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A Preliminary Attempt to Personalize Risperidone Dosing Using Drug–Drug Interactions and Genetics: Part I

From the University of Kentucky Mental Health Research Center, Eastern State Hospital, Lexington, KY; Eastern State Hospital, Lexington, KY; and the College of Medicine, University of Kentucky, Lexington, KY. Send correspondence and reprint requests to Jose de Leon, M.D., Mental Health Research Center at Eastern State Hospital, 627 West 4th St., Lexington, KY 40508. e-mail: jdeleon{at}uky.edu
© 2008 The Academy of Psychosomatic Medicine

ABSTRACT

TOP ABSTRACT INTRODUCTION OPTIMAL RISPERIDONE DOSING AND... PHARMACODYNAMIC FACTORS REFERENCES

 
BACKGROUND: Personalized prescription is described even in lay journals, but there has been no attempt to propose personalizing dosing for any specific psychiatric drug. OBJECTIVE: Any attempt to develop personalized dosing needs to be anchored in our understanding of the pharmacological response of each drug in each person’s environment, particularly drug–drug interactions (DDIs) and how genetic make-up influences drug response. METHOD: Risperidone (R) is used as an example. R’s pharmacologic response is reviewed in detail by focusing on our current knowledge of its pharmacodynamic and pharmacokinetic actions. The influences of the environment and genetics on these two actions are reviewed. RESULTS: R’s antipsychotic action is probably mainly explained by the blocking of dopamine receptors, particularly D₂ receptors. There are polymorphic variations of this gene (DRD₂), but it is not clear that they have clinical relevance in predicting adverse drug reactions (ADRs) or antipsychotic response. CONCLUSION: Previous exposure to antipsychotics increases the need for higher R dosing, but the mechanism for this tolerance is not well understood. Other brain receptors, such as other dopamine, serotonin, and adrenergic receptors may explain some of these ADRs. Some polymorphic variations in these receptors have been described, but they cannot yet be used to personalize R dosing.

Key Words: Risperidone • Dosing • Genetics

INTRODUCTION

TOP ABSTRACT INTRODUCTION OPTIMAL RISPERIDONE DOSING AND... PHARMACODYNAMIC FACTORS REFERENCES

 
The most important factor in risperidone (R) pharmacokinetics is the enzyme cytochrome P450 2D6 (CYP2D6), which metabolizes R to 9-hydroxyrisperidone (9-OHR). CYP2D6 poor metabolizers have lower rates of R elimination and more toxic plasma profiles (R>9-OHR). The enzyme cytochrome P450 3A (CYP3A) may also be important. Thus, there is evidence that R metabolism and, presumably, R dosing, can be influenced by CYP2D6 polymorphisms, inhibitors, and inducers. The p-glycoprotein pump, a transporter located in the plasma membranes of protective structures, such as the blood–brain barrier, may also influence R pharmacokinetics. Renal excretion also contributes to R clearance and may contribute to the need for lower R dosing in geriatric patients.

We are providing a review for clinicians on how to interpret plasma R concentrations in order to establish the effects of these genetic and environmental factors in R pharmacokinetics. We will describe two plasma ratios, the plasma R/9-OHR concentration ratio and the total concentration-to-dose (C/D) ratio. They can be used to guide R dosing modifications. Finally, we provide a descriptive table suggesting those patients for whom to personalize R dosing, using CYP2D6 genetic variations, co-medication with inducers or inhibitors, age-group (pediatric and geriatric), and previous exposure to antipsychotics. This is a preliminary attempt based on our current knowledge. However, randomized prospective studies, particularly exploring the effects of CYP2D6 polymorphisms, are needed to verify these guidelines for R dosing. Limited information is available on long-acting R or paliperidone pharmacokinetics.

The development of new technologies that permit parallel genetic testing (testing for many genetic variations) and the description of the human genome have brought hope for a new era in medicine.¹ The importance of these new technologies can be understood when we remember that the human genome may have 20,000 genes and millions of variations, including the so-called single-nucleotide polymorphism (SNP). More recently, some authors have stressed that other types of genetic variations, such as deletions or duplications, the so-called copy-number variations, may have been neglected.² One of the major technological breakthroughs has been the introduction of the Affymetrix GeneChip,³ a DNA microarray that has allowed parallel genetic testing by introducing microchip technology; this has expanded to testing RNA and protein arrays, and arrays including DNA, RNA, and proteins. As a result of these technological breakthroughs, the journal Science⁴ predicted 10 years ago that "personalized prescription" ("tailoring drugs to a patient’s genetic makeup") will "soon" reach clinical practice. More precise estimations for the generalized use of personalized prescription have been provided: 2015, according to the lay journal Time,⁵ and 2020, by JAMA.⁶ If the estimations for general medical use of personalized medicine are that this will occur in the next 8 to 13 years, then one should notice preliminary steps toward personalized prescription already occurring. Unfortunately, very limited steps are currently being taken toward clinical applications of personalized prescription in medicine generally or, more particularly, in psychiatry.

Personalizing prescription is completely the opposite of the traditional marketing of medications by pharmaceutical companies. This is one of the main reasons that personalizing prescription is moving so slowly. Drug marketing and all the studies related to drug registration are geared toward recommending an "average" dosage for an "average" patient. However, any clinician knows that there are some patients who are not average. Moreover, study patients used by pharmaceutical companies to register drugs are relatively healthy patients with no comorbidities and few co-medications. In the "real" clinical world, many patients can be unusual, different from the average patient, for genetic or environmental reasons. Moreover, one environmental factor, polypharmacy, is becoming the norm in the Consultation–Liaison (C–L)/Med–Psych setting and in all psychiatric settings.

There have been very limited attempts to propose personalizing dosing for psychiatric drugs. Kirchheiner et al.⁷ developed an attempt to personalize dosing with studies of blood levels, assuming that these medications may follow linear kinetics. They proposed modifying some antipsychotic (AP) and antidepressant dosages based on the fact that some of them are metabolized by some polymorphic cytochrome P450 (CYP) enzymes. We attempted to make guidelines more friendly to clinicians by focusing on clinically-relevant changes, using our clinical experience with genotyping and acknowledging that not all antidepressants follow linear pharmacokinetics.⁸ More recently, it has become clear that the concept of the therapeutic window is necessary in understanding how CYP polymorphic variation may influence personalizing prescription.⁹

This review is a preliminary attempt to personalize R dosing. Any attempt to develop personalized dosing needs to be anchored in our understanding of the pharmacologic response of each drug,¹⁰ its pharmacodynamic and pharmacokinetic actions, and our awareness that they can be influenced by the environment, particularly DDIs, and by genetic variations. Environmental influences tend to be temporary, present only as long as the environmental factor is present, while genetic variations would tend to be long-standing and permanent. Information on the relative importance of genetic effects on AP response is limited by the difficulty of conducting twin and family studies in this area.¹¹

The authors believe that any attempt to develop personalized R dosing, or any other personalized dosing, will have to take into account multiple complex variables, including genetic influences. As described later, DDIs due to the intake of inhibitors or inducers of R metabolism can cause patients to need higher- or lower-than-average dosages. For example, in a French study of 500 patients taking R, 61% of the patients were not taking average R dosages because of the effects of co-medication.¹² As will be described later, a further subset of almost 10% of the patients were unusual metabolizers for genetic reasons. In summary, focusing merely on pharmacokinetic factors, only one-third of the patients in that French study were average patients needing average dosages, whereas two-thirds needed personalized prescription because of environment or genetics. Although other studies suggest that only approximately half of patients may need "unusual" doses because of pharmacokinetic factors,¹³ it is obvious that there is a need to pay careful attention to personalizing R dosing and that many patients need doses higher or lower than those usually recommended.

Clinical psychiatrists are sophisticated in their understanding of how to use pharmacodynamic variations to personalize R dosing. As a matter of fact, Williams,¹⁴in an excellent review, focused on how to use our clinical understanding to modify R dosing according to factors that influence R’s pharmacodynamic actions. Unfortunately, Williams failed to address completely the pharmacokinetic part of the equation related to drug response.¹⁰ In this multi-part article, we review R’s pharmacological response, focusing on our current knowledge of its pharmacodynamic and pharmacokinetic actions; we include the following sections: 1) in this part, R optimal dosing in the average patient, according to clinical trials; 2) pharmacodynamic factors; 3) clinical applications of pharmacodynamic factors; 4) pharmacokinetic factors; 5) in an upcoming segment, clinical applications of pharmacokinetic factors (including R levels); 6) a table to summarize the preliminary recommendations to personalize R dosing; and 7) the areas of limited knowledge on long-acting R and the main R metabolite, 9-hydroxyrisperidone (9-OHR), recently introduced in the U.S. market under the name paliperidone.

OPTIMAL RISPERIDONE DOSING AND CLINICAL TRIALS

TOP ABSTRACT INTRODUCTION OPTIMAL RISPERIDONE DOSING AND... PHARMACODYNAMIC FACTORS REFERENCES

 
Clinical Trials and Post-Marketing Use in the Clinical Environment
Pharmaceutical trials are designed to prove that a medication is effective and safe under ideal conditions by comparing this medication with a placebo and sometimes with an active compound. These trials usually include healthy adult subjects with no other major comorbid medical or psychiatric conditions beside the one for which the medication is designed; namely, schizophrenia, in the case of the APs. These trials also exclude most co-medications. The goal is usually to determine an average dosage that will be the best dosage for an "ideal" average adult patient. These clinical trials usually include a few hundred patients under blind conditions, and, even with open follow-up, they typically include no more than a few thousand patients, usually less than 5,000. Clinical trials usually have short follow-ups of a few months, with open follow-up of no more than 1–2 years. Thus, clinical trials provide information about adverse drug reactions (ADRs) in the short term in these relatively ideal patients.

Once the medication is approved by the Food and Drug Administration (FDA), or other regulatory agencies, practicing physicians use the medication in large numbers of patients, sometimes hundreds of thousands or even millions. R was originally marketed in the United States for schizophrenia, then was approved for bipolar mania, and, more recently, for irritability in autistic disorders. In recent years, R and other atypical APs have been widely used in children¹⁵ and in adults with other psychiatric disorders.¹⁶ Other frequent off-label uses are dementia, depression, obsessive-compulsive disorder, posttraumatic stress disorder, personality disorders, and Tourette’s syndrome.¹⁷ When physicians use R for less-established indications or for off-label conditions, they are extrapolating from the original schizophrenia studies and therefore taking a substantial risk that the R dosing may not be correct. As a matter of fact, in a clinical sample, schizophrenia and related psychoses accounted for fewer than half of the R prescriptions in a clinical adult sample.¹³ In summary, because of the wide use of R, recommendations to personalize its dosing may have much wider use, not limited only to schizophrenia patients, but for a wide number of psychiatric disorders from pediatric to geriatric patients.

Although there are no data comparing the prevalence of R prescription for approved versus off-label use, we know that R has been one of the three most frequently prescribed APs in the United States in the last 10 years.¹⁸ As R becomes generic in the U.S., and its cost is reduced, it is likely that it will become even more frequently prescribed. Personalizing R dosing may be a major public health issue. As R costs become substantially lower than other atypical APs, techniques to promote personalization, such as genotyping or plasma levels, may become cost-effective.

Optimal Dosage in the Average Patient
The U.S. double-blind studies of schizophrenia lasted 8 weeks and examined doses of 2 mg, 4 mg, 10 mg, and 16 mg/day.¹⁹ There was significant improvement in psychosis on 6 mg and 16 mg/day when compared with placebo and 20 mg/day of haloperidol. The extrapyramidal symptoms (EPS) and the use of anticholinergics increased with doses higher than 6 mg/day. The Canadian double-blind studies of schizophrenia had the same duration and doses as the U.S. study.²⁰ They showed a significant improvement in patients taking 4 mg, 10 mg, and 16 mg/day when compared with placebo and haloperidol. The EPS and the use of anticholinergics on R increased progressively from doses of 2 mg/day. An international double-blind study of schizophrenia lasted 8 weeks, did not include a placebo, and examined doses of 1 mg, 4 mg, 8 mg, 12 mg, and 16 mg/day.²¹ The optimal dose was considered to be 4 mg–8 mg/day. The EPS and the use of anticholinergics on R increased progressively from the R dose of 1 mg/day.

Williams,¹⁴ reviewing these controlled studies and naturalistic studies, suggested that 4 mg to 8 mg/day was the optimal range for the average patient for maximal efficacy and minimal ADRs. Thus, dose recommendations were a target dosage of 6 mg/day, titrated in 2-mg increments over 3 days, with subsequent adjustment of the dose to 4 mg or 8 mg/day, depending on efficacy and ADRs. The subjects of early trials were generally chronic patients who had experienced many years of medication and high doses of medication. As described in the pharmacodynamic section, clinicians became aware that the recommended doses in patients other than middle-aged persons with relapsing schizophrenia need to be different.¹⁴

A review of brain-imaging studies found that PET studies suggested an occupancy of at least 65% of the D₂ receptors is needed for clinical response to APs, and occupancy rates exceeding 72% and 78%, respectively, are associated with higher risk of hyperprolactinemia and EPS.²² The review suggested that the R doses leading to 65% of occupancy were approximately 2 mg/day and that doses of 2 mg–4 mg/day should be sufficient.²² The review suggested that higher doses, beyond 6 mg–7 mg/day of R (equivalent to 6 mg of haloperidol) will saturate all receptors.

Risperidone May Be a Narrow Therapeutic-Window Drug
As described above, the double-blind studies^19–21 suggested that at more than 6 mg/day, patients begin to have more adverse drug reactions, particularly EPS. Soon after its introduction, clinicians learned that lower doses were better tolerated. In the first year after approval, in a U.S. academic center particularly sensitive to EPS, which treated 285 patients, the mean R dosage associated with EPS was 3.5 mg/day.²³ Lemmens et al.,²⁴ after combining 27 double-blind and open studies, suggested that 4 mg/day was the optimal dosage and that R was associated with a dose-dependent increase of EPS over the range of 8 mg–16 mg/day. Combining the U.S. and Canadian double-blind studies, Simpson and Lindenmayer²⁵ suggested that EPS increased with R dosing in a linear fashion, but 16 mg/day was better than 20 mg/day of haloperidol.

As the above paragraph describes, clinicians soon realized that, in the average patient, using R doses greater than 6 mg/day was associated with significant increases of EPS, and it was harder to see the benefit of R versus typical APs. As a matter of fact, some naturalistic studies suggest that R had a better EPS profile than haloperidol, but not better than low-potency APs.²⁶ In summary, the high level of 16 mg/day used in the U.S. study appears very high. There is no standard definition of what constitutes a narrow therapeutic-window drug. R appears to have a narrow range, since typical recommended doses are 4 mg/day, with higher recommended doses of only 8 mg/day. The highest recommended dose of 8 mg/day is only twice the highest maximum recommended dosage, 4 mg/day. Clinicians in the U.S. currently rarely use doses higher than 10 mg/day.¹³ The initial double-blind studies^19–21 that used doses as high as 16 mg/day were conducted when the typical APs were the standard treatment, and the North American studies used a very high dosage of 20 mg/day of haloperidol as the comparison. Among risperidone ADRs, extrapyramidal symptoms and hyperprolactinemia are clearly dosage-related²⁷ and are expected to increase as doses increase; this is a concern for a narrow therapeutic-window drug. The U.S. double-blind studies also suggested that 16 mg/day is associated with a high prevalence of somnolence (9%, versus 3% in other doses).¹⁹

Personalizing Doses: Safety Versus Efficacy Approaches
Roses²⁸ described safety and efficacy pharmacogenetics. Safety pharmacogenetic testing helps clinicians and selected patients decide if they should "not take that drug" or "take this low or high dose," which is called safety pharmacogenetics. Although it has not been systematically studied, risperidone ADRs are probably mainly independent of psychiatric diagnosis if other aspects, such as dosing, treatment duration, and co-medication are controlled, particularly if we are talking about average adult patients. Thus, many risperidone ADRs in the average patient are mainly related to dosing, and, in similar doses, may be similar across different diagnoses.

Efficacy pharmacogenetics is much more complicated, since it depends on how response is defined. The response of psychotic symptoms in schizophrenia may tell us little about R response in mania or autistic disorders. Typically, studies for approving drugs focus on significance, but another statistical concept, effect size, may be more relevant to clinical practice,²⁹ particularly when considering the competing concern of ADRs.³⁰ Although the effect size of R efficacy has not been compared across conditions, on the basis of our clinical experience, the effect size of R on some off-label conditions is rather small, as compared with those seen in schizophrenia. For example, the effect of R, or any AP in borderline personality disorder, is rather small. This means that, when compared with schizophrenia response, the effect of R on personality disorders may be much more easily lost if one uses a small study or there is too much "noise" in the sample.

R response in different conditions (schizophrenia, mania, dementia, or autism) may be influenced not only by different effect sizes but also by different time-courses and symptoms. Thus, personalizing R to establish better efficacy may be much more complicated than personalizing R for safety reasons. Pharmacokinetic factors may be relatively more important in safety, whereas antidopaminergic properties, a pharmacodynamic factor, are crucial in understanding AP efficacy. Efficacy in off-label conditions is very poorly understood, although R’s antidopaminergic properties may be important.

In summary, personalizing R dosing to avoid ADRs is going to be much easier than personalizing R to establish optimal response to the various conditions for which R is prescribed. To translate these concepts into the language of therapeutic windows and R levels (see section on R levels), safety pharmacogenetics focuses on the upper range of the therapeutic window, whereas efficacy pharmacogenetics focuses on the lower range of the therapeutic window.

PHARMACODYNAMIC FACTORS

TOP ABSTRACT INTRODUCTION OPTIMAL RISPERIDONE DOSING AND... PHARMACODYNAMIC FACTORS REFERENCES

 
The influence of some clinical variables on R dosing, presumably through pharmacodynamic factors, is well understood by clinicians.¹⁴ However, our detailed understanding of how these or other pharmacodynamic factors, genetic or environmental, influence R dosing is rather limited and difficult to understand, because of limited understanding of how APs really work and the difficulties of studying the brain "in vivo."

Our current understanding of R’s influence on brain receptors suggests that, first and most importantly, the blockade of dopamine-2 receptors (D₂) continues to be the cornerstone of our understanding of R’s AP action and of the most frequent ADRs, particularly EPS and hyperprolactinemia. Our limited understanding of the genetic variations in the D₂ receptor gene (DRD2) is reviewed. Other R response factors to consider include 2) other dopamine receptors; 3) adrenergic receptors; 4) 5-hydrotryptamine (5-HT) or serotonin receptors; 5) histamine receptors; and 6) pharmacodynamic systems other than neurotransmitter receptors.

Ideally, we should present for each brain receptor the information about the genetic and environmental variations that may influence R response. Before starting the review of each pharmacodynamic target, we provide a general introduction to the genetics of neurotransmitter receptors and the limitations of what is known in that area. The environmental variants that may modify R binding to pharmacodynamic targets have not been studied because it will require in-vivo studies in patients, using brain-imaging that can measure receptor-binding, such as positron-emission tomography (PET) or single-emission computed tomography (SPECT) studies. Unfortunately, these techniques are relatively new, expensive, invasive, and complicated by the use of isotopes, making large studies difficult. We would hope these techniques may be used in the future to explore the influence of environmental (and genetic) variations in R, or AP response. Because our knowledge of environmental factors influencing pharmacodynamic factors is almost absent, we have developed another area of known clinical factors that presumably influence pharmacodynamic response to R.

Introduction to Genetic Influences on Neurotransmitter Receptors
In-vitro data clearly suggest that different APs have different receptor binding, and the differences in these profiles have been associated with differences in APs’ ADRs.³¹ Moreover, as many APs share with R the same receptor blockade, one can assume that genetic variations are likely to have similar influences in those APs sharing with R the same receptor-antagonistic properties. Genetic research on AP response will become much more complicated if genetic variations result in differential influencing of the receptor blockade by different APs, as an in-vitro study has suggested.³²

Unfortunately, the pharmacogenetic approach, using brain-receptor polymorphisms, has provided inconsistent results, and possibly-significant findings have rarely been replicated.¹¹ As a matter of fact, for antipsychotics, the pharmacogenetics of pharmacodynamic genes appears much more complicated than the pharmacogenetics of some specific pharmacokinetic genes.⁸ There are several reasons explaining the relatively slow progress in this area when compared with pharmacokinetic genes: 1) the difficulty of establishing associations between genetic variations and changes in function; 2) the role of silent, non-functional SNPs; and 3) the lack of extensive knowledge of racial variations.

To establish that an SNP influences the expression of a receptor and/or its functionality, one needs to conduct in-vitro studies. In-vitro studies are difficult to extrapolate to the clinical world. The only way to measure receptor-binding in vivo is by brain-imaging studies, which are difficult and expensive. Assuming that a brain receptor variation is present in 10% of the population and that one wants to study its relevance to risperidone ADRs, establishing a significant association may require hundreds or thousands of patients; whereas most PET or SPECT studies tend to have fewer than 100 patients.

Researchers have published many significant associations between an SNP in a brain receptor and AP ADRs, but many of these SNPs are not functional. Using the typical cut-off significance of p<0.05, it is not hard to find an association between a genetic variation and AP response; one only needs to try 20 different ways of defining AP response to find one significant by chance. Because journals tend to publish significant findings, it is not rare that a researcher, after doing a genotyping study, tries many associations until one reaches significance.

The racial variations of many of these pharmacodynamic genes have not been systematically studied. When comparing our knowledge of a pharmacodynamic gene with reasonable face validity, DRD2, versus one of the most studied pharmacokinetic genes, CYP2D6, it becomes clear that our understanding of the genetics of pharmacodynamic influences is far less developed. CYP2D6 has more than 90 known genetic variations and more than 60 alleles. The functional effects of many of these CYP2D6 alleles are known and are not hard to study, using a phenotyping test that requires giving a pill and measuring urine metabolites. The racial variations are relatively well understood, and it is thought that measuring approximately 20 alleles may provide reasonable information to a clinician.³³ These 20 alleles will establish whether or not the enzyme is present, and, if present, whether it has more or less activity than normal. DRD2 has three known genetic variations that are thought to possibly influence function, according to in-vitro studies, but in-vivo brain-imaging studies are missing. The racial variations have not been well-studied. It may be possible that evolution pressure and gene instability are not as high as in the CYP2D6 gene, but it would not be surprising to find that other frequent and important functional genetic variations have not yet been identified.

This article cannot provide a detailed review of all genetic variations studied for their association with APs. Table 1 summarizes for clinicians the limited information that we have on the potential for our knowledge of pharmacodynamic genetic variations to facilitate safety pharmacogenetics in patients taking APs in general and R in particular. A recent extensive review on the pharmacogenetics of APs¹¹ provided a more in-depth discussion of efficacy and safety pharmacogenetics, including tardive dyskinesia, a complicated ADR to study, since it is influenced more by previous AP treatments than by current treatments.³⁴ Surprisingly, efficacy pharmacogenetics, particularly with clozapine, have focused more on the 5-HT_2A gene than on the dopamine-receptor genes.^35,36

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TABLE 1. Pharmacodynamic Genetic Variationsa That May Predict ADRs of Antipsychotics

Introduction to Environmental Influences on Neurotransmitter Receptors
After reading the previous section and realizing that our understanding of the pharmacogenetics of R’s pharmacodynamics is very limited, one would like to hope that our understanding of the environmental influences on R pharmacodynamics is better. Unfortunately, the opposite is true; we have almost no understanding of how environmental factors influence the pharmacology of brain receptors. The only real fact is that some drugs share the receptor-blocking abilities of APs. In spite of this limited pharmacologic knowledge, clinical knowledge suggests that several factors, such as previous exposure to APs, may influence R dosing. This clinical information is described in the next section, on the clinical application of pharmacodynamic factors. The fact is that pharmacologic science currently does not explain the detailed mechanisms by which these clinical variables influence R’s pharmacodynamic response.

Risperidone Blockade of Brain-Receptors
R, as is true of most of the APs, has a "dirty" profile and blocks many brain-receptors. The most important ones are probably the D₂ receptors, which may explain the AP action. Other dopamine-receptors are only briefly reviewed because of R’s lower affinity for them. According to in-vitro studies, clinical doses of R have the potential to block alpha₁, alpha₂, 5-HT_2A, 5-HT_2C, and H₁ receptors.³⁷ All of them are briefly reviewed, since they may contribute to R response, at least for risperidone ADRs. As a matter of fact, R affinity for 5-HT_2A receptors is 10 times higher than for D₂ receptors.^37,38

D₂ Receptors
The linear relationship between D₂ affinity and dosages of typical APs led to the hypothesis that D₂ blockade should explain AP action.³⁹ Clozapine did not fit that schema. Two initial theories were proposed to explain this clozapine discrepancy: 1) the D₄; and 2) the 5-HT₂/D₂ ratio theories. Seeman⁴⁰ hypothesized that clozapine may act through D₄ receptors. However, D₄-selective antagonists do not have AP properties, likely ruling out D₄ as a major influence in AP response.⁴¹ Meltzer et al.⁴² proposed that clozapine and other atypical profiles were explained by the ratio between 5-HT₂ and D₂ receptors. However, some of the typical APs have high ratios, and a 5-HT_2a antagonist does not have AP action.⁴¹ More recently, Seeman and Tallerico⁴³ suggested that clozapine may show a different profile, with low D₂ blocking in in-vivo studies because of low clozapine affinity for D₂, which would allow clozapine to be displaced by dopamine (it is estimated that 25%–40% of D₂ receptors are occupied by endogenous dopamine).⁴¹ Therefore, low affinity and fast dissociation from D₂ receptors would explain the atypicality among some APs, such as clozapine and quetiapine, which can be displaced by dopamine.⁴¹ In a very graphic way, these APs are described as having "hit-and-run" action toward the dopamine D₂ receptor, hitting this receptor with sufficient force (binding affinity) to result in AP effects, yet binding weakly enough to dissociate from the receptor (run) before causing EPS.⁴⁴ The idea that clozapine and quetiapine are the only the "real" atypical APs because of their low affinity and fast dissociation is compatible with their favorable profile in Parkinson’s disease (PD).^45,46 Other atypical APs, such as R and olanzapine, produce many more parkinsonian side effects in PD.^45,46 Thus, according to this theory, there is a continuum from typical APs to R and olanzapine, whereas only quetiapine and clozapine are true atypical APs.

In summary, D₂ blockade probably explains AP action. PET studies indicated that occupancy of at least 65% of the D₂ receptors is needed to get a clinical response and that occupancy rates exceeding 72% and 78% are associated with high risk of hyperprolactinemia and EPS, respectively.²² R affinity for D₂ receptors was high and similar to those of haloperidol and ziprasidone; 9-OHR had slightly higher affinity for D₂ than R.³⁷ Textbooks usually describe AP action as taking place in the dopaminergic mesolimbic or mesocortical systems,⁴⁴ whereas EPS are associated with the blockade of the dopaminergic nigrastriatal system, and hyperprolactinemia with the blockade of the dopaminergic tuberoinfundibular system. In truth, the mesolimbic theory of AP actions was proposed in several articles in the 1970s,⁴⁷ but there is limited empirical evidence to support it.⁴⁸

The D₂ receptors express themselves in two alternative splice-variants, D₂-short and D₂-long, but the relevance of this for AP response is not clear at this time.⁴⁹ It appears safe to say that R’s AP action is probably mainly explained by blocking D₂ receptors and that R causes reversible EPS by blocking D₂ receptors in the nigrostriatal system, and hyperprolactinemia by blocking D₂ receptors in the tuberoinfundibular system. Polymorphic variations in this gene (DRD2) should be crucial for explaining individual differences in R (or any AP) efficacy or in the generation of EPS or hyperprolactinemia. However, it disappointing that the studied polymorphic variations of DRD2 appear to have no relevance in predicting EPS or hyperprolactinemia (Table 1).

Other Dopamine Receptors
It is believed that D₁ has a role in the motor, cognitive, and cardiovascular actions of dopamine.⁵⁰ Although R and other APs have much lower D₁ affinity than D₂ affinity,³⁸ it is possible that D₁ antagonism may contribute to AP action, although several small studies with D₁ antagonists have failed to find evidence of AP action. Moreover, they may even exacerbate psychotic symptoms.⁴⁹ Thus, it is not currently clear how D₁ blockade may contribute to risperidone’s AP action or adverse drug effects.

D₃ receptors are highly expressed in limbic regions, but the highest expression in the human brain appears to be in the ventral striatum.⁵¹ D₃ has pharmacology similar to D₂. In-vitro studies^38,52 and in-vivo human brain studies⁵³ suggest that R may have affinity for D₃, although lower than that for D₂. The role of D₃ in antipsychotic response or in the ADRs of antipsychotics is not well-understood, but it may become better understood when more selective D₃ receptor antagonists are developed.^51,54

Because clozapine had higher affinity for D₄ than for D₂, much hope was given to finding highly-selective D₄ blockers; unfortunately they lack antipsychotic efficacy.⁴⁹ R has lower D₄ than D₂ affinity³⁸ but it is unclear how D₄ blockade may contribute to risperidone’s AP action or ADRs.

Adrenergic Receptors
An in-vitro study suggests that R may be a much more potent blocker (>3 times) of alpha₁ receptors than 9-OHR, and could be the most potent blocker among the atypicals marketed in the United States.³⁷ Alpha₁ antagonism has mainly been associated with orthostatic hypotension and genitourinary ADRs, and occasionally with weight gain. R’s high affinity for alpha₁ receptors may explain its propensity to cause orthostatic hypotension. An important environmental variable to consider is that these receptors appear to be prone to tolerance. Soon after the introduction of chlorpromazine, it was obvious that patients develop tolerance to orthostatic changes.⁵⁵ Thus, there is some pharmacological mechanism not well understood that blocks alpha₁ receptors for a few days, but, after that, its continued blockade is no longer associated with loss of the reflex changes in blood pressure and pulse that occur when R or some other AP that has alpha₁-antagonist properties is started. This tolerance explains the need for titrating R doses until the patient gets used to alpha₁ antagonism.

Sexual dysfunction, particularly ejaculatory dysfunction, is an area usually associated with alpha₁ antagonism.⁵⁶ It is also thought that urinary ADRs of risperidone, such as urinary incontinence, may be associated with alpha₁ antagonism.⁵⁷ Patients with risperidone ADRs may have both sexual and urinary symptoms at the same time.⁵⁸

The alpha₁ antagonists are used to treat benign prostatic hypertrophy. It has traditionally been thought that the blockade of the alpha₁ receptor causes relaxation of the periurethral, prostatic, and bladder-neck smooth muscle. Currently, actions at more central levels (peripheral ganglia, spinal cord, and brain) are also suspected.⁵⁹ Given that some of these alpha₁ receptor antagonists are used to treat benign prostate hypertrophy, they may also influence sexual functioning; there is face validity in thinking that R’s alpha₁ blocking properties may explain risperidone ADRs at the sexual and urinary levels. Other mechanisms besides a blockade of peripheral alpha₁ receptors may be associated with R’s genitourinary ADRs. A rat study on urinary functioning suggests a crucial role for brain mechanisms,⁶⁰ and hyperprolactinemia may contribute to R’s sexual side effects.⁶¹

Little research in genetic variations of the alpha₁ receptor gene has been done.^62,63 Of the ADRs, only urinary incontinence has been studied (in one negative study), and orthostatic hypotension and sexual ADRs have never been studied (Table 1). Medications that interfere with alpha₁ receptors (e.g., prazosin, terazosin, tamusolin, doxazosin, labetalol) are used in the treatment of hypertension or benign prostate hyperplasia. Co-medication with any of these drugs may increase risperidone’s ADRs through increased blockade of alpha₁ receptors.³¹

The alpha₂ receptors are thought to be mostly inhibitory, presynaptic autoreceptors that regulate the release of noradrenaline in the brain.⁶⁴ The in-vitro study comparing APs suggests that R is a more potent blocker of alpha₂ receptors than 9-OHR (>5 times), and R could be the most potent blocker among the atypicals marketed in the United States.³⁷ The role of alpha₂ receptors is not well understood. R’s alpha₂ blockade may block the actions of antihypertensives thought to stimulate alpha₂ receptors, such as clonidine.³¹ Another possibility is suggested by the fact that alpha₂ blockade is the core mechanism of action for the antidepressant mirtazapine.⁶⁵ This feature of R’s receptor blockade profile may contribute to some antidepressant clinical activity.

Serotonin Receptors
The 5-HT_2C receptors are found in the prefrontal cortex, the limbic structures, and the choroid plexus.⁶⁶ R’s affinity for 5-HT_2C receptors was found to be 10 times lower than clozapine and olanzapine affinity. 9-OHR had similar affinity for 5-HT_2C.³⁷ Some authors suggest that 5-HT_2C blockade may contribute to the antianxiety actions of atypical APs,⁵⁰ but that is difficult to prove in the clinical environment. The blockade of 5-HT_2C has been persistently associated with the increased appetite seen in patients taking APs. Mutant mice that lack 5-HT_2C receptors are reported to eat more food, independent of leptin levels.⁶⁷ Several review studies comparing risk of weight gain and in-vitro receptor affinity suggest that greater affinity for 5-HT_2C may be associated with greater risk of weight gain.^68,69 Therefore, it is not surprising that genetic variations in this receptor gene, located on Chromosome X, have been of major interest in predicting AP-induced weight gain.^66,70 Unfortunately, the results have not been consistent (see Table 1). A recent study on weight gain and R showed association with a 5-HT_2C receptor gene variation, other 5-HT gene receptor variations, and some non-genetic factors.⁷¹ We know very little about environmental factors that may influence the R blockade of action at 5-HT_2C receptors. An obvious fact is that if the patient is taking another AP that blocks 5-HT_2C receptors, this may contribute to weight gain in patients taking R.

In a comparative study of AP in-vitro receptor binding, R affinity for 5-HT_2A receptors was very high, almost as high as the most potent 5-HT_2A blocker, ziprasidone. 9-OHR had much lower affinity for 5-HT_2A (10 times lower than R).³⁷ The 5-HT_2A receptors are highly concentrated in cortical pyramidal cells, and, as indicated, a theory has been proposed that 5-HT_2A/D₂ receptor ratios may contribute to an allegedly better profile of some atypical APs for cognition or mood.^44,50 The possibility that 5-HT_2A may be relatively irrelevant for AP efficacy cannot be ruled out, since chlorpromazine has very high affinity for this receptor.⁶⁶ Similarly, the lack of commercializing of ritanserin suggests that 5-HT₂ blockade may be more significant in risperidone’s ADRs than its efficacy. Ritanserin is a specific 5-HT₂ and 5-HT_1C blocker. It does not appear to have AP properties;⁷² moreover, it may worsen psychosis in some patients.⁷³ Ritanserin may have some antiparkisonian,⁷⁴ anti-anxiety,⁷⁵ and antidepressant properties.⁷⁶ Surprisingly, ritanserin caused relatively small weight increases, 1.5 kg–2 kg after 6 months, versus 0.8 kg with placebo,⁷⁷ suggesting that other mechanisms besides 5-HT₂ blockade may contribute to weight gain seen with antipsychotics.

Histamine Receptors
R’s affinity for H₁ receptors is intermediate between olanzapine (maximum affinity) and haloperidol (little affinity). 9-OHR has somewhat more affinity than R for H₁.³⁷

Because of the sedating effects of antihistaminic drugs, it is generally thought that H₁ blockade may also contribute to the sedating properties of APs. Review studies comparing risk of weight gain and receptor affinity suggest that greater affinity for histamine H₁ receptors may be associated with greater risk of weight gain.^68,69 This association may be stronger for H₁ than for 5-HT_2C blockade.⁶⁹ Recently Kim et al.⁷⁸ have demonstrated that mice with deletion of H₁ do not show increased appetite when taking APs. On the other hand, if H₁ blockade is a major determinant of weight gain associated with APs, the antihistamine drugs used in allergy treatment, which are H₁ antagonists, should cause weight gain. They do not cause important weight gains, however, perhaps because they are used in lower doses.⁷⁸ Other authors have proposed that the antagonism of other receptors at the same time as H₁ blockade is the reason APs cause weight gain. A rat study suggested that for H₁ blockade to cause hyperphagia, other receptors, particularly 5-HT₂ and muscarinic receptors, need to be blocked, as well.⁷⁹ Recently, it has been found that a new type of histamine receptor, H₃, may influence appetite and is blocked by antipsychotics.⁸⁰

Ever since chlorpromazine was introduced, it has been obvious that patients develop tolerance to sedation. Since tolerance to the sedating effects of diphenhydramine, an H₁ antagonist, develops in 4 days,⁸¹ it is very likely that the development of tolerance to H₁ blockade during AP treatment may explain tolerance to AP-induced sedation, but this has not been studied.

Little research has been done on the variants of the H₁ receptor gene. There are no association studies on AP-induced sedation and few on weight gain.^82,83 An obvious environmental influence that may contribute to R sedation is that of a patient who also takes antihistaminic drugs that block H₁ receptors, perhaps adding to R’s action at these receptors.

Pharmacodynamic Targets Other Than Neurotransmitter Receptors
Mechanisms other than neurotransmitter receptor-blockade may be important in regulating R response. Genetic variations at those levels may influence R response, but these other mechanisms are even more poorly understood. Two examples of other brain pharmacodynamic components that may influence R response are the dopamine catabolic system (e.g., the catechol-O-methyltransferase, COMT enzyme) and the second messenger system. There is very limited information about genetic variations of these and their association with AP response.¹¹

Blocking some neurotransmitter receptors, particularly H₁ and 5-HT_2C, may explain why R can increase appetite and lead to obesity. However, it is possible that R and other APs may have other direct effects on glucose and lipid metabolism not explained by the blocking of neurotransmitter receptors.³⁰ Newcomer and Haupt⁸⁴ estimated that approximately 25% of the patients who develop type 2 diabetes mellitus on APs do not show substantial weight gain or obesity. Atypical APs may directly increase insulin resistance by decreasing insulin-sensitive glucose transporters, or by causing an inability to stimulate the recruitment of glucose transporters from microsomes to the plasma membrane,^85,86 or by elevating serum free fatty acids, thus producing insulin resistance.⁸⁷ The exact mechanisms and relative importance of these mechanisms is not known. Similarly, it is not known whether R has relevant direct effects on glucose metabolism or these effects are mainly associated with clozapine and olanzapine. Similarly, hyperlipidemia patients taking APs in the absence of obvious weight gain have been described. The mechanisms that cause hypercholesterolemias and/or hypertriglyceridemias are not known. It is also not clear whether these direct effects may occur with R or may only occur with olanzapine, clozapine, quetiapine, and low-potency typical APs.^30,88 Several peptides involved in appetite and glucose and lipid metabolism, such as leptin and neuropeptide Y, may be associated with the metabolic effects of the APs, but the mechanisms are not well-understood, and there are few genetic association studies in this area.¹¹

First R, and, later, other atypicals, were associated with increased risk of cerebrovascular events in dementia patients. The possible mechanisms are not well understood; moreover, it is not clear that the risk is greater than the risk associated with the use of typical APs.⁸⁹ In summary, until the mechanisms are better understood, it is not possible to make suggestions for personalizing R dosing to avoid or decrease the risk of cerebrovascular events in dementia patients taking R.

APs can increase the QTc interval.⁹⁰ It is thought that they cause this effect by blocking ion channels such as the sodium, potassium, and calcium channels, or by interfering with calmomudulin, an intracellular calcium-binding protein.⁹¹ In-vitro studies have shown that R may interfere with these ion channels⁹² and may cause mild increases in QTc.^90,93 However, these actions are probably not clinically relevant for three reasons: 1) R has only very rarely been associated with arrhythmias;⁹³ 2) overdoses of R do not appear to be associated with arrhythmias;⁹⁴ and 3) epidemiological studies do not appear to associate R with increases in sudden deaths secondary to arrhythmias.⁹⁵ The data on increased sudden deaths of patients taking APs refers mainly to typical APs. In summary, the actions of R on ion channels, if they exist, are probably not clinically relevant in patients without heart problems, and the authors do not expect that the pharmacodynamic effects of R on ion channels will be used to personalize R dosing.

ACKNOWLEDGMENTS

 
This article is being presented in two parts. Part 2 will appear in the July–August issue.

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Dept. of the Army or the Dept. of Defense.

Dr. de Leon is the Medical Director of the University of Kentucky Mental Health Research Center, Eastern State Hospital, Lexington; and Professor of Psychiatry, College of Medicine, University of Kentucky, Lexington, and Visiting Professor at the Department of Psychiatry and Institute of Neurosciences, University of Granada, Granada, Spain.

Dr. Sandson is a psychiatrist in the Veterans Affairs of Maryland Health Care System, Director of the Psychopharmacology Consultation Service for the Sheppard Pratt Health System, Towson, MD, and Clinical Assistant Professor in the Department of Psychiatry at the University of Maryland Medical System, Baltimore, MD.

Dr. Cozza is a staff psychiatrist for the Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC, and Assistant Professor of Psychiatry, Uniformed Services University of Health Sciences, Bethesda, MD.

The authors thank Lorraine Maw, M.A., for editorial assistance. The first author is grateful to Marja-Liisa Dahl, M.D., Ph.D., and Adrian Lerena, M.D., Ph.D., who introduced him to pharmacogenetics in 1994; Larry Ereshefsky, Pharm.D., F.C.C.P., who helped him to access the limited R-level literature by sending some posters on R levels in 1997; and Edward Maxwell, M.D., who, for more than 5 years, has encouraged and helped his attempts to translate pharmacogenetic research into language understandable by clinicians.

In the past year, Dr. de Leon has been on the advisory board of Roche Molecular Systems, Inc. He has received investigator-initiated grants from Roche Molecular Systems, Inc., and Eli Lilly Research Foundation; he has lectured supported by Eli Lilly, Janssen, and Roche Molecular Systems, Inc. Roche Molecular Systems, Inc., markets the AmpliChip CYP450 microarray that detects CYP2D6 and CYP2C19 gene variations.

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