Classics in Chemical Neuroscience: Haloperidol - ACS Publications

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Classics in Chemical Neuroscience: Haloperidol Marshall Wells Tyler, Josefa Zaldivar-Diez, and Stephen J. Haggarty ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.7b00018 • Publication Date (Web): 07 Feb 2017 Downloaded from http://pubs.acs.org on February 9, 2017

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ACS Chemical Neuroscience

Classics in Chemical Neuroscience: Haloperidol † †,§ † Marshall W. Tyler, Josefa Zaldivar-Diez, and Stephen J. Haggarty †

Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Chemical Biology Program, Boston, Massachusetts 02114, United States §Centro de Investigaciones Biológicas-CSIC, Madrid, 28040, Spain

ABSTRACT: The discovery of haloperidol catalyzed a breakthrough in our understanding of the biochemical basis of schizophrenia, improved the treatment of psychosis, and facilitated deinstitutionalization. In doing so, it solidified the role for chemical neuroscience as a means to elucidate the molecular underpinnings of complex neuropsychiatric disorders. In this Review, we will cover aspects of haloperidol’s synthesis, manufacturing, metabolism, pharmacology, approved and off-label indications, and adverse effects. We will also convey the fascinating history of this classic molecule and the influence that it has had on the evolution of neuropsychopharmacology and neuroscience.

KEYWORDS: haloperidol, antipsychotic, schizophrenia, dopamine, pharmacology, history

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INTRODUCTION Schizophrenia (MIM 181500), a complex and debilitating neuropsychiatric disorder, places an enormous burden on affected individuals, families, and society as a whole.1 In the late 1900s, physicians divided symptoms into two categories: positive symptoms (hallucinations, delusions, disorganized thoughts, and disordered movement) and negative symptoms (blunting of affect, reduced pleasure, social withdrawal, and cognitive deficits).2 A push towards standardized evaluation methods for the assessment of novel drugs intended to treat the cognitive deficits of schizophrenia led to the characterization of a new category: cognitive symptoms (deficits in working memory, verbal learning and memory, visual learning and memory, verbal comprehension, attention, processing speed, problem solving, and social cognition).3 Schizophrenia is most commonly diagnosed in young adulthood with symptoms appearing, on average, slightly later in women than in men.4-7 The worldwide prevalence of schizophrenia, while difficult to quantitate, is likely around 1%,8 and nearly 5% of people with the disorder will commit suicide.9 Compared to the general population, adults with schizophrenia are 3.6 times more likely to die of cardiovascular disease and 2.4 times more likely to die of lung cancer.10 Accordingly, the average life expectancy for someone living with schizophrenia is reduced by about 20 years.11 Despite advances in treatment, the mortality gap between people with schizophrenia and the general population appears to be worsening.12 Schizophrenia has been recognized as one of the leading causes of disability worldwide13 with an annual financial burden in the tens to hundreds of billions of dollars14 and countless intangible costs such as caregiver burden.15 Individuals affected with schizophrenia are often subject to stigmatization and discrimination,16 an unfortunate fact that has held true throughout history. In the 1800s and early 1900s, asylums were at the forefront of psychiatric treatment.17 These institutions effectively achieved total isolation of patients with severe mental illness from the rest of society. During World War II, more than 200,000 people with the disorder were either sterilized or killed,18 which stemmed in part from the view that medical treatment for these individuals was futile.19 Indeed, prior to the 1950s, care for patients with schizophrenia was primitive and often nonexistent; electroconvulsive therapy and institutionalization were the norm.20 Drugs to treat schizophrenia, known as antipsychotics, emerged in the middle of the 20th century. The synthesis of chlorpromazine (1), a phenothiazine-containing small molecule, in 1952 marked an enormous achievement for psychopharmacology. The drug’s antipsychotic potential was realized almost immediately, and it quickly became a first line treatment for the positive symptoms of schizophrenia.21 The introduction of haloperidol (2) at the end of the same decade22 brought about a new antipsychotic scaffold: the butyrophenone. Haloperidol and chlorpromazine (Figure 1) are now considered typical or first-generation antipsychotics and are no longer frequently prescribed for the treatment of schizophrenia. They have largely given way to the atypical or second generation antipsychotics such as risperidone, quetiapine, paliperidone, olanzapine, and clozapine.23 At the time of its serendipitous discovery, however, haloperidol was a considerable advancement in the realm of neuropsychopharmacology. Not only was it a much more potent drug than its predecessor, but it also produced less anticholinergic side effects (i.e. constipation, blurred vision, urinary retention, dry mouth, and cognitive impairment).24 In the two decades following its introduction to the clinic, haloperidol stimulated a plethora of chemical neurobiology research. Through pioneering work at the University of Toronto by the Seeman Laboratory, after a long-sought-after search,25 it was determined that the


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therapeutic effect of haloperidol and other antipsychotic drugs was a direct result of their antagonism of what is now known as the dopamine D2 receptor encoded by the DRD2 gene (UniProt ID P14416).26-28 Two key pharmacological criteria guiding the search for this receptor were the requirement that: 1) a relevant target site be sensitive to the ~2 nM range of haloperidol and 20 nM chlorpromazine estimated to exist in the cerebrospinal fluid of schizophrenia patients; and 2) there was competitive binding in a stereoselective manner with the antipsychotic drug (+)butaclamol, a molecule also know to have antipsychotic properties but distinct in structure. Following the first report that 8 different antipsychotics antagonized the receptor with affinities highly correlated to their relative clinical potencies as anyipsychotics,26, 27 an expanded study with additional antipsychotics solidified a landmark finding for the fields of psychopharmacology and neuroscience as a whole.28 These discoveries around the affinity of antipsychotics toward the dopamine D2 receptor provided clear support for the dopamine hypothesis of schizophrenia most clearly articulated in 1966 by Jacques Van Rossum: “When the hypothesis of dopamine blockade by neuroleptic agents can be further substantiated,” he wrote, “it may have fargoing consequences for the pathophysiology of schizophrenia. Overstimulation of dopamine receptors could then be part of the aetiology.”29, 30 Prior to this time, as summarized by Baumeister & Francis (2001)31 and Seeman (1987),25 there was only indirect evidence for dopamine dysregulation in schizophrenia. Thus, these ground-breaking studies driven by the desire to understand precisely the therapeutically relevant targets of haloperidol and other antipsychotics laid the conceptual foundation for the strategy of using advances in chemical probe development, biochemistry, and clinical experiments to understand the biological basis of schizophrenia. The field of chemical neuroscience continues to build upon the legacy of these efforts by advancing strategies to probe the biological basis of complex neuropsychiatric disorders and to develop next-generation treatments. In this Review, we will attempt to synthesize some of the diverse literature on haloperidol in an effort to describe basic properties of the drug and the fundamental role it has played in the progression of neuropsychopharmacology and neuroscience. CHEMICAL SYNTHESIS Haloperidol is a butyrophenone with a hydroxyl group that serves as both a hydrogen bond donor and acceptor. The ketone oxygen and the piperidine nitrogen represent two additional hydrogen bond acceptors. It has a molecular weight of 375.14 and a cLogP of 3.49. Together, these properties follow Lipinski’s rules32 and are consistent with haloperidol’s high biological activity in humans. The first synthesis of haloperidol was achieved in the late 1950s by Dr. Paul Janssen’s laboratory. His group had been working with substituted piperidines at Janssen Pharmaceutica, a Beligian company he founded in 1953. At the time, they were particularly interested in pethidine (also known as meperidine) (3), an N-methyl substituted piperidine with morphine-like properties. They sought to improve the clinical efficacy by replacing the methyl group with another moiety. Intriguingly, substituting the methyl with a propiophenone to obtain 4 increased the analgesic potency of meperidine by two orders of magnitude, perhaps owing to enhanced lipophilicity. However, when the length of the alkyl chain was increased by a single carbon to produce the butyrophenone-substituted piperidine 5, the researchers observed a dramatic decrease in the compound’s analgesic properties (Figure 2). The new molecule had a calming effect, mimicking the antipsychotic properties of chlorpromazine. The morphine derivative



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nalorphine was unable to antagonize these effects, further distinguishing haloperidol’s activity from that of pethidine. In an effort to optimize the pharmacological properties of this novel series, the chemists synthesized over 500 derivatives.33, 34 The synthesis of these molecules was achieved by separately constructing the benzophenone and piperidine components followed by a fusion of the two in a simple substitution reaction. In the case of haloperidol, 4-chloro-4′-fluorobutyrophenone was synthesized in a Friedel-Crafts reaction of fluorobenzene (6) and 4-chlorobutyrylchloride (7) to give 4-chloro-1-(4-fluorophenyl)butan-1-one (8). The piperidine was made from the reaction of 4-chloro-α-methylstyrene (9) with formaldehyde and ammonium chloride. The resulting 6-(4chlorophenyl)-6-methyl-6H-1,3-oxazine (10) was converted with excess hydrochloric acid to 4(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (11). The addition of hydrobromic acid gave 4bromo-4-(4-chlorophenyl)piperidine (12) which was then hydrolyzed in water to produce 4-(4chlorophenyl)piperidin-4-ol (13). Finally, 13 and 8 were fused together to form 4(4-(4chlorophenyl)-4-hydroxypiperidin-1-yl)-1-(4-fluorophenyl)butan-1-one (2), also known as haloperidol, via a substitution reaction in a solution of potassium iodide and toluene (Scheme 1).22 Haloperidol decanoate, a haloperidol prodrug which has the purported benefit of slow release of the active drug for a prolonged therapeutic effect,35 can be synthesized in a substitution reaction of haloperidol and decanoyl chloride wherein the hydroxyl group behaves as a nucleophile.36 MANUFACTURING INFORMATION Haloperidol (trade name HaldolTM) can be taken orally (haloperidol tablet or haloperidol lactate liquid), intravenously (haloperidol lactate), or as a long-acting intramuscular injection (haloperidol decanoate). The drug is manufactured by Janssen Pharmaceuticals, Inc., a subsidiary of Johnson & Johnson.37 Haloperidol was first synthesized in February of 1958, and it underwent clinical trials in the same year at the University of Liège for the treatment of psychiatric disorders including paranoid psychosis, mania, and schizophrenia.34 It entered the Belgian market by the end of 1959.34 Janssen Pharmaceuticals obtained a United States patent for haloperidol in 1969, and the drug became widely used in North America thereafter.38 Tablets come in 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, and 20 mg doses, while the injectable forms come in 5 mg/mL for the short acting haloperidol lactate and 50 mg/mL or 100 mg/mL for the long acting haloperidol decanoate.39, 40 The oral haloperidol lactate liquid comes in a 2 mg/mL solution.39 Now manufactured by more than 40 different companies, generic haloperidol is inexpensive, costing around $5 annually for the oral medication and $340 for the injectable haloperidol decanoate formulation.41 Of the typical antipsychotics, haloperidol is the most widely prescribed with over 2.48 million prescriptions written in 2008.42 Haloperidol only recently lost its place as one of the most frequently prescribed drugs for the treatment of chronic schizophrenia,23, 43 and it remains a first line antipsychotic for acute agitation.44 METABOLISM Haloperidol is highly CNS permeable45 with a moderate oral bioavailability (F = 0.6).46, 47 It displays a plasma protein binding of approximately 92% (FU = 0.08) with a plasma half-life of 14 hours following intravenous (IV) administration and 24 hours following oral administration.48, 49 Intramuscular (IM) injection produces a half-life of approximately 21 hours.50 The maximum concentration (Cmax) following oral or intramuscular injection is ~1-2 ng/mL.51 Levels of


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haloperidol in the brain vary with treatment duration and dose,52 with a concentration slightly higher than 300 ng/g in rats,53 and a brain to plasma ratio of around 20.53, 54 Addition of a decanoic acid moiety to haloperidol results in the inactive drug haloperidol decanoate. Enzymatic hydrolysis of haloperidol decanoate to haloperidol is slowly accomplished by esterases.55 This transformation activates the drug over a prolonged period of time following IM injection, resulting in an extended therapeutic effect. The half-life of haloperidol decanoate is approximately 3 weeks, and peak plasma concentration is generally achieved within 7 days.56, 57 Steady state serum concentrations range from 3-4 ng/mL.58, 59 Haloperidol undergoes extensive hepatic metabolism with only ~1% of the administered dose detectable in urine.49 Smoking, an especially common behavior among patients with schizophrenia,60 causes a 44% increase in haloperidol clearance and decreases serum concentrations by 70%.61 At least 9 metabolites 14-22 have been identified or theorized (Figure 3). The majority of the parent compound appears to be metabolized to haloperidol glucuronide (14).62 N-dealkylation to fluorobenzoylpropionic acid (FBPA, 15) and 4-(4-chlorophenyl)-4hydroxypiperidine (CPHP, 16) and carbonyl reduction to reduced haloperidol (17) have also been observed,63, 64 albeit to a much lesser extent than glucuronidation. The reduced form of haloperidol can undergo N-dealkylation to 16 and 4-(p-fluorophenyl)-4-hydroxybutyric acid (FBHP, 18). Haloperidol has been shown to undergo pyridinium formation to HPP+ (19) presumably following dehydration to haloperidol tetrahydropyridine HPTP (20),63, 65 both of which can be further modified by a carbonyl reductase to 21 and 22 respectively.66 The tetrahydropyridine metabolites preceding pyridinium formation (i.e. 20 and 22) have not been detected in vivo, suggesting that these molecules are likely either insignificant intermediates or transient compounds that are not released into circulation at detectable levels.67 Many of the enzymes responsible for haloperidol metabolism have been identified. The UDP-glucuronosyltransferases (UGTs) that catalyze the conversion of haloperidol to 14 include UGT1A4, UGT1A9, and UGT2B7.68 UGT1A4 can also catalyze the N-glucuronidation of haloperidol to form a minor metabolite.68 Cytochrome P450 (CYP) 3A4 has been implicated in the oxidation of 17 to regenerate haloperidol.69 CYP3A4 and to a lesser extent CYP2D6 are involved in N-dealkylation and pyridinium formation of both 2 and 17.70 Serum concentrations of 2 and 17 vary based on CYP2D6 gene expression, and therapeutic efficacy is lessened in individuals with a greater number of active CYP2D6 genes.71 Some evidence for involvement of CYP1A2 comes from the observation that fluvoxamine, a potent inhibitor of CYP1A2, dramatically increases serum concentrations of haloperidol.72, 73 However, the conversions catalyzed by CYP1A2 as well as the relative contribution to metabolic transformation are not well understood. The aforementioned metabolites demonstrate a diverse range of biological effects. Higher concentrations of 17 the may be associated with greater prevalence of extrapyramidal symptoms.74 The pyridinium (19 and 21) and tetrahydropyridine (20) metabolites inhibit presynaptic reuptake of dopamine and serotonin in mouse synaptosome preparations.75 19 and 20 are also capable of increasing dopamine and serotonin release.75 19 has been shown to be neurotoxic and potentially causative for the tardive dyskinesia that can result from chronic haloperidol treatment.76, 77 17, 19, and 22 are all fairly potent inhibitors of CYP2D6, although the clinical relevance of this inhibition has not yet been thoroughly explored.62 17 has also been shown to block σ1 receptors,78, 79 an effect with an unknown influence on efficacy and adverse effects.



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PHARMACOLOGY Haloperidol, unlike many of the atypical antipsychotics, has a narrow spectrum of cellular targets (Table 1). It is most well-known for its high-affinity antagonism of dopamine D2 receptors80 (Ki = 2 nM), with additional antagonist activity at 5-HT2A receptors (Ki = 73 nM), α1A receptors (Ki = 12 nM), and α1B receptors (Ki = 12 nM). Whereas atypical antipsychotics such as clozapine antagonize both 5-HT2A serotonin receptors and D2 receptors, haloperidol is highly selective for the latter.81 D2 receptor occupancy following a twice daily dose of only 4 mg in patients with schizophrenia is 84%,82 while a mere 2 mg per day over the course of two weeks results in a comparably high occupancy (53-74%).83 Haloperidol also has an approximately 100 fold higher affinity for the D2 receptor compared to clozapine (Ki = 150nM),84 and it binds with an 80 fold greater half-life (40 minutes vs. 0.5 minutes).85 This high residence time compared to clozapine and other atypical antipsychotic drugs may account for the extrapyramidal symptoms that are commonly seen with typical antipsychotics such as haloperidol.86 Compared to other antipsychotic drugs, haloperidol has virtually no affinity for muscarinic receptors.87 While haloperidol has nanomolar affinity for dopamine D3 (Ki = 12 nM) and D4 (Ki = 15 nM), the physiological effect of antagonizing these dopamine receptors is not well understood. As previously mentioned, the reduced haloperidol metabolite blocks σ1 receptors (Ki = 3 nM),78, 79 an action that may potentiate the analgesic effects of opioids.88 Beyond discrepancies in D2 affinity and residence time, antipsychotic drugs also appear to differ in their capacity to antagonize the D2 receptor-coupled Gi/o signaling pathway that is responsible for inhibiting cyclic adenosine monophosphate (cAMP) production. On the other hand, an alternative, G-protein independent pathway involving β-arrestin mediated AKT/Glycogen Synthase Kinase 3 (GSK3) signaling can also be inhibited by antipsychotic drugs.89 The discovery that D2 ligands express differential antagonism/agonism of these two pathways has inspired a new generation of biased molecules that may improve antipsychotic efficacy while minimizing adverse motor side effects.90, 91 Unlike other antipsychotics such as quetiapine and clozapine, haloperidol shows minimal bias towards either pathway, antagonizing both Gi/o and β-arrestin signaling at concentrations of less than 1 nM.89 At the level of neurocircutry, haloperidol acts as a dopaminergic antagonist in the basal ganglia, and thalamocortical changes are thought to be secondary to the drug’s action at this brain region.92 This regional specificity is not surprising given the particularly high concentrations of D2 receptors in the basal ganglia.93 The antipsychotic actions of haloperidol may be explained by antagonism of these receptors in the mesolimbic pathway.94 Conversely, the drug’s action at the nigrostriatal pathway may elicit the extrapyramidal symptoms discussed below, and chronic haloperidol treatment increases dopamine receptor binding sites in the striatum.95 APPROVED AND OFF-LABEL INDICATIONS Haloperidol is approved to treat schizophrenia and to control the tics and vocal utterances associated with Tourette’s syndrome.40 Haloperidol can also be used to treat behavioral disorders and hyperactivity, and it is sometimes used off-label for nausea and vomiting (from chemotherapy, advanced or terminal illness, and surgery), chorea (jerky, involuntary movements) associated with Huntington disease, treatment and prevention of delirium in the intensive care unit, obsessive-compulsive disorder (OCD), phencyclidine-induced psychosis, psychosis/agitation associated with dementia, and rapid control of agitation, aggression, and violent behavior.96 Typical antipsychotics such as haloperidol are also used off-label and


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generally in conjunction with other agents to manage the symptoms of bipolar affective disorder, depression, anxiety, and attention deficit hyperactivity disorder (ADHD).42 ADVERSE EFFECTS Incidents of QT interval prolongation, torsades de pointes (TdP), and sudden death have been reported with haloperidol.40 TdP, a type of abnormal heart rhythm, represents a serious and potentially fatal condition. Patients with long QT intervals have an increased risk of TdP, and intravenous haloperidol is contraindicated in these individuals.97, 98 More commonly reported contraindications include hypersensitivity to haloperidol, Parkinson’s disease, severe central nervous system depression, and coma.40 Haloperidol may induce dysphoria,99 a condition defined by a profound sense of dissatisfaction, distress, and general uneasiness. Nearly 50% of patients receiving haloperidol for schizophrenia will experience extrapyramidal symptoms (EPS), including dystonia (twisting, repetitive muscle contractions), parkinsonism (slowness of movements, tremor, and muscle stiffness), akathisia (restlessness), and dyskinesia (involuntary movements).100 These symptoms can sometimes be controlled by anticholinergic medications,101103 a finding that reflects a delicate dopamine-acetylcholine balance underlying motor functions. A rare but serious side effect of antipsychotic exposure is neuroleptic malignant syndrome (NMS), a reaction characterized by muscle rigidity, fever, changes in mental status, and autonomic dysfunction.104-106 NMS occurs in around 0.02% of patients treated with antipsychotic drugs,107 though the specific incidence of NMS in patients treated with haloperidol is unclear. Due to its low affinity for muscarinic receptors, haloperidol does not tend to induce the anticholinergic effects seen with other antipsychotics such as clozapine, thioridazine, olanzapine, and chlorpromazine.108 It can, however, increase prolactin levels (hyperprolactinemia), though the observed elevation is fairly mild compared to many other antipsychotic medications.109, 110 Further distinguishing it from other antipsychotics, haloperidol has minimal effects on weight gain in most patients.111 The relative lack of polypharmacology exhibited by haloperidol compared to the atypical antipsychotics may explain this discrepancy.112 In particular, haloperidol has a lower affinity for the H1 receptor, a distinguishing feature that seems to confer a smaller liability for adverse metabolic side effects.113, 114 Despite the positive aspects of haloperidol, the high incidence of EPS has prompted a shift toward atypical antipsychotic medications in the treatment of schizophrenia. HISTORY AND IMPORTANCE IN NEUROSCIENCE President John F. Kennedy passed legislation in 1963 aimed at replacing the institutionalization of mentally ill patients with a treatment-based approach. He noted that of the 530,000 patients in state mental hospitals at the time, over half of them resided in overcrowded and understaffed institutions that rendered individual care virtually impossible. His principal goal was clear: “we must seek out the causes of mental illness and of mental retardation and eradicate them.” He believed that advances in treatments for disorders such as schizophrenia made it possible for affected individuals to reassume “a useful place in society” if they were given adequate resources.115 Among those treatments, haloperidol has played the dual role of contributing to the deinstitutionalization of mental health patients and providing a mechanistic elucidation of psychiatric illness. Initial clinical trials of haloperidol examined the drug’s efficacy for patients presenting with severe psychomotor agitation.116 Patients were given a single 2 to 5 mg dose of haloperidol. The unintentional and uncontrollable movements ceased within minutes, and sedation lasted for



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hours. Further clinical trials pointed to a beneficial effect on the positive symptoms of schizophrenia.117-119 Some of these early results were presented at the 1959 International Symposium on Haloperidol in Beerse, Belgium, where psychiatrists noted haloperidol’s unparalleled ability to prevent hallucinations.120 Beyond hallucinations, mania, delusions, and aggression were among the symptoms that could be readily controlled by a low daily dose (1-15 mg) of the drug.121 The promising results of these early clinical trials prompted an almost immediate adoption of haloperidol into European clinical practice. The United States, in contrast, was slower to adopt this new antipsychotic drug.34 However, by the end of the 1960s, haloperidol became widely used. Its predecessor chlorpromazine has a much higher affinity for muscarinic receptors, rendering it more likely to cause anticholinergic side effects.24 Chlorproamzine also requires 25 times the dose of haloperidol (100 mg vs. 4 mg) to achieve similar occupancy of dopamine receptors (~80%).82 Finally, chlorpromazine is significantly more likely to cause hypotonia.122 Together, these observations suggest that haloperidol was a powerful new antipsychotic drug with concrete benefits over chlorpromazine. Unfortunately, the incidence of EPS is much higher in patients treated with haloperidol. However, its favorable properties were sufficient to place haloperidol at the vanguard of clinicians’ antipsychotic arsenal at the time. Haloperidol’s introduction to the clinic preceded an understanding of the biological mechanisms underlying its therapeutic effect.25, 31, 80 In 1957, the effects of reserpine, a natural product with antipsychotic and antihypertensive properties, were shown to be antagonized by the dopamine precursor L-DOPA.123 Then, in 1963, researchers at the University of Göteborg in Sweden noticed that mice treated with haloperidol or chlorpromazine had increased levels of 3methoxytyramine and normetanephrine,124 both of which are metabolites of dopamine. They hypothesized that blockade of monoamine receptors by these drugs resulted in a compensatory increase in the production of endogenous agonists (i.e. dopamine and norepinephrine). Three years later in 1966, the first clear articulation of the dopamine hypothesis of schizophrenia was put forth.29 It was noted that patients who experience a loss of dopaminergic neurons in the substantia nigra and develop Parkinson’s disease are not affected by schizophrenia (although this has since been disputed), and that drugs such as amphetamines that elevate dopamine levels can aggravate psychosis. Based on this evidence and the discovery of the effects of antipsychotic drugs on monoamine concentrations, Dr. Jacques Van Rossum at Radboud University in the Netherlands proposed that overstimulation of dopamine receptors might underlie the pathophysiology of schizophrenia.29 Despite an accumulating body of data supporting the dopamine hypothesis of schizophrenia, evidence for direct interactions between antipsychotic drugs such as haloperidol and dopamine receptors was lacking. This changed in the mid-1970s when pioneering efforts by the Seeman group and others used in vitro radiolabeling experiments to confirm dopamine receptor binding of phenothiazine and butyrophenone antipsychotic drugs.26-28, 125-128 The observation that dopaminergic antagonism is responsible for the therapeutic effects of antipsychotic drugs provided strong evidence for a biological basis of schizophrenia. In the years following its emergence, the dopamine hypothesis of schizophrenia has been challenged, and much of the focus has shifted towards a study of mechanisms upstream of dopaminergic dysregulation.129 Some evidence seems to support an alternative NMDA hypofunction hypothesis.130-132 Additionally, most antipsychotic drugs only treat the positive symptoms of schizophrenia with little to no effect on the negative symptoms. Thus, mesolimbic and mesocortical dopamine dysregulation may underlie specific components of the disorder,


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while the full clinical presentation may rely on involvement of other brain regions and/or neurotransmitter systems. Finally, atypical antipsychotic drugs tend to have weaker D2 binding properties than typical antipsychotics, and their polypharmacological nature calls into question a dopamine-centric view of schizophrenia. Clozapine, an atypical antipsychotic that is perhaps the most clinically effective, is also among the most promiscuous with Ki values of less than 500 nanomolar for over 20 different receptors.133 This observation suggests that the modulation of multiple neurotransmitter pathways may be beneficial and perhaps even essential to the development of effective antipsychotics.134 While rational design of a drug that modulates activity at multiple receptors is inherently difficult, recent efforts to achieve multi-target engagement have been met with some success in other areas of medicine.135 However, polypharmacology of a poorly understood nature as is the case for many antipsychotics is clinically associated with a plethora of adverse effects, including weight gain, hyperglycemia, and anticholinergic symptoms. Ultimately, given the etiological and pathophysiological complexity of schizophrenia, either an improved version of a single, clozapine-like molecule optimized for desired multi-target engagement, or co-administration of multiple, highly selective molecules targeting different underlying molecular mechanisms, is likely to be necessary for the development of next-generation, disease-modifying therapies that improve the treatment outcomes of drugs like haloperidol and clozapine. The complex etiology of schizophrenia has expanded the search for novel antipsychotics far beyond D2 antagonists. Still, early drugs such as haloperidol, a molecule that has benefited millions of patients, represent a tremendous success for neuropsychiatric disorders. In fact, analyses comparing antipsychotic drug efficacies as schizophrenia treatments have determined that many atypical antipsychotics, while producing less EPS, perform no better in measures of efficacy or tolerability when compared to haloperidol.136, 137 Beyond its success in the clinic, haloperidol has fostered the creation of novel experimental techniques to predict antipsychotic efficacy. The discovery of its mechanism of action has given substantial credence to the notion of targeted neuropsychopharmacology. Haloperidol fueled a momentous change in society’s understanding and conception of neuropsychiatric disorders, helping to encourage the deinstitutionalization of mentally ill patients. For the lives it has improved, conversations it has stimulated, and scientific inquiry it has inspired, haloperidol is a prime example of a classic in chemical neuroscience. Remarkably, over half a century after the discovery of haloperidol and related D2 receptor antagonists as antipsychotics, recent large-scale, genome-wide association studies (GWAS) aimed at identifying genetic variation associated with risk for schizophrenia have identified single nucleotide polymorphisms (SNPs) within the genetic locus (DRD2) encoding the D2 receptor as a susceptibility factor.138 While the precise nature of how these SNPs in the DRD2 gene impact the function of the D2 receptor (or potentially other genetic factors that are being affected by the SNPs) currently remains unknown, and the odds ratio (a measure of effect size) is low, the pharmacology of haloperidol and other antipsychotics predicts that the genetic association is driven by elevated D2 receptor activity. As the sample size of these studies grows to include hundreds of thousands of samples with eventual whole-genome coverage rather than exome or SNP profiles, such “experiments of nature” may provide insight into how genetic variation determines individual response to haloperidol that has been observed over the half century of its clinical use.139 Furthermore, one could speculate that these genomic studies may lead to the discovery of additional components of the D2 receptor complexes and downstream signaling pathways that may become important drug targets themselves.89, 90, 140 Most



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optimistically, beyond the D2 receptor, these genomic studies provide an exciting new opportunity for the field of chemical neuroscience to consider the use of human genetics to advance the discovery of next-generation therapeutics for schizophrenia in a manner informed by an understanding of the root cause of disease.

AUTHOR INFORMATION Corresponding Authors *E-mail: M.W.T. ([email protected]); S.J.H. ([email protected]) Notes The authors declare no competing financial interests. Dr. Haggarty serves on the scientific advisory board of Rodin Therapeutics, Frequency Therapeutics, and Psy Therapeutics. Author Contributions M.W.T and J.Z. wrote the paper. S.J.H. contributed passages to various sections, provided input to M.W.T. and J.Z. throughout, and edited the final manuscript. REFERENCES [1] For up-to date information on schizophrenia from the National Institute of Mental Health, see https://www.nimh.nih.gov/health/topics/schizophrenia. [2] Kay, S. R., Fiszbein, A., and Opler, L. A. (1987) The positive and negative syndrome scale (PANSS) for schizophrenia, Schizophr Bull 13, 261-276. [3] Nuechterlein, K. H., Barch, D. M., Gold, J. M., Goldberg, T. E., Green, M. F., and Heaton, R. K. (2004) Identification of separable cognitive factors in schizophrenia, Schizophr Res 72, 29-39. [4] Loranger, A. W. (1984) Sex difference in age at onset of schizophrenia, Arch Gen Psychiatry 41, 157-161. [5] Hafner, H., Maurer, K., Loffler, W., Fatkenheuer, B., an der Heiden, W., Riecher-Rossler, A., Behrens, S., and Gattaz, W. F. (1994) The epidemiology of early schizophrenia. Influence of age and gender on onset and early course, Br J Psychiatry Suppl, 29-38. [6] Stromgren, E. (1987) Changes in the incidence of schizophrenia?, Br J Psychiatry 150, 1-7. [7] Takahashi, S., Matsuura, M., Tanabe, E., Yara, K., Nonaka, K., Fukura, Y., Kikuchi, M., and Kojima, T. (2000) Age at onset of schizophrenia: gender differences and influence of temporal socioeconomic change, Psychiatry Clin Neurosci 54, 153-156. [8] Perala, J., Suvisaari, J., Saarni, S. I., Kuoppasalmi, K., Isometsa, E., Pirkola, S., Partonen, T., Tuulio-Henriksson, A., Hintikka, J., Kieseppa, T., Harkanen, T., Koskinen, S., and Lonnqvist, J. (2007) Lifetime prevalence of psychotic and bipolar I disorders in a general population, Arch Gen Psychiatry 64, 19-28. [9] Palmer, B. A., Pankratz, V. S., and Bostwick, J. M. (2005) The lifetime risk of suicide in schizophrenia: a reexamination, Arch Gen Psychiatry 62, 247-253. [10] Walker, E. R., McGee, R. E., and Druss, B. G. (2015) Mortality in mental disorders and global disease burden implications: a systematic review and meta-analysis, JAMA Psychiatry 72, 334-341.


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Figure 1. The first two typical antipsychotic drugs used to treat schizophrenia. Structures of chlorpromazine (1) and haloperidol (2). Figure 1 34x11mm (600 x 600 DPI)



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Figure 2. Substituted piperidines leading to the synthesis of haloperidol. Structures of pethidine (3) and the corresponding propiophenone (4) and butyrophenone (5). Figure 2 34x7mm (600 x 600 DPI)


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Scheme 1: Original Synthesis of Haloperidol by Janssen Pharmaceutica in 1958 Scheme 1 104x55mm (600 x 600 DPI)



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Figure 3. Structures of metabolites of haloperidol (2). 120x64mm (600 x 600 DPI)


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Table 1. Pharmacological profile of haloperidola Target Receptor

Ki (nM)

D 1 D

83 2

D 3 D 4 D 5 5-HT

12 15 147 1202

2

1A

5-HT 1B 5-HT

165 7606

5-HT

>10000

1D

5-HT 5-HT

1E 2A 2C

73 >10000

5-HT 3 5-HT

>10000 2247

5-HT

3666

5

5-HT

6 7

α1A α1B α2A α2B α2C β1 β2 Ca2+ Channel CB1 M 1 M 2 M 3 M 4 M 5 nAChRs GABAA GABAB NMDAR H 1 H 2 H 3 H 4 I 1 PTGER3 PTGER4 VPR3 SERT NET DAT

378 12 8 1130 480 550 >10000 >10000 998 >10000 >10000 >10000 >10000 >10000 657 >10000 >10000 >10000 >10000 3002 1003 >10000 >10000 >10000 >10000 >10000 >10000 3256 2112 >10000

a

Ki values as determined by the NIMH Psychoactive Drug Screening Program. https://pdspdb.unc.edu/pdspWeb/ (accessed January 5, 2017).



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33x17mm (600 x 600 DPI)


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Classics in Chemical Neuroscience: Haloperidol - ACS Publications

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