BIOLOGIC MECHANISMS OF PSYCHOSIS AND ANTIPSYCHOTIC DRUG ACTIONS: FROM DOPAMINE EXCESS TO DOPAMINE STABILIZATION * Bryan L. Roth, MD, PhD ABSTRACT *Based on a presentation given by Dr Roth at a symposium held in conjunction with the 2003 American Psychiatric Association Annual Meeting. Professor, Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio. Address correspondence to: Bryan L. Roth, MD, PhD, Room W438, Department of Biochemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4936. E-mail: roth@biochemistry.cwru.edu. According to the dopamine hypothesis of schizophrenia, symptoms of psychosis arise, in part, from dysregulation of central dopaminergic pathways. The activity of dopaminergic neurons is in turn modulated by several neurotransmitters, including, most prominently, serotonin and glutamate. The first generation of antipsychotic drugs (ie, typical antipsychotics) are characterized by potent D 2 dopamine receptor blockade, whereas most second-generation (ie, atypical) antipsychotics are serotonin-dopamine receptor antagonists. By simultaneously blocking both 5-HT 2A serotonin and D 2 dopamine receptors, atypical antipsychotic drugs attenuate the positive symptoms of schizophrenia with few of the extrapyramidal side effects associated with typical antipsychotic drugs. Unfortunately, atypical antipsychotic drugs (eg, clozapine, olanzapine, risperidone, quetiapine, and ziprasidone) can be associated with potentially serious side effects (eg, weight gain, cardiovascular and hematologic abnormalities). Conventional atypical antipsychotic drugs interact with a multiplicity of receptors, in addition to 5-HT 2A serotonin and D 2 dopamine receptors, including various serotonergic, dopaminergic, noradrenergic, muscarinic, and histaminergic receptors. It is likely that the chance interactions of atypical antipsychotic drugs with these and other receptors lead to the associated side effects. The ideal antipsychotic would, therefore, possess a mechanism of action whereby dopaminergic activity is normalized without adverse effects. (Adv Stud Med. 2003;3(8C):S776-S781) Since the 1970s, excessive dopaminergic activity has been the most prominent pharmacologic model for explaining the pathogenesis of schizophrenia, in large part because all effective antipsychotic drugs inhibit dopaminergic neurotransmission. 1 A number of dopaminergic pathways have been implicated in antipsychotic drug actions (Table 1). 2 Thus, positive symptoms of psychosis are believed to arise from excess dopaminergic activity in the mesolimbic pathway, whereas negative and cognitive symptoms are believed to arise from a deficiency in dopaminergic signaling in the mesocortical pathway. 3,4 First-generation antipsychotic agents suppress positive symptoms through their potent antagonism of D 2 dopamine receptors in the mesolimbic and mesocortical pathways. However, this mechanism of action may further diminish cognition via suppression of dopamine activity in the cortex. 5 Blockade of dopamine activity in the nigrostriatal pathway acutely causes extrapyramidal symptoms (eg, Parkinsonism, acute dystonias) and, chronically, tardive dyskinesia. Suppression of dopaminergic neurotransmis- S776 Vol. 3 (8C) September 2003
sion in the tuberoinfundibular pathway disinhibits prolactin secretion, leading to hyperprolactinemia and subsequent effects on fertility and sexual function. In addition to blockade of D 2 dopamine receptors, many atypical antipsychotic drugs have potent antimuscarinic, antialpha 1 -adrenergic, and/or antihistaminergic actions that produce additional side effects, including cognitive blunting, orthostatic hypotension, and sedation. An abundance of evidence suggests that a dysfunction of serotonin (5-hydroxytryptamine [5-HT]) neurotransmitter systems also contributes to the pathogenesis of schizophrenia and related psychoses. 6-10 5-HT is an indolamine neurotransmitter found in both the central nervous system and in the periphery, where it contributes to a number of physiological functions (eg, cognition, perception, memory, emotion, platelet aggregation, smooth muscle contraction). 8 It has long been recognized that blockade of the 5-HT 2A serotonin receptor subtype is an important part of atypical antipsychotic drug action, 11,12 and recent research is helping us to better understand why. We now know that 5-HT 2A receptors are highly enriched on the pyramidal neurons in the cortex. 13,14 These neurons integrate cognitive, emotional, and perceptual input to the brain prior to outputting the information to higherlevel neurons to create an individual s sense of reality. 5-HT 2A receptors are highly localized to a particular part of the pyramidal neuron that serves as the physical gate for information transfer in the brain (Figure 1). 15,16 Thus, it is now believed that blockade of the 5-HT 2A receptor normalizes the firing of pyramidal neurons, thereby stabilizing perception of reality. This assumption is based on a convergence of evidence relating to the action of a variety of drugs. Thus, hallucinogens, such as lysergic acid diethylamide (LSD) activate 5-HT 2A receptors, whereas all approved atypical antipsychotic drugs are potent 5-HT 2A receptor antagonists. It is believed that long-term treatment with atypical antipsychotic drugs normalizes the receptor-mediated signaling in cortical pyramidal neurons, thereby improv- Table 1. Dopamine Tracks and Effects of Antipsychotics Antipsychotic Dopamine Track Origin Innervation Function Effect Mesolimbic Midbrain Limbic Emotional Hallucinations, ventral structure and and delusions, tegmental nucleus intellectual disordered accumbens cognition Mesocortical Ventral Frontal Emotional Delusions, tegmental cortex and hallucinations, intellectual negative symptoms, disordered cognition Nigrostriatal Substantia Basal Extrapyramidal Motor nigra ganglia system symptomatology movement Tuberoinfundibular Hypothalamus Pituitary Regulates Plasma gland endocrine prolactin functions levels Adapted from DiPiro et al, eds. Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw Hill/Appleton & Lange; 2002. 2 Adapted with permission from the McGraw-Hill Companies. Figure 1. 5-HT 2A Serotonin Receptor I II III IV V VI Cerebral Cortex Cortical Surface White Matter Pyramidal Neuron Apical Dendrite Basal Dendrites Cell Body Inputs typically are scattered over the neuron s dendritic tree Branching axon is the neuron s output (the junction is the synapse) Adapted with permission from Calvin et al. Conversations with Neil s Brain: The Neural Nature of Thought and Language. Oxford, UK: Perseus Publishing; 1995. 16 Advanced Studies in Medicine S777
ing positive and negative symptoms of schizophrenia. When activated, 5-HT 1A serotonin receptors, co-localized on pyramidal neurons with 5-HT 2A receptors, also inhibit the firing of pyramidal neurons. Thus, in theory, an ideal drug for normalizing the firing of pyramidal neurons would both activate 5-HT 1A receptors and antagonize 5-HT 2A receptors. Because pyramidal neurons are glutamatergic, activating 5-HT 1A receptors and inhibiting 5-HT 2A receptors may stabilize glutamatergic neurotransmission. Finally, 5-HT 1A partial agonists stabilize the serotonergic system because they are serotonin autoreceptors. Three approved atypical antipsychotic drugs have these opposing actions on 5-HT 1A and 5-HT 2A serotonin receptors: aripiprazole, clozapine, and ziprasidone. Thus, therapy with aripiprazole, clozapine, or ziprasidone is predicted to be associated with a stabilization of the serotonergic and glutamatergic neurotransmission. The pharmacology of these drugs, and atypical drugs in general, is highly complex, however they interact with numerous other receptors, 17 and interactions with other receptors may modulate the actions of antipsychotic drugs on a number of neurotransmitter systems. RESOURCE FOR IDENTIFYING MOLECULAR TARGETS Determining which pharmacologic actions are essential to achieve therapeutic effects and which generate side effects has become increasingly difficult. The National Institute of Mental Health Psychoactive Drug Screening Program (NIMH-PDSP) has created a unique resource in the public domain that provides information on the abilities of drugs to interact with an expanding number of molecular targets. The NIMH-PDSP database serves as a data warehouse for published and internally derived K i, or affinity, values for a large number of drugs and drug candidates at an expanding number of G-protein coupled receptors, ion channels, transporters, and enzymes. The flexible user interface provides for customized data mining. Planned enhancements include: (1) a searchable database of agonist/antagonist properties of drugs and drug candidates at various molecular targets; and (2) a chemi-informatics interface, which will allow the user to search the database by homology. The query interface is designed to allow search by any field, or a combination of fields to refine search criteria. Both antipsychotics and drugs of abuse are listed in the database, which provides a listing of the various receptors with which the drug has an affinity (including those identified by the human genome project), the chemical structure of the drugs, and a link to the published material. The NIMH-PDSP database is a unique resource in the public domain that provides information on the abilities of drugs to interact with an expanding number of molecular targets. For clinicians, this resource provides a valuable tool for predicting both therapeutic efficacy and side effects of individual medications. It is available at http://pdsp.cwru.edu/pdsp.asp. Using the NIMH-PDSP database, an analysis of molecular targets for clozapine shows that it is likely to occupy not only the D 2 dopamine and 5-HT 2A receptors, but also a large number of other receptors. The analysis of molecular targets also suggests that even at the highest doses of clozapine clinically achievable, dopamine D 2 receptor occupancy will not exceed 70%, and will typically be less. Studies of in vivo receptor occupancy with positron emission tomography scanning have supported such molecular predictions. 18 At the opposite end of the spectrum is aripiprazole, whose structure and in vitro pharmacology is markedly dissimilar from clozapine. Analysis of molecular targets for this drug shows that at the usual clinical dose, it is predicted to occupy more than 90% of dopamine D 2 and D 3 receptors, as well as 5-HT 1A receptors. Clinical studies of aripiprazole show that a dose of 30 mg daily achieved nearly 100% occupancy of striatal D 2 dopamine receptors in normal human volunteers. 19 Although classic pharmacologic theory would indicate that complete occupancy of D 2 receptors will result in significant side effects, clinically, aripiprazole has been found to be nearly devoid of extrapyramidal side effects and does not trigger the elevation of serum prolactin that is reported with use of typical antipsychotic drugs. 20 This seeming contradiction can be explained by a closer analysis of aripiprazole s pharmacology. Because aripiprazole is a partial agonist, when it binds to the D 2 receptor it partially activates the D 2 dopamine receptor, thus resetting the functional activity of the D 2 receptor to a lower level. In this way, partial agonists are unlike antagonists, which set the functional state of occupied D 2 S778 Vol. 3 (8C) September 2003
receptors to zero. Thus, in a situation in which excessive dopamine is released (eg, the acute psychotic state) and D 2 dopamine receptors are fully activated, a partial agonist will reset the receptor tone to a more normal level. In conditions in which too little dopamine is released (eg, in the prefrontal cortex of schizophrenic individuals) one would predict that a partial agonist would yield a net activation of D 2 dopamine receptors. The level of agonist activity seen with partial agonists like aripiprazole is thought to be sufficient to functionally reset the dopaminergic system to achieve the 70% occupancy level seen with clozapine, thereby yielding the same net effect on dopaminergic neurotransmission. A simulation performed by the NIMH-PDSP of aripiprazole s partial agonist activity on dopamine and serotonergic receptor occupancy demonstrates the predicted functional effect (B.L. Roth, manuscript in preparation). years and remains a serious side effect of some antipsychotic drugs. 23,24 The mechanism responsible for antipsychotic drug induced weight gain is somewhat controversial, though clinicians have reported tremendous increases in appetite in schizophrenic patients Table 2. Receptor Pharmacology Reliably Predicts Side Effects* Associated Receptor Side Effect Ari Olz Ris Zip Clz Hal Alpha 1A Hypotension, dizziness + +++ +++ ++ +++ + H 1 Sedation + +++ ++ + +++ + M 1 Blurred vision, dry mouth + + +++ + SIDE EFFECTS AND WEIGHT GAIN A detailed knowledge of receptor pharmacology can also be used to predict the side-effect profiles of individual drugs. By identifying the type and number of receptors occupied, we can reliably predict the likelihood of specific side effects. For example, analysis of clozapine with the NIMH-PDSP database demonstrates extensive interactions with a host of receptors that are responsible for many of the drug s side effects. For example, alpha 1 -adrenergic receptor blockade results in hypotension, and muscarinic receptor blockade results in anticholinergic side effects. A similar analysis of haloperidol s receptor interactions predicts few alpha 1 -adrenergic receptor side effects, little interaction with the H 1 receptor (eg, minimal sedation and weight gain), and little interaction with muscarinic receptors, leading to few anticholinergic side effects. Simulations with aripiprazole also demonstrate little activity with these receptors, predictive of few side effects (Table 2) 17,21,22 ; clinical trials indicate that aripiprazole is associated with few adrenergic, histaminergic, or cholinergic side effects. 20 Weight gain as a side effect of antipsychotic therapy has been noted for more than 30 = no effect; + = minimal side effects; ++ = moderate side effects; +++ = strong side effects. *All data obtained with cloned human receptors. Ari = aripiprazole; Olz = olanzapine; Ris = risperidone; Zip = ziprasidone; Clz = clozapine; Hal = haloperidol. Data from Shapiro et al 21 ; Kroeze et al 22 ; Roth et al. 17 Figure 2. Mean Weight Change at 10 Weeks in Patients Taking Antipsychotics at Standard Dose *4-6 week pooled data from Marder et al. 27 Extrapolated from 6-week data. Adapted with permission from Allison et al. Am J Psychiatry. 1999;156:1686-1696. 25 Copyright 1999, the American Psychiatric Association; http://ajp.psychiatryonline.org. Advanced Studies in Medicine S779
leading to substantial weight gain, 25 with significant implications for metabolic side effects, such as diabetes and hyperlipidemia. 26 To assess correlations between specific antipsychotic drug agents and weight gain, Allison et al conducted a retrospective study that showed a strong association with clozapine and olanzapine use. 25 Figure 2 extrapolates data from Allison s 1999 analysis and pools it with later data from a multicenter trial assessing weight in patients using aripiprazole. 25,27 The mechanism responsible for antipsychotic drug induced weight gain is unknown, although recent studies have suggested an association between weight gain and a silent polymorphism of the 5-HT 2C receptor. 28 Although many antipsychotic drugs interact with 5-HT 2C receptors, 29 the propensity of antipsychotic drugs to induce weight gain does not correlate with their actions at 5-HT 2C receptors, indicating that some other receptor(s) are likely responsible for this serious side effect. Kroeze et al recently reported results based on a test of the hypothesis that the affinity of an antipsychotic for a certain receptor or subset of receptors will predict whether it induces weight gain, and that this group of receptors would differ from those that predict effectiveness. 22 The investigators obtained weight-gain data for antipsychotic drugs from the meta-analysis published by Allison et al 25 and from the multicenter aripiprazole study 27 and utilized receptor affinity data from the NIMH-PDSP to identify correlations between weight gain and receptor affinities. They found 2 receptors that were responsible for predicting with the highest degree of certainty whether a drug will or will not induce weight gain: the H 1 histamine receptor and the alpha 1 -adrenergic receptor. An individual drug s ability to interact with these 2 receptors was highly predictive of its ability to induce weight gain. The binding data from Kroeze s analysis suggests that 2 atypical antipsychotic drugs will not induce substantial weight gain over a 10-week period: ziprasidone and aripiprazole. Clinical trial data also report that aripiprazole and ziprasidone have a relatively low propensity to induce weight gain. CONCLUSION Multiple receptors are occupied by antipsychotic drugs, which may activate or inhibit receptor activity. Drugs with dopamine partial/functional agonism may stabilize the dopaminergic system with minimal extrapyramidal symptoms. Antagonism of the 5-HT 2A receptor stabilizes a number of neurotransmitter systems, likely accounting for the salutary effects of atypical antipsychotic medications on cognition and mood. Drugs with 5-HT 1A receptor agonism further stabilize various neurotransmitter systems (glutamatergic and serotonergic); this action may account for the mood stabilization seen in patients taking certain atypical antipsychotic drugs. 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