The Pharmacokinetics of Paliperidone Versus Risperidone

Med-Psych Drug-Drug Interactions Update

The Pharmacokinetics of Paliperidone Versus Risperidone Jose de Leon, M.D. Gary Wynn, M.D. Neil B. Sandson, M.D.

Background: Several new atypical antipsychotics have become available for use, but knowledge about their pharmacology may not be widespread. Objective: This review aims to increase awareness and knowledge about risperidone (R) and paliperidone (9-hydroxyrisperidone [9-OHR]), their pharmacokinetics, and pharmacodynamics. Method: The authors present a review of the literature on R and 9-OHR. Results: Oral R may be approximately twice as potent as oral 9-OHR. Levels of R and 9-OHR in R-treated patients may help clinicians prescribe 9-OHR. In R-treated patients, the R/9-OHR concentration ratio is an index of CYP2D6 activity; an inverted ratio (⬎1) indicates a CYP2D6 poor metabolizer (PM) or the presence of a powerful CYP2D6 inhibitor. The concentration-to-dose (C/D) ratio, where C includes R⫹9-OHR, is an index of total clearance from the body. A C/D ratio decreased by half is associated with CYP3A inducers or a lack of compliance, whereas an increased C/D ratio may indicate CYP2D6 PM phenotype, use of CYP2D6 and/or CYP3A4 inhibitors, or, possibly, renal insufficiency. In invitro studies, R and 9-OHR have similar receptor binding (except for blocking ␣1). 9-OHR may have less ability to enter the brain because of greater affinity for the transporter P-glycoprotein. The limited available paliperidone pharmacokinetic information suggests that there are four minor metabolic pathways. In contrast to R treatment, being a CYP2D6 PM may not be clinically relevant for paliperidone treatment. Information on paliperidone drug– drug interactions is limited. Renal excretion may be the major route of paliperidone elimination. Conclusion: Clinicians can use R/9-OHR and the C/D ratios to interpret plasma R levels and guide treatment. (Psychosomatics 2010; 51:80 – 88)

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ince risperidone’s (R) arrival in the United States market in 1994, its drug– drug interactions (DDIs) and cytochrome P450 (CYP) polymorphisms have not been systematically studied to the extent currently required of

Received October 13, 2009; accepted November 25, 2009. From the Mental Health Research Center at Eastern State Hospital, Lexington, KY; the Dept. of Psychiatry, Walter Reed Army Medical Center, Washington, DC; and the Dept. of Psychiatry, School of Medicine, Univ. of Maryland, Baltimore, MD. Send correspondence and reprint requests to Jose de Leon, M.D., Mental Health Research Center at Eastern State Hospital, 627 West Fourth St., Lexington, KY 40508. e-mail: [email protected] © 2010 The Academy of Psychosomatic Medicine

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newer drugs by the Food and Drug Administration (FDA). The FDA requirements in the early 1990s were limited, but in, 1996, deaths associated with terfenadine caused by pharmacokinetic DDIs were reported.1 Since that crucial point, the withdrawal of several drugs because of DDIs2 has led to progressively greater requirements for pharmacokinetic and DDI studies. R is mainly metabolized by the polymorphic cytochrome P450 2D6 (CYP2D6) to the active metabolite, 9-hydroxyrisperidone (9-OHR). The initial studies from R’s marketer suggested that R and its main metabolite Psychosomatics 51:1, January-February 2010

de Leon et al. 9-OHR had similar pharmacodynamic activity,3 and implied that the total plasma R moiety (sum of plasma R and 9-OHR concentrations) determined R’s clinical activity.4 If correct, this eliminated concerns about the CYP2D6 metabolism of R in CYP2D6 poor metabolizers (PMs), since a decline in 9-OHR will be almost perfectly countered by a corresponding increase in R. The published information supporting the concept that being a CYP2D6 PM phenotype was irrelevant for R treatment was based on an R study in healthy volunteers, using single R doses. Only 11 subjects (2 PMs and 9 EMs [extensive metabolizers]) were studied by CYP2D6 phenotyping.5 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,6 proposing that CYP2D6 polymorphism expression and CYP2D6-mediated DDIs were therapeutically unimportant for R. Several articles on R pharmacology by the authors7,8 discussed the reasons that R and 9-OHR may not be equally potent, as well as the reasons why CYP2D6 PMs (those who do not have CYP2D6) may have more adverse drug reactions (ADRs) on risperidone.8 The hypothesis was stated that R7,8 may be more potent, and subsequently more toxic, than 9-OHR (paliperidone). This review uses our knowledge of R pharmacokinetics to try to understand the similarities and differences between R and paliperidone. This review provides a short summary of R pharmacology (focusing on the interpretation of R levels), provides information on paliperidone pharmacology, reconsiders the interpretation of R levels based on paliperidone studies, and makes a clinical comparison of R and 9-OHR. SUMMARY OF RISPERIDONE PHARMACOLOGY Table 19 –13 (presented as an online data supplement; Psychosomatics 51:1) summarizes R’s pharmacokinetics and pharmacodynamics and compares them with our current knowledge of paliperidone. Table 213–20 (online data supplement) summarizes which R-treated subjects may be unusual metabolizers. It is not clear that unusual metabolizers may be as important for paliperidone. Clinicians must remember that paliperidone is not really a new drug. Most patients taking oral R have 5–10 times more 9-OHR (paliperidone) than R in their blood. Thus, an understanding of what is already known about interpreting R and 9-OHR levels is crucial in gaining clues to 9-OHR’s clinical efficacy (see Table 3; online data supplement).9,13,21–34 Psychosomatics 51:1, January-February 2010

Clinicians can use two major ratios35 in the interpretation of plasma R and 9-OHR concentrations: the R/9OHR ratio and the total concentration/dosage ratio (C/D ratio; see Table 4; online data supplement). Plasma R/9-OHR ratio The R/9-OHR concentration ratio is an index of CYP2D6 activity, since the aliphatic hydroxylation of R is mainly performed by CYP2D6. Other CYP isoenzymes with less affinity also carry out this hydroxylation; CYP2D6 PMs, who lack CYP2D6 activity, still produce small quantities of 9-OHR. The normal plasma R/9-OHR ratio is ⬍1, with an average of approximately 0.1– 0.2 (described elsewhere8). An R/9-OHR ⬎1, called a plasma inverted ratio (R concentration ⬎9-OHR concentration), indicates a CYP2D6 PM or the presence of a powerful CYP2D6 inhibitor (e.g., fluoxetine, paroxetine, or bupropion;8 Table 4 [online data supplement]). Plasma Risperidone Total Concentration/Dose (C/D) Ratio The sum of plasma R and 9-OHR concentrations (called total R concentration or total moiety), divided by the dose, is the total concentration/dose (C/D) ratio (Table 4 [online data supplement]). The multicenter study from R’s marketer9 and the first author’s studies11–13 indicate that R follows linear pharmacokinetics and has a C/D of 7 (described in de Leon et al.8). This number is constant across doses, indicating that R follows linear kinetics. A change of R clearance (or C/D) by a factor of 2 is probably meaningful for clinicians.11 For example, in a patient taking a dose (D) of 6 mg/day, one should find a total plasma R concentration (C) of 42 ng/ml. Thus, the C/D in this patient would be 7 (42/6⫽7). If this patient’s total plasma R level exceeded 84 ng/ml, we should suspect a genetic and/or environmental factor causing the patient to metabolize R at half the rate of an average patient. This level (84 ng/ml) is equivalent to the blood level of an average patient taking 12 mg of R daily and corresponds to a C/D of 14. Similarly, if the patient takes 6 mg/day and his/her total blood R level is lower than 21 ng/ml after ruling out lack of R compliance, one should suspect that some genetic and/or environmental factor is causing the patient to metabolize R twice as rapidly as the average patient. This level (21 ng/ml) is equivalent to the blood level of an average patient taking 3 mg of R daily and corresponds to a C/D of 3.5.35 http://psy.psychiatryonline.org

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Med-Psych Drug–Drug Interactions Update CYP3A4-inducers decrease the R C/D ratio, and CYP2D6/3A4 inhibitors increase the R C/D ratio. Fluoxetine is a particularly detrimental inhibitor of R metabolism since it is a powerful CYP2D6 inhibitor, and its main metabolite, norfluoxetine, is a moderate CYP3A inhibitor.32,33 PALIPERIDONE PHARMACOLOGY Paliperidone is 9-OHR; published information on 9-OHR involves reviews36 –44 and a few double-blind studies.45–49 Paliperidone Pharmacodynamics 9-OHR is a racemate, but both enantiomers may have similar pharmacokinetic profiles.50 Table 551,52 (online data supplement) provides a description of R and 9-OHR receptor affinities. However, these receptor studies need to be interpreted in a clinical context. To reach the brain, the drugs need to be absorbed and metabolized and need to cross the blood– brain barrier (BBB). 9-OHR may have more difficulty crossing the BBB than R (Table 6 [online data supplement]).53–61 Affinity for D2 receptors is slightly higher for 9-OHR than it is for R (Table 6 [online data supplement]). R may be a much more potent blocker (⬎3 times) of ␣1 receptors than 9-OHR; in fact, R could be the most potent blocker among the atypical antipsychotics marketed in the United States (Table 6 [online data supplement]). This pharmacodynamic difference explains why R is apt to induce orthostatic hypotension and why it requires careful dose titration, whereas paliperidone is much less likely to cause orthostatic hypotension and does not require titration. In relapse-prevention studies, the incidence of orthostatic hypotension was 5% in patients treated with paliperidone-ER and 2% in those who received placebo. Rates of orthostatic hypotension in the pooled analysis of the acute-treatment trials were 2% for paliperidone-ER and 1% for placebo. However, 9-OHR-induced orthostatic hypotension appeared to be dose-related. In the three trials of acute treatment, orthostatic hypotension occurred in 4% of patients treated with paliperidone-ER 12 mg/day, and in only 1% to 2% of those treated with doses ⱕ9 mg/day. The labeling for paliperidone-ER includes a warning that orthostatic hypotension may occur, particularly when treatment is initiated or restarted, or when the dose is increased; furthermore, cautious use is recommended in patients with cardiovascular disease.40 The ␣2 receptors are thought to be mostly inhibitory 82

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pre-synaptic autoreceptors that regulate the release of noradrenaline in the brain.62 The in-vitro study comparing atypical antipsychotics suggests that R is a more potent blocker (⬎5 times) of ␣2 receptors than 9-OHR and could be the most potent blocker among the atypical antipsychotics marketed in the United States. 9-OHR’s affinity for 5-HT2C receptors is lower than it is for R (Table 5 [online data supplement]). The blockade of 5-HT2C has been associated with the increased appetite seen in patients taking antipsychotics, but perhaps it should be associated with the blockade of other receptors, particularly histamine receptors.63 9-OHR’s affinity for 5-HT2A receptors is also lower than R’s affinity. 5-HT2A/ D2 receptors may contribute to an allegedly better profile of some atypical APs for cognition or mood.64 The possibility that 5-HT2A may be irrelevant for atypicality cannot be ruled out, since chlorpromazine has very high affinity for this receptor.65 If one believes that the ratio of 5-HT2/D2 receptors is related to atypicality,66 then 9-OHR would have a worse profile than R. 9-OHR and R have similar affinities for H1 and much lower affinity for H1 than olanzapine or clozapine (Table 5 [online data supplement]). H1 blockade probably contributes to the sedation and increase in appetite seen with some antipsychotics, particularly clozapine and olanzapine. Tachycardia is probably a symptom secondary to blockade of several receptors (including muscarinic and adrenergic receptors). Reflex tachycardia has been reported with drugs that have ␣1-blocking activity.40 The proportion of patients who experience tachycardia with paliperidone-ER was 2% in patients treated with 3 mg/day and 7% in patients treated with 6 mg/day-to-15 mg/day. Increases in heart rate were dose-dependent, with the greatest mean standard deviation (SD) change (6.8 [12.9] beats/min.) occurring in patients who received paliperidone-ER 15 mg/day. In the double-blind phase of that trial, the incidence of an increase in heart rate (defined as an increase ⬎15 beats/min., with a value ⬎100 beats/min.) was higher in those treated with paliperidone-ER (15%) than placebo (8%). Rates of tachycardia were 7% in the paliperidone-ER group and 2% in the placebo group (statistical comparison not reported).40 Paliperidone Pharmacokinetics A study of 9-OHR metabolism described five male volunteers (2 CYP2D6 PMs and 3 CYP2D6 EMs) who were given 1 mg of labeled 9-OHR.50 Approximately 60% Psychosomatics 51:1, January-February 2010

de Leon et al. of the compound was eliminated unchanged in the urine; the percentages were similar in CYP2D6 EMs and PMs. There were no differences in the overall plasma pharmacokinetics of paliperidone between the PMs and EMs. Four metabolic pathways were identified as being involved in the elimination of 9-OHR, each of which accounted for up to a maximum of 6.5% of the biotransformation of the total dose. Biotransformation of the drug occurred through oxidative N-dealkylation, monohydroxylation of the alicyclic ring, probably by CYP2D6, alcohol dehydrogenation, and benzisoxazole scission, the latter in combination with glucuronidation or alicyclic hydroxylation. The unchanged drug and four metabolites were detected in the urine. Two other metabolites were detected in feces. The monohydroxylated metabolite was present only in the urine samples of the CYP2D6 EMs, whereas another metabolite, monohydroxylated at the alicyclic ring system, was present in the feces of the PMs, as well. The authors concluded that 9-OHR was not extensively metabolized and was primarily excreted renally.50 A preliminary report of 619 patients included in three 6-week trials suggested that the 5% of the sample who were CYP2D6 PMs did not have an increase in ADRs (odds ratio [OR]⫽1.1; confidence interval [CI]: 0.5–2.6).67 Although it has not been studied in humans, plasma 9-OHR in rats did not reach the level of plasma R in the brain. Table 6 (online data supplement) describes the accumulated evidence in animal and in-vitro studies demonstrating that 9-OHR may cross the BBB with more difficulty than R. This may explain the greater potency and toxicity of R than 9-OHR68 and explain why similar R and 9-OHR plasma concentrations would lead to higher R concentrations in the brain. The lower level of 9-OHR entering the brain is due to the presence of an extruding transporter in the BBB, the P-glycoprotein (P-gp) transporter, which has greater affinity for 9-OHR than for R. P-gp 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. P-gp has overlapping substrates, inhibitors, and inducers that overlap with those of CYP3A. In the intestine, CYP3A and P-gp work in tandem and are major contributors to what is called first-pass metabolism, which is further explained by the contribution of hepatic effects. In the BBB, P-gp is one of the main transporters69,70 and is especially notable at the luminal endothelial cell, but also at other cells, including neurons and astrocytes.70 Psychosomatics 51:1, January-February 2010

The DDIs mediated by P-gp are not as well understood as those mediated by CYP. It is believed that quinidine, verapamil, nicardipine, and cyclosporine are P-gp inhibitors.71,72 It is believed that CYP3A inducers (such as carbamazepine, phenytoin, and rifampin) may also be P-gp inducers. 9-OHR is a P-gp substrate and can probably be induced. Moreover, even if CYP3A plays a small role in 9-OHR metabolism under normal conditions, CYP3A can play a much more important role in induction. This is what occurs in the case of topiramate. Under normal conditions, only 20% is metabolized in monotherapy, but topiramate clearance increases twofold when it is taken with carbamazepine or phenytoin.73 R metabolism by CYP3A74 may explain why CYP3A-inducers influence R metabolism. Carbamazepine, phenytoin, phenobarbital, and rifampin are powerful CYP3A-inducers. The clinical relevance of CYP3A-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.75 Co-administration of carbamazepine (a CYP3A4-inducer), with R resulted in marked decreases in plasma levels of both R and 9-OHR.11,76 –78 A study using the C/D ratio estimated that CYP3A-inducers reduced total R levels on average by almost half (Table 2 [online data supplement]). The observed decrease in plasma levels of 9-OHR in patients taking R and carbamazepine was explained by assuming that carbamazepine also stimulated the biotransformation of the metabolite or it preferentially induced the metabolism of R through pathways other than 9-hydroxylation.43 In the single-dose study in healthy volunteers, renal excretion was the major route of elimination, with 59% of the dose excreted unchanged in the urine. About half of the renal excretion was thought to occur by active secretion.50 Renal clearance of 9-OHR ranged from 51.4 ml/min.to 67.5 ml/min.; this was approximately twofold higher than the clearance by glomerular filtration, which ranged from 17.0 ml/min. to 36.5 ml/min. This result indicated that active tubular secretion probably played a significant role in the renal clearance of 9-OHR.50 Therefore, as 9-OHR is a cation at physiological pH, it is possible it may be a substrate of a group of transporters called organic cation transporters.79 The organic cation transporters are part of a group called uptake-carrier transporters; they are different from P-gp, which is a component of the efflux-carriers.80 Uptake-carriers tend to facilitate passage of the subhttp://psy.psychiatryonline.org

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Med-Psych Drug–Drug Interactions Update strate into the cell. Efflux-carriers tend to facilitate passage of the substrate out of the cell.81 Our understanding of paliperidone DDIs at the transporter level is limited.82 Trimethroprim is thought to be an inhibitor of at least one of the organic cation transporters in the kidney, since it influences creatinine uptake.83 Trimethroprim appears not to have a noticeable influence on 9-OHR pharmacokinetics after single-dosing in 30 male subjects.79 Half-Life One of the major differences between R and 9-OHR is half-life (Table 7 [online data supplement]). Half-life has several important clinical implications: the length of time required to eliminate a drug after discontinuation; the length of time required to wait before drawing a sample for blood level (see Table 2 [online data supplement]); the number of times per day a drug is taken, and the amount that a level fluctuates during the day. Clinicians need to know how long a drug remains in the body after it is discontinued, since persistent drug levels may explain beneficial or detrimental drug effects. Half-life provides an approximation of the time necessary for the residual drug to be removed from the body once drug therapy is discontinued. After drug administration, it takes approximately five half-lives to eliminate 97% of the residual drug and six half-lives to eliminate 98%.84 Although the concept of half-life has been criticized,85 because this parameter depends upon both the clearance and volume of distribution of a drug, half-life provides a useful tool for assessing the time required to reach steady-state drug levels and is a valuable indicator of the duration of drug presence in the body. Given a drug’s half-life, administering R twice per day instead of once per day may decrease some ADRs, since the patient with twice-daily administration will have lower peak levels.

proximately twice as potent as 9-OHR (the average of 4 mg– 6 mg/day is 5 mg/day, and the average of 6 mg–12 mg/day is 9; 9/5⫽1.8, close to 2). Brain-imaging studies appear to verify that R is more potent than 9-OHR. Lower R doses cause binding similar to that of higher doses of 9-OHR. Arakawa and associates87 stated that 3 mg/day of paliperidone caused 58% D2 occupancy; 9 mg/day of paliperidone caused 77% D2 occupancy; and 15 mg/day of paliperidone caused 80% D2 occupancy. Kapur and colleagues88 reported that 2 mg/day of risperidone resulted in 66% D2 occupancy; 4 mg/day resulted in 73%; and 6 mg/day resulted in 79% D2 occupancy.88 Unfortunately, there are no published studies of 9-OHR levels; however, at therapeutic doses (3 mg–12 mg), paliperidone-ER follows linear pharmacokinetics.40 COMPARING CLINICAL EFFECTS OF RISPERIDONE AND PALIPERIDONE Table 7 (online data supplement) compares the clinical effects of R and 9-OHR. The 9-OHR controlled-release formulation introduced some peculiarities. 9-OHR should be avoided in individuals with gastrointestinal narrowing39 because it may hinder passage of the capsule through the gastrointestinal tract. Patients should be informed that the tablet shell and insoluble inner core may appear in the stool.40 There are not enough data to compare R and 9-OHR profiles regarding extrapyramidal symptoms (EPS), sedation, weight gain, metabolic abnormalities, or prolactin levels. The mean weight gain of 0.6 kg–1.9 kg in the acute treatment trials of paliperidone-ER appears to be consistent with the amount of weight gain reported for R. A separate study that compared pharmacokinetically-timed effects of paliperidone-ER and R on prolactin elevation found nearly identical increases in prolactin elevation with the two agents.89

REINTERPRETING TOTAL R LEVELS ON THE BASIS OF AVAILABLE 9-OHR DATA

CONCLUSION

There are no controlled studies comparing 9-OHR levels after taking R versus taking 9-OHR. Only one preliminary report compared dosing in 145 patients taking R and 215 taking 9-OHR; it was obtained by combining the R and 9-OHR registration studies. This comparison suggested that 4 mg– 6 mg/day of R had the same efficacy as 6 mg–12 mg/day of 9-OHR.86 Using these data, R was ap-

Unfortunately, there is limited information on 9-OHR pharmacokinetics; 9-OHR may be less toxic than R. This hypothesis is supported by recent information from the manufacturer that oral R is approximately twice as potent as oral 9-OHR. Clinicians can utilize the R/9-OHR and the C/D ratios to interpret plasma R levels. The R/9-OHR concentration

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de Leon et al. ratio is an index of CYP2D6 activity. The normal plasma R/9-OHR ratio has an average of approximately 0.1– 0.2. An R/9-OHR ⬎1, called a plasma inverted ratio (R concentration ⬎9-OHR concentration), indicates a CYP2D6 PM or the presence of a powerful CYP2D6-inhibitor. The C/D ratio is an index of the total R clearance from the body. The average C/D is 7, according to studies by the manufacturer and the first author. A C/D ratio decreased by half (⬍3.5 in the manufacturer’s and the first author’s studies) is associated with the intake of CYP3A-inducers or a lack of compliance. A C/D ratio increased by more than 60% (⬍11 in the manufacturer’s and the first author’s studies) may be associated with the intake of CYPinhibitors or a CYP2D6 PM phenotype. It is possible that renal insufficiency may also increase the C/D ratio. 9-OHR data may provide clues for interpreting R levels. Assuming that R is twice as potent as 9-OHR, the R C/D ratio and the C for efficacy and ADR studies should be C⫽R⫹1/2 9-OHR. In in-vitro studies, R and 9-OHR have similar receptor binding, although R may be a more potent ␣1 blocker (⬎3 times). It may be more important to note that animal studies suggest that 9-OHR may have less ability to enter the brain (because of its greater affinity for P-gp, a transporter in the BBB). The limited 9-OHR pharmacokinetic information suggests that there are four metabolic pathways, each of which accounts for a maximum of 6.5% of the biotransformation of the total dose. CYP2D6 is one of them. The information published by the manufacturer suggests that being a CYP2D6 PM may not be clinically relevant for 9-OHR treatment. Naturalistic studies have suggested that CYP2D6 PMs may have more problems with R, since they have decreased clearance (lower C/D ratio) and a more toxic plasma profile (inverted R/9-OHR). There is limited information on 9-OHR’s DDIs. Renal excretion may be the major route of elimination (more than half of 9-OHR clearance), including filtration and active secretion. Renal insufficiency requires adjusting 9-OHR doses. 9-OHR has a longer half-life than oral R, allowing for once-daily dosing, and up to 5 days may be required to see the effects of a 9-OHR dose increase.

9-OHR has a controlled-release formulation, but it should be avoided in individuals with gastrointestinal narrowing. There are not enough data to compare R and 9-OHR profiles regarding EPS, sedation, weight gain, metabolic abnormalities, and prolactin levels, but they may be similar after accounting for dosage differences. The authors thank Lorraine Maw, M.A., for editorial assistance. Dr. de Leon is the Medical Director of the University of Kentucky Mental Health Research Center, Eastern State Hospital, Lexington; Professor of Psychiatry, College of Medicine, University of Kentucky, Lexington, and Visiting Professor at the Dept. of Psychiatry and Institute of Neurosciences, University of Granada, Granada, Spain. Dr. de Leon is currently a co-investigator in an NIH Small Business Innovation Research Grant awarded to Genomas, Inc. In the past 4 years (since October 1, 2005), Dr. de Leon has received two researcher-initiated grants, one from Roche Molecular Systems, Inc., for this study, and one from Eli Lilly (the latter as co-investigator). He was on the advisory board of Roche Molecular Systems, Inc. (2006). He personally develops his presentations for lecturing and has never lectured using any pharmaceutical company presentations. In the last 4 years (since October 1, 2005) he has received lecture support from Roche Molecular Systems, Inc. (2006), Eli Lilly (2006), Janssen (2006), and Bristol-Myers Squibb (2006). He has never been a consultant and has no other financial arrangements with pharmacogenetic or pharmaceutical companies nor owns any of their stock. Dr. Wynn is Assistant Chief, Inpatient Psychiatry Services, Dept. of Psychiatry, Walter Reed Army Medical Center, Washington, DC, and Assistant Professor of Psychiatry, Uniformed Services Univ. of Health Sciences, Bethesda, MD. Dr. Sandson is Clinical Associate Professor, Dept. of Psychiatry, School of Medicine, Univ. of Maryland, Baltimore, MD. 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.

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