Atypical Antipsychotics

From Bench to Bedside

John C. Csernansky, John Lauriello

• Publisher: CRC Press
• Year: 2004
• ISBN:
  9781135534950
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

Showcasing the latest studies in the field, this reference unveils recent breakthroughs in the use of atypical antipsychotics for the treatment of a variety of patient populations-tracking developments in the management of patients with schizophrenia and affective psychotic disorders, as well as therapeutic regimens for children and adolescents.

1 Atypical Antipsychotic Drugs: Theories of Mechanism of Action

Scott Filippino and John G.Csernansky

Washington University School of Medicine, St.Louis, Missouri, U.S.A.

I. INTRODUCTION

The advent of antipsychotic drugs occurred via a process that is both colorful and serendipitous. Ironically, war was the force that initially propelled the development of this group of drugs that has helped bring peace to so many patients with schizophrenia. The phenothiazines and their derivatives, including methylene blue, were well known to 19th-century industrial chemists, but largely as dyes. Then, when methylene blue was discovered to possess antimalarial properties, numerous additional derivatives of methylene blue were synthesized by the Germans in World War I and by the Allies in World War II for this purpose. At the time, quinine, a derivative of a tropical tree bark, was the only treatment for malaria, and access to the trees that produced quinine was very tenuous. Thus, the development of a synthetic antimalarial became strategically essential for modern armies who conducted global campaigns.

While the Germans succeeded in synthesizing quinacrine, the Allies chanced upon the aminoalkyl phenothiazines. Although such compounds lacked antimalarial properties, painstaking work by French researchers demonstrated that these drugs had antihistamine properties superior to other compounds available at the time. The development of this new class of antihistamines led to the synthesis of promethazine.

Soon after World War II, Henri Laborit, a surgeon of the French navy, began experimenting with novel forms of anesthesia that blended narcotics, sedatives, and hypnotics (1). He noted that promethazine was useful in combination with anesthetic agents for reducing perioperative stress, and suggested the development of a new antihistamine that would be more sedating than promethazine. The compound developed by the Rhône-Poulenc Laboratories in 1951 to satisfy this need was chlorpromazine. Laborit and his colleagues then observed that while chlorpromazine produced the desired sedation, it also produced a type of disinterest in their surgical patients that they felt might be useful in psychiatric patients with agitation.

By 1952, several French psychiatrists, including Delay, Deniker, Harl, Hamon, Paraire, and Velluz, had begun to test chlorpromazine in patients with schizophrenia and other psychotic disorders, and while there remains some debate about who should be given credit for the first use of this drug, there is certainly no debate about its profound effects on the treatment of psychiatric patients.

Under the trade name Largactil (and later Thorazine), chlorpromazine was soon made available to psychiatrists throughout the world, and a number of studies confirmed its value in treating schizophrenia. Perhaps the most important of these studies was that of the U.S. Veterans Administration Collaborative Study Group, led by Leo Hollister. This study not only definitively demonstrated chlorpromazine’s efficacy using a controlled clinical trial design, but did so at a time in American history when most clinicians were focused on psychoanalysis and resistant to the idea that schizophrenia had a biological basis and could be chemically treatable.

Soon after the availability of antipsychotic drugs became widespread, clues to their mechanism of action began to appear. In a paper in 1963 (2), Arvid Carlsson and Margit Lindqvist noted that haloperidol and chlorpromazine “exerted a characteristic effect on the metabolism of brain catecholamines” and suggested that the most likely mechanism of doing so was to “block monoaminergic receptors in the brain.” It took only a few more years to isolate the particular monoamine affected by antipsychotics. In 1964, Anden, Roos, and Werdnius noted elevated metabolites of dopamine in rabbit striatum after chlorpromazine or haloperidol (3), and in 1970 Anden and colleagues examined the ability of numerous antipsychotics to block monoamine receptors in rats (4), and concluded that “the most potent and specific neuroleptics seemed to influence mainly the brain [dopamine] receptors.” Later, several subtypes of dopamine receptors were discovered, and the relationship between antipsychotic activity and dopamine receptor blockade became narrowed to the D₂ subtype.

Perhaps ironically, the first atypical antipsychotic drug, clozapine, was synthesized by Wander Pharmaceuticals in 1959; yet, it would take almost three decades before this drug would trigger a second pharmacological revolution in psychiatry. In another irony of antipsychotic drug development, the potential of clozapine as an antipsychotic drug was initially overlooked because its pharmacologic profile suggested it would not produce effects on the brain’s motor pathways. Thus, in the context of beliefs that antipsychotic efficacy and extrapyramidal effects were always linked, clozapine was considered to be “defective” (5). Nonetheless, despite this label, psychiatrists in Germany, Switzerland, and Austria worked with clozapine throughout the 1960s and were impressed with its success in the treatment of patients with schizophrenia, especially those that had been resistant to other drugs (6). After several patients in Finland developed lethal agranulocytosis (7), clozapine was withdrawn from further use. Fortunately, clozapine’s superiority in treating otherwise resistant patients was not forgotten, and in 1988, the results of a double blind study were reported comparing clozapine with chlorpromazine in treatment resistant patients (8). The results of this study gave the first indisputable evidence of clozapine’s superiority over the typical antipsychotic, chlorpromazine, and rapidly led to clozapine’s introduction into clinical use in the United States under FDA guidelines designed to reduce the risk of undetected agranulocytosis.

II. MECHANISMS OF ACTION: WHAT MAKES A DRUG ATYPICAL?

Soon after clozapine’s introduction as an antipsychotic in the United States, it soon became the pharmacological prototype for a new generation of antipsychotic drugs. The fact that clozapine was effective as an antipsychotic drug but only rarely produced acute adverse effects on the motor system that had been previously linked to the blockade of dopamine D₂ receptors suggested that there might be new pharmacological avenues to achieving an effective antipsychotic drug. Moreover, clozapine was found not to elevate plasma levels of prolactin (i.e., a neurohormone whose release is under dopaminergic control), which further challenged the notion that efficacy and side-effects of antipsychotic drugs were inseparably linked by the common mechanism of dopamine D₂ receptor blockade. Thus, the search began for other drugs that might be able to capture the “atypical” properties of clozapine without its limiting propensity to cause agranulocytosis.

Receptor binding studies revealed that clozapine bound to a number of neurotransmitter receptors other than the dopamine D₂ receptor, often with greater affinity than its affinity at the dopamine D₂ receptor. Because of these many other actions of clozapine, a variety of competing theories were brought forward to explain clozapine’s atypical profile. In the past decade, one has clearly emerged as dominant—that is, the hypothesis that clozapine’s atypical profile is due to its combined antagonist actions at serotonin 5-HT_2A and dopamine D₂ receptors (i.e., the 5-HT_2A/D₂ hypothesis). As reviewed below, the 5-HT_2A/D₂ hypothesis may be credited with inspiring the development of several new atypical drugs. However, other theories have also been brought forward, and two of these (i.e., the fast dissociation hypothesis and the partial D₂ agonist hypothesis) have also been linked to the specific atypical antipsychotic drugs. All three of these popular theories will be reviewed in detail below.

III. THE 5-HT_2A/D₂ HYPOTHESIS

The 5-HT_2A/D₂ hypothesis has influenced the development of several of the atypical antipsychotic drugs in use today, including risperidone, olanzapine, and ziprasidone, as well as other agents (e.g., iloperidone) under consideration (9). The origin of this theory lies, in part, in the observation that clozapine is a potent antagonist of 5-HT_2A receptors and that blockade of these receptors mitigates antipsychotic drug-induced movement disorders (i.e., catalepsy) in rodents. In an early experiment by Sulpizio and colleagues, clozapine, but not typical antipsychotic drugs, antagonized the effects of fenfluramine, which promotes the release of serotonin from presynaptic stores, on temperature regulation in rodents (10). On the basis of this result, the investigators conjectured that clozapine may “[preserve] a dopamine-serotonin balance” and suggested that clozapine’s anti-serotonergic properties deserved further scrutiny. Later experiments then more directly demonstrated the binding of clozapine to serotonin receptors and suggested a similar explanation for the relationship between the blockade of 5HT receptors and clozapine’s atypical profile (11).

In regard to these findings and their interpretation, it is important to remember that a relationship between serotonin and the motor pathways of the brain had been established some time before the appreciation of clozapine’s atypical profile. In 1975, Costall and associates explored the role of the serotonergic pathways in the production of antipsychotic drug-induced motor abnormalities (12), and showed that lesions of the dorsal or medial raphé nuclei (from which serotonergic neurons arise) in mice reduced haloperidol-induced catalepsy. Similarly, it was also demonstrated that direct injections of serotonin into the nucleus accumbens of rats decreased hyperactivity induced by dopamine injection, and conversely that the ability of typical antipsychotic drugs to reduce dopamine-induced hyperactivity in rats was antagonized by methysergide and cyproheptadine (13). Perhaps, then it should not be surprising that patients with schizophrenia who receive 5-HT₂ antagonists demonstrated improvement in antipsychotic drug-induced extrapyramidal side-effects (14,15).

Surprisingly, however, the connection between clozapine’s effect on serotonin receptors and the effects of serotonin on the motor pathways of the brain did not draw substantial attention throughout the early 1980s. Rather, clozapine’s mechanism of action and its atypical profile were at first hypothesized to occur through its action at special populations of dopamine receptors (16); that is, it blocked mesolimbic dopamine receptors but not mesostriatal neurons where it would produce the extrapyramidal side-effects so typical of other antipsychotic drugs (17). Finally, in 1989, Meltzer brought the action of clozapine on serotonin systems into the foreground, and proposed that clozapine’s atypical profile, including its benefits for negative symptoms, were related to its combined blockade of dopamine and serotonin (5HT_2A) receptors (with a relative preference for serotonin receptors) (18,19). In a seminal article of the 5-HT_2A/D₂ hypothesis of clozapine’s action, Meltzer compared the relative affinity of many atypical and typical antipsychotic drugs on the D₂ and 5HT_2A receptors to provide convincing support for this hypothesis (20).

In the same year, Meltzer and colleagues also published a metanalysis of receptor binding data to compare the affinities for D₁, D₂, and 5-HT_2A receptors in 20 antipsychotic drugs, in conjunction with clinical knowledge of their typicality or atypicality, to generate a discriminant function capable of predicting the properties of an unknown drug (21). Upon testing the discriminant function on the original 20 reference compounds as well as 17 additional drugs, the function correctly predicted the properties of a given drug for 33 of the 37 drugs. Further, the stepwise discriminant function analysis, determined that the pK_i values for D₁ did not significantly contribute to the classification of an antipsychotic drug as typical or atypical. Rather, the atypical and typical antipsychotic drugs were best differentiated by the ratio of their affinities for the 5-HT_2A and D₂ receptors alone. Atypical antipsychotic drugs had consistently higher 5-HT_2A/D₂ ratios than typical drugs.

Given the empirical relationship between drugs with atypical profiles and serotonin receptor blockade, we should now consider the mechanisms that might underlie it. Reviewing the neuroanatomy of the midbrain and basal ganglia (22), it is known that serotonergic fibers from the dorsal raphé project to the cell bodies of dopamine neurons in the substantia nigra, and decrease the firing rate of these dopamine neurons via activation of 5-HT₂ receptors (23,24). Similarly, serotonergic fibers from the dorsal raphé also project to the cortex and the striatum (22), where they exert a negative regulatory role on dopamine release. Thus, by blocking 5-HT₂ receptors, atypical antipsychotics may decrease the influence of serotonergic neurons that inhibit dopamine activity. Disinhibition of dopamine neurons would then increase the amount of dopamine released into the synaptic cleft, and since the occupancy of dopamine receptors by antipsychotic drugs can be influenced by the concentration of endogenous dopamine, antipsychotic drug-induced dopamine receptor blockade and the extrapyramidal side-effects produced by such a blockade would be mitigated. In addition, some atypical antipsychotic drugs also act as agonists at 5-HT_1A autoreceptors located on the 5-HT₂ neurons, thereby providing a secondary mechanism by which such drugs could block serotonergic activity in the brain.

It has also been hypothesized that hypodopaminergia in the prefrontal cortex may be the underlying cause of the negative symptoms of schizophrenia (25,26). As noted above, serotonergic neurons synapse on and down-regulate activity of dopaminergic neurons in the prefrontal cortex, and therefore, antagonism of cortical 5-HT₂ receptors on dopam...

Table of contents

• Cover Page
• Medical Psychiatry
• Title Page
• Copyright Page
• Preface
• Contributors
• 1 Atypical Antipsychotic Drugs: Theories of Mechanism of Action
• 2 Probing the “Receptorome” Unveils the Receptor Pharmacology of Atypical Antipsychotic Drugs
• 3 Neurophysiological Effects of Atypical Antipsychotic Drugs
• 4 Behavioral Models of Atypical Antipsychotic Drug Action in Rodents
• 5 Metabolic Regulation and Atypical Antipsychotic Drugs
• 6 The Nosology of the Psychotic Disorders
• 7 Acute Efficacy of Atypical Antipsychotic Drugs
• 8 Long-Term Efficacy, Effectiveness, and Safety of Atypical Antipsychotic Drugs
• 9 Assessing the Effects of Atypical Antipsychotics on the CNS Utilizing Neuroimaging
• 10 Evolving Use of Atypical Antipsychotic Medications in Childhood Psychiatric Conditions
• 11 Use of Atypical Antipsychotic Drugs for the Treatment of Affective Disorders
• 12 New Targets for Antipsychotic Drugs
• About the Editors