, di-N-demethylation, and 5-sulfoxidation of CPZ. Additionally, CYP2D6, with the assistance of CYP1A2, has been shown to be the primary isozyme that carries out the 7-hydroxylation of CPZ.29, 35-37



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A genetic component of pharmaceutical drug metabolism has been reported as a contributing factor 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 specifically, the CYP2D6 polymorphism is known as the debrisoquine/sparteine polymorphism.29,38 Such polymorphisms 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.

Figure 1: Scheme of primary metabolites found in urine samples.34-37


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Pharmacology CPZ demonstrates high affinity for dopamine (DA) receptors and acts as a receptor antagonist by inhibiting adenylate cyclase activity. The first in its class, CPZ has become the “gold standard” against which other first-generation, and even second-generation, antipsychotics were compared.39-40 While CPZ has several active metabolites which 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 occupying a range of 60-80%. Therapeutic concentrations resulting in levels of D2R occupancy above 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 longer period of time than many atypical antipsychotics, which wear off quickly following oral dose. This increased duration of occupancy is due to the tighter binding of CPZ, and other typical antipsychotics, to D2Rs in comparison to atypical antipsychotics. Such prolonged stimulation of D2Rs by CPZ contributes to the high rates of EPS observed in patients.42 While the binding affinity of CPZ for other dopamine receptors has been tested, the D1, D3, and D4 receptors show low affinity, designating low likelihood of these receptors playing a role in the antipsychotic activity (Table 2).41-43 For a majority of its history, CPZ was mainly studied as a D2R antagonist. More recently, study of the binding interactions of CPZ have been expanded beyond the DA system to include other receptor sites. In particular, the serotonin (5-HT) system has been extensively investigated; however, there remains some question as to the efficacy and blockage of the 5-HT neuronal system by CPZ. For most 5-HT receptors a low binding affinity is reported.41,44 A notable exception to this is the 5-HT2A receptor subtype which exhibits Ki values similar to the D2R (Table 2).42-45 However, the high 5-HT2A occupancy does not necessarily provide a unique clinical profile for CPZ because atypical antipsychotics, like clozapine, share similar blockage of this receptor, signifying that D2Rs most likely play the largest role in the clinical profile of the antipsychotic activity of the drug. Therefore, at typical clinical dosage, blockage of the 5-HT2A receptor by CPZ appears to be just as



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likely as blockage by atypical antipsychotics.45 Additionally, contrasting studies report that while CPZ demonstrates 5-HT2A receptor inhibition in vitro, this pharmacological profile is lost in vivo.46 CPZ is also a known adrenoceptor antagonist, which contributes to its antipsychotic effect. CPZ has shown high affinity towards the α1A and α1B subtypes of this receptor, which is coexpressed in the frontal cortex and thalamus.47 Within rats, CPZ has a 4-fold higher affinity for the α1A adrenoceptor subtype, which is higher than that exhibited at D2Rs.47-49 The inhibitor α1A adrenoceptor could account for the antipsychotic activity of CPZ since psychosis is a symptom due to hyperactivity of adrenergic receptors.49 Additionally, at high doses, CPZ has also been shown to increase hippocampal acetylcholine release. While several atypical antipsychotics can induce this response at a lower dose, it is suggested that CPZ increases acetylcholine release through inhibition of terminal muscarinic M2 autoreceptors.50 Table 2: Summary of Select Inhibitor Constants Associated with Chlorpromazine

Receptor Serotonin44 5-HT1A 5-HT1B 5-HT1D 5-HT1E 5-HT2A 5-HT2C 5-HT3 5-HT5A 5-HT6 5-HT7 Dopamine44 D1 D2 D3 D4 D4.2 D4.4 D5 Adrenoceptor47 α1A α1B

Ki Value (nM) 3115 1489 452 344 3.32 15.55 977 118 12 21 112 2 5 10.8 26.2 15.9 133 1.5 5.6


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Structure-Activity Relationship (SAR) Although CPZ has been extensively characterized as binding to a variety of targets (Table 2), relatively few structural binding mechanisms have been elucidated owing to the age of CPZ. First crystallized from solution by McDowell in 1969, the functional propylamine moiety present on CPZ was found to be facing the A-ring with its chlorine substituent.51 This conformation was initially of some debate, but simple overlay studies of this A-ring facing conformation with DA placed both the A-ring and protonatable tertiary amine in similar positions to those of DA (Figure 2).52 These observations were eventually validated by potential energy calculations and molecular dynamics simulations with phenothiazine, xanthine, 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 increased 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 3rd 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 6th transmembrane helix that sits on one side of the binding crevice in a cluster of aromatic residues is considered a molecular switch responsible for D2R activation. DA binding to the D2R results in flipping of this molecular switch and conformational change whereas CPZ binding does not.56,57 This most likely owes 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 in order to exert its effects. An additional area of which some characterization has occurred in is the binding of CPZ to cationselective pentameric ligand gated ion channels (pLGICs), such as nAChRs and the 5-HT3R.58 These receptors



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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 Photoaffinity 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. Owing to 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 due to 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 furthered 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 which 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 due to their easily quantifiable morphological index, this principle could be applied to other lipid bilayers due to their universally anionic inner leaflets.


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Figure 2: Structural similarities between DA and CPZ. An early overlay study by Horn and Snyder 52 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



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Adverse Effects CPZ is an antipsychotic medication that works at all levels of the central nervous system, 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. Orthostatic 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 occur when D2Rs are highly occupied, resulting most often in acute dystonic reactions or tardive dyskinesia.42 These are usually seen when 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 were initially thought to be indicators 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 less than 600 mg/day reduced the risk of the onset of EPS to levels equivalent with 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: 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


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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 are 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 properties, but research on known phenothiazines was halted due to 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 Concurrently, 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 surgery77 consistent with the reported use of promethazine as a sedative to calm patients with manic depression.78 At Rhône-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. Based on 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. Based on such observations, Laborit predicted the implication of these agents in treating psychiatric disorders.81 Pharmacodynamic and pharmacokinetic studies showed that CPZ possessed a broad



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range of pharmaceutical activities including, but not limited to, antipyretic, anticonvulsant, adrenolytic, antiemetic, and antifibrillatory.80 Based on this wide range of pharmacological activity, CPZ was commercialized in 1952 in France by Rhône-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 three-week period, 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 significantly higher dose than Laborit reported was necessary to achieve these effects when CPZ was administered alone.85 Based on the observed effects, Delay proposed the term neuroleptic to classify CPZ and any agent producing a similar slowing in motor activity.86 The use of CPZ in psychiatry spread quickly through Europe to the Psychiatrische Universitätsklinik in Switzerland where Felix Labhardt published 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 The Elkes’ study was blind and self-controlled and notably introduced randomized trials and placebo-controlled research methodology into psychiatry.73,82,90 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 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 which 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 US and brought CPZ to market in 1954 under the name Thorazine®. Originally approved by the US Food and Drug Administration (FDA) as an antiemetic, CPZ was first used in the US as a hypothermic agent during surgery rather than in psychiatric use;73,91 however, in 1953, Frank Ayd (Baltimore) had become the first ACS Paragon Plus Environment

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psychiatrist authorized by the FDA to study CPZ. Nevertheless, in 1954, N. William Winkelman (Philadelphia) and Willis H. Bower (Boston) independently published 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 months5 resulting in 75 million dollars in gross sales for Smith Kline & French in 1955.73 Agranulocytosis98, liver toxicity, and EPS were observed and reported, but the neuroleptic effect of CPZ was determined to outweigh the risks for most patients.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 optimum;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 retrospect93 and, while the Elkes’ contribution to the development of these methods was significant73,82,90,112 the Elkes’ study reported the effect of CPZ in a number of psychotic conditions which included only 13 patients with schizophrenia.89 The first large-scale controlled studies of CPZ in schizophrenic patients were conducted in numerous US Veterans Administration (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, cross-over study that lasted 24 weeks in total and found the efficacy of CPZ was significantly greater than 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 ACS Paragon Plus Environment


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to those newly admitted with no hospitalization in the prior 12 months and utilizing mixed-gender groups for each treatment at each of the 9 collaborating hospitals. The therapeutic efficacy of thioridazine and fluphenazine were 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 on 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 catecholamines117 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 CPZ blockade of dopamine receptors was reported in the mid-1970s124-126 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 integrated into society and normalized mental health care within communities.6,7,10,131 In the US, with the help of federal funding of deinstitutionalization,132 it is estimated that the number of institutionalized patients declined from more than 500,000 in the mid- 1950s to 60,000 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


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same year with the Nobel Prize in Medicine for his contributions to the synthesis of antihistamines135 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 psychopharmacology90,93,112,136,137 including the development of standardized screening methods and protocols for large-scale, multi-hospital double-blind controlled tests which 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-Psychopharmacologicum (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, chlorpromazine 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 to test the clinical efficacy of new antipsychotic agents143 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 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.



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Author Contributions K.G. wrote the section on drug metabolism and pharmacokinetics, B. L. wrote the section on chemical synthesis, T. M. wrote the section on structure activity relationships, N.S. wrote the section on pharmacology and 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.

Conflict of Interest The authors report no conflict of interest.

Funding Sources The authors have no funding sources to declare.


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Journal: ACS Chemical Neuroscience Manuscript ID: cn-2018-002588 Title: "Classics in Chemical Neuroscience: Chlorpromazine" Author(s): Boyd-Kimball, Debra; Gonczy, Katelyn; Lewis, Benjamin ; Mason, Thomas ; Siliko, Nicole; Wolfe, Jacob


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Classics in Chemical Neuroscience: Chlorpromazine - ACS Publications

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