Metabolic Drug Interactions with Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants

Neuroscience & Biobehavioral Reviews, Vol. 22, No. 2, pp. 325–333, 1998 䉷 1998 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0149-7634/98 $32.00 + .00

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Metabolic Drug Interactions with Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants G.B. BAKER*, J. FANG, S. SINHA AND R. T. COUTTS Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Alberta T6G 2B7, Canada

BAKER G. B., J. FANG, S. SINHA, R. T. COUTTS. Metabolic drug interactions with selective serotonin reuptake inhibitor (SSRI) antidepressants NEUROSCI BIOBEHAV REV 22(2), 325–333, 1998.—The selective serotonin reuptake inhibitor (SSRI) antidepressants have become an important component of the therapeutic armamentarium in psychiatry and have attracted a great deal of public attention. Another interesting aspect of the SSRIs is their interaction with various isozymes of the cytochrome P450 (CYP) system which are responsible for metabolism of numerous drugs. This effect on the CYP isozymes has drawn attention to the importance of metabolic drug–drug interactions when dealing with drugs used to treat psychiatric disorders. Such interactions are of great relevance since psychiatry patients are frequently treated with multiple drugs and often these drugs undergo extensive biotransformation to metabolites which contribute to therapeutic and/or adverse effects. The present review deals with various aspects of metabolism mediated by CYP isozymes, particularly as they relate to pharmacokinetic interactions between the SSRIs and other drugs which are coadministered with them. 䉷 1998 Elsevier Science Ltd. All rights reserved. Anticonvulsants Antidepressants Antipsychotics Anxiolytics Cytochrome P450 Isozymes Metabolism Selective serotonin reuptake inhibitors (SSRIs)

Genetic polymorphism

anticonvulsants and other commonly used drugs (see (21,29,30,39,53,66,91,92,99,109) for reviews). Given the fact that many psychiatric patients are taking more than one drug and that often those drugs are extensively metabolized, it is important to be aware of these possible interactions involving SSRIs. Specific examples will be discussed in this review.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)

FLUOXETINE (PROZAC威) has become one of the most frequently prescribed antidepressants and as such has received a great deal of media attention. After its introduction on the market about 8 years ago, it was soon followed by several other related drugs, including fluvoxamine, paroxetine, sertraline and citalopram (7,19,62,147) (Fig. 1). All these drugs are classified as selective serotonin (5hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs); they are potent inhibitors of 5-HT reuptake but, unlike the tertiary amine tricyclic antidepressants (TCAs) such as imipramine, amitriptyline and clomipramine, if the SSRIs undergo metabolism, the metabolites are not strong inhibitors of noradrenaline reuptake. In addition to being popular antidepressants, the SSRIs have also been reported to be effective in the treatment of other disorders such as obsessive compulsive disorder and panic disorder (16,20,37,70,72,116,133,147). The fact that most SSRIs are also inhibitors of one or more cytochrome P450 (CYP) isozymes involved in the metabolism of other drugs which may be coadministered with them has also stimulated a great deal of interest (9,22,43,50,102,129,144,145). There is now a voluminous literature describing metabolic drug–drug interactions of SSRIs with drugs such as antidepressants, antipsychotics,

IMPORTANCE OF CYTOCHROME P450 ISOZYMES (CYPs) IN THE METABOLISM OF PSYCHOTROPIC AGENTS

Virtually all known drugs and xenobiotics are metabolized in the body to some extent prior to their excretion. While many enzymes are involved in drug metabolism reactions, the CYPs are of particular importance in the oxidative metabolism of endogenous substances and foreign chemicals. Human CYP isozymes have been allocated to 10 different gene families (denoted 1–4,7,11,17,19,21,26) based on the degree of similarity in the amino acid sequences of the CYP proteins. The last six of these families (7–26) are involved in endogenous steroidal syntheses and these family numbers reflect the sites of oxidation on the steroid nucleus. The other four (families 1–4) are implicated in the metabolism of numerous drugs and xenobiotics (57,109, Table 1). Some of the gene families, especially family 2, contain subfamilies, each of which is designated a

* Corresponding author. Tel.: +1 403 4926591; Fax: +1 403 4926841; E-mail: [email protected].

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FIG. 1. Structures of the selective serotonin reuptake inhibitor (SSRI) antidepressants, fluoxetine, fluvoxamine, paroxetine, sertraline and citalopram.

different capital letter. Members of the same subfamily have greater than 59% amino acid sequence similarity. Individual CYPs within a subfamily are distinguished by a terminal Arabic number (95,96). A knowledge of which specific CYP isozymes are involved in particular metabolic processes may be important for the safe clinical use of therapeutic agents. These enzymes can influence the clinical outcome of drug therapy in a number of ways, as discussed briefly below. Enzyme polymorphism The genes that encode for some of the P450 isozymes exhibit the phenomenon of polymorphism, defined as the occurrence in the population of two or more genetically determined forms in frequencies at which the rarest of them could not be maintained by mutation alone. Polymorphic genes can produce proteins that are normal, but in some cases poorly functioning or completely non-functional enzymes are synthesized which may have serious consequences for the biotransformation of any substrate of the isozymes (39,59,80,84). Human polymorphism has been well established with CYP2D6 (also named debrisoquine/ sparteine oxidase) and some members of the CYP2C subfamily (28,31,53). The polymorphism of CYP2D6 is by far

the best characterized. Most individuals are extensive metabolizers of debrisoquine/sparteine (substrates for CYP2D6), but approximately 5–10% of Caucasians and 2% Orientals are poor metabolizers of debrisoquine/sparteine because they lack the ability to synthesize CYP2D6 or produce functionally abnormal or inactive CYP2D6 (28,52). Numerous drugs have been identified as substrates of CYP2D6 (31,38,46,48,87,109) (see Table 1), and the metabolism of these drugs can be impaired in poor metabolizers of debrisoquine/sparteine. In addition, mutations have been identified in certain individuals who display excessively high CYP2D6 activity. In these individuals (ultra-rapid metabolizers), gene amplification has resulted in elevated expression of the CYP2D6 genotype (13,79). Enzyme inhibition If a patient is administered concomitantly two or more drugs which are significantly metabolized by and/or inhibit the same CYP isozyme (as often occurs in psychiatric patients), then there will likely be competition for the enzyme, and the pharmacokinetic properties of each drug may differ from those observed when each drug is individually administered. Specific examples involving SSRIs will be discussed later in this review.

DRUG INTERACTIONS WITH SSRIs

327 TABLE 1

EXAMPLES OF DRUGS METABOLIZED BY CYP ENZYMES CYP1A2 Antidepressants: amitripytline, clomipramine, imipramine Antipsychotics: clozapine b-Blockers: propranolol Miscellaneous: caffeine, paracetamol, theophylline, R-warfarin CYP2C9/10 phenytoin: S-warfarin, tolbutamide CYP2C19 Antidepressants: citalopram, clomipramine, imipramine Barbiturates: hexobarbital, mephobarbital, S-mephenytoin b-Blockers: propanolol CYP2D6 Antiarrhythmics: encainide, flecainide, mexiletine, propafenone Antipsychotics: haloperidol, perphenazine, risperidone, thioridazine b-Blockers: alprenolol, bufarolol, metoprolol, propranolol, timolol Miscellaneous: debrisoquin, 4-hydroxyamphetamine, perhexiline, phenformin, sparteine Opiates: codeine, dextromethorphan, ethylmorphine SSRIs: fluoxetine, N-desmethylcitalopram, paroxetine TCAs: amitriptyline, clomipramine, desipramine, imipramine, N-desmethylclomipramine, clomipramine, nortriptyline, trimipramine Other Antidepressants: venlafaxine, m-CPP (metabolite of nefazodone and trazodone) CYP3A3/4 Analgesics: acetaminophen, alfentanil, codeine, dextromethorphan From Preskorn, 1996 (110) with permission.

Enzyme induction

Formation of active metabolites

Some drugs are capable of inducing different groups of CYP isozymes (101), which will enhance the metabolism of some drugs normally metabolized by those isozymes. For example, it is known that phenobarbital is an inducer of several CYP izozymes, including 3A4, 2C9 and 2C19 (53,64). Carbamazepine, which is often coadministered with other psychotropic drugs, is also a potent inducer of CYP3A4 (53).

Biologically active metabolites can be produced from various psychotropic drugs, and it is unfortunate that formation of such metabolites is often not taken into consideration in basic or clinical psychopharmacology studies, the assumption being that it is the drug itself that is the active factor. Some of the metabolites may contribute to the overall therapeutic effects and/or to the adverse effects of the parent compounds (93,115,130). Such contributions have

TABLE 2 EXAMPLES OF METABOLICALLY MEDIATED PHARMACOKINETIC DRUG–DRUG INTERACTIONS AND THEIR TYPICAL CLINICAL PRESENTATION a Type

Presentation

Affected drug

Causative drug

CYP enzyme

Build of drug levels due to inhibition of clearance

Increase in incidence and/or severity of expected dosedependent adverse effects

Reduction of drug levels due to induction of clearance

Loss of efficacy

carbamazepine dextromethorphan phenytoin propranolol theophylline TCAs TCAs warfarin disopyramide oral contraceptives theophylline propranolol quinidine warfarin

erythromycin paroxetine fluoxetine cimetidine fluvoxamine fluoxetine fluvoxamine fluvoxamine phenytoin carbamazepine pheytoin rifampin phenobarbital secobarbital

3A3/4 2D6 2C9/10 1A2, 3A3/4 1A2 2D6 1A2, 3A3/4 1A2 3A4/4 3A3/4 1A2 3A3/4 3A3/4 1A2

Blockade of the production of an active metabolite

Loss of efficacy

codeine

paroxetine

2D6

Increased accumulation of an unusual toxic parent drug or metabolite

Unexpected toxicity based on the usual pharmacology of the drug

astemizole terfenadine

ketoconazole ketoconazole

3A3/4 3A3/4

a The above list is in no way an exhaustive list of ‘‘causative’’ or ‘‘affected’’ drugs for either a type of interaction of for a specific CYP enzyme, but simply representative examples. From Preskorn, 1996 (109) with permission.

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been well demonstrated, for example, with various classes of antidepressants (6,71,73,74,105,107,108). In many cases, these metabolites are formed by the actions of CYP isozymes, and thus the ratio of parent drug to metabolites may be influenced markedly by coadministration of other drugs which compete for these isozymes. Although it has been known for many years that such interactions occur with, for example, coadministered drugs, such as the TCAs and the phenothiazine antipsychotics (54,60,83,98), the introduction of the SSRIs into psychiatric therapy seems to have markedly stimulated interest in such drug–drug interactions. Presented in Table 2 are examples of metabolically mediated drug–drug interactions involving CYP isozymes and their typical clinical presentations.

INTERACTIONS OF SSRIs WITH CYP ISOZYMES

Fluoxetine is N-demethylated to norfluoxetine which is an active metabolite having strong serotonin reuptake inhibitor properties itself and a longer half-life (7–15 days) than the parent compound (10). It is also of great interest that both fluoxetine and norfluoxetine are potent inhibitors of CYP2D6 (22,34). Fluoxetine is also a relatively potent inhibitor of 3A4 and 2C19 (109). Administration of fluoxetine could thus interfere with the metabolism of many drugs, as will be discussed below. There is still uncertainty about the complete metabolic fate of fluoxetine, with up to 50% of its metabolism still unaccounted for (2,11). The CYP isozyme 2D6 is thought to contribute to the metabolism of fluoxetine (109), but other CYP isozymes could also be involved. Paroxetine is a potent inhibitor of CYP2D6, in addition to its own metabolism being catalyzed by that isozyme (109,117,118). The SSRI fluvoxamine is metabolized by oxidative demethylation to metabolites that are pharmacologically inactive with respect to serotonin reuptake (137), but there is a paucity of information available about which CYP isozymes are responsible. It is known that fluvoxamine is a potent inhibitor of CYP1A2 (23), but it also inhibits 3A4 and 2C19 (109). Sertraline is metabolized by oxidative demethylation to N-desmethylsertraline, a metabolite which is about 25-fold weaker than the parent drug at inhibiting serotonin reuptake (17,109). It is thought that CYP3A3/4 contributes to this demethylation (109). Sertraline is a relatively potent inhibitor of CYP2D6 in vitro (34), and metabolic drug–drug interactions with concomitantly administered drugs may be less of a problem with this drug than with fluoxetine or paroxetine in the clinical situation (109), although this remains a matter of debate (99,109). Citalopram is metabolized by CYP2C19 to N-desmethylcitalopram which is further metabolized by CYP2D6 (119). Citalopram is a weaker inhibitor of CYP2D6 than are the other SSRIs (8,9) and drug–drug interactions with citalopram may not be as much of a problem as with other SSRIs. However, it should be remembered that N-desmethylcitalopram, a metabolite of citalopram, is 5–10 times stronger than the parent drug at inhibiting CYP2D6 in vitro in human liver microsomes (34,120) and is almost as potent as fluoxetine at inhibiting 2-hydroxylation of imipramine in vitro in such a model (120). There is a paucity of information available at present about the significance of this degree of inhibition of CYP2D6 in the clinical situation.

EXAMPLES OF INTERACTIONS OF SSRIs WITH COADMINISTERED DRUGS

Other antidepressants The pharmacokinetic interactions of SSRIs with other antidepressants are worthy of consideration since SSRIs are sometimes given in combination with TCAs to refractory depressives (97,147,148), and hypnotic antidepressants such as trazodone are sometimes coadministered with SSRIs to help overcome the insomnia effects of the latter drugs (45). There are now abundant reports of clinically significant interactions of fluoxetine with TCAs (3,12,15,29,97,109,138,139). It has been shown in several clinical studies that fluoxetine will markedly increase the plasma concentration of desipramine and other TCAs when the drugs are coadministered. This effect has been attributed to the inhibition of CYP2D6 by fluoxetine, which impairs the conversion of desipramine to its metabolite, 2-hydroxydesipramine, and results in elevated plasma levels (3,150). By impairing hydroxylation, fluoxetine would probably elevate the levels of any coadministered TCA. It has also been reported that fluoxetine coadministered with trazodone will markedly increase trazodone plasma levels (3), but the precise nature of the metabolic interaction was not discussed. Rotzinger et al. (113), in a study using a panel of human microsomes followed by experiments with human CYP isozymes expressed in a human cell line, recently reported that CYP3A4 catalyzed the metabolism of trazodone to m-chlorophenylpiperazine (m-CPP) and that fluoxetine, norfluoxetine and fluvoxamine inhibited the formation of m-CPP, whereas paroxetine did not. It has been shown that when paroxetine is coadministered with desipramine, total desipramine clearance is markedly decreased in extensive metabolizers of sparteine (23). Paroxetine is a potent inhibitor of CYP2D6 and has also been reported to be a weak inducer of the glucuronidation of 2-hydroxydesipramine (21,23). Albers et al. (1) recently conducted a study on a single dose of imipramine before and after treatment with paroxetine and reported that paroxetine produced elevations of approximately 50% in half-life, area under the curve and C max of imipramine and decreased clearance two-fold. Although fluvoxamine apparently has only a minimal effect on CYP2D6 (34,120), it causes a marked inhibition of N-demethylation of tertiary amine TCAs (15,65,89,114,120,123,124). It is assumed that inhibition of a CYP isozyme other than CYP2D6 is responsible for this inhibition of demethylation (23,149). CYPs 1A2, 3A4 and 2C19 are good candidates since fluvoxamine is known to inhibit these isozymes (23,109). As mentioned previously in this review, there is some controversy about the degree of the effect of sertraline on metabolism of TCAs (24,99,109). It appears to the authors of this review that the effect on desipramine increases with an increasing dose of sertraline (154), but there is some disagreement about the usual clinically effective dose of sertraline (24,99). Baettig et al. (4) reported that co-administration of citalopram with amitriptyline or clomipramine did not result in an increase in plasma levels of these TCAs. However, Gram et al. (61) proposed that N-desmethylcitalopram may inhibit the hydroxylation of desipramine.

DRUG INTERACTIONS WITH SSRIs

Antipsychotics The co-administration of haloperidol with the SSRIs fluvoxamine or fluoxetine can result in elevated plasma levels of haloperidol (36,56). These interactions were thought to be the result of competition by fluvoxamine or fluoxetine with HAL for CYP isozymes. Addition of fluoxetine to clozapine therapy has been proposed as a useful strategy in the treatment of positive and negative symptoms of schizophrenia (55), but both fluoxetine and fluvoxamine have been shown to increase serum levels of clozapine when coadministered with this antipsychotic drug (27,69,78,82). There has been considerable research on the metabolism of clozapine in recent years (14,25,35,106,109), and it will be of interest to learn more about the specific CYP isozymes involved in metabolism and the effects of SSRIs. Risperidone is believed to undergo two main metabolic pathways: (1) alicyclic hydroxylation of the tetrahydropyridopyrimidinone ring at the 7- and 9-positions; and (2) oxidative N-dealkylation, resulting in two acidic metabolites, one derived from risperidone itself and the other from the metabolite, 9-hydroxyrisperidone (68). Hydroxylation of risperidone at the 9-position is apparently the most important metabolic pathway (25,67,28). Risperidone and 9-hydroxyrisperidone have similar pharmacological profiles and constitute the antipsychotic fraction (90,134). Much remains to be investigated with regard to the metabolism of risperidone. We have recently demonstrated the involvement of CYP2D6 in the 9-hydroxylation of risperidone using cloned human CYP2D6 expressed in a cell line (46), but little is known about which enzyme is responsible for the N-dealkylation of risperidone and 9-hydroxyrisperidone. As this N-dealkylation pathway leads to inactive metabolites, the inhibition of the enzyme(s) responsible should increase the levels of the active fraction. There is a paucity of information available about SSRI-risperidone interactions, but this is an important area of future research in view of the recent popularity of risperidone as an antipsychotic. Gram et al. (61) found that coadministration of the antipsychotic levopromazine with the SSRI citalopram caused a small increase in steady-state levels of N-desmethylcitalopram (a metabolite of citalopram whose metabolism is thought to be mediated, at least in part, by CYP2D6). Drugs other than antidepressants and antipsychotics There is now a voluminous literature describing drug– drug interactions of fluoxetine with drugs such as: anticonvulsants (e.g. carbamazepine and phenytoin) (63,76,100,103,152); the b-blocking cardiac drug metoprolol (146); the anticoagulant warfarin (153); the benzodiazepines diazepam and alprazolam (62,85,86); the anti-Parkinson drug deprenyl (128); and the antihistamine terfenadine (128). However, von Moltke et al. (142), in an in vitro study in which they predicted clinical effects of SSRIs on terfenadine metabolism, predicted that none of the SSRIs at usual clinical doses would impair terfenadine clearance to a degree that would be of clinical importance. Coadministration of fluvoxamine has been reported to cause increases in plasma levels of warfarin (136), theophylline (40,122,132), carbamazepine (18,51,88), propranolol (10,137); bromazepam (137); diazepam (104);

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alprazolam (49); and theophylline (111,122). Sertraline has been reported to increase plasma concentrations of carbamazepine and tolbutamide (38), substrates of CYP3A4 and CYP2C19, respectively, although Rapeport et al. (110) found that sertraline had no effect on the pharmacokinetics or pharmacodynamics of carbamazepine. von Moltke et al. (141) have reported inhibition of hydroxylation of alprazolam and desipramine by paroxetine in vivo. In a recent study in vitro using human liver microsomes (143), it was reported that several SSRIs caused inhibition of formation of hydroxylated metabolites of triazolam, but they were much weaker than ketoconazole in this regard.

FUTURE DIRECTIONS

In addition to providing a useful new group of drugs with which to treat psychiatric disorders, the SSRIs have had the added advantage of making us very aware of the importance of metabolic drug–drug interactions when multiple drugs are administered concurrently (polypharmacy). The commercial availability of human liver microsomes, specific cDNA-expressed human CYP microsomes, and more recently, human hepatocytes (on a trial basis), have given an added impetus to this exciting avenue of research. Their availability will permit the performing of extensive in vitro screening of new psychotropic drugs on a routine basis and decrease the need for extensive metabolic studies in animal models in order to investigate metabolism and potential drug–drug interactions. Although in vitro screens are very useful, it is necessary to be able to relate these findings to therapeutic drug and metabolite concentrations in human subjects in order to establish clinical relevance, as emphasized by Preskorn (109). In this regard, some researchers are now using in vitro–in vivo scaling models which utilize in vitro K i values, typically clinically relevant doses and plasma concentrations of the inhibitors of interest, and liver:water partition ratios determined in vitro to predict the degree of drug–drug interactions in humans (140,142). When the clinical relevance of a drug is considered, pharmacogenetics and polymorphism should also be considered. Phenotyping and genotyping procedures are available to provide information on whether patients are poor metabolizers, extensive metabolizers or ultra-rapid metabolizers (31,58,84), and these techniques may be applied more frequently in the future. As indicated earlier in this review, the various SSRIs available differ considerably in profiles with regard to inhibition of CYP isozymes. Fluoxetine inhibits CYP2D6, 3A4 and 2C19; paroxetine inhibits 2D6; fluvoxamine inhibits 1A2, 3A4 and 2C19; and sertraline inhibits 2D6. Data available to date indicate that citalopram generally only weakly inhibits CYP isozymes (8). Such advance knowledge of the profiles of the SSRIs can obviously be used when drug combinations are being considered for the treatment of patients, in order to minimize potentially dangerous increases in plasma levels of the coadministered drug. Such information could also conceivably be utilized to reduce the formation of potentially toxic metabolites of coadministered drugs. For example, haloperidol is a frequently used antipsychotic which produces a relatively high incidence of motor disorders. Halperidol is known to

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be metabolized to a 1,2,3,6-tetrahydropyridine analog (HTP) and the corresponding pyridinium metabolite (HP þ) (44,47,135) which are similar in structure to MPTP and MPP þ, the dopaminergic neurotoxin to which MPTP is converted. It has been proposed that the pyridium metabolite is also neurotoxic and contributes to the side effects of haloperidol (112,126). If this is the case, a knowledge of the CYP isozyme primarily responsible for the formation of HTP and HP þ could be helpful in the selection of coadministered drugs, such as a specific SSRI, to inhibit that specific CYP, thus reducing or eliminating potential adverse effects. Another aspect of drug action that has been highlighted by the popularity of the SSRIs is the possible importance of chirality (5). Many psychiatric drugs that possess one or more asymmetric carbon atoms are administered as racemates, despite the fact that pharmacological activity may reside primarily in one of the enantiomers (32,33). When drug levels in blood are being evaluated, it is not uncommon to measure levels of total drug, despite the fact that only one enantiomer may be active (41,77). Conventional analytical techniques often do not differentiate enantiomers, and it must not be assumed that enantiomers will be present in equal amounts. Indeed, one enantiomer may very well be absorbed and/or metabolized and/or excreted at rates that differ from those of the other enantiomer (26,33,42, 81,94,121,131). The enantiomers may also differ in some pharmacological properties, as evidenced by the marked differences in the abilities of the R- and S-enantiomers of

norfluoxetine (151) and citalopram and demethylcitalopram (75) to inhibit serotonin reuptake. Such considerations should now be extended to CYP isozyme inhibition since the R- and S-enantiomers of fluoxetine and norfluoxetine have been demonstrated to differ markedly in their inhibiting actions on CYP2D6 (125). This is not of importance with paroxetine or sertraline, even though both drugs possess a chiral centre, since only a single enantiomer of each drug is currently used in clinical practice. In summary, the recent introduction of the SSRIs has not only had a profound effect on treatment patterns of psychiatric disorders, but has also resulted in an increased awareness of the importance of drug metabolism and pharmacokinetic drug–drug interactions (for a summary of factors to be considered, see the expert group report: (92)). The relevance of drug metabolism in clinical situations and a knowledge of the importance of CYP isozymes can be gained by studying SSRIs. This should result in more logical assessment of future psychiatric drugs and in a safer use of drugs in general. ACKNOWLEDGEMENTS

The authors are grateful to Ms Sally Omura for typing this manuscript. Funding for this research has been provided by the Medical Research Council of Canada, the Alberta Heritage Foundation for Medical Research (Alberta Mental Health Research Fund) and the Faculty of Medicine, University of Alberta.

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