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Antipsychotics: Pharmacology and Clinical Decision Making


Donald S. Robinson, MD

Primary Psychiatry. 2007;14(10):23-25

Dr. Robinson is a consultant with Worldwide Drug Development in Burlington, Vermont. Disclosure: Dr. Robinson has served as a consultant to Bristol-Myers Squibb, CeNeRx, Epix, Genaissance, Medicinova, Ono Pharmaceuticals, Pfizer, and Somerset.

The introduction of several new atypical antipsychotics over the past decade poses uncertainties about what constitutes optimal drug therapy for an individual patient, both in choosing initial drug therapy and ongoing management. The advent of the second-generation antipsychotics (SGAs) bred a new category of drugs with some advantages over traditional agents, although the extent of superiority in efficacy and tolerability over first-generation antipsychotics (FGAs) remains unclear. SGAs are a pharmacologically heterogeneous group of drugs with differing liabilities, depending on the agent. Two recent monographs review the pharmacology and therapeutics of the antipsychotics and summarize available data to provide the most current information to guide clinical practice.1,2 Therapeutic indications for antipsychotics include short-term management of acute psychoses and agitated states as well as long-term treatment of chronic psychotic disorders such as schizophrenia and delusional disorders. SGAs have largely replaced FGAs in clinical practice, although the limited data from comparative trials do not show SGAs to be clearly superior. Purported therapeutic advantages of SGAs, which vary depending on the specific agent, appear relatively modest compared with traditional antipsychotics employed in moderate dosage and with adjunctive antiparkinson medication, if needed.1,3,4 As noted in a recent editorial,5 emerging data on SGAs make it apparent that the significant side-effect burden of antipsychotic drug therapy has shifted, not disappeared.

Mechanism of Action of Antipsychotics


Although antipsychotics emerged in the 1950s with the introduction of chlorpromazine (the result of a serendipitous discovery), the principal mechanism of action of antipsychotics remained unclear for nearly a decade thereafter. In a milestone publication reviewing pharmacologic evidence elucidating the neuropathology of schizophrenia, Matthysse6 pointed out that dopamine agonists precipitate or worsen psychosis while dopamine antagonists (eg, antipsychotics) effectively treat chronic psychosis and mania. In ensuing years, the focus of drug discovery centered on dopamine-receptor antagonists, primarily dopamine (D)2-receptor blockers. Potent antidopaminergic drugs, while highly

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effective, also carried a significant risk of extrapyramidal symptoms (EPS) and tardive dyskinesia. A major advance in understanding the pharmacology of antipsychotics derives from a clinical trial involving clozapine, the first of the SGAs.7 This trial compared clozapine and chlorpromazine in schizophrenic patients who failed a prior course of high-dose haloperidol and found clozapine superior to chlorpromazine, while devoid of the adverse neurologic effects of other antipsychotics.7 Clozapine was labeled atypical because it combined superior efficacy with low risk of EPS. This term subsequently was applied broadly (and uncritically) to all of the SGAs despite having significant pharmacologic heterogeneitychemically, pharmacologically, and clinically.1

Neuropharmacology of Antipsychotics
The weight of the evidence indicates that dopamine-receptor blockade is essential to clinical antipsychotic activity, especially for controlling hallucinations and delusions, but emerging data suggest this may not be the only mechanism of action. Despite the advances in cloning neuroreceptor subtypes and defining specific receptor-binding characteristics of individual antipsychotics, a unifying theory of the mechanism of action of antipsychotics has not emerged. The ideal pharmacologic profile for an antipsychotic remains an unanswered question.1 Given its low propensity for EPS and unexcelled clinical efficacy, the pharmacologic profile of clozapine became the subject of intense scrutiny in designing new antipsychotics. The pharmacology of clozapine is especially complex; it binds loosely (and transiently) to D2 receptors as well as other dopamine receptor subtypes, and also binds with high affinity to histamine (H1), acetylcholine muscarinic (M1), -adrenergic ( 1), and multiple serotonin (5-HT2A, 5-HT2C, 5-HT7) receptors. This complexity leaves the minimal EPS risk and unexcelled antipsychotic effectiveness of clozapine unexplained.1 However, emerging data suggest that significant binding to 5-HT2A receptors in addition to D2 receptors confers lower risk of EPS. The receptor-binding profiles of the atypical antipsychotics exhibit significant differences amongst the SGAs. Understanding and appreciating these distinctions can guide in selecting pharmacotherapy for the individual patient, a task that can be daunting. Clinicians are confronted with many options that span drug choice, dose optimization, adjunctive and augmentation therapy, and the decision to switch drugs. Given unclear evidence of therapeutic superiority of SGAs3-5 and their heterogeneous pharmacology, a panel of psychopharmacologists recently convened to address unresolved therapeutic issues and to offer guidance in clinical decision making.2 One factor deemed important by the panel was acquiring a thorough understanding of the differing pharmacologic profiles of the SGAs.

Receptor Affinities and Choice of Antipsychotic Drug


While comparative trials, if available, are useful in choosing pharmacotherapy, the panel stressed that knowledge of the pharmacodynamic profiles of the SGAs is helpful, given the modest differences in antipsychotic efficacy but clear-cut safety differences. The pharmacodynamic effects of an antipsychotic are dictated by its receptor-binding properties, both with respect to efficacy and adverse effects. While traditional antipsychotics bind principally and most avidly to D2 receptors, SGAs exhibit high affinities for other receptors equal to or exceeding that for the D2 receptor. SGAs can be grouped according to patterns of receptor affinities and dissociation. For example, clozapine, olanzapine, and ziprasidone have higher affinity for 5-HT2A receptors relative to D2 receptors, a binding profile differing somewhat

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from other SGAs.1 Positron emission tomography (PET) studies show that the SGAs clozapine, olanzapine, quetiapine, and ziprasidone (but not aripiprazole and risperidone) have moderate affinity and low avidity (ie, rapid dissociation) for D2 receptors in the basal ganglia, a pattern consistent with low EPS liability. The anticholinergic effects of clozapine and olanzapine also may limit risk of EPS and avoid a need to add an antimuscarinic antiparkinson agent, as often required with conventional antipsychotics to rebalance critical dopamine-cholinergic functions in the basal ganglia. 1 Clozapine and olanzapine (which resembles clozapine structurally and pharmacologically) have high affinities relative to the D2 receptor for M1, H1, 5-HT2C, and 5-HT2A receptors, in that order respectively. This profile of receptor interactions informs about both the therapeutic and side-effect profiles of these two SGAs, eg, well-established antipsychotic efficacy with minimal risk of EPS and significant liability for excessive weight gain and sedation (Table).2

Quetiapine exhibits high affinities relative to the D2 receptor for H1 and 1-adrenergic receptors, reflecting a propensity for causing sedation and postural symptoms. Risperidone binds significantly to 5-HT2A, 1, and D2 receptors, and may have a somewhat higher propensity for EPS than other SGAs. Ziprasidone, like risperidone, has high affinity for the 5-HT2A receptor relative to D2 receptors but differs from risperidone by binding to multiple dopamine-receptor subtypes as well as to 5-HT2C and 5-HT1A receptors.

Drugs Acting as Partial Agonists


Binding of a drug to a receptor can theoretically result in either an agonist or antagonist action, or in partial agonism, as discussed in a previous column.8 A drug acting as an antagonist blocks receptor activation and takes a receptor out of play, while an agonist functions like an endogenous neurotransmitter to fully activate a receptor.2 A partial agonist exhibits affinity for a receptor but lacks the full effect of the endogenous neurotransmitter. It competes with the natural transmitter and thereby produces an attenuated response. Aripiprazole has high-binding affinity for D2 receptors (as well as 5-HT1A and 5-HT2A receptors) and PET studies demonstrate high occupancy of D2 receptors (>90%) at therapeutic doses. However, its pharmacologic action as a partial agonist attenuates full response and diminishes receptor activation by the endogenous neurotransmitter dopamine. Ziprasidone exhibits high affinity for 5-HT1A receptors where it functions as a partial agonist. In addition, it binds with moderate affinity to the serotonin transporter in brain tissues. It is postulated that these pharmacologic properties potentially convey efficacy of ziprasidone in anxiety and depressive states in addition to psychosis.1

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Polypharmacy
On combining drugs or switching antipsychotic therapy, the additive receptor-binding properties of two concurrent SGAs should be considered. In general, D2-receptor blockade of !50% is needed for antipsychotic efficacy, while the threshold for risk of EPS is considered to be !80% occupancy (aripiprazole is an exception because it possesses high affinity for D2 receptors but acts as a partial dopamine agonist). Combined use of antipsychotics may have a greater propensity for side effects than either drug alone, depending on similar receptor-binding properties (Table).2 Another pharmacologic consideration is the fact that the brain adapts to psychotropic medications through a series of compensatory mechanisms, eg, upregulation of receptors in response to a drug acting as an antagonist, and downregulation of receptors in response to treatment with an agonist drug. 2 The possibility of pharmacologic adaptation needs to be considered when switching drugs, since withdrawal effects may ensue from the withdrawn drug but be mistakenly attributed to the new medication. For example, abrupt discontinuation of a sedative SGA on switching to aripiprazole or ziprasidone, which do not block histamine receptors, may cause transient activation due to a pharmacologic withdrawal syndrome. As another example, on switching from an antipsychotic with potent muscarinic anticholinergic properties (M1 antagonist) to one with little anticholinergic activity, abrupt discontinuation may cause transient cholinergic rebound. This may be erroneously attributed to the new antipsychotic rather than to withdrawal of the prior drug, and lead to premature changes in therapy or drug dose.

Conclusion
SGAs do not differ substantially in efficacy from traditional antipsychotics but have differing side-effect burdens. Because of the pharmacologic heterogeneity of this group of drugs, an understanding of the specific receptor-binding properties of each antipsychotic can be helpful in selecting appropriate drug therapy for the individual patient. PP

References
1. Gardner DM, Baldessarini RJ, Waraich P. Modern antipsychotic drugs: a critical review. CMAJ. 2005;172(13):1703-1711. 2. Weiden PJ, Preskorn SH, Fahnestock PA, et al. Translating the psychopharmacology of antipsychotics to individualized treatment of severe mental illness: a roadmap. J Clin Psychiatry. 2007;68(suppl 7):6-46. 3. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness if antipsychotic drugs in patients with chronic schizophrenia. N Eng J Med. 2005;353(12):1209-1233. 4. Rosenheck RA, Leslie DL, Sindelar J, et al. Cost-effectiveness of second generation antipsychotics and perphenazine in a randomized trial of treatment of chronic schizophrenia. Am J Psychiatry. 2006;163(12):2080-2095. 5. Freedman R, Carpenter WT, Davis JM, Goldman HH, Tamminga CA, Thomas M. The cost of drugs for schizophrenia. Am J Psychiatry. 2006;163(12):2029-2031. 6. Matthysse S. Antipsychotic drug actions: a clue to the neuropathology of schizophrenia? Fed Proc. 1973;32(2):200-205. 7. Kane J, Honigfeld G, Singer J, Meltzer HY. Clozapine for the treatment resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45(9):789-796. 8. Robinson DS. CNS receptor partial agonists: a new approach to drug discovery. Primary Psychiatry. 2007;14(8):22-24.

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