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Psychosomatics 49:347-361, July-August 2008
doi: 10.1176/appi.psy.49.4.347
© 2008 Academy of Psychosomatic Medicine
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* Atypical Neuroleptics

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

Jose de Leon, M.D., Neil B. Sandson, M.D., and Kelly L. Cozza, M.D.

From the University of Kentucky Mental Health Research Center, Eastern State Hospital, and The College of Pharmacy, 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

Key Words: Risperidone • Dosing • Genetics

  INTRODUCTION

 
TOP
 INTRODUCTION
CLINICAL APPLICATIONS OF...
 PHARMACOKINETIC FACTORS
 REFERENCES
 
This article is Part 2 of this Drug–Drug Interaction column. Part 1 was presented in the May–June issue (Psychosomatics 2008; 49:258–270).


  CLINICAL APPLICATIONS OF PHARMACODYNAMIC FACTORS

 
TOP
 INTRODUCTION
 CLINICAL APPLICATIONS OF...
PHARMACOKINETIC FACTORS
 REFERENCES
 
Antipsychotic Polypharmacy
The guidelines developed by experts in schizophrenia recommend monotherapy treatment and avoidance of co-prescription of several antipsychotics (APs).96,97 The pharmacologic reason for AP monotherapy is that all APs (except aripiprazole, a partial agonist) are antagonistic to D2 receptors, so that adding more than one AP will only create greater dopamine blockade and, according to brain-imaging studies, more risk of extrapyramidal symptoms (EPS), but no additional therapeutic benefit. If one believes that the low affinity binding for clozapine contributes to its peculiarities, one could try to argue about the possibility of supplementing clozapine with other APs with higher D2 affinity. However, from the pharmacologic point of view, assuming that risperidone (R) causes its AP effects through D2 blockade, there is no pharmacologic reason to add other APs to R treatment. AP polypharmacy may not appear rational to academic psychiatrists,98,99 but it is becoming increasingly frequent in actual clinical practice. In a United States study,13 12% of R patients were also taking a typical AP, and 14% were taking other atypicals. In a French study,12 27% of R patients were taking other APs. In summary, although the prevalence of co-prescription of APs may vary from area to area, it is probably one of the most prominent and frequent environmental factors that may influence R pharmacodynamic response. Pharmacokinetic drug–drug interactions (DDIs) depend on the pharmacokinetic profiles of the co-prescribed APs.37 Besides the obvious avoidance of polypharmacy, the best recommendation for personalizing R dosing in patients taking other APs is that if the patient is going to be continued long-term on more than one AP, the dosages may need to be reduced, since both APs may be binding to the same brain receptors.

Lack of Previous Exposure to Antipsychotics
Williams14 reviewed the literature on first-episode patients and recommended a starting dose of 1 mg/day, an initial target of 2 mg/day, with maximum recommended doses of 4 mg/day. In summary, the dosage for the first episode would be approximately half of that used in average schizophrenia patients.

Some old concepts developed in the typical-AP era can help in understanding this issue: Haase, a German pharmacologist, proposed that after reaching AP action, there is a point at which EPS will start appearing: "the neuroleptic threshold."100 Beyond this threshold, further increases of AP dosage will be of no benefit; moreover, there will be a progressive increase in EPS. As Haase suggested, clinicians have used handwriting, a subtle sign of parkinsonism, to detect the neuroleptic threshold.101 McEvoy and coworkers,102,103 in a series of key studies, used the onset of parkinsonian signs to assess the neuroleptic threshold of haloperidol. In a controlled study, they established that AP-naïve patients have a lower neuroleptic threshold (2.1 [SD: 1.1] mg/day of haloperidol versus 4.3 [2.4] mg/day). As a matter of fact, all 32 naïve patients reached the neuroleptic threshold with 5 mg/day, whereas 38% (28/74) of the non-naïve patients had thresholds higher than 5 mg/day, with a maximum threshold of 11 mg/day.103 The neuroleptic threshold has never been studied in R patients, but it is believed that R and haloperidol doses are roughly equivalent.104 In a double-blind, randomized, controlled trial with flexible doses, in first-episode psychosis, patients were treated with a mean/modal dose of 3.3 mg/day for R and 2.9 mg/day for haloperidol. The EPS were significantly greater in the haloperidol group, and prolactin levels were higher in the R group.105

Reviews focused on first-episode patients106 have suggested that naïve patients need to be treated with a lower dose of APs in general, and R in particular. Assuming that this is true, exposure to APs may make patients "tolerant," requiring higher R doses; this phenomenon is called "tolerance" in the pharmacologic literature. Using pharmacological knowledge, one can predict that tolerance of R may be explained by an increase in D2 receptors or a decrease in their response, or the combination of both. As far as the authors know, dopaminergic receptor tolerance has not been well studied in animals; more importantly, in the in-vivo literature using brain-imaging studies; the authors found few references to the possibility of AP tolerance. Kurachi et al.107 suggested that there was an increase in dopamine metabolism in several brain areas, including the caudate putamen in rats exposed to haloperidol decanoate. More recently, Samaha et al.108 studied continued exposure to haloperidol in two rat models to try to model the loss in response to haloperidol. They found that continuous exposure was associated with a 20%–40% increase in D2 receptors and an increase in sensitivity (100%–160% increase in the proportion of receptors in the high-affinity state for dopamine). In summary, previous exposure to APs is one of the environmental factors that probably acts through pharmacodynamic changes that influence R response and needs to be considered when personalizing R dosing.

Aging
When Williams14 reviewed the literature on elderly patients, he suggested that R doses of 2 mg/day are most appropriate. He recommended a starting dose of 0.25 mg/day, using a slow titration. Some patients may need 3 mg–4 mg per day. In summary, the average final doses for elderly patients (> 65 years old) would be approximately half of those used in average schizophrenia patients, but with an even lower starting dose.

As described later, R dosing differences associated with aging are partly explained by pharmacokinetic factors, with reduced R elimination, but it is likely that there is a pharmacodynamic component as well—a change in dopaminergic tone with aging that would make the brains of elderly patients more sensitive to adverse drug reactions (ADRs). This mechanism is not well studied, but one can hypothesize that it may be explained by a loss of dopamine neurons associated with aging, since both brain-imaging and postmortem histological studies support this idea.109 Aging brings significant reductions in pre-synaptic markers (neuronal loss and dopamine biosynthesis and reuptake). Dopamine metabolism by MAO-B increases significantly in later life. There are decreases in the densities of post-synaptic D1 and D3 receptors; however, the rate of receptor decline (linear or exponential), the effects of gender and heterogeneity, and the mechanisms by which these changes occur remain undetermined. Limited data suggest there is a significant association between postsynaptic receptor density and specific aspects of motor and cognitive functioning.109 In their review, Stark and Pakkenberg110 reported that many histological studies report a reduction of overall volume of substantia nigra with aging, but they emphasize the limitations of the studies and the difficulty in interpreting what this means for dopaminergic functioning.

The effect of aging in neurotransmitter systems other than dopamine has not been well studied. DeVane and Mintzer111 suggested that elderly patients may be more sensitive to the blockade of cholinergic, histaminic, and adrenergic receptors. According to Palmer and DeKosky,112 there is an age-related loss of noradrenergic cell bodies from the locus coeruleus, but most studies indicate normal concentrations of noradrenaline in target areas. There is also evidence for reduced serotonergic innervation of the neocortex and, less convincingly, the neostriatum. Regardless of the mechanism, clinicians are aware that the need for slower R titration in aged patients is probably related to greater risk of orthostatic changes in older patients.14 Obviously, pharmacodynamic DDIs may contribute to orthostasis if the patient is taking any cardiovascular medication that may cause hypotension or interfere with the reflex mechanism combating orthostatic changes. It is likely that elderly patients not taking other medications may still be more susceptible to orthostatic changes for several reasons, including reflex impairment.

Presence of a Dementing Illness
When Williams14 reviewed the literature on dementia patients, he suggested R dosages of 1 mg/day with a maximum dosage of 1.5 mg/day. He recommended a starting dose of 0.5 mg/day.

Alzheimer's disease is associated with major changes in pharmacokinetic targets, with pronounced cholinergic, noradrenergic, and serotonergic denervation. Dopaminergic innervation of the neostriatum tends to be intact, although dopamine neurons are probably dysfunctional in this region.112

Parkinson’s Disease (PD)
The PD literature may help to provide a new understanding of the vulnerability to AP-induced parkinsonism or drug-induced parkinsonism (DIP). PD increases with aging, and most cases of PD appear sporadically. The most frequent environmental factors associated with PD are rural living, well-water usage, and exposures to pesticides or heavy metals.113,114 More recently, there has been an interest in familial forms of PD that follow Mendelian patterns with both early and late onset. The estimated sibling risk ratio for PD is around 1.7 (70% increased risk for PD if a sibling has the disease) for all ages, and it may increase by more than 7 times for those younger than 66 years.115 Several hereditary PD genes have been described in the ubiquitin–protease pathway. The degradation of proteins in this pathway is believed to lead to Lewy bodies, the pathognomonic sign of PD. Candidate genes include the genes of the protein {alpha}-synuclein and dardarin. The dardarin gene is called leucine-rich repeat kinase–2 (LRRK–2).113 LRRK-2 variants may be relatively frequent in Chinese patients with sporadic PD and may be used as risk factors in them, but appear to be rare in Caucasians.116 As a matter of fact, genome-wide scans have not shown common genetic variations that exert large genetic risks for late-onset PD in white North Americans.115

The traditional view of PD is that it has a long preclinical period and that by the time the symptoms are apparent, 60%–70% of nigrastriatal neurons have degenerated, and 80%–90% of the nigrastriatal dopamine has been depleted.117 Approximately 10% of asymptomatic persons age 50 or older have Lewy bodies, and their prevalence increases with age. Incidentally, Lewy bodies are associated with nigral cell loss and have traditionally been considered a sign of preclinical parkinsonism117 and a marker of the early stages of PD.118 It has been proposed that DIP, which typically increases with age, represents early or latent PD made evident by the dopaminergic-antagonist effects of APs and other drugs.117 Clinicians estimate that approximately 10%–30% of patients with DIP may develop persistent PD.119

Thus, assuming that an AP may unmask early or latent PD, the identification of subjects vulnerable to PD may help in personalizing R or AP treatment. The PD literature describes three main methods for identifying latent or subclinical PD: 1) genetic testing; 2) gene expression; and 3) brain-imaging. As indicated above, genetic testing is in its infancy, at least in identifying patients at risk for sporadic PD, who are probably the important cases with regard to preventing typical cases of parkinsonism in patients taking R. Although it has not been studied, one should assume that in the rare event that a patient taking R (or any other AP) reports a familial form of PD in his/her family, lower R doses and careful follow-up for avoiding DIP may be required, since the patient may have one or two copies of the familial gene. A promising step is that once the pathophysiology of PD is better understood, it may be possible that gene expression in blood120 could be used to identify individuals at risk for PD. Assuming that type of test could work in the practice of neurology, a secondary use may be to identify psychiatric patients at risk for DIP.

Currently, the most researched method to identify subclinical forms of PD is brain-imaging. Measuring dopamine receptor-binding with PET or SPECT has the problems of expense and the associated risk of using radioactive isotopes. In recent years, Berg121 has used transcranial sonography (TCS) as a method for the visualization of the brain parenchyma through the intact skull. Using TCS, increased echogenicity at the substantia nigra (SN) is found in about 90% of patients with PD. In contrast, increased substantia nigra echogenicity is rarely found in patients with atypical parkinsonian syndromes, providing a valuable tool for differential diagnosis. Interestingly, increased SN echogenicity can also be found in about 8%–10% of healthy subjects. In PET analyses, more than 60% of these clinically healthy individuals show a subclinical reduction of the striatal dopa uptake, indicating an alteration of the dopaminergic nigrostriatal system and nigral cell loss. Furthermore, subjects with an increased echogenicity of the SN developed more frequent and more severe DIP when treated with APs. Longitudinal studies indicate that the ultrasound signal does not change in the course of the disease. Presymptomatic carriers of mutations associated with monogenetic PD display the same echofeatures as their relatives already affected by the disease. These findings indicate that increased SN echogenicity may constitute a biomarker for vulnerability of the nigrostriatal system in healthy subjects, and eventually PD in a subgroup of persons with additional risk factors.

In the future, psychiatrists interested in personalizing R (or another AP) dosing may need to keep one eye on the neurology literature to determine whether TCS, genetic testing, or blood gene expression become reliable methods to identify patients with PD vulnerability, which can be used to identify patients at risk for DIP when taking R (or other APs).

Finally, this section focuses on how a new understanding of PD may help us in personalizing R dosing in patients without evident PD, but it does not talk about personalizing R dosing in psychotic patients with PD. The reason is obvious; the literature suggests avoding R in patients with PD. Clozapine, and more recently quetiapine, appear to be better antipsychotics for patients with PD than is risperidone.45,46

Association Between Parkinsonian Symptoms and Schizophrenia
Many years before the introduction of APs, Reiter122 proposed that some patients with schizophrenia have clear parkinsonian symptoms. More recently, Caliguri et al.123 reported that approximately one-third of AP-naive patients exhibit parkinsonian symptoms before starting AP treatment; others have verified this observation.124–126 De Eurasquin127 proposed that there is a distinct phenotypical subgroup of schizophrenia patients that present with parkinsonism before they are treated. If there is a subgroup of patients with schizophrenia who have parkinsonian symptoms even before they are treated, it appears reasonable to think that they may need to be treated with very low doses of R and other APs—lower than the typical naive patient. As a matter of fact, Chatterjee et al.’s study124 suggests that patients with spontaneous EPS were more prone to develop rigidity on typical APs. However, Kopala et al.128 reported that three patients with spontaneous EPS were free of EPS after low doses of R.

Mental Retardation and Developmental Disabilities (MR/DD)
Atypical APs, and particularly R, are frequently prescribed to patients with MR/DD disabilities.129 There are very limited empirical data to support its use and no thoughtful published discussion of whether the brain abnormalities associated with MR/DD involve pharmaco-dynamic changes that will require dosing adjustments when prescribing R. A panel chosen by R’s marketer reviewed the use of atypical APs in patients with MR, with particular emphasis on R.130 The panel reviewed initiation and target doses for the use of R for adults with MR. The panel considered four major indications for R treatment: psychosis, aggression, irritability, and impulse-control disturbances, and the doses varied in some of these indications, depending on the severity of the symptoms. A simplified version of their recommendations can be summarized by separating psychosis from the three other target symptoms (aggression, irritability, and impulse-control disturbances). For psychosis in patients with MR, the panel recommended initial doses of 1 mg–2 mg/day and target doses of 4 mg–6 mg/day. For very severe cases of the other target symptoms, initial doses of 1 mg–2 mg/day and target doses of 2 mg–4 mg/day were recommended, whereas lower doses were recommended for less-severe cases.

An 8-week, double-blind, randomized study indicated that R was effective and well tolerated for the treatment of tantrums, aggression, and self-injurious behavior in children with autistic disorders.131 This multicenter trial was one of the two used for FDA approval of R for irritability in autistic disorders.132 The package insert recommends dosages of 0.25 mg/day at initiation for patients weighing <20 kg, increasing to a recommended dosage of 0.5 mg/day after 4 days, and, if there is not enough response after 2 weeks, increasing in increments of 0.25 mg/day at ≥2-week intervals. The package insert recommends dosages of 0.5 mg/day at initiation for patients weighing ≥20 kg, increasing to a recommended dosage of 1 mg/day after 4 days, and, if there is not enough response after 2 weeks, increasing in increments of 0.5 mg/day at ≥2-week intervals. The published literature shows no agreement concerning the dosages indicated for autistic-spectrum disorders.133

Children With Other Disorders
R (and other atypical APs) are frequently used in other childhood psychiatric disorders besides MR/DD, including schizophrenia, bipolar disorder, tics, obsessive-compulsive disorder, and disruptive-behavior disorders, but the studies are rather limited.134–136 There are no good data indicating how younger age may influence R’s pharmacodynamic targets in the brain, but it is thought that children may have a higher density of D2 receptors.136 The package insert describes different initiation doses for weight higher or lower than 20 kg and suggests avoiding R in children with weight lower than 15 kg.

Presence of Organic Brain Problems in General
"Organicity" has traditionally been considered a risk factor for AP-induced EPS.137 As a matter of fact, several of the illnesses reviewed above, such as dementing illnesses or MR, would be included in the no-longer-used concept of "organicity." This traditional concept may have some value, given that some kind of "organic lesion" was present in almost one-third of the sample (31%) from the first author’s naturalistic R study, and it significantly increased the risk of risperidone ADRs (odds ratio [OR]: 1.7; confidence interval [CI]: 0.96–2.9). It may explain up to approximately 45% of the ADRs in patients in the first author’s naturalistic R study.34 Sensitivity in predicting ADRs was 40%; specificity was 61%; and accuracy was 71%.138 However, the presence of an organic lesion did not significantly predict R discontinuation due to ADRs.13


  PHARMACOKINETIC FACTORS

 
TOP
 INTRODUCTION
 CLINICAL APPLICATIONS OF...
 PHARMACOKINETIC FACTORS
REFERENCES
 
Two metabolic enzymes, CYP2D6 and the cytochrome P450 3A (CYP3A) subfamily of isoenzymes, as well as a transporter, p-glycoprotein (PgP), are crucial components in our understanding of R pharmacokinetic handling. These proteins are subject to genetic variations and are influenced by the environment. Particularly, DDIs associated with the intake of inhibitors and inducers may influence CYP or PgP. (For an excellent and highly informative description of possible drug–drug interaction patterns with metabolic inhibitors and inducers, see a previous update.)139

Cytochrome P450 2D6
CYP2D6 metabolizes several APs and antidepressant drugs,140 including R. According to Yasui-Furakori et al.,141 CYP2D6 regulates R hydroxylation to the two enantiomers, (+)–9OH and (–)–9OH. The CYP2D6 enzyme is expressed constitutively in several tissues, particularly the liver, so the types of CYP2D6 alleles expressed in a subject primarily define enzyme activity. The only significant environmental factor possibly modifying the phenotype is the intake of inhibitors. Paroxetine, bupropion, and fluoxetine are potent CYP2D6 inhibitors.

More than 60 alleles and more than 130 genetic variations (by combining SNPs and copy-number variations) have been described for this gene, located on Chromosome 22.142 The activity of the CYP2D6 enzyme is extremely variable because of various CYP2D6 alleles, but CYP2D6 activity can be expressed as one of four main phenotypes.143 The ultra-rapid metabolizer (UM) has three or more copies of the active CYP2D6 gene and exhibits extremely high CYP2D6 activity. The normal subject, or extensive metabolizer (EM), has one or two functional copies of the CYP2D6 gene and displays typical CYP2D6 activity. Intermediate-metabolizer (IM) status usually refers to subjects with one non-functional CYP2D6 allele co-expressed with a low-activity allele,143 although other definitions for IMs have been proposed.7 The poor metabolizers (PM) are subjects with two non-functional CYP2D6 alleles and no CYP2D6 activity. A numeric system can be used to approximate CYP2D6 activity, where the UMs would have an activity of ≥3, the EMs, <3 and ≥1, the IMs, <1 and >0, and the PMs, 0.144 (See Figure 1 and Figure 3.)


Figure 1
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FIGURE 1.  Estimations of the R/9-OHR Ratio Calculated Using the Manufacturer’s Multicenter Study (N=223)201

R/9-OHR: plasma risperidone/9-hydroxyrisperidone(R/9-OHR) ratio.



Figure 3
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FIGURE 3.  Estimations of the C/D ratio (C in ng/ml and D in mg/day) Calculated With Data From the Manufacturer’s Multicenter Study (N=223)201

The C/D ratio was 7.05 in the 2 mg/day dose, 7.15 in the 6 mg/day dose, 7.28 in the 10 mg/day dose, and 6.95 in the 16 mg/day dose.


Studies suggest that CYP2D6 PMs comprise 7% of the Caucasian population and 1% to 3% of other races. The published prevalences for CYP2D6 UMs are 1%–10% in European Caucasians and up to 29% in North Africa and the Middle East.8,145,146 It is possible that these UM prevalences may be too high, since they include subjects with any allele duplications, although some allele duplications are not associated with higher activity, which is the core aspect defining a UM. As a matter of fact, duplications of alleles with no activity, not rare in African Americans, may even be associated with a PM phenotype.147 Using a UM definition of at least three active CYP2D6 alleles, in more than 4,000 patients in Kentucky, the first author found a prevalence of CYP2D6 UMs of 1%–2% in Caucasians and African Americans.9 An unresolved issue is that some authors have hypothesized that CYP2D6 duplications do not identify all the genetic variations present in CYP2D6 UMs and that other genetic mechanisms may be behind the CYP2D6 UM phenotype.147 That is one possible hypothesis: CYP2D6 UMs are under-identified by our current genetic tests. The alternative hypothesis is that the phenotyping studies identifying higher frequencies of UMs may be incorrect because CYP2D6 phenotyping methods are crude tools measuring urine metabolites, which may be overestimating the number of UMs, since there is no discrete category for UMs using phenotyping methods but, rather, a continuum between EMs and UMs.147

IMs are much more frequent in East Asian populations, where the PM phenotype is rare, and the low-functioning allele *10 is very frequent. One has to acknowledge that we may not have definitive understanding of all the alleles that may have null activity versus those that have low activity in Black Africans and African Americans.33,148,149 The literature suggests that allele *17, typical of Black Africans, is associated with low CYP2D6 activity for metabolizing several CYP2D6 substrates,150 but we have found that R levels suggest that *17 has normal metabolic activity for metabolizing R.33 Because the *17 gene can present with duplications, we have recalculated the prevalence of CYP2D6 UMs in 4,000 patients to reflect the peculiarities of *17 on R metabolism and have generated a CYP2D6 UM prevalence of 1.5% (95% CI: 1.2% to 1.9%) in the total sample with 1.4% of Caucasians (CI: 1.0% to 1.8%) and 2.7% African Americans (CI: 1.2% to 4.2%).

One of the problems of thinking in terms of average patients is that the average patient in each of the different races may have substantial variation in R metabolic ability. The average patient among Caucasians is a CYP2D6 EM, whereas the average patient among East Asians is a CYP2D6 IM.

The FDA granted market approval for the first pharmacogenetic test using a DNA microarray, the AmpliChip CYP450, for CYP2D6 and CYP2C19 genotyping. It uses the Affymetrix technology of the GeneChip (Fodor)3 and has software to elucidate the four phenotypes and tests for 27 CYP2D6 alleles, including deletions and duplications.138,147 Approximately 16,000 oligonucleotides are inserted in the glass microarray to test for these SNPs and other genetic variations (deletions and duplications). Other systems using parallel testing to genotype for CYP2D6 exist but have not pursued FDA approval.147

The initial studies from R’s marketer suggest that R and its main metabolite 9-OHR have similar pharmacodynamic activity,151 and have implied that the total plasma R moiety (sum of plasma R and 9-OHR concentrations) determines R’s clinical activity.152 If correct, this eliminates concerns about the CYP2D6 metabolism of R, since a decline in 9-OHR is almost perfectly countered by a corresponding increase in R in CYP2D6 PMs. The published information supporting the concept that being a CYP2D6 PM phenotype is irrelevant for R treatment was based on an R study in healthy volunteers, using single R doses, measuring prolactin levels and plasma levels where PMs and EMs had similar total plasma concentrations of total R moiety (R+9-OHR). Only 11 subjects (2 PMs and 9 EMs) were studied by CYP2D6 phenotyping (Table 1).153 Taking single R doses using different routes can hardly be considered similar to clinical practice. Nonetheless, this initial study led to R’s package insert that proposed that CYP2D6 polymorphism expression and CYP DDIs were therapeutically unimportant for R.


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TABLE 1. Current Approximations for Personalizing Risperidone (R) Dosing by Combining Pharmacodynamic and Pharmacogenetic Influences



In a pilot R study, all five identified CYP2D6 PMs experienced ADRs while taking R.154 Case reports suggested that CYP2D6 UMs may need higher R doses.155,156 In our more recent R study, of 360 patients on R and 252 discontinued from R, after we corrected for confounding variables, CYP2D6 PMs had over three times the risk (OR: 3.4) of significant risperidone ADRs and six times more risk of discontinuing R (OR: 6.0) because of ADRs (versus other reasons for discontinuation).13 Thus, for CYP2D6 PM subjects (individual perspective), the CYP2D6 PM phenotype’s effects were consistent, powerful, and relevant. The main way to avoid risperidone ADRs in CYP2D6 PMs resided with prescribing small R doses.138 From the group perspective, being a CYP2D6 PM only explained 16% of the risperidone ADRs and 9% of the discontinuations due to ADRs.138

Cytochrome P450 3A
The CYP2D6 enzyme cannot be induced.157 The puzzling finding that carbamazepine induced R metabolism in one case led us to hypothesize that CYP3A also metabolizes R.158 This was later verified by in-vitro studies.159,160 CYP3A4 is the most important enzyme of the CYP3A subfamily, and there are no known cases of CYP3A4 PMs, although, recently, an allele with low activity has been described.161 However, another member of this isoenzyme family, CYP3A5, does exhibit pronounced genetic variation and shares high homology with CYP3A4; it appears to metabolize many of the same substrates. However, the clinical relevance of the CYP3A5 PM phenotype remains unclear.162 If a subject has two null alleles (CYP3A5*3 or CYP3A5*6), this results in inactive CYP3A5 expression,163 and the finding can be used to classify patients as CYP3A5 PMs. The CYP3A5 PM phenotype did not appear to influence R levels144 or risperidone ADRs13 in the first author’s study (Figure 1).

R metabolism by CYP3A4 may explain why CYP3A4 inhibitors and inducers influence R metabolism (see Figure 2 and Figure 4). Carbamazepine, phenytoin, and phenobarbital are powerful CYP3A4 inducers.164 The clinical relevance of CYP3A4 induction was clearly demonstrated in a double-blind, placebo-controlled study in which adding R to carbamazepine was no different for adjunct treatment of mania than adding a placebo to carbamazepine.165 However, adding R to lithium and valproic acid proved to be an adjunct manic agent. The lack of response to R in carbamazepine treatment can easily be explained by the lower R levels; they were 2.5 times lower that the R levels in patients taking lithium or valproic acid. In summary, in Yatham et al.’s study,165 the usual R doses were appropriate for patients taking valproic acid and lithium but were too low for carbamazepine patients because of metabolic induction.


Figure 2
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FIGURE 2.  Median R/9-OHR Ratio Calculated From de Leon et al.’s Study (N=277)144

UM: ultra-rapid metabolizer; EM: extensive metabolizer; IM: intermediate metabolizer; PM: poor metabolizer.

Among patients not taking CYP inhibitors, the median R/9-OHR ratio (and 25th, 75th percentiles) for 6 CYP2D6 UMs was 0.02 (0.02, 0.05); for 159 EMs, it was 0.08 (0.04, 0.16); for 15 IMs, it was 0.50 (0.27, 1.1); and for 12 PMs, it was 2.4 (1.6, 3.7). Among patients taking CYP inhibitors: for 2 CYP2D6 UMs, it was 0.28 (0.09, 0.47); for 60 EMs, it was 0.51 (0.17, 1.18); for 15 IMs, it was 1.0 (0.56, 2.6); and for 8 PMs, it was 3.1 (2.0, 4.9).



Figure 4
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FIGURE 4.  Median C/D Ratio Calculated From de Leon et al.’s Study (N=277)144

UM: ultra-rapid metabolizer; EM: extensive metabolizer; IM: intermediate metabolizer; PM: poor metabolizer.

Among patients not taking CYP inhibitors or inducers, the median C/D ratio (and 25th, 75th percentiles) for 6 CYP2D6 UMs was 5.5 (4.6, 7.8); for 151 EMs, was 6.8 (4.8, 9.3); for 13 IMs, was 7.3 (5.7, 10.3); and for 11 PMs, was 11.9 (4.5, 16). Among patients taking CYP inhibitors and not inducers, for 2 CYP2D6 UMs, it was 10.4 (6.3, 14.5); for 57 EMs, it was 9.0 (6.5, 13.6); for 15 IMs, it was 11.0 (4.5, 12.3); and for 7 PMs, it was 11.0 (7.5, 13.3). Among patients taking CYP inducers (with or without inhibitors), for 12 EMs, it was 3.0 (2.4, 4.5); for 2 IMs, it was 2.6 (2.1, 3.0); and for 2 PMs, it was 5.3 (3.3, 7.3).


P-Glycoprotein
The concept that CYP2D6 PMs are more prone to toxicity during R treatment does not fit well with the belief that R and 9-OHR have similar pharmacodynamic activity. The first author proposed that the plasma profile of CYP2D6 PMs (characterized by higher R than 9-OHR concentrations) may be more "toxic."166 Although it has not been studied in humans, in rats, plasma 9-OHR had more problems reaching the brain than did plasma R.167,168 A recent rat study demonstrated that R may cross the blood–brain barrier (BBB) more easily than 9-OHR.169 This may explain the greater toxicity of R than 9-OHR. The lower level of 9-OHR entering the brain is due to the presence of a transporter in the BBB, P-glycoprotein (PgP), which has greater affinity for 9-OHR than for R.169 The DDIs mediated by PgP are not as well understood as those mediated by CYP, but it is believed that quinidine, verapamil, nicardipine, and cyclosporine are PgP inhibitors.170,171 A recent study of 12 male volunteers suggested that verapamil, a PgP inhibitor, has only modest effects on R bioavailability.172

PgP is an ATP-dependent efflux pump located in the small intestine, brain, kidney, and other organs, where it may influence drug levels and tissue exposure to drugs. PgP has overlapping substrates, inducers, and inhibitors with CYP3A. In the intestine, CYP3A and PgP work in tandem and are major contributors to what is called first-pass metabolism. In the BBB, PgP is one of the main transporters173,174 and is particularly located at the luminal endothelial cell, but also other cells, including neurons and astrocytes.174 The P-glycoprotein role at the BBB is very poorly understood and includes substrates with very different structures that bind to more than one site of action.173 The effect of PgP on antipsychotics has been demonstrated by an in-vitro study by Boulton et al.175 showing that some antipsychotics, including R, are PgP substrates. Another study verified that some other APs are also PgP substrates.176 A knock-out mouse with a genetic disruption of the PgP gene showed higher brain penetration of several antidepressants.177 Recently, using in-vitro and in-vivo experiments in animals, it has been proposed that PgP may decrease R intestinal absorption, whereas CYP3A4 may have no effect.178 In general, it is not known how these basic-science models may extrapolate to human in-vivo conditions. Recently, PgP at the blood–brain barrier has been measured in-vivo using PET; the effects of a PgP inhibitor were lower than expected from knock-out mouse models.171

The gene that controls PgP (also called MDR1 or ABCB1) is located in the same chromosome as the CYP3A gene (Chromosome 7). A human variant of the PgP gene (C3435T, in exon 26) has attracted interest because of its association with increased levels of a PgP substrate, digoxin. T/T patients had increased digoxin levels after oral administration179 and increased risk for nortriptyline-induced postural hypotension.180 This specific PgP variant is silent, but may be tightly associated with other functional variants in the PgP gene, including G2677 (A, T), in exon 21.181,182 The exon-21 variant presents two possible mutations, T and A. It is believed that the T allele in exon 26 may have lower activity, based on its linkage with the variation in exon 21. It is not easy to briefly summarize the literature on PgP pharmacokinetics of various drugs and its clinical relevance because there are multiple conflicting reports. Several reviews have been published.183–185 More recently, researchers are focusing on ABCB1 haplotypes.183,186 In a study of 75 Japanese patients taking R, the T/T variants in exons 21 and 26 were not associated with R or 9-OHR levels.187 In an R study, the T/T variants in exons 21 and 26 were not associated with risperidone ADRs,13 and most of the analyses on R levels with these variants or some haplotypes were also not significant.144 A major criticism of our current way of testing for specific SNPs in a gene is that common SNPs may not reflect the most relevant functional variations in that gene. Moreover, genetic variations in the PgP gene could have substrate-dependent effects if the level of PgP is not altered. To establish the same level of knowledge concerning PgP genotypes and phenotypes that we have for CYP2D6 will be an arduous task that may take several years to accomplish more fully. Moreover, ABCB1 genetic variants may influence CYP3A activity.188

Traditionally, it has been understood that the pituitary is outside of the BBB. Thus, atypical antipsychotics such as R, with a propensity for prolactin elevation, had a higher pituitary versus striatal D2 receptor occupancy.189 Undoubtedly, PgP is part of the BBB, but the interaction between PgP, R, and prolactin is not well understood. Pituitary cells have been described as capable of closing or opening the access to the vessels,190 and they appear to express PgP.191 As a matter of fact, some small studies192–194 have suggested that R-induced prolactin properties may be correlated with plasma R 9-OHR concentrations and not with R concentrations, but the first author’s research suggests that the influence of R versus 9-OHR on prolactin levels may be influenced by gender and possibly by ABCB1 genetic variations.

Other Variables, Including Aging, Influencing Risperidone Pharmacokinetics
Snoeck et al.195 described how decreased creatinine clearance, due to aging or renal insufficiency, decreased R elimination, most likely because R and 9-OHR are eliminated in the urine.196 In their sample, Balant-Gorgia et al.197 described age as increasing total plasma R (sum R and 9-OHR) concentrations. More recently, Aichorn et al.198 and de Leon et al.144 verified that the decrease in R elimination with age may have clinical relevance in geriatric patients. Besides this demonstrated effect of aging on R elimination through decreasing renal clearance, drug reviews frequently warn about other possible pharmacokinetic changes associated with aging, including decrease in body water, albumin levels, or hepatic flow, and increases in body fat, particularly in women.50,199 Currently there are no data supporting these nonspecific changes as having any clinical relevance in patients taking R. Similarly, reviewers frequently quote changes in CYP activity with aging, but there are no good data to support this. CYP2D6 activity does not appear to change remarkably with aging. It is possible that aging, particularly in men, may decrease CYP3A activity for at least some substrates.200


  ACKNOWLEDGMENTS

 
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 Llerena, 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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