Clinically significant drug interactions with atypical antipsychotics.

CNS Drugs (2013) 27:1021–1048 DOI 10.1007/s40263-013-0114-6

REVIEW ARTICLE

Clinically Significant Drug Interactions with Atypical Antipsychotics William Klugh Kennedy • Michael W. Jann Eric C. Kutscher

•

Published online: 30 October 2013 Ó Springer International Publishing Switzerland 2013

Abstract Atypical antipsychotics [also known as secondgeneration antipsychotics (SGAs)] have become a mainstay therapeutic treatment intervention for patients with schizophrenia, bipolar disorders and other psychotic conditions. These agents are commonly used with other medications—most notably, antidepressants and antiepileptic drugs. Drug interactions can take place by various pharmacokinetic, pharmacodynamic and pharmaceutical mechanisms. The pharmacokinetic profile of each SGA, especially with phase I and phase II metabolism, can allow for potentially significant drug interactions. Pharmacodynamic interactions arise when agents have comparable

W. K. Kennedy Department of Pharmacy Practice, Mercer University College of Pharmacy and Health Sciences, Atlanta, GA 76107, USA W. K. Kennedy Department of Psychiatry, School of Medicine, Mercer University, Savannah, GA, USA W. K. Kennedy Department of Behavioral Medicine, Memorial University Medical Center and Mercer University, 5002 Waters Avenue, Savannah, GA 31404, USA M. W. Jann (&) Department of Pharmacotherapy, University of North Texas System College of Pharmacy, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA e-mail: [email protected] E. C. Kutscher Department of Pharmacy Practice, College of Pharmacy Sioux Falls, South Dakota State University, Sioux Falls, SD, USA E. C. Kutscher Sanford School of Medicine at the University of South Dakota, Sioux Falls, SD, USA

receptor site activity, which can lead to additive or competitive effects without alterations in measured plasma drug concentrations. Additionally, the role of drug transporters in drug interactions continues to evolve and may effect both pharmacokinetic and pharmacodynamic interactions. Pharmaceutical interactions occur when physical incompatibilities take place between agents prior to drug absorption. Approximate therapeutic plasma concentration ranges have been suggested for a number of SGAs. Drug interactions that markedly increase or decrease the concentrations of these agents beyond their ranges can lead to adverse events or diminished clinical efficacy. Most clinically significant drug interactions with SGAs occur via the cytochrome P450 (CYP) system. Many but not all drug interactions with SGAs are identified during drug discovery and pre-clinical development by employing a series of standardized in vitro and in vivo studies with known CYP inducers and inhibitors. Later therapeutic drug monitoring programmes, clinical studies and case reports offer methods to identify additional clinically significant drug interactions. Some commonly co-administered drugs with a significant potential for drug–drug interactions with selected SGAs include some SSRIs. Antiepileptic mood stabilizers such as carbamazepine and valproate, as well as other antiepileptic drugs such as phenobarbital and phenytoin, may decrease plasma SGA concentrations. Some anti-infective agents such as protease inhibitors and fluoroquinolones are of concern as well. Two additional important factors that influence drug interactions with SGAs are dose and time dependence. Smoking is very common among psychiatric patients and can induce CYP1A2 enzymes, thereby lowering expected plasma levels of certain SGAs. It is recommended that ziprasidone and lurasidone are taken with food to promote drug absorption, otherwise their bioavailability can be reduced. Clinicians must be aware of the variety of

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factors that can increase the likelihood of clinically significant drug interactions with SGAs, and must carefully monitor patients to maximize treatment efficacy while minimizing adverse events.

1 Introduction Patients who suffer from schizophrenia, bipolar disorders or any other medical condition that requires the use of antipsychotic drugs face two major realities. First, these medical conditions are chronic, incurable and lifelong. Secondly, individuals suffering from these illnesses generally require lifelong medication to reduce the risks of clinical relapse and functional decline. The overall goal in antipsychotic use is to maximize the patient’s quality of life and ability to function on a daily basis, but unfortunately these agents have inherent adverse effects. It is common in clinical practice—although rarely evidence based—for antipsychotics to be used in combination with other psychotropic medications to treat various psychiatric disorders. When these medications are combined, the drug interaction potential increases, leading to increased adverse effects in addition to any anticipated increase in efficacy and effectiveness. If increased adverse effects occur in the patient, this can lead to decreased medication adherence on the part of the patient, further complicating pharmacotherapy and disease state management. Clinicians are tasked with the difficult position of maximizing the therapeutic antipsychotic benefits while minimizing side effects and drug interactions. A good understanding of clinically significant drug interactions, careful patient monitoring, titration and an individualized drug regimen with regular follow-up are crucial to positive therapeutic outcomes. Both the first-generation or typical antipsychotics (FGAs; e.g. haloperidol, perphenazine, thiothixene and fluphenazine) and second-generation antipsychotics (SGAs) possess pharmacological binding affinity to a wide variety of receptor systems, including dopaminergic, histaminic, muscarinic, serotonergic and a-adrenergic receptors. This article focuses on clinically significant drug interactions with SGAs; however, it is important to note that efficacy, adverse effects and drug interactions share many commonalities with FGAs and occur at receptor sites for neurophysiological modulation [1]. These side effects include sedation, weight gain, orthostatic hypotension, cognitive impairment, sexual dysfunction, prolactin effects (amenorrhoea, galactorrhoea, gynaecomastia and sexual dysfunction), cardiac changes (including corrected QT [QTc]-interval prolongation) and drug-induced movement disorders (pseudoparkinsonism, akathisia, acute dystonia and tardive dyskinesia). SGAs have been shown to improve positive symptoms of schizophrenia and have not been proven to worsen negative symptoms of schizophrenia. SGAs have less potential to cause drug-induced movement

W. K. Kennedy et al.

disorders, relative to FGAs. Also, selected SGAs (e.g. aripiprazole) may minimize elevations in serum prolactin levels. The purpose of this article is to review the available literature on drug interactions with SGAs [2–6]. For a review of drug interactions with FGAs, readers are referred elsewhere. We conducted a thorough literature search using PubMed through November 2012 and examined the references cited in the articles on this topic. Significant case reports were also included, and only articles published in the English language were utilized for this review.

2 Pharmacokinetic and Pharmacodynamic Principles of Drug Interactions Drug interactions can be classified into two main categories: pharmacokinetic and pharmacodynamic. Pharmacokinetic drug interactions result in changes in the drug and/ or its metabolites, absorption, distribution, metabolism or elimination. Pharmacodynamic drug interactions occur at the site of drug action and produce a change in the drug’s activity without altering its pharmacokinetic properties [7]. Unfortunately, not all clinical patient scenarios or potential drug–drug interactions can be thoroughly evaluated in clinical studies; utilizing knowledge of a medication’s pharmacokinetic and pharmacodynamic profiles can assist clinicians in predicting potential drug interactions. Although the majority of known and predictable drug interactions occur by either pharmacokinetic or pharmacodynamic processes, a third possible area of concern is general pharmaceutical drug interactions. These interactions are physical chemical interactions, which may occur in vitro as well as in vivo. For example, when drugs are mixed together before administration, an insoluble precipitate may form because of physical incompatibilities between the drugs, leading to malabsorption of the medications. The potential for pharmaceutical drug interactions is beyond the scope of this article, and the reader is referred to standard textbooks that review this topic. 2.1 Pharmacokinetic Properties of Second-Generation Antipsychotics A comparative profile of the SGAs’ pharmacokinetic properties is presented in Table 1. This table presents information regarding the oral formulations that were initially available when the drugs first became approved for clinical use. Several of these drugs now have other formulations available such as oral liquids, injectable formulations for acute conditions, extended-release oral preparations and long-acting injections. Formulation differences in a product do not prevent potential drug interactions but may affect the interaction potential and clinical

CL clearance, CYP cytochrome P450, t elimination half-life, tmax time to reach the peak serum drug concentration, UGT uridine diphosphate-glucuronosyltransferase, Vd volume of distribution

CYP3A4, CYP1A2, CYP2C19 (minor/partial), CYP2D6 (minor/ partial) 95 % 9–53 L/h 9–17 Clozapine [60]

1–4

2–7 L/kg

CYP3A4, CYP2D6 (minor/partial)

UGT, CYP1A2, CYP2D6 (minor/partial) 93 %

83 % 55–87 L/h

26 L/h 16 L 33

6

6

1.5

Olanzapine [12, 59]

Quetiapine (immediate-release) [33, 69]

513–710 L

CYP2D6, CYP3A4 (minor/partial) 9-hydroxyrisperidone 89 %, 77 % (9hydroxrisperidone) 5.0 mL/min/kg 22 1

1.0 L/kg

UGT, CYP3A4 (minor/partial), CYP2D6 (minor/partial)

CYP3A4, CYP2D6 99 %

74 % 1.4–8.2 L/h

3.4 L/h 4.9 L/kg 75

24

3–5

24

Aripiprazole [51, 52]

Paliperidone (extended-release) [46, 54] Risperidone [58, 61, 67]

70–192 L

Aldehyde oxidase, CYP3A4 (minor/partial), CYP1A2 (minor/ partial)

CYP1A2, UGT 95 %

99 % 5.08 mL/min/ kg

0.867 L/min 1,700 L

1.03 L/kg

24

4–10

1

4

Asenapine (sublingual) [49]

Ziprasidone [11, 53]

CYP3A4, CYP2D6, CYP1A2 (minor/partial)

CYP3A4 99 %

93 % 47–102 L/h

3.902 L/min 6,173 L

2,527 L

29–37

14

1–3

2–4 Iloperidone [45, 46]

Lurasidone [43, [44]

Protein binding CL Vd t (h) tmax (h) Drug

Table 1 Summary of the pharmacokinetic parameters of second-generation antipsychotics

Primary metabolic pathways

Clinically Significant Drug Interactions with Atypical Antipsychotics

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presentation, which must be taken into consideration when evaluating the potential for drug interactions. Patients’ responses to drugs and drug interactions can vary significantly, depending on many factors, including the individuals’ genetics. This variability can affect the drug’s clearance (CL), volume of distribution (Vd), hepatic CL and renal CL [7, 8]. Additionally, the drug molecule itself may contribute to variability in drug interactions. Antipsychotic medications are highly lipophilic, resulting in high Vd values, which may affect the potential for drug interactions. Hepatic CL of a drug is dependent upon various properties, including liver blood flow, drug metabolism and plasma drug concentrations. A key group of enzymes involved in drug metabolism are the cytochrome P450 (CYP) enzymes. The CYP enzymes are a group of glycolproteins found in abundance in the hepatic system, with three major families: CYP1, CYP2 and CYP3. The CYP families are responsible for phase I metabolism (see Sect. 2.1.1) of many drugs, including SGAs [3, 8, 9]. A final factor that can affect drug interactions is the drugs’ protein binding. When two or more drugs that are highly protein bound are co-administered, competition for the protein binding sites occurs. It is important to note that drugs bound to plasma proteins are not membrane permeable and not pharmacologically active. It is only the unbound (free) drug that exerts pharmacological effects within the body [10]. Depending on the degree of protein binding of the drugs in question and the relative binding affinities (stickiness), the active or free plasma concentrations of each drug could be increased or decreased, rendering the drug unexpectedly potent or impotent. The effect of protein binding is most clinically significant with drugs that are highly protein bound and that also have low therapeutic indices, such as warfarin and digoxin. Since most SGAs are highly protein bound ([90 %), co-administration with warfarin and/or digoxin could theoretically produce a clinically significant protein binding displacement interaction. These potential drug interactions are often reviewed prior to clinical approval (see Sect. 3.1), and it is important to note that SGAs have not been reported to significantly alter the effects of warfarin or digoxin. The exact reason for this lack of interaction is not well understood but is most likely explained by SGA drugs’ low extraction ratios, which make protein binding displacement interactions less likely to be clinically significant [10]. 2.1.1 Phase I Oxidative Metabolism Hepatic phase I oxidative metabolism is catalyzed primarily by CYP enzymes and represents the major pathway of metabolism and elimination of SGAs. Most of the antipsychotics listed in Table 1 are metabolized primarily by CYP enzymes. However, exceptions exist—for example, ziprasidone is metabolized primarily by the aldehyde

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oxidase pathway, and olanzapine is primarily metabolized by the uridine diphosphate glucuronosyltransferase (UGT) pathway [11, 12]. These two drugs are still metabolized by the CYP enzyme system, but to a much lower extent, and thus it is still possible for clinically significant drug interactions to occur. For paliperidone, the main metabolism and elimination pathway is not hepatic but renal, and only 32 % of the drug is converted to metabolites. These metabolites are created through glucuronidation, dehydrogenation and benzisoxazole, which are not phase I or CYP enzymes [13]. Because of this, paliperidone has so far demonstrated minimal clinically significant metabolism drug interactions. Most significant drug interactions with SGAs do occur within the CYP system [2–5]. When two drugs that utilize the same CYP enzyme system for metabolism are given together, metabolic inhibition or metabolic induction can occur. These effects can be either reversible or irreversible, depending on the medication and the CYP enzyme involved. For reversible mechanisms, CYP function is restored rapidly after the inhibitory agent has been eliminated from the body. With irreversible inhibition, a new enzyme must be synthesized by the liver before full CYP activity is restored. If the specific CYP system is a highcapacity system such as CYP3A4 (not easily saturated), then in many cases two drug substrates can be metabolized simultaneously without clinically significant inhibition or induction effects. Knowledge of the properties of the most common CYP metabolic pathways can provide some clues to clinicians as to the likelihood of a clinically significant drug interaction occurring. Finally, individual genetic variations in CYP enzymes also occur and must be considered when evaluating the potential for drug–drug interactions. These variations are measured as single nucleotide polymorphisms (SNPs) and exist within various CYP families (e.g. CYP2D6). Individuals who possess inactive SNP alleles are called poor metabolizers (PMs), and persons who metabolize drugs at the expected rate are termed extensive metabolizers (EMs). Ultra-rapid metabolizers (UMs) metabolize drugs very rapidly because they have multiple gene copies and high levels of gene expression. Interestingly, the current literature suggests that SGAs are not significantly influenced by SNP genetic variations, possibly because of the various metabolic pathways these drugs utilize [7].


oxidative, reductive and hydrolytic processes that utilize the CYP system, phase II reactions are conjugative. These types of chemical reactions occur through glucuronidation, sulfate, glycine, glutathione, acetylation and methylation pathways. Even drugs that are inactivated primarily via CYP must often be further metabolized by phase II conjugation before they can be eliminated from the body. This is because conversion from a lipophilic molecule to a hydrophilic molecule is necessary before a drug can be excreted renally. Some drugs directly undergo phase II metabolism without phase I reactions [7]. The mood stabilizers valproic acid and lamotrigine, and the benzodiazepines lorazepam and oxazepam, are not metabolized by phase I (e.g. CYP) but undergo only phase II metabolism [14, 15]. Glucuronidation is a major metabolic pathway and represents the primary mechanism for drug conversion prior to excretion. Like the CYP system, glucuronidation via UGT has many known subtypes, with at least 33 variations categorized into two main groups: UGT1 and UGT2 [16]. Both UGT families have been shown to have clinically significant genetic variations (i.e. genetic polymorphisms) and can be altered by various environmental conditions. Factors such as chronic cigarette smoking can significantly alter metabolism of certain medications such as carbamazepine, while chronic ethanol use can inhibit UGT activity [1]. A specific example of a phase II interaction is the interaction between probenecid and olanzapine. Probenecid is a known UGT inhibitor and was coadministered with olanzapine and risperidone in a study of 12 healthy volunteers [17]. Probenecid increased the mean (± standard deviation [SD]) peak serum olanzapine concentration (Cmax) by roughly 20 % on average (from 6.8 ± 2.4 to 8.1 ± 2.2 ng/mL, p = 0.024), the mean (±SD) area under the plasma concentration–time curve (AUC; from 95 ± 47 to 120 ± 36 ngh/mL, p = 0.002) and the mean (±SD) disassociation constant (ka; from 1.05 ± 1.14 to 1.65 ± 1.36, p = 0.024). The pharmacokinetic parameters of risperidone were unaltered by probenecid. Thus, certain drugs as well as UGT genetic variations should be considered when attempting to understand unusual dose–response associations with olanzapine. 2.2 Role of P-Glycoprotein Interactions with SecondGeneration Antipsychotics

2.1.2 Phase II Glucuronidation Phase II drug interactions are often overlooked but have the potential to be a clinically important factor in dosing decisions and identification of metabolic causes of unexpected and unintended clinical outcomes. Unlike phase I hepatic metabolism drug reactions, which involve

P-glycoprotein is an adenosine triphosphate (ATP)-dependent efflux transporter located mainly in the gastrointestinal tract and the blood–brain barrier [18]. P-glycoprotein is also known as ATP-binding cassette sub-family member B1 (ABCB1) and multidrug resistance protein 1 (MDR1). P-glycoprotein is found in many tissues (e.g. renal tubules),


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but the gastrointestinal tract and the blood–brain barrier are thought to be the most important sites for P-glycoprotein drug interactions. P-glycoprotein protein binding is considered to be a protective mechanism, as it sequesters exogenous substances. These exogenous substances are then pumped out by active transport, counteracting drug absorption though the gastrointestinal tract and restricting access to the central nervous system (CNS) [19]. The P-glycoprotein structure and its molecular efflux action have been described with two separate binding sites for either lipophilic or hydrophilic molecules [20]. A significant overlap occurs with drugs that are substrates of and inhibitors of CYP3A4 and P-glycoprotein (e.g. ketoconazole, protease inhibitors). The US Food and Drug Administration (FDA) recently issued guidance that the P-glycoprotein mechanism of potential drug interactions should be explored thoroughly [21]. The contribution of P-glycoprotein to pharmacokinetic drug interactions has been shown with a number of pharmacological agents, although no clinically relevant interactions have been documented for SGAs [22–25]. Studies have reported 10 times higher brain risperidone concentrations in knock-out mice than in control mice despite relatively equivalent plasma concentrations [26]. A similar study in rats, where fluphenazine was co-administered with the known P-glycoprotein inhibitor ciclosporin, also showed that brain concentrations were increased without any corresponding increase in serum fluphenazine concentrations. As a result, these types of interactions have the potential to cause a pharmacodynamic effect with or without any measurable pharmacokinetic changes when the present one-compartment pharmacokinetic models are used. However, there is no current method to clinically assess the CNS to plasma compartment ratio of drug concentrations.

combined with other agents that also have this activity, the potential for significant adverse effects may be magnified, and clinically significant outcomes such as delirium may occur [27]. Alternatively, additive decreases in blood pressure may occur when antihypertensive agents that have potent a-adrenergic antagonism are combined with SGAs. Iloperidone has moderately high orthostatic hypotensive properties when compared with other SGAs, and extreme caution should be exercised when combining this agent with other agents that have a-adrenergic properties [27]. Additionally, since many SGAs are CNS depressants, combining them with other CNS depressants (e.g. alcohol or sedative hypnotics) can potentiate sedation and other adverse effects [7]. Another type of pharmacodynamic interaction has been reported when SGAs are combined with nonspecific monoamine oxidase inhibitors (MAOIs) [28]. Serotonin syndrome was reported in a patient 23 days after tranylcypromine was added to low-dose ziprasidone 40 mg/ day. Although serotonin syndrome is more commonly observed when selective serotonin-reuptake inhibitors (SSRIs) and serotonin norepinephrine-reuptake inhibitors (SNRIs) are added to MAOI treatment, SGAs’ serotonergic activity may account for this potential interaction. Clinicians should monitor patients carefully for several weeks after discontinuation of an MAOI when adding or discontinuing medications that affect monoamines. Although this review focuses on oral formulations of SGAs, the pharmacodynamic interaction between the short-acting intramuscular formulation of olanzapine and intramuscular benzodiazepines is worth noting, as this is the only SGA injectable that has a formal regulatory warning [29]. The exact mechanism of this interaction is unknown. Olanzapine possess a-adrenergic binding properties and has been associated with hypotension, which may contribute to this interaction. Olanzapine also has significant sedative properties, and the short-acting intramuscular formulation produces Cmax values five times higher than those achieved via the oral route. These actions may be a factor leading to the adverse effects of sedation and cardiorespiratory depression that have been described in patients receiving this combination. Several cases of severe hypotension have been reported in patients who received short-acting intramuscular olanzapine and intramuscular lorazepam within a 1 h time period [23, 30, 31]. The European Medicines Agency has warned that patients who have had a short-acting intramuscular injection of olanzapine should not receive benzodiazepines for at least 1 h after the olanzapine dose is given. The ‘General Precautions’ section of the package insert states that the combination of short-acting intramuscular olanzapine and parenteral benzodiazepines has not been studied and is not recommended. If the combination is used, careful evaluation for excessive sedation and cardiorespiratory

2.3 Pharmacodynamic Interactions with SecondGeneration Antipsychotics Pharmacodynamic interactions are not well studied or reported in the literature; however, they must always be considered, since they may cause clinically significant changes in expected outcomes. As previously discussed, changing drug concentrations and pharmacological activity at drugs’ sites of action may occur without changes in the measurable drug concentration at the periphery, and these interactions are likely to have clinical ramifications. For example, the effects of a medication that has potent anticholinergic properties could further aggravate anticholinergic adverse effects (e.g. constipation) when added to an SGA that has minimal to moderate effects on muscarinic receptors. For example, clozapine and quetiapine possess significant anticholinergic properties and, when they are

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depression is recommended. This example illustrates the varying potential for pharmacodynamic interaction with different formulations and routes of administration of the same drug. The effects of antipsychotics on the QTc interval are well known [32]. A significant cardiovascular drug interaction may occur if other drugs that prolong the QTc interval are used concomitantly, if physiological conditions occur that can exacerbate dysrhythmias or if cardiovascular pathology is present. Clinicians should carefully monitor the patient’s cardiovascular status. Many SGAs’ package inserts have various statements in the ‘Drug Interactions’ section, explaining that drugs that are known to cause an electrolyte imbalance or to increase the QTc interval should be used cautiously [33]. Specifically, two case reports have described QTc prolongation with quetiapine doses below 600 mg/day [34, 35]. Both patients had either significant hypokalaemia or significant hypomagnesaemia that required treatment and may have precluded the occurrence of QTc prolongation. Fortunately, both patients recovered uneventfully. Additionally, QTc prolongation was also reported in a patient who overdosed with quetiapine [36]. However, various phase III multicentre clinical trials, as well as naturalistic clinical studies, have not shown significant QTc-related issues with quetiapine [37, 38].

guidelines; exceptions will occur because of patient variables and variability in the psychiatric illness being treated. The AGNP-TDM Consensus Group uses various levels of recommendation for the clinical applicability of monitoring plasma SGA concentrations. The strongest level of recommendation is presented for clozapine and olanzapine. Risperidone has the second-highest level of recommendation. Quetiapine is given a ‘useful’ recommendation. Ziprasidone has the lowest recommendation of ‘probably useful’, perhaps because of its lack of widespread usage compared with other agents, which have been available longer in the clinical setting [39]. Therapeutic serum concentration ranges have been suggested in the literature for paliperidone and aripiprazole, but these concentrations are not explicitly recommended in the current AGNP-TDM guidelines [40, 41]. In some early studies, the stated therapeutic serum clozapine concentrations included the concentration of its metabolite norclozapine (desmethylclozapine). Nowadays, however, most clinicians and laboratories use only serum clozapine concentrations and exclude norclozapine from the reported serum concentration. The possibility of elevations in norclozapine concentrations should be considered if serious dose-related adverse effects occur while clozapine concentrations are not elevated. To date, the newest SGAs (iloperidone, asenapine and lurasidone) have not been used sufficiently in the clinical arena to determine the value of monitoring serum levels.

3 Review of Clinically Significant Drug Interactions with Second-Generation Antipsychotics

3.1 Studies Conducted During Drug Development of Second-Generation Antipsychotics

For a clinically significant drug interaction to occur, several basic parameters have to be met. A fundamental concept of drug interactions with clinical impacts is the existence of a desired and necessary change in serum drug concentrations. Patients with serum drug concentrations below the patient’s individual therapeutic range would have subtherapeutic treatment and would not receive the full benefits of the medication. Patients with plasma drug concentrations above the patient’s individual therapeutic range would tend to have pronounced adverse effects without further desired clinical effects. Suggested therapeutic serum concentrations ranges for FGAs have been proposed but are beyond the scope of this review. For the SGAs, Table 2 summarizes the findings of the expert consensus statement from the Arbeitsgeneinschaft fu¨r Neuropscyhopharmakologle und Pharmakopsychiatire Therapeutic Drug Monitoring (AGNP-TDM) Consensus Group [39]. The suggested therapeutic ranges for each SGA were derived by reviewing a variety of clinical studies and published reports that evaluated optimal clinical responses. These ranges are only to be used as

Severe adverse effects from drug interactions have led regulatory agencies to introduce prescribing restrictions, drug withdrawals and early terminations of drugs in development [42]. In 2006, the FDA issued updated guidelines for in vitro and in vivo drug interaction studies of drugs in development. These guidelines were intended to provide standardization and improve communication of risk to health providers and patients about potentially significant drug interactions. Initially, these guidelines encompassed mainly CYP-mediated drug interactions but, more recently, P-glycoprotein drug interactions have been added. Additionally, the FDA has suggested a minimum standard for drug CL changes to be considered clinically significant. On average, a change of 30 % in drug CL has been proposed for CYP-mediated reactions, whereas 30 % inhibition theoretically could yield a 40 % increase in drug exposure. This would potentially cause a value in excess of bioequivalence standards and may result in a clinically significant change in outcome [42]. A list of drug interactions with SGAs revealed during drug-development trials is shown in Table 3. For example, the potent specific CYP inhibitors ketoconazole (CYP3A4)


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Table 2 Suggested therapeutic plasma concentration ranges of second-generation antipsychotics [39–41]

metabolism occurs via aldehyde oxidase; there is only a minor role for CYP3A4 and CYP1A2 enzymes in ziprasidone metabolism [11, 53]. Paliperidone undergoes limited hepatic biotransformation and is therefore minimally influenced by CYP3A4 and CYP2D6; it is primarily excreted unchanged in the urine. Interestingly, paroxetine produced only minimal effects with CYP2D6 inhibition, while co-administration of carbamazepine resulted in a 50 % decrease in the Cmax and AUC of paliperidone. Valproic acid was used as a potent UGT inhibitor and, upon co-administration, it caused a 50 % increase in the paliperidone AUC. As UGT is a minor pathway of paliperidone elimination, valproic acid does not affect plasma concentrations of risperidone’s active moiety. Co-administration of valproic acid and carbamazepine caused at least a 50 % change in the disposition of paliperidone, so a dosage adjustment was recommended [46, 54–56]. Trimethoprim (a potent organic cation transporter) was reported not to significantly affect the disposition of paliperidone in healthy volunteers [57]. Risperidone is converted by CYP2D6 to 9-OH risperidone (paliperidone). CYP2D6 inhibitors produced a substantial increase in serum risperidone concentrations, whereas carbamazepine brought about a 50 % decrease in serum concentrations of the active moiety (risperidone ? 9-OH risperidone), with dosage adjustments being advised [58]. Quetiapine CL was significantly inhibited by ketoconazole. Phenytoin was assessed instead of carbamazepine as a general CYP inducer, and the results showed that quetiapine CL substantially increased by 5-fold [33]. Dosage changes are most likely needed when quetiapine is given with a potent CYP3A4 inhibitor or inducer. Olanzapine disposition in smokers and non-smokers (see Sect. 3.6) was significantly influenced by fluvoxamine and carbamazepine, with dosage adjustments being recommended [59]. Clozapine drug interaction studies were not specifically required or conducted for these regulatory agencies at the time of that drug’s development. Data from clinical studies and case reports provided the information presented in Table 3. Fluvoxamine increased the mean trough concentrations of clozapine and its metabolite by 3-fold, whereas paroxetine produced only minor changes. Phenytoin was reported as ‘may’ decrease serum clozapine concentrations. Dosage adjustments with inhibitors and inducers were suggested. Unlike other SGAs, carbamazepine was stated to increase plasma clozapine levels, and so concomitant use of carbamazepine is not recommended (see Sect. 3.4) [60]. Recommendations regarding dosage adjustments have been made on the basis of the pharmacokinetic changes encountered during ‘standardized’ drug interaction studies. These drug interactions studies are based upon the foundations of the agent’s CYP metabolism profile and in vitro models [42]. However, in vitro models do not always

Plasma concentration (ng/mL or lg/L)

Level of recommendation

Clozapine

350–600 [39]

1 (strong)

Risperidone ( ? 9-hydroxyrisperidone)

20–60 [39]

2 (recommended)

Paliperidone

20–52 [40]

2 (recommended)

Olanzapine

20–80 [39]

1 (strong)

Quetiapine

70–170 [39]

3 (useful)

Ziprasidone

50–120 [39]

4 (probably useful)

Aripiprazole

150–300 [41]

5 (not recommended)

Iloperidone

None recommended

Asenapine

None recommended

Lurasidone

None recommended

Drug

or paroxetine (CYP2D6) and CYP inducers (e.g. carbamazepine or rifampicin) are usually selected for drug interaction studies. At times, nonspecific CYP inhibitors such as cimetidine (CYP2D6, CYP3A4 and CYP1A2) are employed to determine possible drug interactions in conjunction with specific CYP inhibitors. A selected CYP inhibitor is normally matched with the agent’s CYP metabolic profile. For example, an agent that is metabolized by CYP3A4 is usually assessed in a clinical study using ketoconazole to determine the possible interaction and, if present, the extent of the drug interaction [42]. Dose adjustment recommendations are often based upon the magnitude of changes in pharmacokinetic parameters and the likelihood of a clinically significant outcome in patients. The drug product information will then specifically provide the information found in these studies. For example, lurasidone has a specific recommendation not to be co-administered with potent CYP3A4 inhibitors and inducers [43, 44]. However, with a moderate CYP3A4 inhibitor such as diltiazem, a maximum daily lurasidone dose of 40 mg is suggested. Alternatively, the dosage of iloperidone is recommended to be reduced by 50 % when CYP inhibitors are present [45–47]. On the basis of iloperidone’s CYP profile, significant reductions in the AUC by CYP inducers or increases in drug CL would require dosage adjustments. Inhibition of asenapine metabolism by fluvoxamine (a CYP1A2 inhibitor) was found not to be significant, and a caution is noted in the prescribing information [48–50]. Valproic acid was used as a potent UGT inhibitor but, interestingly, it did not cause significant changes in asenapine concentrations [50]. Aripiprazole dose adjustments were recommended with CYP inhibitors and inducers [51, 52]. Quinidine was used instead of paroxetine as the CYP2D6 inhibitor for aripiprazole, and those results were extrapolated to include paroxetine and other CYP2D6 inhibitors [51]. Ziprasidone’s primary route of

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Table 3 Summary of drug–drug interaction studies of second-generation antipsychotics (SGAs) conducted during drug development Drug

Inhibitor

Inducer

Pharmacokinetic effects on SGA

Lurasidone

Ketoconazole, diltiazem

Rifampicin

Lurasidone Cmax : 6.9-fold and AUC : 9-fold with ketoconazole; lurasidone should not be co-administered with ketoconazole. Lurasidone Cmax and AUC : 2-fold with diltiazem; lurasidone dose limit 40 mg/day. Lurasidone Cmax and AUC ; 80 % with rifampicin; lurasidone should not be coadministered with rifampicin [43, 44]

Iloperidone

Ketoconazole, paroxetine

[Not done]

Iloperidone AUC : 57 % with ketoconazole and : 2- to 3-fold with paroxetine; ; iloperidone dose by 50 % [45–47]

Asenapine

Fluvoxamine, cimetidine, paroxetine, valproic acid

Carbamazepine

Asenapine AUC : 29 % with fluvoxamine; co-administer fluvoxamine with caution; no dose adjustments needed with other drugs [48–50]

Aripiprazole

Ketoconazole, quinidine

Carbamazepine

Aripiprazole AUC : 63 % with ketoconazole, AUC : 112 % with quinidine, Cmax and AUC ; 70 % with carbamazepine; adjust dose by 50 % [51, 52, 112]

Ziprasidone

Ketoconazole

Carbamazepine

Ziprasidone AUC ; or : by 35–40 %; no dosage adjustment suggested [53]

Paliperidone

Paroxetine, valproic acid

Carbamazepine

Paliperidone AUC : 16 % with paroxetine, Cmax and AUC : 50 % with valproic acid, Cmax and AUC ; 50 % with carbamazepine [54, 63]

Risperidone

Fluoxetine, paroxetine

Carbamazepine

Risperidone Cpss : 2.5- to 9-fold with inhibitors, Cpss ; 50 % with inducers; adjust doses accordingly [58, 67, 81, 101]

Quetiapine

Ketoconazole

Phenytoin

Quetiapine CL ; 84 % with ketoconazole, CL : 5-fold with phenytoin; adjust doses [69, 121]

Olanzapine

Fluvoxamine

Carbamazepine

Olanzapine AUC : 54 % in nonsmokers, AUC : 108 % in smokers with fluvoxamine, CL : 50 % with carbamazepine; adjust doses [89–91, 107, 108]

Clozapine

Fluvoxamine, paroxetine, cimetidine

Phenytoin

Required clozapine dose adjustments included in manufacturer’s prescribing information [60, 85–89, 100, 153]

AUC area under the plasma concentration–time curve, CL drug clearance, Cmax peak serum drug concentration, Cpss serum drug concentration, : increase(d), ; decrease(d)

predict a clinically significant drug interaction, and in vivo human studies remain the paramount assessment to determine clinical relevance. Over the past decade, regulatory agencies have supported additional measures beyond those completed during drug development to identify significant drug–drug interactions, which are described further in the remainder of this article. 3.2 Clinical Studies Conducted Post-Approval A drug interaction study conducted during investigational drug development is only one method to detect potentially clinically significant interactions. Population pharmacokinetic modelling analyses can also be used to detect factors that affect the potential for drug–drug interactions [61–63] Other systematic methods of detection are often conducted and may include (1) investigator-initiated studies in healthy volunteers or in patient populations, which examine possible drug interactions on the basis of their metabolic or pharmacological profiles; (2) therapeutic drug monitoring programmes of SGAs used in the clinical setting under naturalistic clinical circumstances, which provide information about drug interactions in the ‘real world’ context in which patients are commonly receiving these medications to treat a variety of comorbid medical and psychiatric conditions [64–66]; (3) case reports and subsequent aggregation and meta-analyses, representing the final

component in revealing and understanding clinically significant drug interactions (unfortunately, situations leading to such a report often occur after an adverse event, when clinicians are seeking an explanation for the incident, which may include drug interactions as a root cause); and (4) finally, published review articles on specific SGAs, which describe the reported drug interactions from clinical studies and case reports [67–69]. It is beyond the scope of this article to review every aspect of this category of publications. The focus of this article is to present the significant, interaction class-related patterns in drug–drug interactions for SGAs and discuss their impact in the clinical setting. 3.3 Antidepressants SNRI and SSRI antidepressants are commonly prescribed with SGAs. Tricyclic antidepressants continue to be used in clinical practice; however, their overall utility in today’s pharmacotherapy precludes an in-depth review, and readers are referred to other previously published antipsychotic– antidepressant drug interaction articles [1]. 3.3.1 Serotonin Norepinephrine-Reuptake Inhibitors Compared with SSRIs, SNRIs possess only modest to moderate CYP inhibition properties and usually do not lead


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to significant drug interactions with SGAs. Venlafaxine is a weak inhibitor of CYP1A2, CYP3A4 and CYP2D6. In a study of healthy volunteers (N = 30) given a single risperidone dose of 1 mg, venlafaxine 150 mg/day administered for 11 days produced a modest increase in the mean risperidone ? 9-OH risperidone AUC (from 139.25 ± 35.29 to 149.30 ± 36.04 ng h/mL, p = 0.01) [70]. Although statistically significant, the AUC and total drug amount increase was not considered to be a clinically significant change. Desvenlafaxine (the O-desmethylvenlafaxine metabolite) is metabolized by the UGT system and, to a minor extent, the enzyme CYP3A4 [71]. Desvenlafaxine produced only modest changes in the AUC of the tricyclic antidepressant desipramine (used as a CYP2D6 substrate) compared with paroxetine, which produced a 4-fold increase in the AUC of desipramine [72]. Therefore, it is unlikely, and so far unreported, that desvenlafaxine would cause any significant drug interactions with SGAs. Duloxetine is metabolized by CYP2D6 and CYP1A2, and displays modest to moderate CYP26 inhibition [73]. One therapeutic drug monitoring service reported that the median concentration/dose (C/D) ratio of risperidone in patients treated with duloxetine ? risperidone (N = 14; 3.2 nmol/mg) did not significantly differ from that in patients on risperidone monotherapy (N = 70; 1.9 nmol/ mg) [74]. Similar findings occurred with aripiprazole, as the median C/D ratio of aripiprazole in patients co-prescribed duloxetine ? aripiprazole (N = 7; 26.3 nmol/mg) did not differ from that in patients treated with aripiprazole alone (N = 37; 23.1 nmol/mg). However, in another study, patients treated with risperidone and duloxetine (N = 7) experienced a significant increase mean change (±SD) in risperidone concentrations from baseline to week 2 (from 9.0 ± 4.0 to 18.0 ± 7.0 ng/mL, p \ 0.01). At week 6, the mean plasma risperidone concentrations were slightly higher (23.0 ± 11.0 ng/mL, p \ 0.01 versus baseline). No significant changes in the mean plasma 9-OH risperidone concentrations occurred throughout the study (37.0 ± 10.0 ng/mL at baseline versus 34.0 ± 8.0 ng/mL at week 6). The total mean plasma concentrations of the active moiety significantly increased from baseline to week 6 (from 46 ± 12 to 58.0 ± 14.0 ng/mL, p \ 0.01). Only a few patients experienced ‘mild’ gastrointestinal symptoms and vertigo, which decreased or subsided with continued treatment. One patient experienced mild extrapyramidal side effects (tremors and akathisia) at week 2, as plasma concentrations of the total active moiety increased from 51 to 72 ng/mL. This finding produced a higher value than the suggested therapeutic range for risperidone (shown in Table 2), which could account for the increased adverse effects. The patient was treated effectively with biperiden 4 mg, with complete resolution of symptoms [75].

Adjunctive use of duloxetine was reported to not significantly affect steady-state plasma concentrations of clozapine and olanzapine in patients (N = 7 and N = 8, respectively) treated with these SGAs. Other reports suggested that interactions between duloxetine and olanzapine or quetiapine should not occur, as these agents are not CYP2D6 substrates [73]. 3.3.2 Selective Serotonin-Reuptake Inhibitors SSRIs remain the most commonly prescribed antidepressant agents because of their safety and efficacy profile, as well as their near-ubiquitous availability as generic formulations. Still, SSRIs can elicit significant drug interactions through CYP inhibition and should not be considered safe for every person. These agents differ in their potency and types of CYP enzyme inhibition. For example, fluoxetine and paroxetine are potent CYP2D6 inhibitors [3]. Fluvoxamine is a potent inhibitor of CYP1A2 and CYP2C19, and fluvoxamine and fluoxetine (and its main metabolite, norfluoxetine) are moderate CYP3A4 and CYP2C19 inhibitors [3, 76, 77]. Sertraline is only a moderate CYP2D6 inhibitor, while citalopram and escitalopram appear to lack CYP inhibition properties [3, 78]. On the basis of the CYP-inhibitory profiles of SSRIs and the metabolic profiles of SGAs (shown in Table 1), drug interactions between SSRIs and SGAs can be foreseen and are concentration dependent. However, the clinical magnitude and outcome of these interactions may be difficult to predict solely on the basis of their CYP profiles [42]. Since drug interaction studies—which are required by regulatory agencies during SGA drug development (Table 3)—traditionally use paroxetine and fluvoxamine as model inhibitors, the prediction of interactions with other SSRIs from these studies is incomplete [42]. Specifically, clinicians must combine this information with information from other published clinical studies to predict the most accurate drug information concerns to optimize treatment and prevent adverse consequences. A summary of clinical findings regarding drug interactions between SSRIs and SGAs is presented in Table 4. 3.3.2.1 Fluoxetine Fluoxetine is metabolized by CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and also significantly inhibits CYP2D6 and CYP3A4. Fluoxetine has been reported to cause increased serum clozapine concentrations in a comparison of patients receiving clozapine monotherapy (N = 17) and those receiving fluoxetine plus clozapine (N = 7) [79]. The mean serum clozapine concentrations were 247 ± 131 ng/mL during monotherapy and 434 ± 247 ng/mL during combined treatment (p B 0.05). A subsequent study conducted under naturalistic treatment conditions in outpatients compared

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Table 4 Summary of the effects of selective serotonin-reuptake inhibitors (SSRIs) on second-generation antipsychotics (SGAs) SSRI Fluoxetine Fluvoxamine

Paroxetine

SGA

Comments

Clozapine

40–70 % : in plasma clozapine concentrations [79, 80]

Risperidone

: plasma risperidone and active moiety concentrations, Parkinson’s side effects noted in a few patients [81]

Clozapine

5- to 10-fold : in plasma clozapine concentrations in patients with dose-dependent fluvoxamine effects [85–88]

Olanzapine

1- to 2-fold : in serum olanzapine concentrations and dose-dependent effects [89–91]

Quetiapine

159 % : in quetiapine C/D ratio noted, most likely due to CYP3A4 inhibition [64, 66, 69]

Clozapine

: plasma clozapine levels similar to fluoxetine [80]

Risperidone

: total active moiety concentrations with dose-dependent effects

Clozapine

: plasma clozapine levels similar to fluoxetine [80]

Risperidone

Sertraline 50 and 100 mg doses had no changes in total drug Cpss, but 150 mg/day was reported to : total drug Cpss by 36 % in 1 patient and by 52 % in another [96]

: extrapyramidal side effects and Parkinson’s side effects in some patients [94] Sertraline

C/D concentration/dose ratio, Cpss serum drug concentration, CYP cytochrome P450, : increase(d), ; decrease(d)

serum clozapine concentrations in patients treated with monotherapy (N = 40) and patients treated with various SSRIs and clozapine (N = 40) [80]. The three SSRIs that were used were sertraline (mean daily dose 92.5 ± 50.1 mg), fluoxetine (mean daily dose 39.3 ± 22.3 mg) and paroxetine (mean daily dose 31.2 ± 13.6 mg); the clozapine doses were stabilized for at least 1 month. The mean serum clozapine concentration in the monotherapy group was 265 ± 143 ng/mL. Significantly higher mean serum clozapine concentrations (p \ 0.05) were found with each SSRI combination treatment: 334 ± 179 ng/mL with sertraline, 345 ± 190 ng/ mL with fluoxetine and 417 ± 373 ng/mL with paroxetine. Although clozapine is only partially metabolized by CYPE2D6, it appears that CYP2D6 inhibition resulted in the increased serum drug concentrations. The metabolism of clozapine by CYP3A4 may play a role in this interaction; however, fluoxetine has only modest effects on CYP3A4 inhibition. Clinical patient outcomes were not reported, but it was stated that one patient in the monotherapy group (versus 10 patients who received combined SSRI and clozapine treatment) had serum clozapine concentrations [1,000 ng/mL. The mean serum clozapine concentrations for the combined SSRI and clozapine group were within the therapeutic range; therefore, adverse effects related to this drug interaction are unlikely. Fluoxetine 20 mg/day has been reported to significantly increase steady-state serum risperidone concentrations (reported as the active moiety, risperidone ? 9-OH risperidone). Ten patients were stabilized on risperidone 4–6 mg/day for at least 4 weeks; blood samples were obtained prior to fluoxetine use and at 2 and 4 weeks after combined treatment [81]. The mean plasma risperidone levels increased from baseline to 2 weeks (from 12 ± 9 to 49 ± 19 ng/mL, p \ 0.001), yet the mean plasma 9-OH risperidone levels slightly decreased from 43 ± 13 to

42 ± 9 ng/mL. The total mean active moiety increased from 55 ± 17 to 91 ± 26 ng/mL (p \ 0.001). The active moiety slightly increased further at week 4 to 96 ± 33 ng/ mL, with a total mean increase of 75 % (p \ 0.001 compared with baseline). Seven of the patients were genotyped for CYP2D6 polymorphism and were found to be either homozygous or heterozygous, indicating EM status (normal). Additionally, two patients developed parkinsonian symptoms, which required biperiden 4 mg/day to alleviate the adverse effects; no other extrapyramidal side effects were reported in the other patients. SSRI antidepressants have been reported to cause akathisia without antipsychotic therapy, denoting a possible pharmacodynamic interaction. Fluoxetine produced significant CYP2D6 inhibition, which resulted in significant increases in serum risperidone concentrations above suggested therapeutic levels, without affecting 9-OH risperidone levels. The effects of fluoxetine 60 mg/day were evaluated in 26 patients treated with quetiapine 600 mg/day. The addition of fluoxetine increased the AUC of quetiapine by 12 %, increased the Cmax by 26 % and increased the minimal serum concentration (Cmin) by 8 %, with a 14 % decrease in CL. These effects were not considered statistically or clinically significant [69]. This slight increase in quetiapine exposure upon fluoxetine addition could be attributed to modest CYP3A4 inhibition. Similar results were reported with olanzapine when fluoxetine 60 mg/day was given for 8 days to 15 nonsmoking healthy volunteers [12]. The pharmacokinetic profiles of olanzapine 5 mg in a single dose prior to and with co-administration of fluoxetine revealed only a 15 % decrease in CL, without a significant effect on the elimination half-life (t). 3.3.2.2 Fluvoxamine Fluvoxamine is metabolized by and is also a potent inhibitor of CYP1A2 and CYP2C19, with modest to mild CYP3A4 inhibition [76, 77]. Its drug


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interaction with clozapine and olanzapine is among the most studied interactions between SSRIs and SGAs [3–6]. Only key examples of this interaction are presented in this article, with other listed publications referred to elsewhere. Clozapine metabolism follows two main metabolic routes to form desmethylclozapine and clozapine N-oxide. Other metabolic routes include hydroxylation and formation of a protein-reactive metabolite. Clozapine was reported to be metabolized to desmethylclozapine via CYP1A2, CYP3A4, CYP2C9, CYP2C19 and CYP2D6 [82, 83]. Conversion of clozapine to clozapine N-oxide takes place via CYP3A4, and the metabolite is partially converted back to clozapine by reversible metabolism [84]. Early case reports presented a dramatic increase in plasma clozapine concentrations when a patient was placed on clozapine 400 mg and fluvoxamine 100 mg was added to the therapy [85]. After only 4 days, plasma clozapine levels jumped from 267 to 2,165 ng/mL, with the patient experiencing mild psychotic symptoms, nausea and dizziness. By day 8, the plasma clozapine concentration reached 3,151 ng/mL, necessitating drug discontinuation. Two other patients were reported to have plasma clozapine concentrations exceeding the ‘greatly elevated’ level upon fluvoxamine co-administration. One patient on clozapine 300 mg/day plus fluvoxamine 75 mg/day had a drug level of 1,678 ng/mL, and another patient on clozapine 500 mg/ day and fluvoxamine 150 mg had a drug level of 2,689 ng/ mL. A routine therapeutic drug monitoring analysis of plasma clozapine concentrations from 1989 to 1992 was conducted, which included 978 samples from 468 patients [86]. The clozapine C/D ratio was calculated for all observations, and the results from only three patients showed that fluvoxamine had a profound effect upon plasma clozapine concentrations. One patient was treated with only clozapine 12.5 mg/day, and the addition of fluvoxamine 200 mg/day resulted in a plasma clozapine concentration of 73 ng/mL (C/D ratio 5.84). A second patient treated with clozapine 50 mg/day and fluvoxamine 100 mg/day had a reported plasma clozapine concentration of 446 ng/mL (C/D ratio 8.92). The third patient had numerous changes in clozapine daily doses to attempt to maximize therapy. The patient started on clozapine 700 mg/day and was reduced to 550 mg/day after concurrent use of fluvoxamine 150 mg/day, but this led to a high plasma clozapine concentration of 3,781 ng/mL (C/D ratio 6.87). The last sample (#11) taken during treatment was from a patient receiving clozapine 100 mg/day with fluvoxamine 100 mg/day, with a plasma clozapine level of 1,390 ng/mL (C/D ratio 13.90). The remaining patients (N = 124) on clozapine monotherapy had a mean C/D ratio of 0.78 (range 0.67–0.90). Patients on known CYP2D6 inhibitors (N = 64) had a mean clozapine C/D ratio of 0.69 (range 0.58–0.82). These extraordinarily high

plasma clozapine concentrations seen in the clinical setting led to intensive investigations of clozapine and fluvoxamine drug interactions. In vitro and in vivo evaluations have been conducted to examine the interaction between fluvoxamine and clozapine [87]. Using a human liver microsomal model, fluvoxamine and furafylline (a known and preferred CYP1A2 inhibitor in in vitro models) significantly reduced formation of clozapine to desmethylclozapine by 42.2 and 48.5 % (p \ 0.01), respectively. Troleandomycin and erythromycin (known CYP3A4 inhibitors, with troleandomycin being preferred in in vitro models) produced only modest reductive effects (18.3 and 21.0 %, respectively) on clozapine formation to desmethylclozapine. The formation of clozapine N-oxide was significantly reduced by 44.5 % by troleandomycin and by 45.0 % by erythromycin. Furafylline had only modest effects, with 19.2 % inhibition of clozapine N-oxide formation. The in vivo study included nine patients with schizophrenia, who were phenotyped by dextromethorphan testing and were shown to be CYP2D6 EMs. Caffeine phenotyping was also conducted for CYP1A2 activity, and the results indicated the lack of any unusual metabolizers. Fluvoxamine 50 mg/day was given for 13 days and on day 14, fluvoxamine 50 mg and clozapine 50 mg were co-administered, and a pharmacokinetic profile was obtained via blood sampling 48 h postdose. The mean clozapine AUC significantly increased by 2.84-fold (from 780.0 ± 259.6 to 2,218.9 ± 776.1 ngh/ mL, p \ 0.01) and CL significantly decreased by 3.15-fold (from 0.060 ± 0.021 L/kg/h to 0.019 ± 0.013 L/kg/h, p \ 0.01). Decreased mean AUC values for desmethylclozapine (9.0 %) and clozapine N-oxide (18.8 %) were also noted. These findings convincingly demonstrate the fluvoxamine inhibition mechanism of clozapine metabolism in which both major pathways can be affected, leading to elevated plasma clozapine concentrations. However, drug interactions could have a clinical benefit and utility when their mechanisms are fully elucidated. Coadministration of fluvoxamine with clozapine has been reported to reduce the required clozapine dose in refractory schizophrenic patients [88]. Eighteen patients (including eight smokers) who were prescribed clozapine 100 mg/day for 14 days were given fluvoxamine 50 mg for the next 28 days, and blood samples were obtained on days 14 and 28. The mean plasma clozapine levels were raised from baseline to day 28 in both smokers (from 153.5 ± 99.4 to 371.0 ± 229.4 ng/mL, p \ 0.001) and nonsmokers (from 211.6 ± 95.5 to 437.7 ± 196.1 ng/mL, p \ 0.001). Interestingly, patients tolerated the treatment without significant adverse effects. This therapeutic approach occasionally achieved clinically recommended plasma levels and therapeutic effects, using low clozapine doses augmented by fluvoxamine to achieve therapeutic levels. Clinicians need

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to be very careful utilizing this technique, as it would require consistent dosing and complete patient adherence, which can be challenging in patients with schizophrenia. During its development, olanzapine was evaluated for its drug interaction with fluvoxamine. Olanzapine is converted to a major metabolite, N-desmethylolanzapine, via CYP1A2 [12]. Fluvoxamine 100 mg/day was given to ten healthy volunteer smokers for 6 days, then olanzapine 7.5 mg in a single dose was given prior to and co-administered with fluvoxamine. Fluvoxamine increased the olanzapine AUC from 0 to 24 h (AUC24) by 119 % and decreased CL by 50 % (p \ 0.05). The N-desmethylolanzapine AUC24 decreased by 77 % (p \ 0.05). However, the t of olanzapine was not significantly affected. The effects of fluvoxamine were described during a therapeutic drug monitoring programme of olanzapine treatment [89]. Patients on olanzapine monotherapy (N = 124) had a mean dose of 16.4 ± 7.2 mg/day, and the fluvoxamine plus olanzapine group (N = 10) had a mean dose of 17.7 ± 6.8 mg/day. Despite the comparable olanzapine doses in the two groups, the mean serum olanzapine concentrations and C/D ratios were significantly higher in the fluvoxamine plus olanzapine group (80 ± 54 ng/mL and 5.3 ± 2.6, respectively) than in the olanzapine monotherapy group (34 ± 21 and 2.3 ± 1.4, respectively, p \ 0.005). Fluvoxamine 50–150 mg/day increased the C/ D ratio by as much as 4.2-fold in some patients, with a group comparison of 2.3-fold. Dose-dependent fluvoxamine inhibitory effects upon olanzapine disposition were evaluated in patients with schizophrenia (N = 10) during a single 10 mg olanzapine dose study [90]. The study had three phases: a single olanzapine 10 mg dose alone, then fluvoxamine 50 mg/day for 13 days followed by fluvoxamine 50 mg plus olanzapine 10 mg on the next day, and finally fluvoxamine 100 mg/day for 13 days and olanzapine 10 mg on the final study day. A pharmacokinetic olanzapine profile was obtained during each study phase. Fluvoxamine significantly decreased the mean olanzapine CL (from 13.0 ± 4.60 L/h at baseline to 9.60 ± 3.06 L/h with fluvoxamine 50 mg and 8.01 ± 2.55 L/h with fluvoxamine 100 mg, p \ 0.001), with the higher fluvoxamine dose having a pronounced effect. The mean olanzapine AUC from time zero to infinity (AUC?) also significantly increased with fluvoxamine co-administration (from 910 ± 499 ngh/mL at baseline to 1,182 ± 527 ngh/mL with fluvoxamine 50 mg and 1,414 ± 621 ngh/mL with fluvoxamine 100 mg, p \ 0.001), with incremental AUC? elevations based upon the fluvoxamine dose. On the basis of these findings, clinicians have utilized the fluvoxamine interaction with olanzapine to augment olanzapine therapy and enhance therapeutic improvement in patients. A small study was done on patients with


schizophrenia (N = 8) who were treated with olanzapine 10–20 mg/day for at least 3 months [91]. Fluvoxamine 100 mg/day was added for the next 8 weeks, with plasma olanzapine levels obtained at weeks 0, 1, 4 and 8. Fluvoxamine resulted in mean increases in plasma olanzapine concentrations from week 0 (31 ± 15 ng/mL) to week 1 (49 ± 27 ng/mL) and week 8 (56 ± 31 ng/mL). The plasma olanzapine levels increased by 1.58-fold by week 1 and slightly further increased by 1.81-fold at week 8. Patients tolerated the combination treatment well with minimal adverse effects, and negative symptoms were shown to improve. Patient improvement was noted without side effects, which may be attributed to two factors: (1) plasma olanzapine levels were increased but remained within the therapeutic range; (2) the addition of fluvoxamine provided a pharmacodynamic benefit in augmenting serotonergic actions. In another study, low-dose fluvoxamine 25 mg/day was assessed in patients (N = 10) who were also treated with olanzapine as an adjunct to reduce olanzapine dose requirements, as a cost-saving measure [92]. The mean olanzapine dose of 17.5 ± 4.2 mg/day was reduced to 13.0 ± 3.3 mg/day after addition of fluvoxamine. No significant changes in plasma olanzapine concentrations were reported (those data were not provided in the paper), and the patients tolerated the addition of a nontherapeutic fluvoxamine dose. Clinicians need to be careful with this type of therapeutic approach, as long-term patient safety can be an important factor in chronic treatment and has not been adequately evaluated in the literature. During a therapeutic drug monitoring programme with quetiapine, using patient data (N = 1,123) collected from June 2001 to December 2004, it was reported that addition of fluvoxamine (N = 11) resulted in the most significant change in the C/D ratio (a 159 % increase, p = 0.001) [64]. The mean quetiapine C/D ratio for the population was 0.18 (95 % confidence interval [CI] 0.17–0.19), compared with 0.45 for fluvoxamine plus quetiapine (95 % CI 0.26–0.79). It is surprising that only in a few patients did such a notable impact with fluvoxamine significantly influence plasma quetiapine concentrations. Although fluvoxamine is a potent CYP1A2 inhibitor and quetiapine is a substrate for CYP3A4, the most likely explanation for this drug interaction is that fluvoxamine is also a moderate CYP3A4 inhibitor, which is overlooked by clinicians [65, 66]. A case report of neuroleptic malignant syndrome was described when a patient was prescribed quetiapine 150 mg/day and had fluvoxamine 100 mg added [93]. After 10 days of concomitant therapy, the patient developed muscle rigidity and stopped eating and drinking. Three days later, the patient was admitted to hospital with an elevated temperature, severe extrapyramidal side effects, high blood pressure, tachycardia and stupor.


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Laboratory test showed that the patient’s creatinine phosphokinase level was 7,500 IU/L and the white blood cell count was 1.3 9 1010/mm3. All medications were discontinued, and a dantrolene infusion was started. The patient recovered 3 weeks later, and all laboratory values returned to normal limits. This rare case report underscores the need for clinicians to carefully monitor patients, as in this case, a low quetiapine dose and addition of fluvoxamine may have led to a very serious adverse event. Fluvoxamine had only modest effects upon asenapine (shown in Table 3), with only a 29 % increase in the AUC? and a 13 % increase in the Cmax of asenapine when fluvoxamine 50 mg was added [49]. Caution was recommended upon using this combined therapy, and it remains unknown at this time if higher fluvoxamine doses would further enhance this drug interaction. Our interpretation of the data we report here is that of all of the SSRIs—indeed, of all of the antidepressants—fluvoxamine has an extremely high relative drug interaction potential in the clinical setting.

doses (p \ 0.05); however, the extrapyramidal side effect score also significantly increased in the 20 and 40 mg dose groups (p \ 0.05). Interestingly, at baseline, patients were within the recommended therapeutic range in the 10 mg dose group. The paroxetine 20 and 40 mg doses resulted in a large increase in active moiety concentrations, which were above the therapeutic range, but they also improved negative symptoms and increased extrapyramidal side effects. Paroxetine’s interactions were evaluated with other SGAs (shown in Table 3) during their development, and only iloperidone had a significant effect, with a 2- to 3-fold increase in plasma concentrations. A dose reduction of 50 % is recommended when paroxetine or other CYP2D6 inhibitors are prescribed with iloperidone. These findings present clinicians with therapeutic challenges to optimize the use of SGAs by using plasma concentrations with pharmacodynamic outcomes while balancing the risks and benefits of therapy.

3.3.2.3 Paroxetine Paroxetine is metabolized by and inhibits CYP2D6. Paroxetine’s effects upon risperidone disposition were reported in two clinical studies. In the first study, patients (N = 10) were stabilized on risperidone 4–8 mg/day and then paroxetine 20 mg/day was added for 4 weeks [94]. Blood samples were obtained prior to paroxetine doses and at 2 and 4 weeks afterwards. Like the results with fluoxetine, paroxetine produced a significant increase in plasma concentrations of risperidone and the active moiety, without affecting plasma 9-OH risperidone concentrations. The mean plasma concentrations of the active moiety increased from 137 ± 47 to 191 ± 58 nmol/L (p \ 0.05) from baseline to 2 weeks and to 198 ± 54 nmol/ L at 4 weeks, indicating a 62 % increase (p \ 0.05). The suggested risperidone active moiety therapeutic range is 50–150 nmol/L, which is analogous to 20–60 ng/mL. Five of the ten patients had active moiety concentrations[150 nmol/ L, with one patient developing Parkinsonian symptoms, treated with biperiden 4 mg/day. The second study used incrementally increasing paroxetine doses of 10, 20 and 40 mg/day, given at 4-week intervals. Patients (N = 12) were treated with a fixed risperidone 4 mg/day dose throughout the study [95]. Paroxetine resulted in a dosedependent increase in plasma concentrations of risperidone and the total active moiety without changing 9-OH risperidone levels. The mean active moiety concentration at baseline was 48.4 ± 35.2 ng/mL. Subsequent mean active moiety concentrations for paroxetine were 61.0 ± 37.2 ng/ mL for the 10 mg dose, 75.5 ± 43.8 ng/mL for the 20 mg dose and 91.1 ± 64.3 ng/mL for the 40 mg dose (p \ 0.05 only for the 40 mg dose). Significant improvement was noted in the negative symptoms of schizophrenia at all paroxetine

3.3.2.4 Sertraline Sertraline is metabolized by CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 but does not appear to induce or inhibit any CYP enzymes. Sertraline 50 mg was added to treatment for concomitant depressive symptoms in patients with schizophrenia (N = 13) stabilized on risperidone 4–6 mg/day for at least 4 weeks [96]. Sertraline 50 mg/day did not alter risperidone levels or plasma concentrations of the mean active moiety from baseline to week 2 (52 ± 11 and 53 ± 12 ng/mL, respectively) and week 4 (55 ± 10 ng/mL). Five patients had sertraline increased to 100 mg/day, which resulted in a slight increase in the mean risperidone active moiety concentrations from baseline (from 54 ± 15 to 62 ± 12 ng/mL) but was not considered a clinically significant change (p = 0.074). Sertraline 150 mg/day was achieved in two patients, with noticeable increases in total active moiety concentrations from baseline without any clinically significant adverse effects (from 48 and 59 ng/ mL to 73 and 80 ng/mL, respectively). Extrapyramidal side effects were not reported in any patients, and depressive symptoms improved in all patients. It appears that sertraline produces dose-dependent CYP2D6 inhibition, but not to the extent of paroxetine or fluoxetine. Published reports or evaluations of sertraline interactions with SGAs are limited. Clinicians should be aware when prescribing sertraline that increasing the sertraline dose may result in increasing CYP2D6 inhibitory actions on SGA metabolism, potentially resulting in clinically significant drug interactions. 3.4 Antiepileptics or Mood Stabilizers Antiepileptic drugs or mood stabilizers are used in combination with SGAs for the treatment of a variety of

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psychiatric disorders. Over the past decade, in addition to carbamazepine and valproic acid, other agents such as lamotrigine, oxcarbazepine and topiramate have been used extensively as adjunctive agents with SGAs. Drug interactions between SGAs and carbamazepine, phenytoin and phenobarbital are well known, as they are potent enzyme inducers of the CYP and UGT systems [97]. Lamotrigine is suggested to be a weak UGT inducer, oxcarbazepine is a mild inducer of CYP3A4 and UGT, and topiramate is also a mild CYP3A4 inducer and CYP2C19 inhibitor [97]. Valproic acid was reported to be a CYP3A4 and P-glycoprotein inducer, but it inhibits UGT and has modest inhibitory effects on CYPs—most notably, CYP2C9 [97]. Depending on SGA metabolic profiles and whether an antiepileptic drug is an enzyme inducer or inhibitor, clinically significant drug interactions are possible, and clinicians must monitor patients carefully during their treatment. Using the C/D ratio as an indicator of change from a drug interaction, a change by a factor of 29 was suggested to be clinically meaningful [97]. Besides C/D ratios, other pertinent data are reviewed so that clinicians can use their best judgment in determining the potential for drug interactions with SGAs (Table 2). This section reviews the major SGA drug interactions with antiepileptic drugs and mood stabilizers. Oxcarbazepine and topiramate have been reported not to significantly influence plasma concentrations of risperidone, olanzapine, clozapine and quetiapine, thus they are not discussed below [97, 98]. A summary of the drug interactions between these agents and SGAs is presented in Table 5.

3.4.1 Carbamazepine The effects of carbamazepine on serum antipsychotic concentrations have been well described in the literature. Carbamazepine is a potent CYP3A4, CYP1A2, CYP2D6 and UGT inducer, which produces a potentially clinically significant decrease in drug concentrations. Carbamazepine also exhibits auto-induction properties, with induction occurring during the first 2 months of treatment. In early studies, carbamazepine was reported to decrease serum clozapine concentrations by 30.7–62.9 % (mean 46.8 %, p \ 0.005) [99]. These findings would be expected on the basis of carbamazepine’s and clozapine’s pharmacokinetic properties [100]. In a therapeutic drug monitoring programme, the mean clozapine doses were higher in patients treated concomitantly with carbamazepine (484 ± 260 mg/ day, N = 17) than in those receiving clozapine monotherapy (386 ± 145 mg/day, N = 124) [86]. The mean C/D ratio was significantly lower in the carbamazepine plus clozapine group than in the clozapine monotherapy group (0.39:1 [95 % CI 0.28–0.53] versus 0.78:1 [95 % CI 0.67–0.90], p \ 0.005). One patient had a dramatic drop in the C/D ratio from 0.84 to 0.055 ng/mL/mg/day (a drop to one fifteenth of the original plasma clozapine concentration). Also, the mean plasma clozapine concentrations were significantly lower in the carbamazepine plus clozapine group (117 ng/mL, 95 % CI 65–229 versus 357 ng/mL, 95 % CI 164–435). Most of the monotherapy patients had plasma clozapine levels within the therapeutic range. In contrast, none of the carbamazepine plus clozapine-treated

Table 5 Summary of drug–drug interactions between mood stabilizers and second-generation antipsychotics (SGAs) Drug Carbamazepine

SGA

Pharmacokinetic effects of mood stabilizer on SGA

Clozapine

Plasma clozapine concentrations ; 50 % [99, 100]

Risperidone

Total active moiety concentrations ; 50 %, risperidone CL : 2-fold [61, 101]

Olanzapine

Median serum concentration ; by about 59 % and C/D ratio ; 71 % [104, 105]

Quetiapine

C/D ratio dramatically ; 9-fold, CL : 7.49-fold [109]

Ziprasidone

AUC ; 36 % with modest induction [111]

Aripiprazole

Mean AUC ; 71 % and CL : 4-fold [112]

Lamotrigine

Clozapine Risperidone

No significant changes [114] No significant changes [114]

Olanzapine

No significant changes detected in 2 in-depth pharmacokinetic studies [115, 116]

Phenobarbital

Clozapine

Significantly ; plasma concentrations; when phenobarbital was discontinued, a 56 % : in the plasma clozapine concentration was seen [119, 120]

Phenytoin

Quetiapine

CL : 5-fold [121]

Valproic acid

Clozapine

Variable results reported (: and ;) [79, 124–126]

Risperidone

No significant changes [101]

Olanzapine

Plasma concentrations ; 53 % with : psychosis in 3/4 patients, another study reported a 20 % ; in plasma concentrations [127, 128] AUC ; 26 % with CL : 24 % [129]

Aripiprazole

AUC area under the plasma concentration–time curve, C/D concentration/dose ratio, CL clearance, : increase(d), ; decrease(d)


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patients ever reached the lower limit of the clozapine therapeutic range. The effect of carbamazepine was examined in patients treated with risperidone for at least 4 weeks (mean dose 5.9 ± 1.0 mg/day) either as monotherapy (N = 23) or combined with carbamazepine (N = 10, mean dose 764 ± 266 mg/day) [101]. Active moiety concentrations were measured 5 days later, and the median amounts of the active moiety were significantly lower in the carbamazepine group (44 versus 150 nmol/L, p \ 0.001), which fell below the recommended therapeutic level shown in Table 2. Another report confirmed a 50 % lower active moiety concentration in patients with schizophrenia. This large effect in lowering the total active moiety concentration had clinical consequences. Evaluation of CYP2D6 genotype variations may play an important role in understanding this complex interaction [102, 103]. A population pharmacokinetic analysis was conducted using data from patients (N = 407 and 5,359 plasma concentrations) during the drug-development studies of risperidone in the treatment of bipolar I disorder [61]. The nonlinear mixed-effects model (NONMEM, version 5, level 1.1) showed that carbamazepine had a statistically significant effect upon risperidone and 9-OH risperidone CL (p \ 0.0001). Risperidone CL significantly increased from 2.84 L/h (SD 28.1 %) to 6.49 L/h (SD 33.0 %) without a significant increase in 9-OH risperidone CL [5.99 L/h (SD 5.4 %) versus 6.22 L/h (SD 10.2 %)]. Since metabolite CL remained unaffected in spite of increased concentrations of the parent drug, CYP3A4 and possibly CYP2D6 induction conversion from risperidone is the most likely mechanistic approach to this interaction. A pharmacokinetic drug interaction study between carbamazepine and olanzapine was completed in healthy volunteers (N = 11) where a single 10 mg dose of olanzapine was evaluated [104]. Carbamazepine 400 mg/day was given for 18 days, and olanzapine was administered prior to carbamazepine initiation and co-administration on the last day. The results exhibited a significant decrease in the olanzapine mean AUC? [from 336 ± 103 to 223 ± 59 lgh/L (p \ 0.001)] with an increase in the mean CL [from 32.6 ± 10.4 to 47.6 ± 12.0 L/h (p \ 0.001)]. Induction likely occurs via the CYP1A2 system and not via the CYP3A4 system. Various therapeutic drug monitoring services have described the effects of carbamazepine upon serum free olanzapine concentrations and C/D ratios [105]. From a population of 545 patients in a naturalistic setting, only ten patients were given carbamazepine and olanzapine. Despite olanzapine doses twice as high as those in the monotherapy group (N = 44), the carbamazepine plus olanzapine group had a 59 % lower median serum concentration and a 71 % lower median C/D ratio. A similar finding occurred when

the median olanzapine C/D ratio was 36 % lower (p \ 0.05) in patients treated with carbamazepine and olanzapine (N = 5) than in those receiving olanzapine monotherapy (N = 22) [106]. Serum concentrations of free and glucuronidated olanzapine were evaluated in a therapeutic drug monitoring setting in patients treated with olanzapine monotherapy (N = 31) and olanzapine combined with carbamazepine (N = 16) [107]. The median free olanzapine C/D ratio was 38 % lower in the carbamazepine and olanzapine group (3.6 versus 5.8 nmol/L/mg, p \ 0.01). The median glucuronidated fraction in the carbamazepine group was significantly higher than that in the monotherapy group (79 versus 43 %, p \ 0.01). These results indicate that carbamazepine lowers the free olanzapine concentration by increasing metabolism to its glucuronidated metabolite, which subsequently increases in concentration. Using a population pharmacokinetic mixedeffects model, olanzapine covariates that significantly influence drug CL were examined [62]. The population (N = 163) included a variety of concomitant medications, with only two patients taking carbamazepine. The mean C/D ratio of the overall group was 2.3 ± 1.4. The carbamazepine-treated patients had a lower mean C/D ratio of 0.48 ± 0.077. The model detected a significant effect (p = 0.006) from only two patients, indicating a potential systematic monitoring technique available to clinicians. A case report showed that carbamazepine was discontinued and, over the course of 4 weeks, plasma olanzapine levels continued to increase from 21 to 45 ng/mL (a 114 % increase) [108]. The patient was treated with olanzapine 15 mg/day and carbamazepine 600 mg/day for 9 weeks, and then carbamazepine was stopped, as it did not appear to benefit the patient. Plasma olanzapine levels increased by a similar factor with carbamazepine discontinuation as compared to induction, with the maximal effect taking place at about 4 weeks. A pharmacokinetic drug interaction study with carbamazepine and quetiapine was conducted in patients with schizophrenia (N = 18). The quetiapine dose was titrated to 600 mg/day over 5 days [109]. Carbamazepine was started and its dose was titrated to 600 mg/day by day 13 and maintained to day 33. Quetiapine 600 mg was continued through day 33. The quetiapine pharmacokinetic study was conducted on day 6 prior to carbamazepine initiation and on day 34 when both drugs were co-administered. Carbamazepine had a striking 7.4-fold effect in lowering the mean quetiapine AUC during the dosage interval (AUCs) at steady state (AUCs–ss) from 4,650 ngh/ mL to 621 ngh/mL (ratio of means 0.13) and increasing the mean quetiapine CL 7.4-fold from 65 to 483 L/h (ratio of means 7.49). A therapeutic drug monitoring programme for quetiapine compared the population (N = 1,123) with patients concomitantly receiving carbamazepine [64]. The

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mean C/D ratio was significantly lower in the carbamazepine-treated patients than in the population (0.02 [95 % CI 0.02–0.03] vs 0.18 [95 % CI 0.17–0.19], p \ 0.001). The clinical implications from carbamazepine affecting plasma quetiapine levels can be significant, as measurable concentrations could not be detected (the limit of detection was 25 lg/L) despite 700 mg/day being given to three patients who were previously placed on carbamazepine 400–800 mg/day as a mood stabilizer for treatment of their epilepsy. The patients’ psychopathology did not improve despite combined drug therapy [110]. A therapeutic drug monitoring programme for quetiapine reported that coadministration of carbamazepine in 11 patients resulted in significantly higher quetiapine CL values (p \ 0.01) than those in other quetiapine-treated patients [66]. In a study with healthy volunteers (N = 19), carbamazepine was co-administered with ziprasidone and compared with placebo plus ziprasidone [111]. Ziprasidone 40 mg/day was given for 3 days prior to administration of carbamazepine or placebo. The carbamazepine dose was titrated up to 400 mg/day for 9 days and was maintained at that dose for the next 19 days. Ziprasidone 40 mg/day was then given again during the last 3 days with carbamazepine. The pharmacokinetic profile of ziprasidone was completed, and carbamazepine lowered the mean AUC from 0 to 12 h (AUC12) by 36 % from 445 ± 155 to 285 ± 79 ngh/mL (p \ 0.001). This was suggested to be a modest induction, as the mean Cmax was slightly lowered by 27 % from 65 ± 25 to 48 ± 13 ng/mL (p \ 0.001). Although statistically significant, the clinical impact remains to be determined, and the manufacturer recommends no dosage adjustments at this time. The effects of carbamazepine upon aripiprazole disposition were evaluated in nine patients with schizophrenia or schizoaffective disorder [112]. Aripiprazole 30 mg/day was given for 14 days and then carbamazepine for the next 4–6 weeks; the dose was titrated to achieve serum carbamazepine concentrations of 8–12 mg/L. Aripiprazole blood samples were obtained prior to and during carbamazepine co-administration, with a pharmacokinetic profile being determined. Carbamazepine decreased the mean aripiprazole AUCs by 71 % from 10,016 ± 3,903 to 2,914 ± 1,853 ngh/mL (p \ 0.001), with a 4-fold increase in CL from 57 ± 22 to 227 ± 115 mL/min. An additional pharmacokinetic and pharmacodynamic study was conducted, investigating the effects of carbamazepine in aripiprazole-treated patients (N = 18) given 12 and 18 mg/ day for 3–5 weeks [113]. Carbamazepine 800 mg/day was added for 1 week, with blood samples taken prior to carbamazepine administration and repeated 1 week later. Carbamazepine use resulted in significant drops in the mean baseline serum aripiprazole concentration (from 273.5 ± 113.3 to 99.1 ± 50.9 ng/mL, p \ 0.001) and in


the mean baseline serum dehydroaripiprazole concentration (from 123.3 ± 44.0 to 40.7 ± 15.5 ng/mL, p \ 0.001). It was noted that there was a clinical improvement in the psychopathology rating scales and that augmentation with carbamazepine could improve patient outcomes. These findings present an interesting clinical response, as the mean baseline plasma aripiprazole concentrations were in the upper therapeutic range (see Table 2), with several patients above 300 ng/mL. The patients did not relapse, and the addition of carbamazepine lowered plasma aripiprazole concentrations in those patients from [300 to \300 ng/mL. Perhaps the clinical improvement observed in those patients could have been a result of the combination of decreased plasma drug levels from excessively high aripiprazole levels and the pharmacodynamic actions of carbamazepine, leading to fewer adverse effects. Currently, the generally accepted clinical recommendation is for aripiprazole doses to be doubled to account for the induction effects of carbamazepine. 3.4.2 Lamotrigine Utilization of lamotrigine in psychiatry continues to grow, and it has been FDA approved for the treatment of bipolar disorders. Lamotrigine is metabolized not by the CYP system but by the UGT route—specifically, UGT1A4 [13]. It is well known that valproic acid inhibits lamotrigine metabolism and reduces plasma olanzapine concentrations (see Sect. 3.4.4). Therefore, potential drug interactions would be anticipated to occur between lamotrigine and SGAs. A large therapeutic drug monitoring programme (N = 829) evaluated lamotrigine in a linear mixed-effects model, where 35 other drugs were assessed to determine if they could affect the lamotrigine C/D ratio. Olanzapine, clozapine, quetiapine and risperidone were not found to significantly affect lamotrigine C/D ratios [114]. An in-depth study on patients with schizophrenia and bipolar disorder (N = 35) was conducted in patients treated with clozapine (N = 11, 200–500 mg/day), risperidone (N = 10, 3–6 mg/day) and olanzapine (N = 14, 10–20 mg/day) [115]. The lamotrigine dose was gradually increased to 200 mg/day. The results showed that lamotrigine had no significant effect upon the mean plasma clozapine levels (baseline 384 ± 103 ng/mL versus 402 ± 91 ng/mL with lamotrigine 200 mg/day) and the mean risperidone (active moiety) concentrations (baseline 39 ± 11 ng/mL versus 43 ± 11 ng/mL with lamotrigine 200 mg/day). Only plasma olanzapine levels were reported to be significantly increased (baseline 31 ± 7 ng/mL versus 36 ± 9 ng/mL with lamotrigine 200 mg/day, p \ 0.05); however, the levels remained within the recommended therapeutic range (see Table 2), and so this interaction is


unlikely to be clinically significant. Another therapeutic drug monitoring programme reported a 17 % decrease in quetiapine C/D ratios in patients treated with lamotrigine (N = 147) compared with quetiapine monotherapy (N = 1,123). Olanzapine metabolism also involves the UGT system, and an in-depth pharmacokinetic study in healthy volunteers with lamotrigine was conducted [116]. Lamotrigine doses were titrated to 50 mg/day by day 3, and a single olanzapine 5 mg dose was given to 14 nonsmokers prior to lamotrigine initiation and coadministered after 2 weeks. No significant changes in lamotrigine disposition were found, and only a prolonged mean time to reach the Cmax (tmax) of lamotrigine was found (from 1.9 ± 1.3 to 4.0 ± 3.0 h, p = 0.025), which could be attributed to olanzapine’s anticholinergic property of slowing passage through the gastrointestinal tract. In a similar study, the effects of lamotrigine and olanzapine co-administration were evaluated in healthy volunteers (N = 43), where lamotrigine doses were gradually increased to 200 mg over 42 days and olanzapine doses were increased to 15 mg/day over 3 days [117]. Lamotrigine and olanzapine were co-administered for 9 days, and pharmacokinetic parameters were determined for lamotrigine and olanzapine. The mean AUC24 and Cmax values of lamotrigine were 24 and 20 % lower, respectively, during co-administration. Olanzapine’s pharmacokinetic parameters remained unchanged. A population pharmacokinetic study (N = 163; 360 plasma samples) reported that nonsmoking patients taking lamotrigine with olanzapine had a 10 % lower mean plasma concentration than nonsmoking patients not taking lamotrigine (see Sect. 3.6) [62]. These results suggest that olanzapine dosing may not need adjustment during lamotrigine co-administration. However, lamotrigine exposure was moderately decreased, and the possible need for lamotrigine dose adjustments when used in conjunction with olanzapine cannot be excluded. Aripiprazole has not been shown to influence lamotrigine disposition in bipolar I patients (N = 18) under lamotrigine steady-state conditions [118]. Aripiprazole was added, and the dosage was increased up to 30 mg for 8 days; a lamotrigine pharmacokinetic profile was obtained prior to aripiprazole use and during co-administration. The lamotrigine Cmax and AUCs values were reported to be slightly lower, but the differences were not statistically significant. The mean Cmax in patients receiving lamotrigine monotherapy was 26 ng/mL (coefficient of variation [CV] 38 %) compared with 23 ng/mL (CV 32 %) in those receiving lamotrigine plus aripiprazole, and the mean AUCs values in the two groups were 434 ngh/mL/dose (CV 44 %) and 394 ngh/mL/dose (CV 40 %), respectively. Therefore, no lamotrigine dose adjustments would be needed when aripiprazole is added.

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3.4.3 Phenobarbital and Phenytoin Both phenobarbital and phenytoin are well known CYP inducers and can lead to numerous drug interactions [97]. In one study, patients with schizophrenia (N = 15) were treated with clozapine, while another group of schizophrenic patients (N = 7) receiving clozapine had phenobarbital added for treatment of concomitant epilepsy [119]. The patients received clozapine and phenobarbital therapy for at least 6 months. The mean clozapine doses did not significantly differ between the groups (clozapine ? phenobarbital 307 ± 53 mg/day versus clozapine alone 295 ± 48 mg/day). The phenobarbital group had a significantly lower mean plasma clozapine concentration than the clozapine monotherapy group (232 ± 104 versus 356 ± 13 ng/mL, p \ 0.05). Plasma desmethylclozapine plasma levels did not differ between the two groups, but plasma clozapine N-oxide concentrations were significantly higher in the phenobarbital group (115 ± 49 versus 53 ± 31 ng/mL, p \ 0.01). A case report described elevated plasma clozapine and metabolite levels after discontinuation of phenobarbital. A patient was treated with clozapine, and the dose was increased up to 600 mg/day until a seizure occurred. Phenobarbital 60 mg/day was given to prevent further seizures, and the clozapine dose was reduced to 400 mg, which prevented further seizures [120]. The plasma clozapine level was reported to be 346 ng/mL, with a desmethylclozapine level of 241 ng/mL and a clozapine N-oxide level of 65 ng/mL. Phenobarbital was then to be tapered off over the next month. Two weeks after phenobarbital was stopped, the plasma clozapine level was 608 ng/mL, the desmethylclozapine level was 602 ng/ mL and the clozapine N-oxide level was 253 ng/mL. The plasma clozapine and metabolite concentrations became lower after 4 weeks, with clozapine at 280 ng/mL, desmethylclozapine at 87 ng/mL and clozapine N-oxide at 96 ng/mL. These findings support the induction effects of phenobarbital, and similar to carbamazepine, these induction effects may take several weeks to diminish as the hepatic enzymes ‘equilibrate’ to a normal activity level. Prior to the use of carbamazepine as the induction agent to examine drug interactions, phenytoin was occasionally used in interaction studies. In a pharmacokinetic study of patients with schizophrenia and schizoaffective disorder (N = 17), quetiapine doses were titrated upwards to 750 mg/day over 10 days and then maintained for the next 14 days. Phenytoin 300 mg/day was added during the last 10 days of quetiapine treatment, and a quetiapine pharmacokinetic profile was determined. Phenytoin produced a substantial decrease in the mean quetiapine AUC from 0 to 8 h (AUC8) from 3,642 ± 1,375 to 728 ± 445 ngh/mL (p \ 0.0001), with a geometric mean ratio of 18.8 %. Quetiapine CL increased more than 5-fold from

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80.3 ± 35.9 to 440 ± 214 L/h. These results suggest that quetiapine dose adjustments will be required if enzyme inducers such as carbamazepine and phenytoin are added to a drug regimen including quetiapine [121]. 3.4.4 Valproic Acid The use of valproic acid over the past decade has encompassed a vast array of neurological and psychiatric disorders, and use of valproic acid in combination with SGAs is more common than use of other mood stabilizers. In psychiatry, regulatory agencies have approved valproic acid for bipolar disorder, but this agent is often prescribed for patients with schizophrenia and schizoaffective disorder, as well as other clinical situations where mood or impulse control are key symptoms. In vitro and in vivo models using pooled human liver microsome data show that valproic acid competitively inhibits CYP2C9, weakly inhibits CYP3A4 and CYP2C19, and is an inhibitor of UGT (specifically, UGT1A4 and UGT2B7) [122]. Valproic acid was shown in transient transfection reporter assays in HepG2 cells to induce CYP3A4 and P-glycoprotein gene expression, and this presents a complex and sometime unpredictable interaction with other drugs [123]. These results together may explain the inconsistent effects of valproic acid on SGAs, observed among patients and healthy subjects alike. Of note, valproic acid has not been reported to influence the asenapine Cmax and AUC?, although the asenapine N-glucuronide metabolite Cmax and AUC? were significantly reduced in the presence of valproic acid. Valproic acid co-treatment in patients being prescribed clozapine represents an interesting challenge for clinicians because of the side effects that each of these drugs can produce. Variable results have been reported, where plasma clozapine concentrations are either slightly increased or decreased with valproic acid addition to therapy. Early studies reported that valproic acid slightly increased plasma clozapine levels in patients receiving combined therapy (N = 11) compared with those receiving clozapine monotherapy (N = 17) from 247 ± 131 to 388 ± 121 lg/mL (p \ 0.01). The mean plasma desmethylclozapine levels slightly decreased from 229 ± 134 to 176 ± 57 lg/mL, with a modest increase in the mean plasma clozapine N-oxide concentrations from 57.0 ± 31.5 to 73.8 ± 36.0 lg/mL [79]. A similar pattern of change with plasma clozapine (only 20 % higher), desmethylclozapine and clozapine N-oxide concentrations was also described in another study in patients treated with valproic acid and clozapine [124]. Smoking could add an additional factor in the drug interaction between valproic acid and clozapine (see Sect. 3.6). It was reported that a 21 % decrease in the mean plasma clozapine


concentrations occurred in four patients who received valproic acid and clozapine, from 457.5 to 270.0 ng/mL. In a similar report, seven patients had a 15 % decrease in mean plasma clozapine levels from 353 ± 179 to 298 ± 79 lg/mL (p = 0.05), with a marked drop in plasma desmethylclozapine levels from 394 ± 221 to 138 ± 43 lg/mL (p = 0.04) [125, 126]. These early reports suggest that valproic acid has modest but different effects upon plasma clozapine concentrations, and the clinician needs to cautiously interpret these findings and correlate the drug’s serum concentration with the patient’s symptoms. Valproic acid has also been reported to cause inconsistent changes in serum risperidone concentrations. Therapeutic drug monitoring of risperidone compared patients receiving risperidone monotherapy (N = 23) with patients being treated with valproic acid (mean dose 979 ± 189 mg/day) and risperidone [101]. The mean risperidone dose in both groups was 5.9 ± 1.0 mg/day, which was not significantly different between the two treatment groups. There was a slightly greater amount of risperidone in the combined treatment group (168 ± 47–335 versus 150 ± 54–347 nmol/L). Four case reports recorded significant decreases in serum olanzapine concentrations when valproic acid (1,000–2,700 mg/day) was added [127]. The mean serum olanzapine concentrations declined by 53 % (from 201 ± 170 to 94 ± 109 ng/mL) from 6 to 12 days after addition of valproic acid. As a consequence, three of the four patients experienced acute exacerbations of psychotic symptoms, which required olanzapine dose adjustments. A clinical study in patients with schizophrenia and schizoaffective disorder (N = 21) was conducted to examine the effects of valproic acid upon olanzapine [128]. Seven of the patients were smokers. The patients were stabilized on olanzapine 5–20 mg/day for 1 month prior to starting valproic acid. The mean olanzapine and valproic acid doses were 12.9 ± 5.3 and 1,055.6 ± 312.9 mg/day, respectively. Blood samples were obtained 2 and 4 weeks after co-treatment. The mean plasma olanzapine concentration fell from 32.9 ± 9.7 to 27.4 ± 9.8 ng/mL (p = 0.02) at week 2 and remained stable at week 4 [26.9 ± 9.2 ng/mL (p = 0.001)]. Co-administration was well tolerated, without any clinical patient decline in psychopathology. Smoking appeared to not have a significant effect on the separation of the two study groups. These results suggest that addition of valproic acid can be associated with a slight drop in plasma olanzapine concentrations without clinical consequences. A similar finding was reported with aripiprazole, where valproic acid co-administration in patients with schizophrenia and schizoaffective disorder (N = 10) was associated with a 26 % decrease in the aripiprazole AUCs from


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7,474 ngh/mL to 7,041 ngh/mL and an increase in CL from 67.9 ± 12.3 to 90.3 ± 22.4 mL/min [129]. Plasma valproic acid concentrations during the study were reported to be greater than 50 lg/mL in all patients. A possible explanation for this occurrence is that aripiprazole is metabolized by CYP3A4 and P-glycoprotein. Theoretically, CYP induction could take place via hepatic mechanisms, and increased P-glycoprotein gene expression could decrease drug absorption in the gastrointestinal tract. Further studies are needed to investigate the induction effects of valproic acid on SGA drugs.

stopped after 2 days because of an elevated liver function test. The serum clozapine concentration prior to antibiotic treatment was 850 ng/mL, and 3 days after starting ciprofloxacin (1 day after cessation), the concentration was reported to be 1,720 ng/mL. Fortunately, no other clinical sequelae were observed or reported. In a clinical study, seven patients with schizophrenia were stabilized on clozapine (mean dose 304 ± 106 mg/ day) for several weeks [133]. Six of the patients were smokers. Ciprofloxacin 500 mg/day was added for 7 days, and plasma clozapine and desmethylclozapine concentrations were measured prior to antibiotic use and on day 7 during co-administration. Ciprofloxacin produced a mean increase in plasma clozapine levels of 29 % (range 6–57 %, p \ 0.01) and a mean plasma desmethylclozapine level increase of 31 % (range 0–63 %, p \ 0.05). Even with use of this modest ciprofloxacin dose, a significant increase was found in plasma clozapine concentrations, and the magnitude of the interaction appeared to be dose dependent, as with fluvoxamine. It is important to note that smoking may be another factor affecting this drug–drug interaction, and it may have diminished the ciprofloxacin inhibitory effects (see Sect. 3.6). Erythromycin 750 mg/day for 10 days was used to treat a patient for pharyngitis, being added to a regimen of clozapine 800 mg/day, which had been stable for 3 weeks [134]. After 7 days, the infection resolved, but the patient experienced a seizure, and a plasma clozapine level was obtained and reported to be 1,300 ng/mL. The antibiotic was discontinued, and clozapine was withheld for 2 days. Clozapine was restarted and titrated back to 800 mg/day over several weeks, and a follow-up plasma concentration was reported to be 700 ng/mL. Another case report described a patient who was empirically prescribed erythromycin 999 mg/day for a lower respiratory tract infection. This patient had been stable on clozapine 600 mg/day for several months [135]. The day after erythromycin was started, the patient displayed somnolence and difficulty in coordination. The patient was admitted to the hospital for incoherent speech, disorientation and incontinence. A plasma clozapine level obtained at the time of admission was 1,150 lg/L. Clozapine and erythromycin were discontinued, and clozapine was restarted after the infection and adverse effect symptoms resolved. After clozapine 600 mg/day was reached and under steady-state conditions, a plasma clozapine concentration was determined to be 385 lg/L. The suggested mechanism for the drug interaction was proposed to be CYP3A4 inhibition. A clinical study in nonsmoking healthy volunteers (N = 12) was conducted, where erythromycin 1,500 mg day was given and a single 12.5 mg clozapine dose was administered before and during erythromycin treatment [136]. No significant differences were found in the mean clozapine

3.5 Anti-infective Agents and Other Drugs 3.5.1 Antibiotic Agents Drug interactions with anti-infective agents continue to be an area of concern and interest, with various new antibiotics having been approved in the last few years. An early case report described a 72-year-old Caucasian male on clozapine 18.75 mg/day when he was admitted to the hospital for agitation and placed on ciprofloxacin 1,000 mg/day for skin and soft tissue ankle ulceration [130]. His plasma clozapine concentrations were reported to be at least 80 % higher during ciprofloxacin treatment, leading to the antibiotic being discontinued. Since that report, other case studies have documented this interaction. Ciprofloxacin and other fluroquinolones are reported to be potent CYP1A2 inhibitors, and interactions are likely to occur with clozapine and with other SGAs metabolized by the CYP1A2 system. A more recent case report depicted a patient on clozapine 750 mg/day and ciprofloxacin 1,500 mg/day for a groin infection [131]. Serum clozapine levels by day 4 of antibiotic treatment increased from 0.55 to 2.57 mg/L (the therapeutic threshold is 0.35 or 350 ng/ mL). Subsequently, the patient’s clozapine dose was decreased to 450 mg/day, and the patient completed ciprofloxacin treatment without any reports of adverse effects. Another case report portrayed two patients who had elevated serum clozapine concentrations with ciprofloxacin [132]. Patient 1 was on clozapine 900 mg/day and developed urosepsis, and intravenous ciprofloxacin 800 mg/day was given for 5 days. After 4 days, the patient responded well and was discharged. Three days later, the patient was admitted for rhabdomyolysis with a creatine phosphokinase level of 195,000 IU/L. Immediate treatment procedures were instituted, and the medications were discontinued. A plasma clozapine level was then obtained 3 days after ciprofloxacin cessation and 1 day after clozapine discontinuation, which was still elevated at 890 ng/mL. Patient 2 was treated with clozapine 300 mg/day and had a suspected urinary tract infection and/or pneumonia. Ciprofloxacin 400 mg/day was given intravenously but was

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AUC? (1,348 ± 633 nmolh/L versus 1,180 ± 659 nmolh/L), although the mean clozapine CL was slightly increased (from 34.2 ± 15.3 to 45.9 ± 36.6 L/h, p = 0.09). The lack of an observed interaction may be due to the very low clozapine dose that can be safely given to healthy volunteers, and higher doses used in patients could provide a more accurate determination. Ciprofloxacin was suspected in another drug interaction where a patient received olanzapine 10 mg/day and was placed on ciprofloxacin 500 mg/day for 7 days for empirical treatment of a urinary tract infection [137]. Immediately prior to the last ciprofloxacin dose, a plasma olanzapine level was measured to be 32.6 ng/mL. Three days after ciprofloxacin was ceased, another plasma olanzapine concentration was determined and found to be 14.6 ng/mL (a [50 % decrease). Again, CYP1A2 inhibition was considered the likely mechanism for the drug interaction with olanzapine. Although not currently reported in the literature, it would be interesting to note if asenapine would have a similar effect with a fluoroquinolone, as its CYP metabolic profile is very similar to that of olanzapine. In a clinical study of patients (N = 19) with schizophrenia and schizoaffective disorder, quetiapine 400 mg/ day was given alone and then co-administered with erythromycin 1,500 mg/day [138]. Quetiapine pharmacokinetic parameters were determined prior to dosing of erythromycin. Erythromycin resulted in significant increases in the mean quetiapine Cmax (from 670 ± 314 to 1,136 ± 459 lg/L, p = 0.001) and AUC? (from 5,514 ± 4,120 to 12,649 ± 6,945 lgh/L, p \ 0.0001), and a decrease in the mean quetiapine CL (from 67.2 ± 26.6 to 34.3 ± 12.5 L/h, p \ 0.0001). In another case report, clarithromycin (a potent CYP3A4 inhibitor) was administered to a patient treated in a psychiatric unit with quetiapine 300 mg/day [139]. The antibiotic was prescribed for community-acquired pneumonia and, after the second day’s dose, the patient gradually became more somnolent and required transportation to the internal medicine service. A plasma quetiapine level of 826.8 lg/L was obtained 14 h post-dose, with severely impaired consciousness and respiratory depression being present. The medications were discontinued, and the patient recovered during the following week.


significant changes in SGA pharmacokinetics, including those of lurasidone, iloperidone and aripiprazole [11, 53]. Ketoconazole was reported to cause dramatic changes in the lurasidone AUC, where a 9-fold increase was found. Ketoconazole is not to be used in conjunction with lurasidone [42, 43]. Dosage adjustments are recommended for iloperidone and aripiprazole when they are used with ketoconazole [45, 51]. Ketoconazole was shown to significantly alter quetiapine pharmacokinetics in healthy volunteers (N = 12), where only a single quetiapine 25 mg dose was given before and during ketoconazole administration of 200 mg/day for 4 days [109]. The mean quetiapine Cmax increased by 235 % from 45 ng/mL (SD not given) to 150 ng/mL, the mean quetiapine AUC increased by 522 % from 181 to 1,123 ngh/mL, and the mean quetiapine CL decreased by 84 % from 138 to 22 L/h. Clinicians need to be cautious when prescribing ketoconazole with quetiapine. When studied, clozapine pharmacokinetics were found to be unaffected in schizophrenic patients given ketoconazole and itraconazole [140, 141]. The reason for this lack of drug interaction is postulated to be that the multiple CYP enzymes involved with clozapine metabolism partially cancel each other out, making it difficult to attribute any plasma concentration change or lack thereof and precluding any predictable clozapine–itraconazole/ketoconazole drug interactions [142]. Therefore, at low clozapine doses, CYP1A2 inhibition predominates, whereas CYP3A4 drug interactions can become more important with higher clozapine doses. Itraconazole 200 mg for 7 days was reported to affect risperidone and 9-OH risperidone disposition in patients with schizophrenia (N = 19) who were treated with doses of 2–8 mg/day [143]. The dose-normalized plasma risperidone concentration significantly increased from 0.9 ± 0.8 to 1.6 ng/mL/mg (p \ 0.01) and 9-OH risperidone increased from 6.9 ± 3.3 to 11.3 ng/mL/mg (p \ 0.01). Both dose-normalized plasma concentrations returned to baseline levels within 1 week after itraconazole was discontinued. These findings point towards CYP3A4 involvement in risperidone metabolism. Although the CYP3A4 metabolic pathway is a minor pathway for risperidone, significant effects were found with a potent CYP3A4 inhibitor. 3.5.3 Antituberculosis Agents

3.5.2 Antifungal Agents Ketoconazole and itraconazole are antifungal agents that are known to be potent CYP3A4 inhibitors. Ketoconazole has been tested in clinical studies during the development of various SGAs that are metabolized by CYP3A4, as shown in Table 3 [41]. With the exception of ziprasidone, co-administration with ketoconazole has resulted in

Rifampicin is commonly prescribed in conjunction with isoniazid for the treatment of tuberculosis. Rifampicin is also a potent CYP3A4 inducer, like carbamazepine, and was used in drug interaction studies with lurasidone during its development (Table 3) [41]. The results indicated that rifampicin led to a significant decrease in the lurasidone Cmax and AUC, and the recommendation is that this agent


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should not be used with lurasidone [42, 43]. The recommendations of not co-administering drugs represents a significant change in the product labelling, compared with the usual dose adjustment statements of years past. Clinicians must exercise appropriate judgment in prescribing potent enzyme inducers and inhibitors with lurasidone and other antipsychotics. A case report of isoniazid’s inhibition of clozapine metabolism was reported in a patient stabilized on clozapine 400 mg/day and subsequently prescribed isoniazid 300 mg/day after a diagnosis of tuberculosis [144]. Prior to use of isoniazid, the plasma clozapine level was 397 ng/mL and the desmethylclozapine level was 384 ng/mL. Three days later, clozapine measurements were obtained, and the results were clozapine at 569 ng/mL and desmethylclozapine at 520 ng/mL; 9 days later they were even higher, with clozapine at 756 ng/mL and desmethylclozapine at 725 ng/mL, which necessitated dropping the clozapine dose down to 200 mg/day. A plasma clozapine level 21 days later was 385 ng/mL and the desmethylclozapine level was 379 ng/mL. Finally, after discontinuation of isoniazid (9 months later), the patient’s plasma clozapine concentration was reduced to 239 ng/mL and the desmethylclozapine concentration was reduced to 221 ng/mL. Isoniazid has been reported to be a CYP1A2 inhibitor, and this mechanism is the likely the cause of this drug interaction.

combinations [148–150]. A case reported described a HIV-positive patient who attempted suicide by taking a quetiapine overdose of 8,000 mg [151]. The patient was also taking lamuvidine, ritonavir, atazanavir and tenofovir. The initial plasma quetiapine level obtained was 2,384 ng/ mL, with a calculated t of 62.4 h. The patient recovered over the course of treatment in the intensive care unit. Metabolic CYP2D6 and CYP3A4 inhibition of the SGA was suggested to occur, as measurements of plasma concentrations were not conducted. A case report of an increased serum aripiprazole concentration of 1,100 ng/ mL was reported in a patient taking concurrent duloxetine, darunavir and ritonavir [152]. The patient had no signs of CNS toxicity, and aripiprazole was discontinued. It is possible that all three drugs contributed towards the CYP3A4 and CYP2D6 inhibition of aripiprazole metabolism, leading to this elevated plasma level.

3.5.4 Protease Inhibitors Concomitant treatment with protease inhibitors and SGAs represents a new challenging paradigm for many clinicians who treat HIV-positive patients with comorbid psychiatric conditions. This is becoming especially more complicated as the FDA approves various combination medications for HIV-positive patients. In vitro models report that agents such as indinavir are moderate CYP3A4 inhibitors, whereas ritonavir is a potent CYP3A4 inhibitor without significant inhibitory effects on CYP2D6, CYP2C9 and CYP2C19 [145, 146]. Ritonavir also has induction properties for CYP1A2 and the UGT system [146]. In healthy volunteers (N = 14), ritonavir was shown to significantly decrease the mean olanzapine AUC? from 501 ngh/mL (95 % CI 443–582) to 235 ngh/mL (95 % CI 197–294, p \ 0.001), and to increase mean olanzapine CL from 20 L/h (95 % CI 18–23) to 43 L/h (95 % CI 38–51, p \ 0.001) [147]. Olanzapine dose adjustments may be needed for patients treated with this combination. Significant extrapyramidal side effects, sedation, disorientation and possible weight gain were reported to occur in a series of case reports when risperidone and quetiapine were added to ritonavir/ indinavir, atazanavir/ritonavir and lopinavir/ritonavir

3.5.5 Other Drugs Providing a detailed summary of every possible drug interaction with SGAs is beyond the scope of this review, but those that are considered clinically important are noted. A case report of cimetidine-induced clozapine toxicity was reported when a patient treated with clozapine 900 mg/day took cimetidine to treat gastroesophageal reflux [153]. Three days after cimetidine initiation, the patient complained of diaphoresis, dizziness, vomiting and weakness. Upon hospital admission, cimetidine was discontinued, and the clozapine dose was lowered to 200 mg/day; after 5 days, the patient’s symptoms resolved. Unfortunately, plasma clozapine levels were not obtained. Omeprazole is a well-known CYP1A2 inducer, and two case reports have described significant reductions in plasma clozapine concentrations by 42–47 % [154]. Both patients were treated with clozapine 325 mg/day. After 14 days, the plasma level of 762 ng/mL was reduced to 385 ng/mL in one patient and the other patient’s plasma clozapine level dropped from 369 to 207 ng/mL, without changes in clinical presentation. Cyamemazine is an antipsychotic medication (not available in the USA) with anxiolytic properties and has been prescribed with risperidone in patients with schizophrenia [155]. It was reported that risperidone administered in conjunction with cyamemazine resulted in significantly higher median plasma risperidone levels than those seen in patients treated with risperidone alone (31.5 versus 5.0 ng/ mL, p \ 0.05), but plasma 9-OH risperidone levels were significantly lower (16.5 versus 39.0 ng/mL, p \ 0.05). Total active moiety concentrations did not significantly differ between the patient groups. Cyamemazine inhibits the conversion of risperidone to its metabolite via CYP2D6.

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Quetiapine was reported to significantly increase the mean C/D ratio of (R) methadone by 21 % (p = 0.026), but not those of (S) methadone or racemic (R,S) methadone [156]. The (R) form of methadone is the active component of the drug. Patients (N = 14) were treated with methadone in an addiction maintenance programme. Methadone doses remained stable (median 81 days), and low-dose quetiapine (mean dose 137 ± 87 mg/day) was added, with blood samples for methadone assessment obtained at baseline and 30 days later. Adverse events were not observed by the staff or reported by the patients; however, caution is warranted with the use of this combination, given the significant elevations in serum methadone concentrations that may occur. Methadone is primarily metabolized by CYP3A4 and CYP2B6, while CYP2D6 plays a minor role. Quetiapine’s major route of metabolism occurs via CYP3A4 and also, to a minor extent, via CYP2D6 [69, 157]. Additionally, these patients were genotyped for CYP2D6 status (11 patients were EMs and 3 patients were PMs) and for P-glycoprotein ABCB1 SNP 3435 CT or CC (11 patients) and SNP 3435 TT (3 patients). The increases in the (R) methadone C/D ratios occurred in patients with CYP2D6 EM status and the ABCB1 SNP 3435 CT and CC genotypes. Therefore, the likely mechanism for quetiapine producing increased methadone C/D ratios could be due in part to interactions with CYP2D6 and/or the P-glycoprotein transporter system (see Sect. 2.2). These cases and studies illustrate that metabolic CYP inhibition and induction can lead to clinically significant pharmacokinetic and pharmacodynamic changes in SGAs, and it is essential for clinicians to carefully monitor patients. 3.6 Influences of Smoking, Food and Caffeine on Second-Generation Antipsychotics The polycyclic aromatic hydrocarbons (PAHs) of cigarette smoking are known to induce or stimulate hepatic CYP enzymes. PAHs have been shown to primarily induce three CYP enzymes: CYP1A1, CYP1A2 and CYP2E1. Therefore, drugs that are CYP1A2 substrates would be the most likely agents to be clinically impacted by changes in smoking habits. Papers have been published that examined the impact of smoking on psychotropic agents [158]. This section focuses only on SGAs and on recently published studies. It has been reported since the 1990s that patients who smoke have consistently and significantly lower serum concentrations of clozapine and olanzapine [12, 158]. An olanzapine pharmacokinetic study revealed that smoking increased CL by 23 % (p = 0.03) via CYP1A2 induction [12]. It was reported that 7–12 cigarettes/day were sufficient to produce maximum enzyme induction and a


significantly lower mean clozapine C/D ratio in smokers than in nonsmokers (2.8 ng/mL/mg/day [range 0.52–5.63] versus 6.0 ng/mL/mg/day [range 2.91–12.03], p = 0.004) [159]. A similar study also detected a lower mean olanzapine C/D ratio in smokers than in nonsmokers (6.1 ng/ mL/mg/day [range 1.7–11.8] versus 12.8 ng/mL/mg/day [range 4.06–20.3, p = 0.001]) [160]. Smoking more than 12 cigarettes/day did not produce any further induction properties or lower C/D ratios of clozapine and olanzapine. A population pharmacokinetic study (N = 197 patients, 519 plasma samples) with clozapine reported that the mean clozapine CL was 18.0 L/h, and smoking increased CL by 6.0 L/h (a 33 % increase) [160]. In a retrospective study (N = 48), patients who smoked had a mean plasma clozapine concentration of 500 lg/L [161]. After the facility initiated a smoke-free hospital policy, the mean plasma clozapine levels increased to 900 lg/L (p = 0.0005). Clozapine doses were not changed during this process. Prior to the smoke-free policy, only 4.2 % of patients had plasma clozapine concentrations [1,000 lg/L. After the policy was implemented, 29 % of the patients had plasma clozapine levels [1,000 lg/L. One patient experienced a convulsion and two patients had myoclonic jerks; neither patient had any prior history of a seizure disorder. A population pharmacokinetic study with olanzapine (N = 523, 1,527 plasma samples) was conducted, and the results showed that the mean olanzapine CL was significantly increased by 55 % (from 20.15 ± 7.50 to 31.23 ± 10.88 L/h, p \ 0.001) in smokers (N = 274) compared with nonsmokers (N = 249), and this accounted for the highest level of variability (26 %) compared with other factors (e.g. sex and race) [162]. Population pharmacokinetic studies allow for analysis of combined factors that could explain the variable effects observed with clozapine, olanzapine and the effects of smoking. For example, the population pharmacokinetic study with clozapine (N = 255, 415 plasma samples) reported that valproic acid appeared to inhibit clozapine metabolism in nonsmokers (effect size E ?16 %), whereas it appeared to induce clozapine metabolism in smokers (E -22 %) [163]. Smoking was reported to have a E value of -20 % in patients not taking valproic acid and a E value of -46 % in patients taking valproic acid. These results suggest that smoking may have a pronounced induction effect on clozapine metabolism, and the induction effect may be more robust when the patient is also receiving valproic acid. This could partially explain the variable effects reported with valproic acid and clozapine drug interactions. Further, plasma olanzapine levels were 41 % lower in smokers who were not taking lamotrigine than in nonsmokers taking lamotrigine. Smokers taking lamotrigine and olanzapine had 11 % lower plasma olanzapine concentrations than nonsmokers taking lamotrigine. Smoking may have a dual effect that


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influences both olanzapine and lamotrigine, making it difficult to predict the clinical outcome. Although asenapine is metabolized via CYP1A2, the effects of smoking have not yet been reported in the literature. The product labels for ziprasidone and lurasidone note that bioavailability is decreased ([50 %) when these drugs are not taken with food. The precise mechanism for food to affect drug absorption remains unknown, but it can be speculated to be caused by transport mechanisms. Ziprasidone was recommended to be taken with a meal [500 kcal, irrespective of the fat content [164]. Low-calorie meals (250 kcal) resulted in 60–90 % lower drug exposure and approached fasting conditions. Lurasidone is also recommended to be taken with C350 kcal meals, since its AUC is increased by 2-fold, Cmax up to 3-fold, and tmax by 0.5–1.5 h when it is administered with food [32]. These two products are among the first SGAs that have a specific recommendation in their labelling for a food–drug interaction; low-calorie amounts impede drug absorption and can be clinically significant in dosing patients. Caffeine was reported to increase the mean clozapine AUC? by 19 % (p = 0.05) and to decrease the mean CL by 14 % (p = 0.05) in a single 12.5 mg dose study in nonsmoking healthy volunteers (N = 12) using caffeine doses of 400–1,000 mg [165]. Caffeine could produce CYP1A2 inhibition and contribute towards the large interpatient variability. Whether or not higher caffeine doses would result in a more pronounced clozapine effect remains to be determined. A case report noted a substantial increase in plasma clozapine and desmethylclozapine levels where a patient taking clozapine 550 mg/day had taken caffeine 200 mg/day in an effort to wake-up in the morning [166]. The patient also consumed a litre of caffeinated iced tea per day (about 1,000 mg), and the reported plasma clozapine and desmethylclozapine concentrations were 1,500 and 630 ng/mL, respectively. The patient was instructed to discontinue all caffeinated products and, 1 week later, lower levels of clozapine and desmethylclozapine at 620 and 330 ng/mL, respectively, were reported. Caffeinated products are found in many commercial foods and over-the counter drug products; clinicians need to advise patients about their usage in conjunction with various SGAs.

metabolism and CYP genetic polymorphisms, forms the foundations to identify and account for drug interactions. Phase II glucuronidation drug interactions are also being recognized as important contributors, with genetic polymorphism also emerging as a clinically significant factor. The P-glycoprotein system can be another source of potential drug interactions, and the impact of P-glycoprotein metabolism has yet to be fully elucidated. In vivo drug interaction mechanisms may involve multiple pathways, increasing the variability in the drug interaction response in patients during treatment. Patient factors, including ethnicity, genetics, sex, smoking status, diet and caffeine intake, can also play an important role in potential drug interactions of some SGAs such as clozapine and olanzapine. Utilizing the knowledge of SGA disposition and metabolic profiles, regulatory agencies and the pharmaceutical industry can collaborate to develop standardized drug interaction studies, which can provide vital information for healthcare professionals and patients early in the product life of a medication. For example, lurasidone’s product labelling recommendation to not co-administer ketoconazole and rifampicin differs from the clozapine product labelling, which recommends careful monitoring and consideration of clozapine dosage adjustments. Further, more specific information on pharmacokinetic changes has now been included in product labelling, compared with that available during the earlier drug development of clozapine. The pharmaceutical industry works closely with regulatory agencies in product labelling regarding drug interactions. Pharmacodynamic drug interactions must also be considered, even without changes in pharmacokinetic parameters, where, for example, increased anticholinergic effects could lead to significant changes in the patient’s clinical status, such as delirium and disorientation. Additional components of clinically significant drug interactions with SGAs include the dose-dependent effects of metabolic inhibitors and inducers, combined with patient variables. In ‘real world’ conditions, prescription of carbamazepine in smokers compounds the potential induction properties when carbamazepine is administered with an SGA. Therapeutic drug monitoring programmes and population pharmacokinetic approaches using linear and nonlinear mixed-effects models can provide additional information on patient variables and combinations of variables that can influence drug disposition and promote rational therapy. Clinicians’ awareness of these multiple factors clearly improves the quality of care we are able to provide to our patients. The time course of drug interactions is often neglected. The maximal increases in plasma concentrations of risperidone and its active moiety produced by fluoxetine have been shown to occur at 2 weeks without further increases

4 Conclusions Our awareness of the clinically significant drug interaction potential of SGAs has greatly improved as advances in the understanding of the associated clinical pharmacology have occurred. The increased knowledge of different metabolic pathways, which include CYP phase I oxidative

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in the subsequent 2 weeks. The serum clozapine concentration has been shown to dramatically increase only 4 days after the addition of fluvoxamine and may continue to increase during co-treatment. Plasma SGA concentrations may rapidly decline 1–2 weeks after addition of carbamazepine and may continue to decrease for up to 1 month. Conversely, when an inducer has been discontinued, plasma drug levels can continue to increase steadily for several weeks. In incidences of drug interactions involving inhibition or induction, the patient’s clinical status can be altered long after the change in drug therapy has been made, increasing the difficulty of correlating the change in drug therapy with the adverse event. Drug augmentation strategies need to be carefully evaluated, and that includes family member support and other environmental factors that support patient adherence to treatment. Clinicians should monitor patients carefully for several weeks and have a clear understanding of the time courses of potential pharmacokinetic/pharmacodynamic alterations (inhibition, induction, Cmax values and t values) of the drugs involved when adding or discontinuing medications concurrently with SGA treatment. This concerns an area of chronotherapy that is not always appreciated in the management of patients receiving multiple chronic drugs and the occasional acute pharmacotherapeutic or dietary addition or deletion. Although therapeutic plasma SGA concentrations have been recommended to assist in reaching and evaluating therapeutic drug response and adverse drug effects, these do not always correlate with the clinical outcome, and such information is not usually included in the product approval package information. These recommended ranges have been determined by clinical trials, through therapeutic drug monitoring services with large patient numbers, and codified in at least one expert consensus statement (from the AGNP-TDM group). Clinicians need to interpret these plasma concentration ranges within the context of the individual patient’s complex clinical presentation. Therapeutic plasma drug ranges can only assist the clinician in optimizing SGA dosing in patients. However, only a few patients with elevated plasma levels beyond these ranges have been reported to experience adverse effects, compared with the large number of patients that are treated. The reasons for these relatively few reported adverse effects can be attributed to the wide margin of safety with SGAs and wide inter-patient variability. This says nothing about the difficulty in interpreting inadequate response. Clinicians must always use experience and good clinical judgment when evaluating plasma SGA concentration data. The topic of drug interaction factors in the clinical use of SGAs is an exciting example of translational research going both ways: from bedside to bench, and from bench to beside. SGA drug interactions have been detected by case


reports, standardized drug interaction studies, reports from therapeutic drug monitoring services, case reports and case series, clinical studies with healthy volunteers and patients, and population pharmacokinetic analyses. Collectively, these data elucidate concepts that are essential to optimizing patient care, maximizing clinical outcomes, preventing significant drug interactions and minimizing adverse effects. Acknowledgments Dr Kennedy has received grant funding for research from Johnson and Johnson and payment for lectures from Merck. Professor Jann has received research funding from Pfizer and Janssen, and is on the speaker’s bureau for Janssen. Dr Kutscher has no conflicts of interest that are directly relevant to the content of this review. No funds were received for the preparation of this article.

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Clinically significant pharmacokinetic drug interactions of antiepileptic drugs with new antidepressants and new antipsychotics.

Clinically relevant interactions between newer antidepressants and second-generation antipsychotics.

Clinically significant drug-drug interactions involving opioid analgesics used for pain treatment in patients with cancer: a systematic review.

Identification of potential clinically significant drug interactions in HIV-infected patients: a comprehensive therapeutic approach.

Constrictive pericarditis associated with atypical antipsychotics.

Clinically relevant anti-epileptic drug interactions.

Niosomes: A Strategy toward Prevention of Clinically Significant Drug Incompatibilities.

Clinically relevant drug-drug interactions between antiretrovirals and antifungals.

Belgian consensus on metabolic problems associated with atypical antipsychotics.

Atypical antipsychotics for psychosis in adolescents.

Clinically significant endometrial cancer risk following a diagnosis of complex atypical hyperplasia.

Clinical pharmacology of atypical antipsychotics: an update.

Aripiprazole versus other atypical antipsychotics for schizophrenia.

Atypical antipsychotics for psychosis in adolescents.

Drug information update. Atypical antipsychotics and neuroleptic malignant syndrome: nuances and pragmatics of the association.

DGIdb 2.0: mining clinically relevant drug-gene interactions.

No clinically significant pharmacokinetic interactions between dolutegravir and daclatasvir in healthy adult subjects.

Cardiac fibroma presenting with clinically significant arrhythmias in infancy.

Metabolic transformation of clinically used drugs to epoxides: new perspectives in drug-drug interactions.

Clinically significant interaction between digoxin and quinidine.

Use of atypical antipsychotics in the elderly: a clinical review.

Elevation of plasma phenytoin by viloxazine in epileptic patients: a clinically significant drug interaction.

Depot Typical Antipsychotics versus Oral Atypical Antipsychotics in Relapse Rate Among Patients with Schizophrenia: A Five -Year Historical Cohort Study.

Mechanism of an unusual, but clinically significant, digoxin-bupropion drug interaction.