42 Antipsychotic Drugs Oliver Freudenreich, MD, Donald C. Goff, MD, and David C. Henderson, MD KEY POINTS • All antipsychotics share dopamine2 blockade as the second-generation antipsychotics, metabolic problems presumed main mechanism of action. (e.g., weight gain, dyslipidemia, hyperglycemia) have • Primary symptom targets of antipsychotics are positive emerged as major problems. symptoms (disorganization, delusions, and • First- and second-generation antipsychotics are equally hallucinations) and agitation; their efficacy for negative effective for non-refractory patients with schizophrenia. symptoms and cognitive deficits of schizophrenia is For refractory patients, olanzapine, and in particular questionable. Increasingly, antipsychotics are used for clozapine, have been the most efficacious. treatment of mood disorders. • Clozapine has minimal or no risk of inducing EPS and • Historically, antipsychotics have been grouped is the most effective antipsychotic. However, its clinical into first-generation antipsychotics (typical or use is limited to refractory patients because of serious conventional antipsychotics, which are all characterized side effects (including metabolic problems and by their risk of extrapyramidal symptoms [EPS]) and agranulocytosis that requires white blood cell count second-generation antipsychotics (with a reduced risk of monitoring). EPS; hence they are called “atypical” antipsychotics). • Currently available antipsychotics have variable efficacy However, antipsychotics within each class are not and tolerability and need to be selected on the basis of necessarily interchangeable. individualized risk–benefit assessments (i.e., balancing • The main risks of first-generation antipsychotics are the degree of symptomatic response with day-to-day neurological side effects (e.g., dystonias, akathisia, tolerability and long-term medical morbidity, parkinsonism, tardive dyskinesia [TD]); for most particularly cardiovascular risk). INTRODUCTION with chlorpromazine and found remarkable tranquilizing effects in their most agitated and psychotic patients.2,3 By In this chapter, we will review the basic pharmacology of 1954,y Dela and Deniker had published six papers on their antipsychotics, emphasizing the differential efficacy and side- clinical experience with chlorpromazine. They noted in 1955 effect profiles between first- and second-generation antipsy- that both chlorpromazine and the dopamine-depleting agent chotics, including clozapine, based on the schizophrenia reserpine shared antipsychotic efficacy and neurological side literature. While antipsychotics are used more broadly than for effects that resembled Parkinson’s disease. They coined the the treatment of schizophrenia, antipsychotic agents have term neuroleptic to describe these effects. In 1956 Frank Ayd4,5 received FDA approval for additional indications, particularly described acute dystonia and fatal hyperthermia with chlor- for the treatment of mood disorders for which they are used promazine. The first reports of tardive dyskinesia (TD) were routinely. A recent meta-analysis found that antipsychotics published by Sigwald and colleagues in 1959.6 were significantly more effective for mania than were mood Smith Kline purchased chlorpromazine from the French 1 stabilizers. The specific treatment considerations with regards pharmaceutical company Rhône-Poulenc, and in 1954 chlor- to choice of an antipsychotic for the major psychiatric syn- promazine received approval from the Food and Drug Admin- dromes (e.g. schizophrenia, bipolar disorder, depression, istration (FDA) for the treatment of psychosis. Almost autism) can be found in the chapters on these conditions. immediately the care of psychotic patients was transformed. In the US the traditional practice of life-long “warehousing” of individuals with schizophrenia in large state psychiatric HISTORY hospitals gave way to the new outpatient community psychia- try movement. An additional 10 antipsychotic compounds Chlorpromazine and the Early Agents were rapidly synthesized and approved for clinical use. This In 1952, Henri Laborit, a French naval surgeon, was experi- included a series of phenothiazines, the thioxanthenes (that menting with combinations of preoperative medications to were derived from phenothiazines), and haloperidol, which reduce the autonomic stress of surgical procedures. He tried a was synthesized from meperidine by Paul Janssen in 1958. In newly-synthesized antihistamine, chlorpromazine, and was 1967 haloperidol, the last “neuroleptic,” was approved by the impressed by its calming effect. He noted that patients seemed FDA and, because of its relative selectivity for dopamine2 (D2) indifferent about their impending surgery, yet they were not receptors and paucity of non-neurological side effects, became overly sedated. Convinced that the medication had potential the market leader. for the care of psychiatric patients, Laborit urged colleagues to By 1964, several multi-center trials sponsored by the Veter- test his hypothesis. Eventually a surgical colleague told his ans Administration and the National Institutes of Mental brother-in-law, the psychiatrist Pierre Deniker, about Leborit’s Health (NIMH) were completed, comparing the rapidly discovery. growing list of antipsychotic agents. These landmark studies Deniker and Jean Delay, who was the chairman of his each enrolled several hundred patients and were the first department at the Hôpital Sainte-Anne in Paris, experimented large clinical trials to be conducted in the new field of 475 Downloaded for Rohul Amin ([email protected]) at Uniformed Services Univ of the Health Sciences from ClinicalKey.com by Elsevier on September 21, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 476 PART X Treatment Approaches psychopharmacology. The phenothiazines were found to be TABLE 42-1 Timeline of Antipsychotics in the United States highly effective and superior to placebo, barbiturates, and reserpine. With the exception of promazine and mepazine, the First-Generation Antipsychotics (11 Agents)* phenothiazines were found to be of equivalent efficacy, Chlorpromazine (Thorazine) 1954 although they differed in their side-effect profiles. In the Haloperidol (Haldol) 1967 NIMH collaborative study of over 400 acutely ill patients, 75% Second-Generation Antipsychotics (10 Agents) of patients were at least moderately improved with chlorpro- mazine, thioridazine, or fluphenazine, compared to only 23% Clozapine (Clozaril) 1989 7 Risperidone (Risperdal) 1993 with placebo. While reports of efficacy were impressive, the Olanzapine (Zyprexa) 1997 goal of identifying differences in efficacy between drugs that Quetiapine (Seroquel) 1997 mightw allo matching of specific drugs with subgroups of Ziprasidone (Geodon) 2001 patients was not realized. Aripiprazole (Abilify) 2002 The discovery by Carlsson and Lindqvist8 in 1963 that Paliperidone (Invega) 2006 chlorpromazine increased turnover of dopamine in the brain Iloperidone (Fanapt) 2009 led to the hypothesis that dopamine receptor-blockade was Asenapine (Saphris) 2009 responsible for antipsychotic effects. This was confirmed in Lurasidone (Latuda) 2010 1976y b Creese and colleagues,9 who demonstrated that the Note: The year given for each agent denotes the year of FDA approval. antipsychotic potency of a wide range of agents correlated *Only the first and last agents are listed for first-generation closely with affinity for the D2 ,receptor which explained the antipsychotics. equivalency of efficacy between agents since all were acting via the same mechanism. The dopamine hypothesis led to a reli- ance on animal models sensitive to D2 blockade as a screen for discovering potential antipsychotic drugs, with the result that new mechanisms were not intentionally explored. efficacy compared to haloperidol. Risperidone and olanzapine rapidly replaced the first generation of neuroleptics, particu- Clozapine, the First Atypical Antipsychotic larly after clinicians became convinced that the risk of TD was substantially lower. However, it soon became apparent that The discovery of the first antidepressant, imipramine, led to risperidone markedly elevated serum prolactin levels and that the synthesis of related heterotricylic compounds, among olanzapine produced weight gain in some patients to a degree which clozapine, a dibenzodiazepine derivative, was synthe- previously seen only with clozapine. Quetiapine, ziprasidone, sized in 1958 by the Swiss company Wander. Clozapine was and aripiprazole were subsequently approved in the US, based initially a disappointment, because it did not produce in largely on reduced EPS; these agents did not convincingly animal models the behavioral effects associated with an anti- demonstrate superior efficacy compared to older neuroleptics. depressant or the neurological side effects associated with an Like risperidone and olanzapine, these last three agents acted antipsychotic. Clinical trials proceeded in Europe but were via D2 and 5-HT2A receptors; aripiprazole differed from the halted in 1975 after reports of 17 cases of agranulocytosis in other second-generation antipsychotics by possessing partial 10 Finland, 8 of which were fatal. However, the impression agonist activity at the D2 receptor rather than full antagonism. among researchers that clozapine possessed unique clinical Risperidone became the first atypical agent available as a long- characteristics led the manufacturer, Sandoz, to sponsor a acting