CNS Drugs 2012

CNS Drugs 2012; 26 (1): 39-67 1172-7047/12/0001-0039/$49.95/0

REVIEW ARTICLE

ª 2012 Adis Data Information BV. All rights reserved.

Clinically Significant Drug Interactions with Newer Antidepressants Edoardo Spina,1,2 Gianluca Trifiro`1,2 and Filippo Caraci3,4 1 Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy 2 IRCCS Centro Neurolesi ‘‘Bonino-Pulejo’’, Messina, Italy 3 Department of Formative Processes, University of Catania, Catania, Italy 4 Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania, Catania, Italy

Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Update on Drug Interactions with Selective Serotonin Reuptake Inhibitors (SSRIs) . . . . . . . . . . . . . . . . . 1.1 Risk of Bleeding with Drugs Interfering with Haemostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Serotonin Syndrome Associated with Triptans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Drug Interactions with Newer Antidepressants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Escitalopram. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Venlafaxine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Desvenlafaxine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Duloxetine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5 Milnacipran . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6 Mirtazapine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7 Reboxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.8 Bupropion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.9 Agomelatine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.10 Vilazodone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abstract

39 41 41 44 45 48 49 53 54 55 56 58 59 60 60 61

After the introduction of selective serotonin reuptake inhibitors (SSRIs), other newer antidepressants with different mechanisms of action have been introduced in clinical practice. Because antidepressants are commonly prescribed in combination with other medications used to treat co-morbid psychiatric or somatic disorders, they are likely to be involved in clinically significant drug interactions. This review examines the drug interaction profiles of the following newer antidepressants: escitalopram, venlafaxine, desvenlafaxine, duloxetine, milnacipran, mirtazapine, reboxetine, bupropion, agomelatine and vilazodone. In general, by virtue of a more selective mechanism of action and receptor profile, newer antidepressants carry a relatively low risk for pharmacodynamic drug interactions, at least as compared with first-generation antidepressants, i.e. monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants

Spina et al.

40

(TCAs). On the other hand, they are susceptible to pharmacokinetic drug interactions. All new antidepressants are extensively metabolized in the liver by cytochrome P450 (CYP) isoenzymes, and therefore may be the target of metabolically based drug interactions. Concomitant administration of inhibitors or inducers of the CYP isoenzymes involved in the biotransformation of specific antidepressants may cause changes in their plasma concentrations. However, due to their relatively wide margin of safety, the consequences of such kinetic modifications are usually not clinically relevant. Conversely, some newer antidepressants may cause pharmacokinetic interactions through their ability to inhibit specific CYPs. With regard to this, duloxetine and bupropion are moderate inhibitors of CYP2D6. Therefore, potentially harmful drug interactions may occur when they are coadministered with substrates of these isoforms, especially compounds with a narrow therapeutic index. The other new antidepressants are only weak inhibitors or are not inhibitors of CYP isoforms at usual therapeutic concentrations and are not expected to affect the disposition of concomitantly administered medications. Although drug interactions with newer antidepressants are potentially, but rarely, clinically significant, the use of antidepressants with a more favourable drug interaction profile is advisable. Knowledge of the interaction potential of individual antidepressants is essential for safe prescribing and may help clinicians to predict and eventually avoid certain drug combinations.

A wide variety of drugs with different mechanisms of action and pharmacological properties is currently available for the treatment of depressive disorders.[1] Older or first-generation antidepressants include monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), which became available for therapy in the 1960s. Newer antidepressants (also referred to as second- and third-generation antidepressants) include several different classes of drugs that were developed mainly in the 1980s and 1990s, starting with selective serotonin reuptake inhibitors (SSRIs). All these antidepressant therapies are effective for treating depression, but each compound has important safety and tolerability concerns. The SSRIs are at present the most widely used agents throughout the industrialized world.[2] The potential for drug interactions represents an important issue in the evaluation of antidepressants. Multiple drug therapy is common in clinical psychiatry practice and antidepressants are often combined with medications used to treat concomitant psychiatric, neurologic or somatic disorders. Polypharmacy carries the risk of drug-drug interaction. While certain drug comª 2012 Adis Data Information BV. All rights reserved.

binations may be used advantageously, in many cases they may be harmful, resulting in either decreased efficacy or increased toxicity. According to Preskorn and Werder,[3] a drug interaction may be considered ‘‘clinically relevant’’ if it results in a treatment outcome that is less than expected. Therefore, clinically relevant drug interactions can produce different outcomes such as occurrence of severe adverse effects, the apparent worsening of the disease or the appearance of a new disease, lack of efficacy, poor tolerability or withdrawal symptoms. There are two basic types of drug interactions – pharmacokinetic (when absorption, distribution, metabolism or excretion are affected) or pharmacodynamic (when target organ or receptor sites are involved). The available antidepressant medications differ considerably in their potential for pharmacological interactions. First-generation antidepressants have been associated with a significant risk of potentially harmful pharmacodynamic drug interactions, which has contributed to a gradual decline in their utilization in clinical practice, as is the case for MAOIs.[4] In addition, TCAs have a relatively high potential for pharmacodynamic CNS Drugs 2012; 26 (1)

Drug Interactions with Newer Antidepressants

interactions as they bind to multiple receptor types (muscarinic cholinergic, a1-adrenergic and H1-histaminergic receptors).[4] Although SSRIs have been considered for many years a homogeneous class of antidepressants, they are not equivalent in their potential to inhibit cytochrome P450 (CYP) isoenzymes thus having different propensities to cause clinically relevant pharmacokinetic interactions with other medications.[5-9] Although adverse drug interactions are often predictable, the use of antidepressants with a low potential for drug interactions is desirable, especially in elderly patients, who may take many medications simultaneously. In 1994, a comparative review of drug interactions with newer and older antidepressants was published in CNS Drugs.[4] Given that various antidepressants have been approved for use since 1994, the aim of the present article was to review the available literature on clinically relevant drug interactions focusing on these newer compounds. Among newer antidepressants, nefazodone was not included because it is no longer used due to rare liver toxicity.[1] Evaluation of the interaction profile of newer antidepressants will be preceded by a short update on drug interactions with those SSRIs already available at that time, i.e. fluoxetine, fluvoxamine, paroxetine, sertraline and citalopram. A literature search of MEDLINE and EMBASE was conducted for original research and review articles published in English between January 1995 and May 2011. Among the search terms were ‘drug interactions’, ‘cytochrome P450’, ‘newer antidepressants’, ‘SSRIs’, ‘escitalopram’, ‘SNRIs’, ‘venlafaxine’, ‘desvenlafaxine’, ‘duloxetine’, ‘milnacipran’, ‘mirtazapine’, ‘reboxetine’, ‘bupropion’, ‘agomelatine’ and ‘vilazodone’. Only articles published in peer-reviewed journals were included, while meeting abstracts were excluded. We examined both human case reports and clinical studies. Information was also obtained from the Micromedex Healthcare Series (a collection of databases containing referenced information about drugs, toxicology and diseases) as well as individual product inserts of each antidepressant drug. Additional drug interaction information literature was also obtained from citations of the articles that were retrieved during our search, and these were also included in our review. ª 2012 Adis Data Information BV. All rights reserved.

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1. Update on Drug Interactions with Selective Serotonin Reuptake Inhibitors (SSRIs) Comprehensive reviews of interactions involving SSRIs have been published.[5-10] It is well documented that these agents may cause clinically relevant pharmacokinetic interactions due to their inhibitory effects on various CYP isoenzymes responsible for the oxidative metabolism of the majority of therapeutic agents.[5-9] Available in vitro and in vivo evidence clearly indicates that SSRIs differ considerably in their potency of inhibition of CYP isoenzymes. Fluoxetine and its metabolite norfluoxetine are potent inhibitors of CYP2D6 and moderate inhibitors of CYP2C9, while they affect mildly to moderately the activity of CYP2C19 and CYP3A4. Paroxetine markedly inhibits CYP2D6, while sertraline inhibits this isoform in a dose-dependent manner. Fluvoxamine is a strong inhibitor of CYP1A2 and CYP2C19 and a moderate inhibitor of CYP2C9 and CYP3A4. On the other hand, citalopram appears to have a more favourable drug interaction profile, being only a weak inhibitor of CYP2D6, whereas it exerts negligible effects on CYP1A2, CYP2C19 and CYP3A4. Table I summarizes the clinically relevant drug interactions with SSRIs, with the exception of escitalopram, which is discussed in section 2.1. An increasing awareness of the risk for potentially harmful pharmacodynamic interactions with SSRIs has recently emerged. A brief overview is provided, focusing on the risk of bleeding with drugs interfering with haemostasis and the serotonin syndrome associated with triptans because these are the most clinically significant interactions. 1.1 Risk of Bleeding with Drugs Interfering with Haemostasis

Over the past decade, case reports and observational studies have consistently documented that the use of SSRIs may be associated with an increased risk of bleeding, in particular upper gastrointestinal bleeding.[11] The blockade of serotonin uptake from circulation into platelets CNS Drugs 2012; 26 (1)


Paroxetine

Increase of theophylline concentrations with possible occurrence of adverse effects; this drug combination should be avoided in clinical practice Increase of warfarin concentrations (65%) with associated prolongation of prothrombin time; monitoring of INR may be necessary Increase of propranolol concentrations (up to 5 times) with a slight reduction in heart rate and blood pressure

Theophylline

Warfarin

Propranolol

Increase of perphenazine concentrations (up to 2–13 times) with associated adverse effects (sedation, EPS and impairment of psychomotor performance) Increase of clozapine concentrations (20–40%)

Perphenazine

Clozapine

Increase of desipramine concentrations (up to 3- to 5-fold) and possible signs of toxicity

Increase of quetiapine concentrations (up to 159%)

Quetiapine

Desipramine

Increase of olanzapine concentrations (100–200%) with possible occurrence of adverse effects

Decrease in plasma concentrations of endoxifen and reduced clinical benefit of tamoxifen; this drug combination should be avoided in clinical practice

Tamoxifen

Olanzapine

Signs of calcium channel blocker-related toxicity such as oedema, nausea and flushing

Nifedipine, verapamil

Increase of clozapine concentrations (up to 5–10 times) and possible occurrence of dose-dependent adverse effects such as sedation and seizures; close pharmacokinetic monitoring is thus necessary

Increased plasma concentration of b-blockers and possible occurrence of severe bradycardia

Propranolol, metoprolol

Clozapine

Increase of the active S-enantiomer of warfarin with augmented risk of bleeding; monitoring of INR may be necessary

Warfarin

Increased concentrations (up to 4-fold) of tertiary amines amitriptyline, imipramine, clomipramine and possible signs of toxicity

Increase of clozapine concentrations (40–70%)

Clozapine

TCAs

Increase of risperidone concentrations (75%) and possible occurrence of adverse effects such as EPS

Risperidone

Fluvoxamine

Increase of TCAs concentrations (200–400%) along with signs of toxicity (sedation, dry mouth, urinary retention)

TCAs

Fluoxetine

Clinical implications

Other drugs

SSRI

Inhibition of CYP2D6



Continued next page

Inhibition of CYP1A2 and CYP2C19

Inhibition of CYP2C9

Inhibition of CYP1A2



Inhibition of CYP1A2 and, to a lesser extent, CYP2C19 and CYP3A4

Inhibition of CYP2C19 and, to a lesser extent, CYP1A2 and CYP3A4

Inhibition of the CYP2D6-mediated formation of active metabolites of tamoxifen



Inhibition of CYP2C9

Inhibition of various CYP isoforms (CYP2C19, CYP2D6 and CYP3A4)

Inhibition of CYP2D6 and, to a lesser extent, CYP3A4

Inhibition of CYP2D6-mediated hydroxylation of TCAs

Proposed mechanisms

Table I. Summary of selective serotonin reuptake inhibitor (SSRI)-induced clinically relevant pharmacokinetic drug-drug interactions[5-10]

42 Spina et al.

CNS Drugs 2012; 26 (1)


AUC = area under the plasma concentration-time curve; CYP = cytochrome P450; EPS = extrapyramidal symptoms; INR = international normalized ratio; TCAs = tricyclic antidepressants.

Desipramine

Increased AUC (40%) of desipramine only at high dosages of citalopram (40 mg/day)


43

Citalopram

Inhibition of glucuronidation Increased plasma concentrations of lamotrigine with signs of toxicity such as fatigue, sedation, confusion and decreased cognition Lamotrigine

Inhibition of CYP2D6 Increased plasma concentrations of risperidone (36–52%) only at high dosages of sertraline (150 mg/day) Risperidone Sertraline

Inhibition of the CYP2D6-mediated formation of active metabolites of tamoxifen Decrease in plasma concentrations of endoxifen and reduced clinical benefit of tamoxifen; this drug combination should be avoided in clinical practice Tamoxifen


Tramadol

Inhibition of the CYP2D6-mediated formation of tramadol active metabolites (-)-M1 and (+)-M1

Increase of AUC of atomoxetine by 3.5-fold

Reduction of the hypoalgesic effect of tramadol and possible occurrence of serotonin syndrome

Atomoxetine

Increase of risperidone concentrations (40–50%) and possible occurrence of adverse effects such as EPS

Proposed mechanisms Clinical implications Other drugs

Risperidone

SSRI

Table I. Contd



induced by SSRIs, leading to reduced platelet aggregation and prolonged bleeding time, may be the underlying biological mechanism for this adverse effect. In this respect, an association between the risk of bleeding and the use of agents with the highest degree of serotonin reuptake inhibition – namely fluoxetine, paroxetine and sertraline – has been found in some, but not all, observational studies.[12-15] However, the bleeding risk associated with SSRIs alone seems to be low, while it substantially increases as a result of the concomitant use of these antidepressants with potentially interacting and bleeding risk-increasing medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants and antiplatelet drugs (including lowdose aspirin).[11] Most of the evidence about the increased risk of bleeding with combined use of an SSRI and warfarin/aspirin or NSAIDs is derived from observational studies that have been carried out by using electronic medical record databases, as summarized below. Current research indicates that the SSRINSAID interaction may increase the risk of gastrointestinal bleeding from 3- to 15-fold.[16-18] A very large population-based case control study from UK primary care found a 15-fold increase in risk of gastrointestinal bleeding in patients treated with both an SSRI and non-aspirin NSAIDs.[16] Likewise, the aspirin-SSRI interaction yielded an increase in the risk, but to a lesser degree (relative risk = 7.2; 95% CI 3.1, 17.1). A more recent cohort study from Denmark found a 12-fold increase in risk of hospital admission for gastrointestinal bleeding in concurrent users of SSRIs and nonaspirin NSAIDs.[17] Interestingly, Tata et al.[18] demonstrated that SSRIs and NSAIDs are associated with a 2-fold risk for gastrointestinal bleeding per se (odds ratio [OR] for SSRIs 2.38 [95% CI 2.08, 2.72]; OR for NSAIDs 2.15 [95% CI 2.02, 2.28]), with a slight increase for concurrent intake of SSRIs and NSAIDs (OR 2.83; 95% CI 2.39, 3.34). A population-based Dutch cohort study confirmed that the combination of SSRIs and NSAIDs increased the risk of gastrointestinal bleeding, whereas the combination of TCAs and NSAIDs did not have this effect.[19] On the other hand, a population-based Canadian CNS Drugs 2012; 26 (1)

44

case control analysis demonstrated that the addition of an SSRI to NSAID therapy did not significantly increase the risk of gastrointestinal adverse effects.[20] Apart from gastrointestinal bleeding, other studies examined the risk of haemorrhagic stroke in patients concomitantly treated with SSRIs and NSAIDs. In a Danish nested case control study, Bak et al.[21] observed a trend toward increased risk of haemorrhagic stroke in persons exposed to both SSRIs and NSAIDs. Overall, contrasting results are available specifically concerning the risk of intracerebral bleeding in SSRI users, irrespective of concomitant use of potentially interacting drugs.[22] Some observational studies have also documented an increased risk of bleeding with concomitant use of SSRIs, in particular fluvoxamine and fluoxetine, and the oral anticoagulant warfarin.[23-28] Wallerstedt et al.[29] performed a cohort study in patients treated with warfarin for atrial fibrillation. Patients concomitantly treated with warfarin and SSRIs had a higher risk of first bleeding than patients treated with warfarin alone (adjusted hazard ratio 3.49; 95% CI 1.37, 8.91), although this finding was based on only 11 patients exposed to both warfarin and an SSRI. Citalopram and escitalopram were the SSRIs used in patients who experienced the bleeding. However, it seems that SSRIs do not directly influence the anticoagulant activity of warfarin, as in this study initiation of SSRI therapy was not associated with a change in warfarin dose or in the international normalized ratio (INR). In a Finnish study based on medical records of 6772 warfarin-treated hospitalized patients, use of SSRIs (mostly, citalopram and fluoxetine) in warfarinized patients was associated with a significantly higher bleeding risk compared with non-use (OR 2.6; 95% CI 1.5, 4.3), while a similar risk was not found with other antidepressants (mostly mirtazapine; OR 1.2; 95% CI 0.3, 4.3).[30] In a population-based, case control study, Schalekamp et al.[31] evaluated the relationship between concurrent use of SSRIs and coumarins and various types of bleeding. In users of coumarins, concomitant administration of SSRIs was associated with a significantly increased risk ª 2012 Adis Data Information BV. All rights reserved.

Spina et al.

of hospitalization due to non-gastrointestinal bleeding (adjusted OR 1.7; 95% CI 1.1, 2.5), but not for gastrointestinal bleeding (adjusted OR 0.8; 95% CI 0.4, 1.5). SSRIs may increase the risk of haemorrhage during warfarin treatment through two different mechanisms. Firstly, SSRIs may reduce platelet aggregation by depleting platelet serotonin levels, directly increasing the risk of bleeding, as mentioned before.[11] Secondly, some SSRIs, particularly fluvoxamine and fluoxetine, may substantially increase the bleeding risk associated with warfarin through inhibition of the CYP2C9mediated oxidative metabolism of the more biologically active (S)-enantiomer of warfarin.[25,27] In conclusion, clinicians should be aware of the bleeding risk associated with concomitant use of SSRIs and warfarin/aspirin or NSAIDs, as these drugs are frequently co-prescribed, especially in elderly patients. Strategies for risk prevention of haemorrhagic events include the use of alternatives to SSRIs, prescription of NSAIDs with the lowest gastrointestinal toxicity profiles (such as ibuprofen or cyclo-oxygenase 2 inhibitors) at the lowest possible doses, use of proton pump inhibitors for gastroprotection, as well as dosage adjustment of warfarin/aspirin and testing of blood clotting.[11,32-34] 1.2 Serotonin Syndrome Associated with Triptans

During the past few years, there has been a growing concern regarding the possible occurrence of the serotonin syndrome following coadministration of SSRIs with triptans. It is well known that combined use of SSRIs with other serotonergic drugs – including MAOIs, some TCAs, serotonin and noradrenaline (norepinephrine) reuptake inhibitors (SNRIs), buspirone, trazodone, Hypericum extracts, analgesics (e.g. tramadol, pethidine [meperidine], fentanyl, oxycodone), drugs of abuse and linezolid (an antibacterial used to treat Gram-positive bacteria) – may lead to the serotonin syndrome, a potentially fatal adverse drug reaction, which may occur as a consequence of an excessive serotonergic agonism at both central and peripheral serotonin receptors.[35,36] CNS Drugs 2012; 26 (1)


Drug combinations potentially causing the serotonin syndrome should therefore be avoided in clinical practice. Triptans and SSRIs are commonly co-prescribed due to the high prevalence of depressive disorders in individuals experiencing migraine and vice versa.[37] Both of these two drug classes have serotonergic effects due to serotonin agonism (in the case of triptans) or inhibition of serotonin reuptake (in the case of SSRIs). As a consequence, a pharmacodynamic interaction may occur with the concomitant use of triptans and SSRIs. Additionally, pharmacokinetic interactions can be observed in clinical practice, as SSRIs may inhibit CYP2D6 (fluoxetine, paroxetine and sertraline), CYP1A2, CYP2C19 and CYP3A4 (fluvoxamine) – isoforms that may play a role in the metabolism of triptans. Accordingly, several pharmacokinetic studies in healthy subjects have reported around a 20% increase in triptan plasma concentrations with concomitant administration of some SSRIs.[38,39] In July 2006, the US FDA issued an alert to warn health professionals about the risk of the life-threatening serotonin syndrome with the concomitant use of SSRIs or SNRIs and triptans, as a result of 29 case reports gathered over a 5-year period.[40] However, the validity of these case reports was subsequently questioned as most of the reported diagnoses did not meet the criteria for the serotonin syndrome. As a consequence, the clinical relevance of the risks of the interaction between SSRIs/SNRIs and triptans was further debated. The molecular mechanisms underlying the involvement of triptans in contributing to a serotonin syndrome, either alone or in combination with SSRIs/SNRIs, are not clear according to preclinical studies.[41] Evidence obtained in animal models suggests that the serotonin syndrome is mediated by serotonin 5-HT2A receptors, although a contribution of 5-HT1A receptors has also been proposed.[42,43] Triptans are agonists of 5-HT1B, 5-HT1D and 5-HT1F receptors, but none of these receptor subtypes is involved in the pathogenesis of the serotonin syndrome, and 5-HT2A receptors are not activated by triptans at indicated therapeutic dosages. Furthermore, from an epidemiological point of view, some experts concluded that insufficient ª 2012 Adis Data Information BV. All rights reserved.

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data were available to judge whether the addition of triptans to the use of SSRIs/SNRIs actually increased the risk of the serotonin syndrome; the same experts stated that cautions are warranted when co-prescribing triptans and SSRIs/SNRIs due to the seriousness of claimed potential risks.[41] On the other hand, the benefit of the adequate treatment of both migraine and depression appears to far outweigh the exceedingly low risk of the serotonin syndrome. In line with this controversial evidence, a position paper from the American Headache Society recently invited the FDA to assemble an impartial advisory panel to review the available data and to consider whether the alert should be revised.[44] 2. Drug Interactions with Newer Antidepressants This review examines the drug interaction profile of the following antidepressants: escitalopram, venlafaxine, desvenlafaxine, duloxetine, milnacipran, mirtazapine, reboxetine, bupropion, agomelatine and vilazodone. Although each of these antidepressants has a unique drug interaction profile, some general considerations are provided. The majority of pharmacokinetic interactions with new antidepressants arise as a consequence of drug-induced changes in hepatic metabolism, through enzyme inhibition or induction.[45] In recent years, the in vitro characterization of the major drug-metabolizing enzymes, in particular the human CYP system, with identification of substrates, inhibitors and inducers of different CYP isoforms, has greatly improved the prediction of metabolic interactions, providing an invaluable resource in helping to anticipate and avoid potential interactions.[46] In principle, concomitant treatment with drugs metabolized by the same enzyme or coadministration of a drug with another medication acting as inhibitor or inducer involves the risk of a drug interaction. However, not all theoretically possible drug interactions that are predicted from in vitro studies will occur in vivo, and some may not be clinically significant anyway. A number of drug-related, patient-related and epidemiological factors may influence the potential occurrence and clinical CNS Drugs 2012; 26 (1)

46

significance of a metabolic drug interaction and contribute to the large intersubject variability in the extent and magnitude.[45] All new antidepressants are extensively metabolized in the liver, mainly by CYP isoenzymes (table II), and therefore may be the target of metabolically based drug interactions. Concomitant treatment with specific enzyme inhibitors or inducers may cause significant changes in the plasma concentrations of new antidepressants. However, due to their relatively wide margin of safety, the consequences of such kinetic modifications may not be clinically relevant.[8,9] Moreover, as most drugs have several metabolic pathways, the inhibition of an enzyme playing a marginal role in the overall clearance of a given drug may have a limited impact on its disposition, presumably resulting in only a minimal increase in plasma concentrations, since another isoform may provide alternative secondary metabolic pathways. On the other hand, as with SSRIs, new antidepressants have the potential to cause metabolic drug interactions.[7-9] As shown in table II, while some antidepressants have only minimal or no modulating effect on drug-metabolizing enzymes at usual therapeutic concentrations, others are able to inhibit the activity of one or more CYP isoforms. Therefore, clinically relevant interactions may occur when they are coadministered with substrates of these isoforms, especially compounds with a narrow therapeutic index. With regard to this, it should be underlined that a difference may exist between in vitro potency and the degree of inhibition that occurs in vivo.[45] The degree of inhibition achieved in vivo is a function of the potency of the drug multiplied by its concentration achieved with usually effective antidepressant doses. For example, bupropion (see section 2.8) may have moderate potency in vitro, but produces substantial inhibition in vivo because its plasma concentrations are so high with clinically relevant doses. Pharmacokinetic drug interactions with new antidepressants may also involve drug transporters, in particular P-glycoprotein, which play a central role in the absorption, distribution and excretion of a wide variety of therapeutic agents.[47,48] P-glycoprotein is a multidrug efflux ª 2012 Adis Data Information BV. All rights reserved.

Spina et al.

transporter, encoded by the ABCB1 gene (previously known as MDR1), highly expressed in the intestine, brain, liver and kidney. It acts as a natural defence mechanism against several substrates by limiting their absorption from the gut and penetration into the brain and promoting their elimination in the bile and urine.[47] Like metabolizing enzymes, the activity of P-glycoprotein can be inhibited or induced by other agents, altering the concentration of substrate drug in circulation. In vitro studies have indicated that some SSRIs, namely paroxetine and sertraline, may inhibit P-glycoprotein.[49] Concerning newer antidepressants, preliminary results from in vitro studies have suggested that venlafaxine, but not its active metabolite desvenlafaxine, is an inducer of P-glycoprotein.[50,51] In theory, as many substrates for P-glycoprotein (such as digoxin, ciclosporin [cyclosporine] and various chemotherapeutic agents) have a narrow therapeutic range and are widely used in the elderly, coadministration with these antidepressants may result in clinically relevant drug interactions. Additional experimental and clinical studies will be necessary to better understand how these observations translate in vivo. Protein binding displacement interactions may also occur with newer antidepressants. Competition between two drugs for binding sites on plasma proteins may cause a rise in the free fraction of the displaced drug in plasma or tissue, thereby potentially increasing its pharmacological effects.[45] However, unless additional mechanisms are at work, these interactions are usually not clinically relevant, because the free drug is rapidly cleared from the plasma. In quantitative terms, displacement interactions may be important only for drugs that are highly bound to plasma proteins (>90%) and, among newer antidepressants, only duloxetine, reboxetine and vilazodone belong to this category (table II). So caution is needed when these antidepressants are administered with other highly protein bound drugs, such as warfarin or phenytoin. Pharmacodynamic interactions occur when two drugs act at the same molecular target or interrelated site of action (receptors, ion channels, transporters, enzymes), generally resulting CNS Drugs 2012; 26 (1)


84

95

50

85

50

>60

90

90

13

9–15

5

30

27

27

Half-life (h)

CYP = cytochrome P450; UGT = uridine diphosphate glucuronosyltransferase.

72

97

80

Desvenlafaxine

Vilazodone

85

92

Venlafaxine

56

80

Escitalopram

Protein binding (%)

Bioavailability (%)

Drug

Table II. Pharmacokinetic parameters of newer antidepressants[8,9]

CYP3A4 CYP2C19 CYP2D6 Carboxylesterase (?)

CYP1A2 (90%) CYP2C9/CYP2C19 (10%)

CYP2B6

CYP3A4

CYP2D6 CYP3A4 CYP1A2

Glucuronidation (20–30%) CYP3A4 (10%) Excreted unchanged (50–60%)

CYP1A2 (major) CYP2D6

UGT CYP3A4 Excreted unchanged (45%)

CYP2D6 (major) CYP3A4

CYP3A4 CYP2C19 CYP2D6

Metabolism

None

None

Hydroxybupropion Threohydrobupropion Erythrohydrobupropion

None

None

None

None

None

Desvenlafaxine

None

Active metabolites

CYP2C8 (uncertain)

None

CYP2D6 (moderate)

None

None

CYP3A4 (weak)

CYP2D6 (moderate)

None

CYP2D6 (weak)

CYP2D6 (weak)

Inhibitory effect on CYP isoenzymes

Drug Interactions with Newer Antidepressants 47

CNS Drugs 2012; 26 (1)

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in additive, synergistic or antagonistic effects. Pharmacodynamic interactions are very common and may be predicted on the basis of the molecular mechanism of action of the involved medications, but are more difficult to identify and measure than pharmacokinetic interactions. The potential for pharmacodynamic interactions differs markedly between the various new antidepressants depending on the respective pharmacological properties. In general, because of a more selective mechanism of action and receptor profile, new antidepressants have a relatively low potential for pharmacodynamic interactions. 2.1 Escitalopram

Escitalopram is the active (S)-enantiomer of citalopram, a commonly used SSRI, and is indicated for the treatment of major depression and anxiety disorders.[52,53] Escitalopram is a highly potent and selective, dose-dependent inhibitor of the human serotonin transporter, thereby inhibiting the reuptake of serotonin into presynaptic nerve terminals and potentiating serotonergic activity in the CNS. Escitalopram is metabolized in the liver, mainly into S-desmethylcitalopram and S-didesmethylcitalopram.[54] According to in vitro studies, the N-demethylation of escitalopram to S-desmethylcitalopram is mediated by three CYP isoforms in parallel: CYP2C19, CYP3A4 and, to a lesser extent, CYP2D6.[55] Further demethylation of S-desmethylcitalopram to Sdidesmethylcitalopram is preferentially mediated by CYP2D6 and an unknown non-CYP-mediated reaction. In vitro studies have documented that, compared with other SSRIs, escitalopram and its metabolites are weak inhibitors of CYP2D6 and negligible inhibitors of CYP1A2, CYP2C9, CYP2C19 and CYP3A4, suggesting a low potential to cause clinically significant interactions with other medications.[55] In addition, these studies have indicated that the weak inhibitory effect of racemic citalopram on CYP2D6 is mainly attributable to the demethylated metabolite of R-citalopram, suggesting an even more favourable profile for escitalopram than racemic citalopram.[54] Concomitant administration of escitalopram with CYP2C19 inhibitors (e.g. omeprazole, ciª 2012 Adis Data Information BV. All rights reserved.

metidine, lansoprazole, ticlopidine, fluvoxamine and fluconazole) may theoretically increase the plasma concentrations of escitalopram. However, as escitalopram is metabolized by various CYP isoforms, it can be hypothesized that inhibition of a single enzyme may not decrease escitalopram clearance to a clinically significant degree. Moreover, given the wide therapeutic index of escitalopram, these interactions are probably of limited clinical significance. Two randomized, placebo-controlled, crossover studies carried out in two groups of 16 healthy subjects, investigated the pharmacokinetics of a single 20 mg dose of escitalopram before and during concomitant administration of cimetidine (400 mg twice daily for 5 days), a nonspecific inhibitor of the CYP system, or omeprazole (30 mg once daily for 6 days), a competitive inhibitor of CYP2C19.[56] Both cimetidine and omeprazole caused a significant increase in the area under the plasma concentration-time curve (AUC) of escitalopram – by 72% and 51%, respectively (both p < 0.05). In a study of nine healthy volunteers, the pharmacokinetics of a single 20 mg oral dose of racemic citalopram were investigated before and during coadministration with omeprazole 20 mg/day for 18 days.[57] Treatment with omeprazole preferentially inhibited the metabolism of the (S)-enantiomer, indicating that CYP2C19 has a more prominent role in the metabolism of escitalopram rather than the (R)-enantiomer. In an open-label, crossover study aimed to investigate the potential interaction between escitalopram and ritonavir, a protease inhibitor used in the treatment of HIV infection and a potent inhibitor of CYP3A4, coadministration of a single dose of escitalopram 20 mg and a single dose of ritonavir 600 mg in 21 healthy subjects did not substantially affect the pharmacokinetics of either agent.[58] Bondolfi et al.[59] studied the effect of comedication with fluvoxamine on the plasma concentrations of the enantiomers of citalopram in seven depressed patients who were non-responders to citalopram. Coadministration of fluvoxamine (50–100 mg/day for 3 weeks) resulted in a 50–100% elevation of plasma concentrations of both citalopram enantiomers, but more pronounced for S-citalopram, presumably due to the action of CNS Drugs 2012; 26 (1)


fluvoxamine, a potent inhibitor of CYP2C19, on the biotransformation of S-citalopram. While many studies have investigated the effect of racemic citalopram on the pharmacokinetics of other medications, limited information is available so far concerning escitalopram. Despite in vitro data indicating little or no inhibition of CYP2D6 by escitalopram, a study in healthy subjects has shown that coadministration of high-dose escitalopram (20 mg/day for 21 days) with a single 50 mg dose of desipramine, a CYP2D6 substrate, produced an increase in the maximum plasma concentration (Cmax) and AUC of desipramine by 40% and 100%, respectively (table III).[60] Similar results were observed in a study aimed to evaluate the effect of coadministration of escitalopram (20 mg/day for 17 days) on the pharmacokinetics of a single 100 mg dose of the b-adrenoceptor blocker metoprolol, another CYP2D6 substrate, in 15 healthy volunteers.[77] Although addition of escitalopram resulted in an 89% increase in the AUC of metoprolol (p < 0.01), no clinically significant effects on blood pressure or heart rate were observed. In a double-blind, placebocontrolled, crossover trial, the effect of escitalopram 20 mg/day on the pharmacokinetics of a single 150 mg dose of the opioid analgesic tramadol was investigated in 15 healthy subjects.[103] Tramadol is O-demethylated to the active metabolite (+)-O-desmethytramadol via CYP2D6. As compared with placebo, the AUC of the active metabolite of tramadol decreased significantly after escitalopram administration (p = 0.0027). However, the hypoalgesic effect of tramadol was not reduced during escitalopram administration. In a study based on a therapeutic drug monitoring database, serum concentrations of aripiprazole, a second-generation antipsychotic metabolized by CYP3A4 and CYP2D6, were approximately 20% higher in patients comedicated with escitalopram than in those taking aripiprazole alone (p < 0.05).[104] As with other SSRIs, coadministration of escitalopram with serotonergic medications – including MAOIs, other SSRIs, SNRIs, lithium, tramadol, triptans and linezolid – may result in the serotonin syndrome.[62] A potential risk to observe this syndrome also exists when escitalopram is combined ª 2012 Adis Data Information BV. All rights reserved.

49

with Hypericum extracts, as observed with other SSRIs.[105] An increased risk of upper gastrointestinal bleeding has been documented when escitalopram is combined with drugs that interfere with haemostasis (e.g. NSAIDs, aspirin and warfarin).[32] The potential pharmacokinetic and pharmacodynamic interactions between the concomitantly administered MAO type B inhibitor rasagiline and escitalopram was investigated in 12 healthy volunteers who received a 10-day regimen of rasagiline 1 mg/day followed by concomitant rasagiline 1 mg and escitalopram 10 mg/day for 7 days.[106] The drug combination was well tolerated and there were no signs of CNS hyperexcitation or changes in vital signs. Addition of escitalopram was associated with an increase by about 42% (p < 0.001) in the AUC of rasagiline, while no changes were observed in the Cmax or half-life of rasagiline. Finally, a clinically significant interaction has been recently observed between low dosages of escitalopram (5 mg/day) and clonidine, with an increase of central effects of clonidine such as hypothermia and sedation.[61] The molecular mechanisms underlying this interaction are presently unknown. Like other SSRIs, escitalopram has been reported to cause hyponatraemia.[107] The risk of developing this adverse drug reaction is probably increased when escitalopram is coadministered with other drugs with potential for hyponatraemia such as carbamazepine, oxcarbazepine and diuretics. 2.2 Venlafaxine

Venlafaxine is an SNRI approved for the treatment of major depression and anxiety disorders. Venlafaxine is more potent in inhibiting serotonin than noradrenaline reuptake and also weakly inhibits dopamine reuptake. At low doses venlafaxine acts mainly as a serotonin reuptake inhibitor, whereas only at higher dosages does it also inhibit noradrenaline reuptake.[108] The drug has virtually no affinity for a1-adrenergic, muscarinic cholinergic or histamine H1 receptors.[109] It is available as immediate- and extended-release formulations. Venlafaxine is predominantly metabolized in the liver to a major active metabolite, O-desmethylvenlafaxine (also referred to as desvenlafaxine) and, in CNS Drugs 2012; 26 (1)


Duloxetine

Desvenlafaxine

Possible occurrence of serotonin syndrome

Decrease in plasma concentrations of endoxifen and reduced clinical benefit of tamoxifen

Tamoxifen

MAOIs, TCAs, SSRIs and other serotonergic agents

Increase of risperidone concentrations (26%) and possible occurrence of adverse effects

Risperidone

Increase in INR values associated with petechiae/purpura; close monitoring of INR may be necessary

Increased AUC of metoprolol (180%)

Metoprolol

Warfarin


Increased Cmax (64%) and AUC (71%) of tolterodine

Tolterodine

Decreased serotonin reuptake

75

79

10

78

77

76

71,73

Continued next page

Displacement of warfarin from protein binding sites

Inhibition of the CYP2D6-mediated formation of active metabolites of tamoxifen

Inhibition of CYP2D6-mediated 9-hydroxylation of risperidone



Significant increase in the Cmax (270%) and AUC (120–290%) of desipramine

73 74,75

72

70,71

69

68

67

66

65

64

63

62

61

Inhibition of CYP1A2 by fluvoxamine and ciprofloxacin

TCAs

References 60

Inhibition of CYP2D6 by paroxetine

Increased AUC of duloxetine (60%)

Increased AUC of duloxetine (460%); according to the SPC these drug combinations are contraindicated and should be avoided in clinical practice

Paroxetine



Inhibition of CYP3A4 by ketoconazole


Excessive serotonergic stimulation



Inhibition of CYP2D6 by terbinafine

Inhibition of CYP2D6 by diphenhydramine


Fluvoxamine; ciprofloxacin






Trazodone or mirtazapine

Increased AUC of desvenlafaxine (43%)

Increased AUC of imipramine (27%) and desipramine (40%)

TCAs

Increased AUC of desipramine (22–36%)

Increased AUC of venlafaxine (26–200% depending on CYP2D6 genotype)

Ketoconazole

Ketoconazole

Increased AUC of venlafaxine (490%)

Terbinafine

TCAs

Increase of venlafaxine concentrations (200%) and possible occurrence of adverse effects


SNRIs and other serotonergic agents

Diphenhydramine

Increase of central effects of clonidine such as hypothermia and sedation

Clonidine

Venlafaxine

Increased Cmax (40%) and AUC (100%) of desipramine only at high dosages of escitalopram (20 mg/day)

Desipramine

Escitalopram Unknown

Proposed mechanisms Inhibition of CYP2D6

Clinical effects

Other drugs

Antidepressant

Table III. Summary of clinically relevant drug-drug interactions of newer antidepressants

50 Spina et al.

CNS Drugs 2012; 26 (1)


Proposed mechanisms

Increased plasma concentration of metoprolol and possible occurrence of severe bradycardia

Decrease in plasma concentrations of endoxifen and reduced clinical benefit of tamoxifen; this drug combination should be avoided in clinical practice

Metoprolol

Tamoxifen

Increased plasma concentration of vilazodone (50%)

81


102

101

100

Inhibition of the CYP2D6-mediated formation of active metabolites of tamoxifen Inhibition of CYP1A2-mediated metabolism of agomelatine

99

97,98

96

95

91-94

90

89

88

87

86

85

84

82,83



References 80

AUC = area under the plasma concentration-time curve; Cmax = peak serum drug concentration; CYP = cytochrome P450; INR = international normalized ratio; MAOIs = monoamine oxidase inhibitors; SNRIs = serotonin and noradrenaline (norepinephrine) reuptake inhibitors; SPC = Summary of Product Characteristics; SSRIs = selective serotonin reuptake inhibitors; TCAs = tricyclic antidepressants.

Ketoconazole

Increased plasma concentrations of venlafaxine (2.5-fold) and possible occurrence of serotonergic adverse effects

Venlafaxine

Vilazodone

Increase of nortriptyline plasma concentrations along with signs of toxicity

Nortriptyline

Marked increase of agomelatine concentrations (60-fold) with fluvoxamine and possible occurrence of adverse effects; according to the SPC these drug combinations are contraindicated and should be avoided in clinical practice


Increase in the Cmax (2-fold) and AUC (5-fold) of desipramine and possible occurrence of adverse effects

Desipramine

Fluvoxamine, ciprofloxacin, amiodarone, mexiletine or zileutin

Induction of CYP2B6-mediated metabolism of bupropion by rifampicin or ritonavir

Reduced half-life and AUC of bupropion (50%)

Rifampicin (rifampin) or ritonavir


Induction of CYP2B6-mediated metabolism of bupropion by carbamazepine

Reduced AUC of bupropion (90%)

Carbamazepine

Inhibition of CYP2B6-mediated metabolism of bupropion by clopidogrel or ticlopidine

Reduction in the AUC of hydroxybupropion (52% and 84%, respectively) and increased concentrations of bupropion

Induction of CYP3A4-mediated metabolism of reboxetine by carbamazepine or phenobarbital


Unknown

Induction of CYP3A4-mediated metabolism of mirtazapine by phenytoin

Induction of CYP3A4-mediated metabolism of mirtazapine by carbamazepine

Inhibition of CYP1A2- and, to a lesser extent, CYP3A4-mediated metabolism of mirtazapine

Inhibition of CYP2D6 by cimetidine

Induction of CYP3A4-mediated metabolism of milnacipran by carbamazepine

Clopidogrel or ticlopidine

Increased AUC of reboxetine (43–58%)

Decreased concentrations of reboxetine

Enhanced risk of restless legs syndrome

Tramadol or dopamineblocking agents

Ketoconazole

Decrease in the AUC of mirtazapine (46%)

Phenytoin

Carbamazepine or phenobarbital

Decrease in the AUC of mirtazapine (60%)

Carbamazepine

Agomelatine

Bupropion

Reboxetine

Increase of mirtazapine concentrations (60%)

Increase of mirtazapine concentrations (300–400%) and possible occurrence of serotonin syndrome

Mirtazapine

Decrease in plasma concentrations of milnacipran (20%)

Clinical effects

Cimetidine

Carbamazepine

Milnacipran

Fluvoxamine

Other drugs

Antidepressant

Table III. Contd

Drug Interactions with Newer Antidepressants 51

CNS Drugs 2012; 26 (1)

52

parallel, to N-desmethylvenlafaxine. In vitro and in vivo studies indicate that CYP2D6 is the main enzyme responsible for the O-demethylation, while CYP3A4 is probably involved in the N-demethylation pathway.[110,111] A recent report has documented that the ratio of desvenlafaxine/venlafaxine concentrations can be used to phenotype individuals as CYP2D6 extensive metabolizers or poor metabolizers.[112] According to in vitro studies, venlafaxine is a weaker inhibitor of CYP2D6 compared with the SSRIs paroxetine, fluoxetine, fluvoxamine and sertraline, and has minimal or no effect on the activity of CYP1A2, CYP2C9 and CYP3A4.[113,114] Different studies have evaluated the potential for other drugs to affect the disposition of venlafaxine. Steady-state plasma concentrations of venlafaxine 150 mg/day were increased significantly by 61% (p < 0.001) during coadministration with the nonspecific CYP inhibitor cimetidine.[115] A pharmacokinetic study in nine healthy subjects evaluated the potential interaction between venlafaxine and diphenhydramine, an H2 receptor antagonist, available in many over-the-counter preparations, known to inhibit CYP2D6 activity.[63] Concomitant administration of diphenhydramine 50 mg twice daily and venlafaxine 18.75 mg twice daily resulted in a 59% decrease in the oral clearance of venlafaxine and a more than 2-fold increase in its plasma concentrations (both, p < 0.05). Eap et al.[116] investigated the effect of quinidine, a potent CYP2D6 inhibitor, on the pharmacokinetic parameters of venlafaxine 18.75 mg orally every 12 hours for 48 hours in seven CYP2D6 extensive metabolizers and five CYP2D6 poor metabolizers. In extensive metabolizers, quinidine decreased the oral clearance of (R)- and (S)-venlafaxine by 12- and 4-fold, respectively, while no changes were observed in poor metabolizers. In a pharmacokinetic study in healthy volunteers, terbinafine, another potent CYP2D6 inhibitor, was found to increase by 490% the AUC of venlafaxine.[64] A clinically significant pharmacokinetic interaction has been documented between bupropion, a moderate CYP2D6 inhibitor, and venlafaxine. In an openlabel pharmacokinetic study in 18 depressed patients treated with venlafaxine, paroxetine or fluoxetine, adjuvant therapy with bupropion ª 2012 Adis Data Information BV. All rights reserved.

Spina et al.

sustained release 150 mg/day for 8 weeks increased steady-state plasma concentrations of venlafaxine by 2.5-fold (p < 0.01), but not those of paroxetine or fluoxetine.[97] The clinical relevance of this interaction has been recently documented in three patients with major depression inadequately responding to venlafaxine who were given bupropion as add-on therapy.[98] Augmentation with bupropion resulted in a significant elevation of plasma concentrations of venlafaxine associated with increased or decreased concentrations of desvenlafaxine. A reduction of venlafaxine dose was needed to avoid serotonergic adverse effects. The effect of ketoconazole, a potent CYP3A4 inhibitor, on the disposition of a single oral dose of venlafaxine (50 mg to extensive metabolizers and 25 mg to poor metabolizers) was evaluated in 14 CP2D6 extensive metabolizers and 6 poor metabolizers. In extensive metabolizers, ketoconazole significantly increased the AUC of venlafaxine by 36% and that of desvenlafaxine by 26% (p < 0.01).[65] Three of the poor metabolizers displayed marked increases in the AUC (81%, 126% and 206%) of venlafaxine upon coadministration of ketoconazole, while in the other three poor metabolizers small or no changes in the AUC of venlafaxine were observed. A number of drug-drug interaction studies have investigated the effect of venlafaxine on the disposition of other medications. In agreement with the in vitro evidence of minimal inhibition of various CYP isoforms, these studies confirmed that venlafaxine has a low propensity to interact with coadministered medications. No substantial modifications in the single-dose pharmacokinetic profiles of drugs metabolized by CYP1A2 (caffeine) or CYP3A4 (diazepam, alprazolam) were reported in healthy volunteers following administration of venlafaxine 150 mg/day.[117-119] Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days), a CYP2D6 substrate, to 18 healthy men was associated with a slight increase in plasma concentrations of metoprolol by approximately 30–40%, without altering the plasma concentrations of its active a-hydroxymetroprolol metabolite.[68] The pharmacokinetic profile of venlafaxine was not modified by metoprolol, whereas CNS Drugs 2012; 26 (1)


venlafaxine reduced the blood pressure-lowering effect of metoprolol.[68] In an open-label study aimed to investigate the effect of co-medication with venlafaxine on the pharmacokinetics of indinavir (800 mg in a single dose), Levin et al.[120] found that coadministration of venlafaxine (150 mg/day for 9 days) resulted in a 28% decrease in the AUC of plasma indinavir (p < 0.05) and a 36% decrease in its Cmax (p < 0.05). Further studies are needed to understand the clinical significance of this interaction. The pharmacokinetics of a single 100 mg oral dose of imipramine were investigated in six healthy volunteers before and during treatment with venlafaxine 150 mg/day for 3 days.[66] Venlafaxine coadministration resulted in a significant increase in the AUC of imipramine and desipramine by 27% and 40% (p < 0.05), respectively. In a study of 30 healthy volunteers, treatment with venlafaxine 150 mg/day for 9 days caused minimal, presumably not clinically relevant, changes in the pharmacokinetics of a single 1 mg oral dose of risperidone, a CYP2D6 substrate.[121] No significant changes in plasma concentrations of clozapine were observed in 11 patients with schizophrenia after coadministration of low to moderate doses of venlafaxine.[122] Differently from fluoxetine and paroxetine, venlafaxine may be safely used in combination with tamoxifen, a selective estrogen receptor modulator used in the treatment and prophylaxis of breast cancer.[10,100] Tamoxifen is a prodrug that is converted to active endoxifen mainly via CYP2D6. Studies in women with breast cancer have documented that venlafaxine minimally affects plasma endoxifen concentrations.[123,124] As with other serotonergic agents, the serotonin syndrome, a potentially life-threatening condition, may occur when venlafaxine is coadministered with other medications that may affect serotonin neurotransmission including MAOIs, TCAs, SSRIs,[68] trazodone,[67] lithium,[125,126] tramadol, triptans, linezolid[68] and Hypericum extracts.[127] Recent studies have shown that, as for SSRIs, the use of venlafaxine is associated with an increased risk of upper gastrointestinal bleeding, particularly in patients concomitantly treated with NSAIDs.[128,129] ª 2012 Adis Data Information BV. All rights reserved.

53

2.3 Desvenlafaxine

Desvenlafaxine, the O-desmethyl active metabolite of venlafaxine, is available for the treatment of adult patients with major depressive disorder.[130,131] Like its parent drug, desvenlafaxine acts as an inhibitor of neuronal reuptake of serotonin and noradrenaline and shows virtually no affinity for a1-adrenergic, muscarinic cholinergic or H1 receptors. Compared with venlafaxine, desvenlafaxine has a relatively higher noradrenaline transporter affinity and lower serotonin transporter affinity. Desvenlafaxine is primarily metabolized by glucuronidation, mediated by uridine diphosphate glucuronosyltransferase and, to a minor extent, by oxidative metabolism via CYP3A4. Approximately 45% of desvenlafaxine is excreted unchanged in the urine.[131] In vitro studies in human liver microsomes have shown that desvenlafaxine has no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2C19, CYP2C8, CYP2C9, CYP2D6 and CYP3A4.[132] As the CYP3A4 pathway plays a role in desvenlafaxine metabolism, there is potential for interactions between desvenlafaxine and drugs affecting CYP3A4. In this respect, in 15 healthy subjects the pharmacokinetics of single 400 mg oral doses of desvenlafaxine extended release were evaluated before and during concomitant administration with the potent CYP3A4 inhibitor ketoconazole (200 mg every 12 hours for 7 days).[69] In the ketoconazole phase, the Cmax and the AUC of desvenlafaxine increased by 8% and by 43%, respectively. On account of its weak inhibitory effect on the hepatic CYP system, desvenlafaxine is expected to have a low propensity to interact with coadministered medications. An open-label, crossover study in 20 healthy volunteers compared the effects of oral desvenlafaxine 100 mg and paroxetine 20 mg, a known CYP2D6 inhibitor, on the pharmacokinetics of a single 50 mg dose of the CYP2D6 substrate desipramine.[70] Desvenlafaxine had a weak inhibitory effect on the pharmacokinetics of desipramine, with an AUC increase of 36% compared with an increase with paroxetine of 419%. In a crossover investigation in 20 healthy subjects, the pharmacokinetics of a single dose of desipramine CNS Drugs 2012; 26 (1)

Spina et al.

54

50 mg were studied before and after multiple doses of desvenlafaxine 100 mg/day and duloxetine 30 mg twice daily.[71] Relative to desipramine alone, increases in the Cmax and AUC of desipramine associated with desvenlafaxine administration (19% and 22%, respectively) were significantly lower that those associated with duloxetine administration (63% and 122%, respectively; p < 0.001) As described in section 2.2 for venlafaxine, a serotonin syndrome may occur when desvenlafaxine is combined with other serotonergic agents, such as MAOIs, TCAs, SSRIs, trazodone, lithium, tramadol, triptans and linezolid.[72] Caution is also needed when desvenlafaxine is coadministered with NSAIDs or antiplatelet agents, due to an increased risk of bleeding.[72] 2.4 Duloxetine

Duloxetine is a potent inhibitor of serotonin and noradrenaline reuptake that is approved for the treatment of depression, generalized anxiety disorder, diabetic neuropathic pain, stress urinary incontinence and fibromyalgia.[133,134] Duloxetine has a low affinity for other neurotransmitter receptors including a1- and a2-adrenergic, dopamine D2, H1 and muscarinic receptors. Duloxetine is extensively metabolized in the liver primarily by CYP1A2 and, to a lesser extent, by CYP2D6 to form various oxidative and conjugated metabolites, which are inactive and excreted mainly in the urine.[135] In vitro studies using human liver microsomes have documented that duloxetine is a moderate inhibitor of CYP2D6.[73] Duloxetine has clinically insignificant inhibition on CYP1A2 and has no effect on the activity of CYP2C9, CYP2C19 and CYP3A4 in vitro, and is not expected to interfere with the metabolism of substrates of these isoforms in vivo.[74,136] The disposition of duloxetine may be affected by coadministration of other drugs, in particular medications affecting CYP2D6 and CYP1A2 activities. In this respect, the results of two drug interaction studies in healthy volunteers have shown that concomitant intake of paroxetine, a potent CYP2D6 inhibitor, and fluvoxamine, a potent CYP1A2 inhibitor, increased the AUC of duloxetine by 60% (p < 0.01) and 460% ª 2012 Adis Data Information BV. All rights reserved.

(p < 0.001), respectively, confirming the in vitro data that CYP1A2 is the main enzyme involved in duloxetine biotransformation.[73,74] Smoking is associated with lower duloxetine serum concentrations due to an induction of CYP1A2 by polycyclic hydrocarbons that are contained in tobacco smoke.[137] The potential of duloxetine to affect other drugs has been evaluated by a number of drug interaction studies. In vivo investigations in healthy subjects have examined the effect of duloxetine on the pharmacokinetics of three CYP2D6 substrates desipramine, tolterodine and metoprolol.[71,73,76,77] In a study of 16 healthy subjects, duloxetine 60 mg twice daily for 3 weeks increased the Cmax and AUC of desipramine, administered as a single dose of 50 mg, by 1.7- and 2.9-fold, respectively (both, p < 0.001).[73] As previously described,[71] in a study comparing the effect of duloxetine 30 mg twice daily and desvenlafaxine 100 mg/day on the pharmacokinetics of a single dose of desipramine 50 mg in healthy subjects, duloxetine administration resulted in a significant increase in the Cmax and AUC of desipramine, while desvenlafaxine had only a minimal effect on desipramine pharmacokinetics. Coadministration of duloxetine 40 mg twice daily with tolterodine 2 mg twice daily in 16 healthy volunteers increased tolterodine steady-state Cmax and AUC by 64% and 71%, respectively, and prolonged its half-life by 14%.[76] Preskorn et al.[77] investigated the pharmacokinetics of a single 100 mg dose of metoprolol before and after 17 days of treatment with duloxetine 60 mg/day. Duloxetine produced a statistically significant increase in Cmax, AUC (by 180%) and elimination half-life of metoprolol (all, p < 0.001) and a decrease in its clearance (p < 0.001). Duloxetine effects on the pharmacokinetics of metoprolol were significantly greater than those observed in the same study with escitalopram 20 mg/day and sertraline 100 mg/day.[77] Collectively, results from these interaction studies confirm that duloxetine is a moderate inhibitor of CYP2D6. Therefore, caution is advised whenever duloxetine is coadministered with other medications primarily metabolized via this enzyme, particularly those with a narrow therapeutic index, such as TCAs, various antipsychotics and CNS Drugs 2012; 26 (1)


class IC antiarrhythmic agents, and tamoxifen. In addition to drug interaction studies in healthy volunteers, few investigations have evaluated the potential of duloxetine to affect other drugs in patients. The potential pharmacokinetic interaction between duloxetine and second-generation antipsychotics was recently investigated in outpatients with psychotic disorders stabilized on clozapine (n = 6), olanzapine (n = 8) and risperidone (n = 7).[78] Duloxetine 60 mg/day for up to 6 weeks did not modify the plasma concentrations of clozapine and olanzapine, which are not CYP2D6 substrates, while it was associated with a modest, but potentially clinically significant, increase in the plasma concentration of the active moiety of risperidone (by a mean 26%), presumably through inhibition of CYP2D6-mediated 9-hydroxylation of risperidone. On the other hand, in a study based on a therapeutic drug monitoring database, coadministration of duloxetine 30–120 mg/day was not associated with significant effects on the serum concentrations of risperidone and aripiprazole, a CYP2D6 substrate.[138] In the last few years, there has been great interest in the possible interaction between antidepressants and tamoxifen.[10] In theory, duloxetine may impair the CYP2D6-mediated biotransformation of the prodrug tamoxifen into the active metabolite endoxifen and, possibly, increase the risk of breast cancer recurrence. Confirming its minimal inhibitory effect on the activity of CYP1A2, coadministration of duloxetine was associated with no significant changes in the pharmacokinetics of theophylline, a CYP1A2 substrate.[74] Specific studies have been conducted to assess the potential for pharmacodynamic interactions between duloxetine and other CNS-acting drugs, such as benzodiazepines and alcohol.[136] Increased sedation was observed in healthy subjects receiving duloxetine and lorazepam in combination. On the other hand, addition of duloxetine did not exacerbate the cognitive and psychomotor impairment produced by alcohol. As with SSRIs and venlafaxine, the combined use of duloxetine with other serotonergic drugs – including MAOIs, lithium, linezolid, triptans, tramadol and Hypericum extracts – has the potential for ª 2012 Adis Data Information BV. All rights reserved.

55

additive pharmacodynamic effects resulting in a serotonin syndrome.[75] Based on the known effects of serotonin reuptake inhibitors on platelet aggregation and the subsequent increased risk for gastrointestinal bleeding, the interaction between duloxetine and NSAIDs or oral anticoagulants should be considered. With regard to this, a case report described a 44-year-old woman stabilized on warfarin treatment who experienced petechiae/purpura associated with an increase in INR values after starting therapy with duloxetine 30 mg/day.[79] Following duloxetine discontinuation, INR decreased to the normal range. Based on different metabolic pathways of duloxetine and warfarin, it is unlikely that the interaction was pharmacokinetic. As both duloxetine and warfarin are highly bound to plasma proteins, displacement of warfarin from protein binding sites was hypothesized. A subsequent study examined the effect of duloxetine 60 or 120 mg/day for 14 days on the pharmacodynamics and pharmacokinetics of once-daily warfarin administration in healthy subjects who had a stable INR with an individualized fixed dosage of warfarin of 2–9 mg/day.[139] The INR was determined daily during concomitant intake of the two drugs and duloxetine had no statistically or clinically significant effect on the anticoagulant effects of warfarin. Moreover, the pharmacokinetics of R- and S-warfarin were not affected by duloxetine. Therefore, these findings do not provide a reasonable explanation for the INR modifications described in the case report. 2.5 Milnacipran

Milnacipran is a dual inhibitor of serotonin and noradrenaline reuptake, available for the treatment of major depression in some countries including France and Japan, and also approved for the treatment of fibromyalgia. In vitro and in vivo data indicate that milnacipran inhibits the reuptake of both serotonin and noradrenaline with approximately equal potency, showing no effect on dopamine reuptake.[140,141] Milnacipran is devoid of interactions at any known neurotransmitter receptors or ion channels. Milnacipran is eliminated primarily by renal excretion of the unchanged drug (50–60%), while CNS Drugs 2012; 26 (1)

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20–30% is conjugated to a carbamoyl-glucuronide and approximately 10% is metabolized by CYP isoforms (mainly CYP3A4).[80,142] Studies in healthy subjects have shown that the pharmacokinetic profile of milnacipran did not differ between extensive metabolizers and poor metabolizers of both CYP2D6 and CYP2C19.[143] These data indicate that the hepatic biotransformation of milnacipran is not mediated by these two polymorphic enzymes. Due to its limited oxidative metabolism, it is unlikely that milnacipran disposition will be affected by concomitant treatment with CYP inhibitors or inducers. Accordingly, coadministration with levomepromazine, a CYP2D6 inhibitor, to 12 healthy volunteers had little impact on milnacipran pharmacokinetics, resulting in a slight increase in the steady-state plasma concentrations by approximately 20%.[80] In a subsequent study in 12 healthy subjects, milnacipran was administered immediately after a 3-week treatment with fluoxetine, another strong CYP2D6 inhibitor, and no significant modifications in the pharmacokinetic parameters of milnacipran were observed.[144] Moreover, coadministration with carbamazepine, an inducer of CYP3A4, 200 mg twice a day for 32 days, caused a 20% decrease in plasma concentrations of milnacipran.[80] The in vitro ability of milnacipran to inhibit and induce CYP isoforms was recently evaluated.[145] In human liver microsomes, milnacipran did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP2D6, while it weakly inhibited CYP3A4 activity. Milnacipran had minimal inducing effects on the activity of CYP isoforms. Based on this biochemical evidence, milnacipran is not expected to significantly affect the disposition of coadministered medications. Consistent with this, clinical drug-drug interaction studies in healthy volunteers have documented that milnacipran causes no inhibition (or induction) of CYP1A2 (with caffeine as the in vivo probe drug), CYP2C19 (mephenytoin) and CYP2D6 (sparteine).[143] In addition, studies in healthy subjects have shown that milnacipran has no effect on the pharmacokinetics of carbamazepine, which is mainly metabolized by CYP3A4, and on the pharmacokinetics of the two warfarin enantiomers, S-warfarin, meª 2012 Adis Data Information BV. All rights reserved.

tabolized via CYP2C9, and R-warfarin, metabolized by CYP1A2 and CYP3A4.[145] Pharmacodynamic interactions of milnacipran have not been investigated systematically. Based on the pharmacological properties of milnacipran, it is likely that its potential for pharmacodynamic interactions is similar to that of the other SNRIs, i.e. venlafaxine, desvenlafaxine and duloxetine.[146] 2.6 Mirtazapine

Mirtazapine is a noradrenergic and specific serotonergic antidepressant that is approved in many countries for the treatment of major depression.[147] Mirtazapine is a racemate and both the S-(+)- and R-(-)-enantiomers are pharmacologically active. The antidepressant effect of mirtazapine presumably derives from a combination of noradrenergic and serotonergic mechanisms. Mirtazapine potentiates noradrenergic and 5-HT1A-mediated serotonergic neurotransmission via antagonism of central a2-adrenergic auto- and heteroreceptors and postsynaptic blockade of 5-HT2 and 5-HT3 receptors.[147] Mirtazapine does not inhibit the reuptake of serotonin and noradrenaline. It has a low affinity for dopaminergic receptors, while it is a potent antagonist of H1 receptors and a moderate antagonist at muscarinic receptors. Mirtazapine undergoes extensive hepatic biotransformation and the major metabolic pathways include demethylation and oxidation followed by conjugation.[148] In vitro studies with human liver microsomes and recombinant enzymes have indicated that CYP2D6 and, to a lesser extent, CYP1A2 are the major isoforms involved in the 8-hydroxylation, while CYP3A4 is responsible for the N-demethylation and the N-oxidation.[149] Mirtazapine has minimal inhibitory effects on the various CYP isoforms in vitro and appears to carry a low risk for drug interactions. In a double-blind, placebo-controlled, pharmacokinetic interaction study in 12 healthy volunteers, coadministration of cimetidine 800 mg twice daily and mirtazapine 30 mg/day resulted in a significant increase in steady-state plasma concentrations of mirtazapine (61%; p < 0.05).[81] In a single-blind, three-way, crossover study inCNS Drugs 2012; 26 (1)


volving 24 healthy subjects, combined administration of mirtazapine 30 mg/day and amitriptyline 75 mg/day for 9 days was found to result in minor, presumably not clinically relevant, changes in the pharmacokinetics of both compounds.[150] The potential pharmacokinetic interaction between paroxetine 40 mg/day and mirtazapine 30 mg/day was investigated in 24 healthy subjects at steady state.[151] While mirtazapine did not affect the pharmacokinetics of paroxetine, the AUC of mirtazapine and demethyl-mirtazapine increased slightly by 17% and 25%, respectively. The inhibitory effect of paroxetine on the CYP2D6mediated metabolism of mirtazapine is the most reasonable explanation for the observed changes in mirtazapine pharmacokinetics. Coadministration of fluvoxamine, a potent inhibitor of various CYP isoforms, 50 and 100 mg/day, in two patients treated with mirtazapine 30 mg/day, resulted in 3- and 4-fold increases in plasma concentrations of mirtazapine, respectively,[82] and a serotonin syndrome has also been reported with this combination.[83] The available in vivo studies that have evaluated the potential for mirtazapine to affect the disposition of other drugs have confirmed the favourable interaction profile observed in vitro. In an open-label, non-randomized, pilot study in six psychiatric patients with concomitant psychotic and depressive symptoms treated with risperidone 2–6 mg/day, addition of mirtazapine 30 mg/day for 2–4 weeks did not alter plasma concentrations of risperidone and its active 9-hydroxy metabolite.[152] Zoccali et al.[153] investigated the possibility of a pharmacokinetic interaction between mirtazapine and the newer antipsychotics clozapine, risperidone and olanzapine in 24 patients with chronic schizophrenia. Concomitant treatment with mirtazapine 30 mg/day for 6 weeks did not significantly affect plasma concentrations of clozapine 200–650 mg/day (n = 9), risperidone 3–8 mg/day (n = 8), olanzapine 10–20 mg/day (n = 7) or their major metabolites during the study period. Due to its minimal inhibitory effect on CYP2D6, it has been suggested that mirtazapine may be used safely in combination with tamoxifen.[100] Two pharmacokinetic investigations evaluated the reciprocal interaction between mirtazapine ª 2012 Adis Data Information BV. All rights reserved.

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30 mg/day and carbamazepine 400 mg/day[84] or phenytoin 200 mg/day[85] in healthy subjects under steady-state conditions. While mirtazapine had no effect on the pharmacokinetic parameters of either carbamazepine or phenytoin, addition of carbamazepine or phenytoin resulted in a mean decrease in the AUC of mirtazapine by 60% and 46%, respectively (both, p < 0.05). The reduction in mirtazapine concentrations is presumably due to induction of CYP3A4-mediated metabolism of mirtazapine by carbamazepine and phenytoin. A recent study in 95 patients with depression reported that smokers had significantly lower plasma mirtazapine concentrations than nonsmokers, confirming the role of CYP1A2, which is induced by cigarette smoking, in the metabolism of mirtazapine.[154] An additive sedative effect has been documented when mirtazapine is coadministered with diazepam.[148] In addition, mirtazapine may potentiate the pharmacological effects of alcohol.[148] Therefore, mirtazapine should not be given in combination with sedating agents due to possible impairment of cognitive and psychomotor performance. As for SSRIs and SNRIs, coadministration of mirtazapine with other serotonergic medications may result in the serotonin syndrome. However, there is still a controversy regarding whether mirtazapine may indeed induce this potentially fatal condition. While different reports have documented that mirtazapine monotherapy or the combination of mirtazapine with other serotonergic agents may lead to the serotonin syndrome,[83,155-158] other investigations have suggested that the syndrome is not induced by mirtazapine.[159,160] In addition, in an animal model of the serotonin syndrome, mirtazapine was found to inhibit hyperthermia, one of the most serious symptoms of this syndrome, possibly through its potent 5-HT2A antagonistic effects.[161] Based on a retrospective chart review study, the combined use of mirtazapine with tramadol or dopamine-blocking agents could enhance the risk of restless legs syndrome, possibly through a pharmacodynamic mechanism.[86] This condition, characterized by paraesthesia and an urge to move, may be caused or worsened by a number of drugs including new antidepressants, in CNS Drugs 2012; 26 (1)

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particular mirtazapine.[162] As mentioned previously (see section 1.1), based on the findings from a large registry study in warfarin-treated patients, mirtazapine was associated with a significantly lower risk for bleeding compared with SSRIs.[30] 2.7 Reboxetine

Reboxetine is the first commercially available noradrenaline reuptake inhibitor developed as a first-line therapy for major depressive disorder.[163] Reboxetine is administered as a racemic mixture: the (S,S)-(+)-enantiomer is more potent at noradrenaline reuptake inhibition, although the (R,R)-(-)-enantiomer is present at higher concentrations in plasma. Reboxetine is a selective inhibitor of noradrenaline transport, but is also a weak inhibitor of serotonin transport. Binding studies have documented that reboxetine has no significant affinity for adrenergic, serotonergic, histaminergic or muscarinic receptors. Reboxetine is extensively metabolized in the liver through three major pathways, including hydroxylation of the ethoxyphenoxy ring, oxidative dealkylation and oxidation of the morpholine ring.[164] In vitro studies in human liver microsomes have shown that CYP3A4 is the major isoform involved in reboxetine biotransformation.[165] Therefore, concomitant treatment with CYP3A4 inhibitors or inducers may affect plasma concentrations of reboxetine. The effect of a 5-day treatment with ketoconazole 200 mg/day, a potent inhibitor of CYP3A4, on the pharmacokinetics of a single 4 mg dose of reboxetine was investigated in 11 healthy volunteers.[87] Ketoconazole increased the mean AUC of (R,R)(-)-reboxetine and (S,S)-(+)-reboxetine by 58% and 43%, respectively (p < 0.02), while the clearance decreased by 34% and 24%, respectively (p < 0.005). These findings suggest that reboxetine dosage should be reduced when coadministered with potent inhibitors of CYP3A4. Conversely, in a case report of two patients treated with CYP3A4 inducers, namely phenobarbital (phenobarbitone) and carbamazepine, serum concentrations of reboxetine were considerably lower compared with median values in patients not treated with CYP3A4 inducers.[88] ª 2012 Adis Data Information BV. All rights reserved.

On the other hand, the pharmacokinetics of a single 1 mg oral dose of reboxetine were not significantly affected by coadministration of quinidine 50 mg, a potent inhibitor of CYP2D6, in eight healthy subjects, indicating that CYP2D6 does not contribute substantially to the biotransformation of reboxetine.[164] In agreement with this, Fleishaker et al.[166] reported that fluoxetine, another strong inhibitor of CYP2D6, had no effect on the pharmacokinetics and pharmacodynamics of reboxetine in healthy volunteers. In human microsomal preparations, both reboxetine enantiomers were found to be weak inhibitors of the activity of CYP2D6 and CYP3A4, but they had no appreciable inhibitory effects on the activity of CYP1A2, CYP2C9 and CYP2C19.[165] The inhibitory effect of reboxetine on CYP2D6 and CYP3A4 is unlikely to be relevant in vivo because it occurs at concentrations well above those achieved clinically. Accordingly, studies in healthy volunteers have shown that reboxetine 8 mg/day does not interfere with the pharmacokinetics of dextromethorphan or alprazolam, model substrates for CYP2D6 and CYP3A4, respectively.[164,167] Moreover, an open-label pharmacokinetic investigation in 14 patients with schizophrenia or schizoaffective disorder with associated depressive symptoms documented no effect of a 4-week treatment with reboxetine 8 mg/day on the plasma concentrations of the second-generation antipsychotics clozapine 250–500 mg/day (n = 7), risperidone 4–6 mg/day (n = 7) and their active metabolites.[168] Pharmacodynamic interactions involving reboxetine have not been examined systematically. In a study designed to evaluate the effects of reboxetine on cognitive and psychomotor function in healthy volunteers, reboxetine doses £4 mg had no significant effects on performance and did not act synergistically with alcohol, in contrast to amitriptyline.[169] In a study aimed to investigate the efficacy of adjunctive triiodothyronine (T3, liothyronine) as a strategy to accelerate remission in patients with major depression, three subjects experienced noradrenergic effects such as anxiety, irritability, increased sweating, tremor, sleep disturbances and urinary symptoms when reboxetine was combined with T3.[170] CNS Drugs 2012; 26 (1)


2.8 Bupropion

Bupropion is an antidepressant that inhibits the neuronal reuptake of dopamine and noradrenaline, and is approved for the treatment of major depression and smoking cessation. It is a more potent inhibitor of dopamine reuptake than noradrenaline reuptake. Bupropion has no effect on the release or transport of other neurotransmitters and has no appreciable affinity for postsynaptic receptors.[171] Bupropion is extensively metabolized in the liver with the formation of three active metabolites, namely hydroxybupropion, threohydrobupropion and erythrohydrobupropion. As these metabolites reach higher steady-state concentrations than those of bupropion, they may be of clinical importance. In vitro studies in human liver microsomes have shown that CYP2B6 is the principal isoenzyme responsible for the formation of the primary active metabolite hydroxybupropion.[172] Formation of the secondary metabolites threohydrobupropion and erythrohydrobupropion is mediated by carbonyl reductase, a non-microsomal enzyme. In vitro and in vivo studies indicate that both bupropion and hydroxybupropion are moderate inhibitors of CYP2D6.[172,173] Since bupropion is metabolized by CYP2B6, it can be expected that coadministration of inhibitors of CYP2B6, including clopidogrel, orphenadrine and ticlopidine, or inducers of CYP2B6, such as carbamazepine and ritonavir, may cause clinically significant changes in plasma concentrations of bupropion and hydroxybupropion. Different in vitro studies have demonstrated that both clopidogrel and ticlopidine inhibited CYP2B6 with the highest potency.[174,175] In a study in 12 healthy subjects given a single 150 mg dose of bupropion, concomitant administration of clopidogrel 75 mg once daily or ticlopidine 250 mg twice daily for 4 days was associated with a reduction in the AUC of hydroxybupropion by 52% with clopidogrel (p < 0.001) and by 84% with ticlopidine (p < 0.001).[89] Orphenadrine is known to inhibit CYP2B6.[176] Although no studies have been conducted in vivo to examine the interaction between orphenadrine and bupropion, caution is needed when orphenadrine is given in combinaª 2012 Adis Data Information BV. All rights reserved.

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tion with bupropion, because it might cause elevated bupropion concentrations, possibly associated with adverse effects such as agitation, anxiety, insomnia and seizure risk. Different interaction studies have evaluated the effect of CYP2B6 inducers on bupropion disposition.[90-94] In a study in 12 patients with mood disorders given a single 150 mg dose of bupropion, concomitant administration of carbamazepine, at a mean dosage of 942 mg/day, was associated with a reduction by 90% in the AUC of bupropion (p < 0.001) and an increase by 50% in the AUC of hydroxybupropion (p < 0.05).[90] Rifampicin (rifampin) is a known inducer of CYP2B6 and a study conducted in 18 healthy subjects demonstrated that daily treatment with rifampicin 600 mg reduced the half-life of bupropion by 50% and induced bupropion clearance 3-fold, increasing peak plasma hydroxybupropion concentrations (p < 0.05).[91] In a pharmacokinetic investigation in 12 healthy subjects given a single 100 mg dose of sustainedrelease bupropion, concurrent treatment with lopinavir/ritonavir 400/100 mg twice daily for 2 weeks resulted in a decrease in the AUC of bupropion and its hydroxy metabolite by 57% and 50%, respectively (both, p < 0.01).[92] These findings were confirmed in a study conducted in 13 volunteers and designed to evaluate the effects of ritonavir on human CYP2B6 in vivo.[93] The authors found that induction of CYP2B6 by ritonavir is rapid, occurring after only 3 days of treatment (ritonavir 200 mg twice daily), and finally resulting in an increased hydroxylation and clearance of bupropion by ritonavir (up to 1.8-fold after 3 days of ritonavir treatment) [p < 0.01]. Furthermore, a recent investigation has demonstrated that the reduction in bupropion concentrations by ritonavir is dose related.[94] Dosage adjustment of bupropion may be needed, especially when this drug is administered with high doses of ritonavir. In view of the moderate inhibitory effect of bupropion and its hydroxy metabolite on CYP2D6 activity, clinically relevant interactions may theoretically occur when bupropion is given in combination with CYP2D6 substrates.[177] In this respect, in an open-label study involving CNS Drugs 2012; 26 (1)

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15 CYP2D6 extensive metabolizers, Jefferson et al.[95] found that coadministration of dosages of bupropion 150 mg twice daily with a single dose of desipramine 50 mg increased the Cmax, AUC and half-life of desipramine by 2-, 5- and 2-fold, respectively. As previously described (see section 2.2), bupropion may cause a clinically significant elevation of plasma concentrations of venlafaxine.[97,98] Some case reports have described nortriptyline or metoprolol toxicity following bupropion co-treatment, confirming that this antidepressant may inhibit CYP2D6 activity.[96,99] Though clinical documentation is lacking, when adding CYP2D6 substrates (such as propafenone) with a narrow margin of safety to bupropion therapy, clinicians should start with low doses.[178] Potent inhibitors of CYP2D6, such as fluoxetine and paroxetine, are known to reduce the clinical benefit of the anticancer agent tamoxifen, by decreasing the formation of its active metabolite endoxifen.[10] Bupropion is a moderate inhibitor of CYP2D6 and recent studies recommend avoiding the use of paroxetine, fluoxetine and bupropion in women taking tamoxifen for the treatment or prevention of recurrence of breast cancer.[100] Since bupropion may lower the seizure threshold, caution is needed when given in combination with other drugs that also reduce the seizure threshold, including antidepressants, antipsychotics, tramadol and theophylline.[179,180] Moreover, care is required when alcohol or benzodiazepines are discontinued abruptly due to the increased risk of seizures during withdrawal conditions. As bupropion increases dopaminergic activity, the potential exists for interactions with dopamine agonists or antagonists. Combined treatment with bupropion and levodopa may lead to a higher incidence of adverse effects of levodopa such as nausea, vomiting and restlessness.[178] 2.9 Agomelatine

Agomelatine is a new antidepressant approved in Europe in 2009 for the treatment of major depression. Agomelatine has a novel mechanism of action: it is a potent agonist of melatonin MT1 and MT2 receptors and is also an antagonist of the 5-HT2C receptor subtype.[181] Binding studies ª 2012 Adis Data Information BV. All rights reserved.

indicate that agomelatine has no effect on monoamine reuptake and no affinity for a- or b-adrenergic, histaminergic, cholinergic, dopaminergic or benzodiazepine receptors. Agomelatine is extensively metabolized in the liver by demethylation and hydroxylation to form inactive metabolites that are rapidly conjugated and eliminated in the urine.[182] The major enzymes involved in the biotransformation of agomelatine are CYP1A2 (90%) and, to a lesser extent, CYP2C9/CYP2C19.[183] Concomitant treatment with medications that interact with these isoenzymes may decrease or increase plasma concentrations of agomelatine. According to the Summary of Product Characteristics,[101] fluvoxamine, a potent CYP1A2 and moderate CYP2C9 inhibitor, markedly inhibits the metabolism of agomelatine resulting in a 60-fold (range 12- to 412-fold) increase of agomelatine exposure. Because CYP1A2 is the major isozyme responsible for hepatic metabolism of agomelatine, drugs that are potent inhibitors of CYP1A2 – such as ciprofloxacin, amiodarone, mexiletine or zileutin – should be avoided.[101] Moderate CYP1A2 inhibitors, including estrogens, may also increase exposure of agomelatine.[101] Conversely, cigarette smoking reduces plasma concentrations of agomelatine by 3- to 4-fold by inducing CYP1A2 activity.[101] In vivo and in vitro evidence indicates that agomelatine does not inhibit or induce the activity of various CYP isoforms and therefore should not affect plasma concentrations of coadministered medications. No evidence of pharmacokinetic or pharmacodynamic interactions with medicinal products that could be prescribed concomitantly with agomelatine in the target population was found in phase I clinical trials: i.e. benzodiazepines, lithium, paroxetine, fluconazole and theophylline. On the other hand, the combination of agomelatine and alcohol is not advisable because of a pharmacodynamic interaction.[101] 2.10 Vilazodone

Vilazodone is a new antidepressant recently approved by the FDA for the treatment of major depressive disorder. It is a novel dual-acting CNS Drugs 2012; 26 (1)


serotonergic antidepressant that combines selective serotonin reuptake inhibition with partial agonism of the 5-HT1A receptor.[184,185] Vilazodone is extensively metabolized in the liver through CYP and non-CYP pathways (possibly by carboxylesterase).[186] According to in vitro studies, vilazodone is metabolized primarily by CYP3A4 and secondarily by CYP2C19 and CYP2D6.[186] Studies in human liver microsomes showed that vilazodone is a significant inhibitor of CYP2C8.[186] Since CYP3A4 is a major elimination pathway for vilazodone, coadministration with inhibitors or inducers of this isoform may affect vilazodone disposition. In agreement with this, concomitant use of vilazodone and potent inhibitors of CYP3A4 (e.g. ketoconazole) can increase vilazodone plasma concentrations by approximately 50%. Conversely, coadministration of vilazodone with inducers of CYP3A4 has the potential to reduce vilazodone systemic exposure. However, the effect of CYP3A4 inducers on vilazodone plasma concentrations has not been evaluated. Concomitant administration of vilazodone with inhibitors of CYP2C19 and CYP2D6 is not expected to alter plasma concentrations of vilazodone, as these isoforms are minor elimination pathways in the metabolism of vilazodone.[102] With regard to the effect of vilazodone on the pharmacokinetics of other drugs, studies in healthy volunteers found no significant effect of vilazodone 20 mg/day for 8–10 days on biotransformation of substrates for CYP1A2 (caffeine), CYP2C9 (flurbiprofen), CYP2D6 (debrisoquine) and CYP3A4 (nifedipine).[102] On the other hand, coadministration of vilazodone with CYP2C8 substrates (i.e. repaglinide, paclitaxel) may lead to an increase in their plasma concentrations. So far, the effect of vilazodone on the pharmacokinetics of CYP2C8 substrates has not been studied in vivo. According to the manufacturer’s prescribing information,[102] due to the potential for the serotonin syndrome, caution is advised when vilazodone is coadministered with other drugs that may affect the serotonergic neurotransmitter systems. Concurrent use of vilazodone with NSAIDs, aspirin or oral anticoagulants may also potentiate the risk of bleeding. ª 2012 Adis Data Information BV. All rights reserved.

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3. Conclusion The present article summarizes the available knowledge on clinically relevant drug interactions involving newer antidepressants marketed after 1994. For those agents more recently introduced into clinical practice, such as agomelatine and vilazodone, information is still limited and mainly based on the available files reporting the Summary of Product Characteristics. In general, because of a more selective mechanism of action and receptor profile, newer antidepressants, as well as SSRIs, carry a relatively low risk for pharmacodynamic drug interactions, at least as compared with first-generation antidepressants. Concerning the potential for pharmacokinetic drug interactions, newer antidepressants are endowed with a more favourable profile compared with certain SSRIs, such as fluoxetine, paroxetine and fluvoxamine. However, they are not equivalent in their potential for metabolic drug interactions. Duloxetine and bupropion are moderate inhibitors of CYP2D6, while the other agents do not significantly affect the different CYP isoforms. Table III summarizes the clinically relevant drug-drug interactions of newer antidepressants. The issue of drug interactions with antidepressants is of great clinical concern, as these agents are widely prescribed by general practitioners, especially for the elderly.[187,188] Moreover, some newer antidepressants are also used to treat psychiatric disorders other than depression (e.g. anxiety disorders) and non-psychiatric conditions (e.g. neuropathic pain and fibromyalgia). However, when comparing prescription data with observed adverse drug events, the prevalence of clinically relevant drug interactions with antidepressants appears to be rather low.[189,190] In addition, the risk of harmful drug interactions may be significantly reduced by avoiding the unnecessary use of polytherapy and by selecting comedications that are less likely to interact. In this respect, knowledge of the interaction potential of each individual antidepressant is of great value for rational prescribing and may help clinicians to predict and eventually avoid certain drug combinations. If the use of potentially interacting drugs cannot be CNS Drugs 2012; 26 (1)

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avoided, adverse clinical consequences may be minimized, as appropriate, by individualized dose adjustments guided by careful monitoring of clinical response and, possibly, plasma drug concentration monitoring. Other intervention strategies, targeted to adequately supply prescribers with information on the risks of clinically relevant drug-drug interactions, may be represented by computerized drug interaction alerts. There is good evidence that electronic decision-support systems, such as automated drug interaction alerts, that are immediately integrated in the prescribing process, can dramatically increase clinicians’ recognition of interacting drug pairs (including antidepressant drugs) by up to 50%, thus leading to a reduction in the number of prescriptions with potentially hazardous combinations.[191] However, these tools should be used very cautiously as these systems also tend to flag several clinically nonsignificant interactions, thus reducing the potential benefit on the prescribing appropriateness.[192] Acknowledgements The preparation of this review was not supported by any external funding. Prof. Spina has previously received honoraria for speaking and consultation from AstraZeneca, BoehringerIngelheim, Eli Lilly, Janssen, Lundbeck and Pfizer. The other authors have no conflicts of interest to declare.

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Correspondence: Prof. Edoardo Spina, Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Policlinico Universitario, Via Consolare Valeria, 98125 Messina, Italy. E-mail [email protected]

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