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Clinically relevant drug interactions in anxiety disorders

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human psychopharmacology
Hum. Psychopharmacol Clin Exp 2012; 27: 239–253.
Published online 7 February 2012 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/hup.2217

REVIEW ARTICLE

Clinically relevant drug interactions in anxiety disorders

Maria Rosaria Muscatello1, Edoardo Spina2*, Borwin Bandelow3 and David S. Baldwin4
1
Section of Psychiatry, Department of Neurosciences, Psychiatric and Anaesthesiological Sciences, University of Messina, Messina, Italy
2
Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy
3
Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany
4
Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK

Objective Certain drugs used in the treatment of patients with anxiety disorders can interact with other psychotropic drugs and with
pharmacological treatments for physical illnesses. There is a need for an updated comparative review of clinically relevant drug interactions
in this area.
Design Relevant literature on drug interactions with medications used in the treatment of anxiety disorders was identified through a search
in MEDLINE and EMBASE.
Results Drug interactions involving medications used to treat anxiety disorders may be pharmacokinetic, such as enzyme inhibition or
induction in the cytochrome P450 system and transporter-mediated drug interactions, or pharmacodynamic, such as additive effects in
causing drowsiness or additive effects at neurotransmitter receptors. Certain selective serotonin reuptake inhibitors (fluoxetine, fluvoxamine,
and paroxetine) are particularly liable to be potentially involved in untoward pharmacokinetic interactions.
Conclusions The potential for drug interactions with medications used in anxiety disorders should be the cause of clinical concern, particularly
in elderly individuals. However, the liability for harmful drug interactions may be anticipated, and the risk reduced. Although not all interactions
are clinically relevant, careful monitoring of clinical response and possible interactions is essential. Copyright © 2012 John Wiley & Sons, Ltd.

key words—anxiety disorders; drug interactions; selective serotonin reuptake inhibitors; serotonin–noradrenaline reuptake inhibitors;
benzodiazepines; pregabalin

INTRODUCTION irreversible monoamine oxidase inhibitors (MAOIs),

Anxiety disorders are among the most prevalent forms
of psychiatric illness (Gustansson et al., 2011). A
variety of pharmacological agents are currently avail-
able for the treatment of the different anxiety disorders
(Baldwin et al., 2005; Bandelow et al., 2008). First-
line medications include selective serotonin reuptake
inhibitors (SSRIs), such as citalopram, escitalopram,
fluoxetine, fluvoxamine, paroxetine, and sertraline;
serotonin–noradrenaline reuptake inhibitors (SNRIs),
such as venlafaxine and duloxetine; benzodiazepines,
such as diazepam, alprazolam, and lorazepam; and the
calcium channel modulator pregabalin. Other medica-
tions, including buspirone, the tricyclic antidepressants
(TCAs) imipramine and clomipramine, the reversible
inhibitor of monoamine oxidase A, moclobemide, and
*Correspondence to: E. Spina, Section of Pharmacology, Department of
Clinical and Experimental Medicine and Pharmacology, University of Messina,
Policlinico Universitario, via Consolare Valeria 98125, Messina, Italy.
Tel: +39 090 2213647; Fax: +39 090 2213300. E-mail: espina@unime.it
are generally considered to be treatments for patients
who have not responded to earlier interventions.
Anxiety disorders are frequently comorbid with other
psychiatric or somatic disorders. As a consequence,
antianxiety drugs are often prescribed in combination
with other medications, and this may result in clinically
relevant drug interactions. The available antianxiety
medications differ considerably in their potential for
drug interactions. Therefore, although adverse drug
interactions are often predictable, the use of antianxiety
agents with a low potential for drug interactions is
desirable, especially for elderly patients who are more
likely to take many medications.
This article aims to provide an updated comparative
review of clinically relevant drug interactions with
first-line antianxiety agents. As many of these com-
pounds are also used for indications other than anxiety
(i.e., depressive disorders, epilepsy, and neuropathic
pain), most of the available information derives from
interaction studies in patients with non-anxiety

Received 12 July 2011

Copyright © 2012 John Wiley & Sons, Ltd. Accepted 6 January 2012
240 m. r. muscatello ET AL.
disorders. Comprehensive reviews of drug interactions
involving TCAs and MAOIs have been published
(Spina and Perucca, 1994; Livingston and Livingston,
1996; Gillman, 2007).
A literature search in MEDLINE and EMBASE was
conducted for original research and review articles
published in English between January 1985 and
May 2011. Among the search terms were drug
interactions, cytochrome P450, antianxiety medica-
tions, SSRIs, citalopram, escitalopram, fluoxetine,
fluvoxamine, paroxetine, sertraline, SNRIs, venlafax-
ine, duloxetine, benzodiazepines, and pregabalin.
Only articles published in peer-reviewed journals
were included, while meeting abstracts were excluded.
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.
DEFINITION AND BASIC TYPES OF
DRUG INTERACTIONS
Drug interaction can be defined as a quantitative or
qualitative modification of a drug effect caused by con-
comitant administration of another drug (Spina, 2009).
According to Preskorn and Werder (2006), a drug
interaction may be considered “clinically relevant” if it
results in a treatment outcome that is less than expected
including occurrence of severe adverse effects, apparent
worsening of the disease, lack of efficacy, poor tolerabil-
ity, or withdrawal symptoms. On the basis of their
mechanisms, drug interactions can be classified as either
pharmacokinetic or pharmacodynamic.
Pharmacokinetic interactions
Pharmacokinetic interactions consist of changes in the
absorption, distribution, metabolism, or excretion of a
drug and/or its metabolite(s) after the addition of
another chemical agent. These interactions are easily
verified by a change in plasma drug concentrations.
Metabolically based drug interactions. The majority
of pharmacokinetic interactions with psychotropic
agents arise as a consequence of drug-induced changes
in hepatic metabolism, through enzyme inhibition or
induction (Lin and Lu, 1998). A central role in the
biotransformation phase is played by the human
cytochrome P450 (CYP) system, a “superfamily” of
more than 50 heme-containing enzymes that are
responsible for the phase I oxidative reactions of many
drugs, nutrients, environmental toxins, and endogenous
substances (Rendic, 2002). The major CYP enzymes
involved in the metabolism of therapeutic agents include
Copyright © 2012 John Wiley & Sons, Ltd.
CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6,
and CYP3A4. The activity of CYPs is genetically
determined and may be influenced by pathophysiologi-
cal and environmental factors, including concomitant
administration of other drugs. Over the past few years,
the different substrates, inhibitors, and inducers of
CYP isoenzymes in man have been identified (Rendic,
2002; Cozza et al., 2003). This knowledge may be of
great value for clinicians in anticipating and eventually
avoiding potential interactions. Coadministration of
two substrates of the same enzyme, or coadministration
of a substrate with an inhibitor or an inducer, entails the
possibility of a drug interaction. As a consequence,
plasma concentrations of the coadministered drugs
may be increased or decreased, leading to clinical
toxicity or diminished therapeutic effect. It is important
to emphasize that not all theoretically possible drug
interactions may have clinical implications. The clinical
relevance of a metabolic drug interaction depends on
a variety of drug-related (i.e., potency and dose/
concentration of the inhibitor/inducer, therapeutic index
of the substrate, extent of metabolism of the substrate
through the affected enzyme, and presence of active
metabolites), patient-related (i.e., age and genetic predis-
position) and environmental factors (i.e., smoking)
(Spina, 2009). In general, a clinically significant
interaction may be expected when a drug with a narrow
therapeutic index is coadministered with a potent
inhibitor or inducer of the major pathway of its metabo-
lism. 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 (US Food and
Drug Administration, 2006; Spina, 2009; Greenblatt
and von Moltke, 2010). The degree of inhibition
achieved in vivo is a function of the potency of the drug
multiplied by its concentration achieved on usually
effective antidepressant doses.
Transporter-mediated drug interactions. Increasing
recognition of the role played by drug transporters,
notably P-glycoprotein (P-gp), in the absorption,
distribution, and excretion of a wide variety of drugs
has suggested that clinically significant transporter-
mediated drug interactions may also (theoretically)
occur (Lin, 2007; Zhang et al., 2011). P-gp is a multi-
drug efflux transporter, encoded by the MDR1 gene
(or ABCB1), highly expressed in the intestine, brain,
liver, and kidney, which acts as a natural defense
mechanism against several substrates by limiting their
absorption from the gut and penetration to the brain
and by promoting their elimination in the bile and urine
(Lin, 2007). It is of interest to note that many drugs that
Hum. Psychopharmacol Clin Exp 2012; 27: 239–253.
DOI: 10.1002/hup
 antianxiety drug interactions
are metabolized by CYP3A4 are also substrates
for P-gp.
Protein binding displacement drug interactions. Phar-
macokinetic interactions may also result from changes
in plasma protein binding when two drugs compete for
the same binding sites (Spina, 2009). Displacement
from plasma proteins will then cause a rise in the
fraction of unbound drug in plasma or tissue, thereby
potentially increasing the effect of the displaced
drug. However, clinical consequences might only be
moderate and short-lived, because free drug is cleared
from the plasma.
Pharmacodynamic interactions
Pharmacodynamic interactions occur when two drugs
act at the same or interrelated site of action (receptors,
ion channels, transporters, and enzymes), generally
resulting in additive, synergistic, or antagonistic effects.
They lead to a modification of the pharmacological
action of a drug without any change in the plasma
concentration. Pharmacodynamic interactions are very
common and may be predicted on the basis of the
known mechanism of action of the involved medica-
tions. However, they are more difficult to identify and
measure than pharmacokinetic interactions and are
commonly inferred to explain drug-induced modifica-
tions in clinical status that cannot be ascribed to a pharma-
cokinetic mechanism. Pharmacodynamic interactions
include additive CNS depression effects (for example,
when two or three sedating drugs are combined, this
could result in oversedation or even respiratory
241
depression) or additive effects at neurotransmitter
receptors (e.g., when two drugs with anticholinergic are
combined, this may result in delirium).
ANTIANXIETY DRUGS: POTENTIAL FOR
DRUG INTERACTIONS
Pharmacokinetic interactions
With the exceptions of lorazepam, which is conjugated
with glucuronic acid, and pregabalin, which is elimi-
nated predominantly through the kidneys, all medica-
tions used for the treatment of anxiety disorders
undergo extensive metabolism via the hepatic CYP
system (Table 1). As a consequence, concomitant
treatment with other medications, acting as inhibitors
or inducers of the enzymes involved in their bio-
transformation, may cause changes in their plasma
concentrations. In this respect, coadministration with
potent inhibitors of CYP1A2 (ciprofloxacin), CYP2D6
(quinidine), CYP3A4 (erythromycin, ketoconazole,
and itraconazole), or inducers (carbamazepine, pheno-
barbital, phenytoin, and rifampicin) may lead
to potentially harmful drug interactions. However,
because of the relatively wide margin of safety of
antianxiety drugs, the clinical consequences of such
kinetic modifications may not be relevant (Nemeroff
et al., 2007; Spina et al., 2008). 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 only in a

Table 1. Medications used in the treatment of anxiety disorders: enzymes involved in metabolism and enzymes inhibited

Enzymes involved in biotransformation Enzymes inhibited

Fluoxetine CYP2D6, CYP2C9, CYP2C19, CYP3A4 CYP2D6 (potent)

CYP2C9 (moderate)
CYP2C19 and CYP3A4 (weak to moderate)
CYP1A2 (weak)
Paroxetine CYP2D6, CYP3A4 CYP2D6 (potent)
CYP1A2, CYP2C9, CYP2C19, CYP3A4 (weak)
Fluvoxamine CYP1A2, CYP2D6 CYP1A2 and CYP2C19 (potent)
CYP2C9 and CYP3A4 (moderate)
CYP2D6 (weak)
Sertraline CYP3A4, CYP2C9, CYP2C19, CYP2D6 CYP2D6 (weak to moderate)
CYP1A2, CYP2C9, CYP2C19 and CYP3A4 (weak)
Citalopram CYP2C19, CYP2D6, CYP3A4 CYP2D6 (weak)
Escitalopram CYP2C19, CYP2D6, CYP3A4 CYP2D6 (weak)
Venlafaxine CYP2D6, CYP3A4 CYP2D6 (weak)
Duloxetine CYP2D6, CYP1A2 CYP2D6 (moderate)
Alprazolam CYP3A4 None
Diazepam CYP2C19, CYP3A4 None
Lorazepam Glucuronidating enzymes None
Pregabalin None None

Based on Hemeryck and Belpaire (2002), Nemeroff et al. (2007), and Spina et al. (2008). Bold characters identify major enzymes responsible for
biotransformation.

Copyright © 2012 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp 2012; 27: 239–253.
DOI: 10.1002/hup
242 m. r. muscatello ET AL.
minimal increase in plasma concentrations, because
another isoform may provide sufficient secondary
metabolic pathways.
Selective serotonin reuptake inhibitors have a high
potential to cause metabolically based drug interac-
tions because of their inhibitory effect on CYP activity
(Hemeryck and Belpaire, 2002; Nemeroff et al., 2007;
Spina et al., 2008). In vitro and in vivo evidence,
summarized by Hemeryck and Belpaire (2002),
Nemeroff et al. (2007), and Spina et al. (2008), shows
that SSRIs are not equivalent in their potency of
inhibition of various CYP isoenzymes (Table 1).
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 mark-
edly 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. Other
SSRIs, such as citalopram and escitalopram, appear
to have a more favorable drug interaction profile being
weak inhibitors of CYP2D6 and negligible inhibitors
of CYP1A2, CYP2C9, CYP2C19, and CYP3A4.
Concerning SNRIs, venlafaxine has minimal or no
effect on the activity of the different CYP isoforms,
but duloxetine is a moderate inhibitor of CYP2D6
(Nemeroff et al., 2007; Spina et al., 2008). Other
pharmacological agents used to treat anxiety disorders,
such as benzodiazepines, buspirone, and pregabalin,
do not significantly induce or inhibit CYP enzymes.
Pharmacokinetic drug interactions with antianxiety
medications may also involve drug transporters, in
particular P-gp. Like CYPs, the activity of P-gp can
be inhibited or induced by other agents, altering the
level of substrate drug in circulation. In vitro evidence
suggests that some SSRIs (paroxetine and sertraline)
may inhibit P-gp (Weiss et al., 2003). In theory, as
many substrates for P-gp, such as digoxin, cyclosporin,
and various chemotherapeutic agents, have a narrow
therapeutic range and are widely used in the elderly,
coadministration with these antidepressants may result
in adverse drug reactions.
Pharmacodynamic interactions
The potential for pharmacodynamic interactions
differs markedly between the various classes of
antianxiety medications, depending on the respective
mechanism of action and receptor profile. With regard
to this, benzodiazepines may have additive sedative
effects when combined with alcohol or other sedating
drugs, including antihistamines, anticonvulsants,
opioids, antidepressants, and antipsychotics.
Copyright © 2012 John Wiley & Sons, Ltd.
In general, SSRIs, SNRIs, buspirone, and pregabalin
have a low potential for pharmacodynamic drug interac-
tions. However, the combined use of SSRIs, SNRIs, or
buspirone with other serotonergic drugs (e.g., clomipra-
mine and other TCAs) may lead to excessive serotonergic
side effects. On the other hand, a severe serotonin
syndrome may occur when MAOIs are combined with
serotonin reuptake inhibitors as a consequence of an
excessive serotonergic agonism at both central and
peripheral serotonin receptors (Lane and Baldwin, 1997;
Boyer and Shannon, 2005; Gillman, 2006; Isbister
et al., 2007; Frank, 2008). The clinical manifestations of
the serotonin syndrome range from barely perceptible to
lethal and include (i) altered mental status (e.g., confusion
and agitation); (ii) autonomic hyperactivity (e.g., profuse
sweating, fever, and tachycardia); and (iii) neuromuscular
hyperactivity (e.g., tremor, hyperreflexia, myoclonus, and
rigidity). A large number of medications including SSRIs,
SNRIs, buspirone, MAOIs, TCAs, some analgesics (e.g.,
tramadol), drugs of abuse, triptans, and linezolid (an
antibiotic used to treat Gram-positive bacteria) have been
associated with the serotonin syndrome. These drugs
potentiate serotonergic neurotransmission via increased
serotonin synthesis, decreased serotonin metabolism,
increased serotonin release, inhibition of serotonin
reuptake, and/or direct agonism of serotonin receptors.
The condition may result from therapeutic drug use or
overdose of causative drugs or, more frequently, from
inadvertent combination of these drugs.
DRUG INTERACTIONS BETWEEN
ANTIANXIETY AND OTHER CNS DRUGS
(TABLE 2)
Interactions between antianxiety drugs
The combined use of different antianxiety drugs is
relatively common, especially in treatment-resistant
patients. In addition to pharmacodynamic additive
CNS effects, antianxiety medications may interact at
pharmacokinetic level (Ciraulo et al., 1995). Early
investigations in healthy volunteers have shown that
fluoxetine and fluvoxamine may impair the elimination
of diazepam and alprazolam, presumably by inhibition
of the major isoforms involved in their biotransforma-
tion, notably CYP2C19 (diazepam) and CYP3A4
(diazepam and alprazolam) (Lemberger et al., 1988;
Greenblatt et al., 1992; Fleishaker and Hulst, 1994;
Perucca et al., 1994). In a subsequent study in
Japanese psychiatric patients, coadministration of
fluvoxamine was associated with a significant, on
average 58%, increase in the plasma concentrations
of alprazolam (Suzuki et al., 2003). However, the
Hum. Psychopharmacol Clin Exp 2012; 27: 239–253.
DOI: 10.1002/hup
 antianxiety drug interactions 243
Table 2. Summary of clinically relevant drug interactions between antianxiety medications and CNS drugs

Antianxiety drug(s) CNS drug(s) Effect Possible mechanism References

Benzodiazepines Alcohol, antidepressants, Increased sedation Additive pharmacodynamic effect Ciraulo et al., 1995
antipsychotics and other
sedative agents
SSRIs MAOIs Possible occurrence of serotonin syndrome; Decreased serotonin reuptake Boyer and Shannon, 2005
SNRIs this drug combinations should be avoided in Gillman, 2006
clinical practice Isbister et al., 2007
Fluoxetine TCAs Increase of plasma concentrations of TCAs Inhibition of CYP2D6-mediated Bergstrom et al., 1992
Paroxetine (200–400%) with signs of toxicity (sedation, hydroxylation of TCAs Preskorn et al., 1994
dry mouth, and urinary retention) Alderman et al., 1997
Fluvoxamine TCAs Increase (up to four times) of plasma Inhibition of CYP2C19- and, Spina et al., 1992
concentrations of tertiary amines amitriptyline, to a lesser extent, CYP1A2- Hartter et al., 1993
imipramine, and clomipramine and possible and CYP3A4-mediated
signs of toxicity demethylation of TCAs
Fluoxetine Risperidone Increase of plasma risperidone concentrations Inhibition of CYP2D6 Spina et al., 2002
Paroxetine (45–75%) and possible occurrence of Bondolfi et al., 2002
extrapyramidal side effects Spina et al., 2001
Saito et al., 2005
Fluvoxamine Clozapine Increase of plasma clozapine concentrations Inhibition of CYP1A2 and, to Hiemke et al., 1994
(up to 5–10 times) and possible occurrence a lesser extent, CYP2C19 and Jerling et al., 1994
of dose-dependent side effects such as CYP3A4 Wetzel et al., 1998
sedation and seizures; this drug combination Szegedi et al., 1999
should be avoided in clinical practice Fabrazzo et al., 2000
Fluvoxamine Olanzapine Increase of plasma olanzapine concentrations Inhibition of CYP1A2 Hiemke et al., 2002
(100–200%) with possible occurrence of
adverse effects
Fluvoxamine Quetiapine Increase of plasma quetiapine concentrations Inhibition of CYP3A4 Castberg et al., 2007
(up to 159%)

SSRI, selective serotonin reuptake inhibitor; MAOI, monoamine oxidase inhibitor; SNRI, serotonin–noradrenaline reuptake inhibitor; TCA, tricyclic antidepressant.

clinical relevance of these interactions is probably
limited, as benzodiazepines have a relatively wide mar-
gin of safety. Conversely, studies in healthy volunteers
showed no evidence for a pharmacokinetic interaction
between paroxetine and alprazolam (Calvo et al.,
2004) or between sertraline and diazepam or alprazolam
(Gardner et al., 1997; Hassan et al., 2000).
Antidepressants
Concomitant intake of SSRIs or SNRIs with older
antidepressants may be therapeutically useful in patients
with anxiety and/or depressive disorders that are fully or
partly resistant to a single medication. Newer and
traditional antidepressants may interact both at the
pharmacokinetic and pharmacodynamic level (Gillman,
2006). The risk for a potentially fatal serotonin
syndrome when SSRIs or SNRIs are associated with
MAOIs or TCAs has been already addressed.
Various SSRIs may cause a remarkable elevation
of plasma levels of TCAs, through inhibition of the
major CYPs responsible for their metabolism, namely
CYP1A2, CYP2C19, CYP2D6, and CYP3A4 (Gillman,
2006; Spina et al., 2008). Pharmacokinetic studies in
depressed patients and in healthy volunteers have
shown that coadministration with therapeutic doses of
fluoxetine or paroxetine causes a twofold to fourfold
increase in plasma concentrations of TCAs, along with
signs of toxicity (Westermeyer, 1991; Bergstrom et al.,
1992; Preskorn et al., 1994; Alderman et al., 1997). This
effect has been attributed to the strong inhibitory effect
of fluoxetine (and norfluoxetine) and paroxetine on the
CYP2D6-mediated hydroxylation of TCAs. Sertraline,
a less powerful inhibitor of CYP2D6, may affect plasma
concentrations of TCAs only when given at dosages of
at least 150 mg/day (Preskorn et al., 1994; Alderman
et al., 1997). Differently from fluoxetine and paroxetine,
fluvoxamine affects predominantly the demethylation
pathways of TCAs, through inhibition of CYP2C19
and, to a lesser extent, CYP1A2 and CYP3A4.
Consistent with this, pharmacokinetic investigations in
patients or in healthy subjects have documented an
increase by up to fourfold in plasma concentrations of
amitriptyline, imipramine, and clomipramine, possibly
associated with signs of toxicity (Spina et al., 1992;
Hartter et al., 1993). If concomitant use of SSRIs and
TCAs is necessary, it is advisable not to use agents
causing extensive interactions such as fluvoxamine,
fluoxetine, or paroxetine.
Antipsychotics
Antipsychotics may be coadministered with antianxiety
drugs in patients with comorbid psychotic illness
and anxiety disorders. Antipsychotics, in particular

Copyright © 2012 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp 2012; 27: 239–253.
DOI: 10.1002/hup
244 m. r. muscatello ET AL.
second-generation compounds, may also be added to
antianxiety drugs to treat refractory OCD and refractory
GAD (Bandelow, 2008; Lorenz et al., 2010).
Fluoxetine (and its metabolite norfluoxetine) and
paroxetine are potent inhibitors of CYP2D6, the major
isoform responsible for the 9-hydroxylation of the
second-generation antipsychotic risperidone. As the
9-hydroxymetabolite is pharmacologically active and
equipotent to parent drug in terms of dopamine
receptor affinity, the term “active fraction” is used to
indicate the sum of the plasma concentrations of
risperidone and its metabolite. Pharmacokinetic
studies in patients with schizophrenia have documen-
ted the occurrence of clinically relevant interactions
between these two SSRIs and risperidone (Spina
et al., 2001, 2002; Bondolfi et al., 2002; Saito et al.,
2005). On the basis of this evidence, a reduction in
risperidone dosage is advisable in case of concomitant
administration of fluoxetine or paroxetine. Early
pharmacokinetic studies in patients with schizophrenia
indicated that fluoxetine, at the dose of 20 mg/day,
may increase plasma concentrations of clozapine by
approximately 40–70% (Centorrino et al., 1994;
Centorrino et al., 1996; Spina et al., 1998). These
kinetic changes may be attributed to the inhibitory
effect of fluoxetine on the activity of various
isoforms involved in the biotransformation of
clozapine, such as CYP2D6, CYP2C19, and CYP3A4.
The evidence for a metabolic interaction between
paroxetine and clozapine, whose biotransformation is
only in part mediated by CYP2D6, is controversial
(Centorrino et al., 1996; Wetzel et al., 1998; Spina
et al., 2000).
Fluvoxamine, a nonspecific inhibitor of various
CYP, may affect plasma concentrations of different
second-generation antipsychotics. Evidence from
formal kinetic studies and case reports have clearly
indicated that addition of fluvoxamine to ongoing
treatment with clozapine is associated with a 5-fold to
10-fold increase in plasma clozapine concentrations,
possibly leading to toxic effects, such as neurologic
(seizures) and gastrointestinal adverse effects (paralytic
ileus) (Hiemke et al., 1994; Jerling et al., 1994; Wetzel
et al., 1998; Szegedi et al., 1999; Fabrazzo et al.,
2000). The strong inhibitory effect of fluvoxamine on
the major CYP isoforms responsible for clozapine
metabolism, such as CYP1A2, CYP2C19, and
CYP3A4, is the more likely explanation for the
occurrence of this interaction (Olesen and Linnet,
2000). Because of the magnitude of this interaction,
clozapine and fluvoxamine should not be used in
combination. Pharmacokinetic investigations in patients
with schizophrenia have shown that fluvoxamine
Copyright © 2012 John Wiley & Sons, Ltd.
may cause a twofold elevation of plasma concentrations
of olanzapine, presumably through inhibition of
CYP1A2 (De Jong et al., 2001; Weigmann et al., 2001;
Hiemke et al., 2002). Data from a therapeutic drug
monitoring service show that serum concentrations of
quetiapine, which is primarily metabolized by CYP3A4,
are higher (by 159%; p < 0.001) in patients co-medicated
with fluvoxamine than in those on quetiapine monother-
apy (Castberg et al., 2007).
As documented by a number of pharmacokinetic
studies in patients with schizophrenia, coadministration
of sertraline or citalopram/escitalopram with newer
antipsychotics is less problematic (Centorrino et al.,
1996; Avenoso et al., 1998; Taylor et al., 1998; Spina
et al., 2000; Weigmann et al., 2001; Castberg et al.,
2007). Recent guidance about avoiding coadministra-
tion of citalopram with medications known to prolong
the QT interval on the electrocardiogram (thereby
including some antipsychotics) stems from concerns
about potentially additive adverse effects on cardiac
function (assessed by QT interval prolongation), rather
than from pharmacokinetic interactions (European
Medicines Agency, 2011).
Concerning pharmacokinetic interactions between
SNRIs and second-generation antipsychotics, venlafax-
ine was found not to affect significantly the pharmacoki-
netic parameters of risperidone and clozapine (Amchin
et al., 1999; Repo-Tiihonen et al., 2005). The potential
pharmacokinetic interaction between duloxetine and
second-generation antipsychotics was recently investi-
gated in outpatients stabilized on clozapine (n = 6),
olanzapine (n = 8), and risperidone (n = 7) (Santoro
et al., 2010). Duloxetine, 60 mg/day for up to 6 weeks,
did not modify the plasma concentrations of clozapine
and olanzapine, while it is 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
(Santoro et al., 2010). 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 or aripiprazole (Hendset
et al., 2010).
Pregabalin has a minimal potential for drug–drug
interactions. In agreement with this, augmentation with
pregabalin (225–600 mg/day) for 5 to 8 weeks was
associated with no changes in serum antipsychotic
concentrations in 11 schizophrenic patients on stable
therapy with second-generation antipsychotics (five
patients with olanzapine, five with clozapine, and one
with aripiprazole) (Englisch et al., 2010).
Hum. Psychopharmacol Clin Exp 2012; 27: 239–253.
DOI: 10.1002/hup
 antianxiety drug interactions
Antiepileptics and/or mood stabilizers
Antianxiety agents may be used in combination with
antiepileptics, in particular with those with mood-
stabilizing properties.
Data on the potential metabolic interaction between
the SSRIs fluoxetine and fluvoxamine and carbamaze-
pine are conflicting. While case reports have documen-
ted increased carbamazepine concentrations and
associated toxic effects (diplopia, blurred vision,
dizziness, and tremor) following coadministration of
fluoxetine (Pearson, 1990; Grimsley et al., 1991) or
fluvoxamine (Fritze et al., 1991; Bonnet et al., 1992),
no changes in steady-state carbamazepine levels were
observed in epileptic patients stabilized on carbamaze-
pine (800–1600 mg/day) after a 3-week coadministra-
tion with fluoxetine, 20 mg/day (eight subjects), or
with fluvoxamine, 100 mg/day (seven subjects) (Spina
et al., 1993). Case reports have indicated that concur-
rent use of fluoxetine and phenytoin can result in
significantly increased phenytoin serum levels leading
to toxicity (Jalil, 1992; Woods et al., 1994). The
moderate inhibitory effect of fluoxetine on the
CYP2C9-mediated biotransformation of phenytoin is
the more likely explanation for this interaction
(Shader et al., 1994). In a placebo-controlled crossover
study of 20 patients with epilepsy, addition of
paroxetine, 10–30 mg/day for 16 days, to ongoing
treatment with phenytoin, carbamazepine, or valproic
acid, caused no significant changes in plasma
concentrations of the anticonvulsants (Andersen
et al., 1991). Two randomized, double-blind, placebo-
controlled studies in healthy volunteers have shown
that sertraline, at a dose of 200 mg/day for 17 days, did
not affect the pharmacokinetics of carbamazepine
(400 mg/day; n = 14) and phenytoin (300 mg/day;
n = 30), substrates for CYP3A4 and CYP2C9, respec-
tively (Rapeport et al., 1996b, 1996c). In an open-label
investigation in 12 healthy volunteers, addition of
citalopram, 40 mg/day for 14 days, to carbamazepine,
administered at the dose of 400 mg/day for 35 days,
did not alter the steady-state pharmacokinetic para-
meters of carbamazepine and its active epoxide
metabolite (Moller et al., 2001).
While benzodiazepines do not influence the disposi-
tion of anticonvulsants, there is evidence that enzyme-
inducing antiepileptic drugs (e.g., carbamazepine,
phenobarbital, and phenytoin) may stimulate the
biotransformation of benzodiazepine compounds
metabolized by CYP3A4 (Spina and Perucca, 2002).
In this respect, carbamazepine has been reported to
increase the clearance and decrease plasma concentra-
tions of diazepam and alprazolam (Furukori et al.,
Copyright © 2012 John Wiley & Sons, Ltd.
245
1998; Spina and Perucca, 2002). Published studies in
healthy subjects have shown that valproate increased
the plasma concentrations of lorazepam and decreased
its clearance, most likely by impairing hepatic
glucuronidation (Samara et al., 1997; Chung et al.,
2008). Lorazepam dose may need to be decreased
when coadministered with valproate. In general, given
the wide therapeutic index of these agents, the clinical
significance of these interactions is presumably limited.
Brodie et al. (2005) investigated the potential
interaction between pregabalin and other antiepileptic
drugs in patients with partial epilepsy. Coadministra-
tion of pregabalin, 600 mg/day, for 7 days did not alter
steady-state concentrations of valproate (16 patients),
phenytoin (11 patients), lamotrigine (12 patients), or
carbamazepine (14 patients). These findings were
confirmed by a recent population pharmacokinetic
analysis showing that pregabalin did not affect
plasma concentrations of carbamazepine, lamotrigine,
phenobarbital, phenytoin, tiagabine, topiramate, and
valproate (Bockbrader et al., 2011).
Drugs for the treatment of dementia
Medications currently available for the treatment of
mild-to-moderate Alzheimer’s disease include the
cholinesterase inhibitors tacrine, donepezil, rivastigmine,
and galantamine.
Tacrine, the first cholinesterase inhibitor approved
by regulatory agencies but not available in many
European countries, is metabolized by CYP1A2. A
clinically relevant pharmacokinetic interaction has
been documented with fluvoxamine, a potent inhibitor
of CYP1A2. In a double-blind, randomized crossover
study in 13 healthy volunteers, the pharmacokinetics
of a single oral dose of tacrine (40 mg) were investigated
during coadministration of fluvoxamine (100 mg/day for
6 days) or placebo (Becquemont et al., 1997). Fluvoxa-
mine caused a significant increase ( p < 0.05) in the area
under the plasma concentrations versus time curve
(AUC) of tacrine and its three monohydroxylated
metabolites as compared with placebo. Five subjects
experienced gastrointestinal adverse effects during
fluvoxamine administration.
While rivastigmine is metabolized by sulfate
conjugation rather than CYP enzymes, donepezil and
galantamine are metabolized by CYP2D6 and CYP3A4.
Therefore, in theory, coadministration of antianxiety
agents such as fluoxetine and paroxetine, inhibitors of
CYP2D6 and CYP3A4, with donepezil or galantamine
may decrease their elimination with a risk of gastrointes-
tinal, cardiovascular, and neurological adverse effects.
Consistent with this, a report has described two
elderly patients treated with paroxetine, at a dosage of
Hum. Psychopharmacol Clin Exp 2012; 27: 239–253.
DOI: 10.1002/hup
246
20 mg/day, who developed gastrointestinal adverse
effects (severe diarrhea), insomnia, agitation, confusion,
and aggression after they received concomitant
donepezil, 5 mg/day (Carrier, 1999). On the other hand,
there is no evidence of a reciprocal metabolic interaction
between sertraline and donepezil, as documented in an
open-label, three-period crossover pharmacokinetic
study in 19 healthy volunteers, coadministered sertraline
(100 mg/day) and donepezil (5 mg/day) for 15 days
(Nagy et al., 2004).
DRUG INTERACTIONS BETWEEN
ANTIANXIETY AND NON-CNS DRUGS
(TABLE 3)
Anti-inflammatory drugs
Over the past decade, case reports and epidemiological
studies have indicated quite convincingly that the use
of SSRIs is associated with a twofold increased risk of
upper gastrointestinal bleeding (Dalton et al., 2006). A
similar risk has been documented to occur also with
venlafaxine (De Abajo and Garcia-Rodriguez, 2008;
Opatrny et al., 2008). The prevention of serotonin
uptake from circulation into platelets induced by SSRIs,
leading to reduced platelet aggregation and prolonged
bleeding time, may be the underlying biological
mechanism for this effect. Patients at particular risk of
m. r. muscatello ET AL.
gastrointestinal bleeding include elderly persons and
subjects receiving other medications that increase the
risk, such as nonsteroidal anti-inflammatory drugs
(NSAIDs), corticosteroids, oral anticoagulants, and
antiplatelet drugs (including low-dose aspirin) (Dalton
et al., 2006). Current research indicates that an SSRI–
NSAID combination increases the risk of gastrointes-
tinal bleeding on the order of 3–15-fold (De Abajo
et al., 1999; Dalton et al., 2003; Tata et al., 2005). A
population-based case–control study reported an in-
creased incidence of upper gastrointestinal bleeding with
SSRIs, although this effect was not found to be modified
by age, sex, dose, or treatment duration (De Abajo et al.,
1999). The effect, however, was enhanced by the concur-
rent use of NSAIDs with a relative risk (RR) of 15.6 (95%
CI, 6.6–36.6), as well as with aspirin, but to a lesser
degree (RR = 7.2; 95% CI, 3.1–17.1). A large cohort
study of antidepressant use in a Danish county found that
the risk of upper gastrointestinal bleeding was higher with
SSRIs compared with non-SSRIs and other antidepres-
sants (Dalton et al., 2003). Concomitant use of aspirin
and NSAIDs further increased the risk by 12.2 and 5.2
times, respectively. Tata et al. (2005) investigated the risk
of gastrointestinal bleeding under SSRI and NSAID
therapy. This study indicated that both classes of drugs
were associated with a twofold risk for gastrointestinal
bleeding per se. In particular, the odds ratio (OR) for
SSRIs was 2.38 (95% CI 2.08–2.72) and for NSAIDs

Table 3. Summary of clinically relevant drug interactions between antianxiety medications and non-CNS drugs

Antianxiety drug(s) Non-CNS drug(s) Effect Possible mechanism References

SSRIs NSAIDs An SSRI–NSAID combination increases Inhibition of serotonin uptake from De Abajo et al., 1999
the risk of gastrointestinal bleeding on circulation into platelets Dalton et al., 2003
the order of 3–15-fold Tata et al., 2005
Fluoxetine Warfarin Increase of the active S-enantiomer of Inhibition of CYP2C9 Duncan et al., 1998
Fluvoxamine warfarin with increased risk of bleeding; Sayal et al., 2000
monitoring of the INR may be necessary
Fluoxetine Propranolol, Increased plasma concentration of beta Inhibition of CYP2D6 Walley et al., 1993
metoprolol blockers and possible occurrence of Drake and Gordon, 1994
severe bradycardia
Paroxetine Metoprolol Increase of metoprolol concentrations Inhibition of CYP2D6 Hemeryck et al., 2000
(up to four times) ad possible occurrence Goryachkina et al., 2008
of bradycardia and orthostatic hypotension
Fluvoxamine Propranolol Increase of propranolol concentrations Inhibition of CYP1A2 and CYP2C19 Spina et al., 2008
(up to five times) with a slight reduction
in heart rate and blood pressure
Fluvoxamine Theophylline Increase of theophylline concentrations Inhibition of CYP1A2 Van den Brekel and
with possible occurrence of adverse Harringtol, 1994
effects; this drug combination should Devane et al., 1997
be avoided in clinical practice
Fluoxetine Tamoxifen Decrease in plasma concentrations of Inhibition of the CYP2D6-mediated Stearns et al. (2003)
Paroxetine endoxifen and reduced clinical benefit formation of active metabolites Jin et al. (2005)
of tamoxifen; this drug combinations of tamoxifen Borges et al. (2006)
should be avoided in clinical practice

SSRI, selective serotonin reuptake inhibitor; NSAID, nonsteroidal anti-inflammatory drug; INR, international normalized ratio.

Copyright © 2012 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp 2012; 27: 239–253.
DOI: 10.1002/hup
 antianxiety drug interactions
2.15 (95% CI 2.02–2.28). The bleeding risk was just
slightly increased by concurrent intake of SSRIs and
NSAIDs (OR 2.83; 95% CI 2.39–3.34).
While the issue of the increased incidence of gastro-
intestinal bleeding associated with an SSRI–NSAID
combination deserves further investigation, clinicians
should be aware of this risk. Strategies to be adopted
to reduce the likelihood of hemorrhagic events include
alternatives to SSRIs, prescription of NSAIDs with a
lower gastrointestinal risk profile (such as ibuprofen),
and concomitant use of proton pump inhibitors (Dalton
et al., 2006; De Abajo et al., 2006; Mort et al., 2006;
Loke et al., 2008).
Cardiovascular drugs
Oral anticoagulants. Case reports and literature
reviews have suggested that SSRIs, in particular
fluvoxamine and fluoxetine, may interact with the oral
anticoagulant warfarin to cause bleeding (Woolfrey
et al., 1993; Dent and Orrock, 1997; Duncan et al.,
1998; Yap and Low, 1999; Sayal et al., 2000; Limke
et al., 2002). SSRIs may increase the risk of hemorrhage
during warfarin treatment by two mechanisms: first,
SSRIs may reduce platelet aggregation by depleting
platelet serotonin levels, directly increasing the risk of
bleeding, as already mentioned (Dalton et al., 2006),
and second, some SSRIs, particularly fluvoxamine and
fluoxetine, may inhibit the CYP2C9-mediated oxidative
metabolism of the more biologically active (S)-enantiomer
of warfarin (Duncan et al., 1998; Sayal et al., 2000).
Pharmacoepidemiological studies have evaluated the
risk of bleeding associated with the use of SSRIs in
warfarin-treated patients. A population-based, case–
control study found no evidence of a significant risk of
hospitalization for upper gastrointestinal bleeding in
elderly patients taking warfarin who had recently started
a treatment with various antidepressants, including
fluoxetine and fluvoxamine (Kurdyak et al., 2005).
Wallerstedt et al. (2009) performed a cohort study in
patients treated with warfarin for atrial fibrillation.
Warfarinized patients concomitantly treated with SSRIs
had a higher risk of bleeding than patients treated with
warfarin alone. The Cox regression analysis revealed an
adjusted hazard ratio of 3.49 (1.37–8.91) for first bleeding
during treatment with a combination of SSRIs and
warfarin, compared with treatment with warfarin only.
In a study based on the medical records of 6772
warfarin-treated hospitalized patients, SSRIs (citalopram
and fluoxetine being the most prescribed) were associated
with a significantly higher bleeding risk than with non-
SSRIs (mirtazapine being the most prescribed) (OR 2.6,
95% CI 1.5–4.3, and OR 1.2, 95% CI 0.3–4.3, respec-
tively) (Hauta-Aho et al., 2009).
Copyright © 2012 John Wiley & Sons, Ltd.
247
Two case reports have suggested an interaction be-
tween the SNRI duloxetine and oral anticoagulants,
leading to unexpected changes in the international
normalized ratio (Glueck et al., 2006; Monastero et al.,
2007). These findings were not confirmed by a subse-
quent study showing that duloxetine, 60 mg/day or
120 mg/day for 14 days, did not influence the pharmaco-
dynamics and pharmacokinetics of once-daily dosing
of warfarin in healthy subjects who had a stable INR
with an individualized fixed dose of warfarin (2–9 mg)
(Chappell et al., 2009).
Beta blockers. Beta blockers are extensively metabo-
lized in the liver by CYP isoforms: metoprolol,
carvedilol, and timolol are predominantly oxidized
via CYP2D6, while propranolol biotransformation is
mainly mediated by CYP1A2 and CYP2C19, with
CYP2D6 playing only a marginal role (Cozza et al.,
2003). Coadministration of fluoxetine or paroxetine,
potent inhibitors of CYP2D6, with metoprolol,
propranolol, or carvedilol has occasionally resulted in
serious adverse events such as severe bradycardia or
complete atrioventricular block (Walley et al., 1993;
Drake and Gordon, 1994; Pae et al., 2003; Onalan
et al., 2008). Formal pharmacokinetic and pharmaco-
dynamic investigations in healthy volunteers and in
patients have examined the possibility of an interaction
between SSRIs or duloxetine and beta blockers.
The effect of paroxetine, 20 mg/day for 6 days, on
the pharmacokinetics and pharmacodynamics of a
single 100 mg oral dose of metoprolol was investigated
in healthy volunteers (Hemeryck et al., 2000). Paroxe-
tine treatment caused a statistically significant increase
( p < 0.001) in the AUC of both (R)-metoprolol and
(S)-metoprolol, with an associated decrease in exercise
heart rate. A pharmacokinetic investigation in 17
patients with acute myocardial infarction who received
metoprolol (mean dose 75 mg/day) as a routine part of
their therapy documented a statistically significant
fourfold increase ( p < 0.001) in the AUC of metoprolol
following coadministration with paroxetine (Goryachkina
et al., 2008). A reduction of metoprolol dosage was
needed in two patients, because of excessive bradycardia
and severe orthostatic hypotension. The pharmacokinet-
ics of a single 100-mg dose of metoprolol was
investigated before and after 17 days of treatment with
escitalopram 20 mg/day, duloxetine 60 mg/day, or
sertraline 100 mg/day in 16 healthy volunteers
(Preskorn et al., 2007). The addition of each drug resulted
in statistically significant changes in metoprolol
pharmacokinetics. The rank order for the change in
metoprolol AUC was duloxetine (180%) > escitalopram
(89%) > sertraline (67%). Duloxetine effects on the
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DOI: 10.1002/hup
248 m. r. muscatello ET AL.
pharmacokinetics of metoprolol were significantly greater
than those observed in the same study with escitalopram
and sertraline. The inhibitory effects of these medications
were considerably less than those produced by either
fluoxetine or paroxetine at their lowest recommended
antidepressant doses (i.e., 400–600%). In a randomized,
double-blind, placebo-controlled study, administration
of fluoxetine, 20 mg/day for 28 days, to 10 patients main-
tained on a carvedilol dose of 25 or 50 mg twice a day
resulted in a stereospecific inhibition in carvedilol metab-
olism without significantly affecting blood pressure, heart
rate, or heart rate variability (Graff et al., 2001). On the
basis of these findings, caution is warranted, and reduc-
tion of the dose of beta blockers may be required in case
of coadministration with potent CYP2D6 inhibitors, such
as fluoxetine and paroxetine. Alternatively, switching to
another beta-blocker such as atenolol, which is not metab-
olized by CYP2D6, should be considered.
A potentially relevant pharmacokinetic interaction
has been reported to occur between fluvoxamine and
propranolol. In healthy volunteers, concomitant intake
of fluvoxamine (100 mg/day) with propranolol
(160 mg/day) resulted in a mean fivefold increase in
plasma propranolol concentrations, associated with a
slight reduction in heart rate and blood pressure (Spina
et al., 2008). This effect is presumably because of the
inhibitory effect of fluvoxamine on CYP1A2 and
CYP2C19, the major isoforms involved in the bio-
transformation of this beta-blocker.
Digoxin. Isolated case reports have described a
remarkable elevation of serum digoxin concentrations
along with signs of toxicity in elderly patients after
coadministration of fluoxetine (Leibovitz et al., 1998)
or paroxetine (Yasui-Furukori and Kaneko, 2006).
This interaction has been attributed to inhibition of
P-gp by these two SSRIs. However, a population-
based case–control study conducted in elderly patients
found no evidence of an increased risk of digoxin
toxicity associated with SSRIs, suggesting that this
mechanism is unlikely to be of major clinical signifi-
cance (Juurlink et al., 2005). An earlier investigation
in 20 healthy male volunteers documented no changes
in plasma concentrations and renal clearance of digoxin
after oral administration of sertraline (Rapeport et al.,
1996a).
Anticancer drugs
Anxiety and depressive symptoms frequently occur in
patients with cancer. A growing number of studies
has documented a potentially clinically relevant
interaction between SSRIs, in particular paroxetine,
and tamoxifen, a selective estrogen receptor modulator
Copyright © 2012 John Wiley & Sons, Ltd.
used in the treatment and prophylaxis of breast
cancer (Desmerais and Looper, 2009; Breitbart,
2011). Tamoxifen is a “prodrug” that is primarily
metabolized in the liver by the CYP system to the
active metabolites 4-hydroxytamoxifen and 4-hydroxy-
N-desmethyltamoxifen (endoxifen) (Desta et al.,
2004). The two metabolites are pharmacologically
equipotent with an affinity for estrogen receptors that
is 100-fold higher than the parent compound. However,
endoxifen is considered the most important metabolite
as it is present in plasma at concentrations 5–10 times
higher than those of 4-hydroxytamoxifen. The poly-
morphic CYP2D6 is one the key enzymes involved in
the conversion of tamoxifen to endoxifen. Several lines
of evidence have indicated that women with breast
cancer, poor metabolizers of CYP2D6, have very low
plasma endoxifen concentrations and a nonfavorable
clinical outcome (Goetz et al., 2007; Scroth et al.,
2009). Therefore, it can be postulated that the use of
potent inhibitors of CYP2D6, such as fluoxetine and
paroxetine, in patients on tamoxifen therapy may reduce
its clinical benefit by decreasing the formation of
the active metabolite. Patients with breast cancer
often undergo psychotropic drug treatment for co-
morbid depression or anxiety disorders. In addition,
clinical trials have documented that SSRIs, SNRIs, and
pregabalin may be beneficial in the management of hot
flashes, a frequent complication of tamoxifen treatment
(Carroll and Kelley, 2009; Loprinzi et al., 2010).
In a preliminary prospective study, 12 women treated
with tamoxifen, 20 mg/day, have been shown to have
statistically significant decreases ( p < 0.01) in endoxifen
concentrations after 4 weeks of paroxetine coadminis-
tration at a dose of 10 mg/day (Stearns et al., 2003). A
further investigation in women with breast cancer con-
comitantly treated with tamoxifen and CYP inhibitors
found that plasma endoxifen concentrations were
slightly reduced in women taking venlafaxine, a weak
inhibitor of CYP2D6, were moderately decreased in
patients receiving sertraline, a weak to moderate inhibi-
tor of CYP2D6, and were substantially reduced in
women treated with paroxetine, a potent inhibitor of
CYP2D6 (Jin et al., 2005). Similar results were reported
in an observational study of 158 women with breast
cancer treated with tamoxifen, showing that coadminis-
tration with potent inhibitors of CYP2D6, such as
paroxetine and fluoxetine, significantly decreased mean
plasma endoxifen concentrations, and concomitant treat-
ment with weak inhibitors of CYP2D6, such as sertraline
and citalopram, was associated with a slight reduction of
the metabolite concentrations, while addition of venla-
faxine did not modify plasma endoxifen concentrations
(Borges et al., 2006).
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DOI: 10.1002/hup
 antianxiety drug interactions
The impact of treatment with SSRIs and SNRIs on
breast cancer recurrence and mortality in women
taking tamoxifen has been addressed by a number of
pharmacoepidemiological studies that yielded mixed
findings. Most investigations found no association
between the use of these medications and the risk of
recurrence (Lehmann et al., 2004; Chubak et al., 2008;
Lash et al., 2008, 2010, 2011; Ahern et al., 2009;
Dezentjé et al., 2010). However, in some studies, the
number of observations was too small to reach signifi-
cance (Lehmann et al., 2004; Chubak et al., 2008),
whereas in others, the majority of exposed cases were
treated with antidepressants, which are weak CYP2D6
inhibitors or noninhibitors (citalopram, escitalopram,
and venlafaxine) (Lash et al., 2008, 2010, 2011; Ahern
et al., 2009). However, a recent retrospective cohort
study, based on a large cancer registry and other health-
care data in Ontario, documented that elderly patients
who received paroxetine in combination with tamoxifen
were at increased risk for death from breast cancer
(Kelly et al., 2010). In particular, absolute increases of
25%, 50%, and 75% in the proportion of time on tamox-
ifen with overlapping use of paroxetine were associated
with 24%, 54%, and 91% relative increases in the risk of
death from breast cancer, respectively ( p < 0.05 for each
comparison). Conversely, no increased risk of breast
cancer mortality was associated with exposure to the
other SSRIs during tamoxifen treatment. These findings
support a hypothesis that paroxetine may reduce or
abolish the benefit of tamoxifen in women with breast
cancer, presumably by inhibiting its CYP2D6-mediated
bioactivation.
In conclusion, it is well established that fluoxetine and
paroxetine can reduce plasma concentrations of endoxi-
fen in women with breast cancer treated with tamoxifen.
Whether decreased levels of endoxifen result in an in-
creased risk of breast cancer recurrence or mortality is
yet to be clarified. However, it seems reasonable to
avoid the use of paroxetine and fluoxetine in women
taking tamoxifen for the treatment or prevention of
recurrence of breast cancer, while moderate (sertraline
and duloxetine) and milder CYP2D6 inhibitors
(citalopram and escitalopram) or noninhibitors
(venlafaxine and pregabalin) represent safer choices.
Others
Many other interactions have been described to occur
between antianxiety medications and non-CNS drugs.
A number of case reports have documented that
concomitant treatment with fluvoxamine may cause a
marked elevation in plasma theophylline levels
associated with signs of theophylline toxicity,
including ventricular tachycardia, anorexia, nausea,
Copyright © 2012 John Wiley & Sons, Ltd.
249
and seizures (Van den Brekel and Harringtol, 1994;
Devane et al., 1997). An explanation for this interac-
tion lies in the potent inhibitory effect of fluvoxamine
on CYP1A2, which is the main isoenzyme involved
in theophylline metabolism. As theophylline toxicity is
a serious, sometimes fatal, medical condition, fluvoxa-
mine should be avoided in patients taking theophylline.
In a formal kinetic study in healthy volunteers, concom-
itant intake of fluoxetine, 20 mg/day for 10 days,
decreased the oral clearance of both S-enantiomer and
R-enantiomer of propafenone, an antiarrhythmic agent
metabolized by CYP2D6, given as a single oral dose
of 400 mg, from approximately 75 to 50 L/h ( p < 0.01)
and from 107 to 70 L/h ( p < 0.05), respectively (Cai
et al., 1999). Anecdotal reports have shown that
coadministration of fluoxetine with the calcium channel
blockers nifedipine and verapamil may be associated
with signs of toxicity such as edema, nausea, and flush-
ing, which disappeared when dosage of the calcium
channel antagonists was reduced (Sternbach, 1991). In-
hibition of CYP3A4-mediated metabolism of verapamil
and nifedipine by fluoxetine and its metabolite norfluox-
etine may explain the occurrence of this interaction.
CONCLUSIONS
The issue of drug interactions with medications used in
the treatment of anxiety disorders is of great clinical
concern, given the increasing number of prescriptions
for these compounds in the general population,
particularly in elderly individuals. However, the risk
of harmful drug interactions may be anticipated and
reduced. Whenever possible, they may be prevented
by avoiding the unnecessary use of polypharmacy
and by selecting comedications that are less likely to
interact. Most combinations of antianxiety drugs are
not supported by evidence from randomized controlled
studies. Knowledge of the interaction potential of each
individual drug used to treat anxiety disorders 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 avoided, adverse clinical conse-
quences may be minimized, as appropriate, by individ-
ualized dose adjustments guided by careful monitoring
of clinical response and, possibly, plasma drug con-
centrations monitoring.
CONFLICT OF INTEREST
Dr. Muscatello has no conflicts of interest to declare.
Prof. Spina has previously received honoraria for
speaking and consultation from AstraZeneca,
Hum. Psychopharmacol Clin Exp 2012; 27: 239–253.
DOI: 10.1002/hup
250 m. r. muscatello ET AL.
Boheringer-Ingelheim, Eli Lilly, Janssen, Lundbeck,
and Pfizer. Prof. Bandelow has been a consultant
for, received grant/research support from, and been
on the speakers/advisory board for AstraZeneca,
Bristol-Myers-Squibb, Glaxo-SmithKline, Merck, Lilly,
Lundbeck, Ono Pharma, and Pfizer. Prof. Baldwin has
acted as a consultant to Asahi, AstraZeneca, Cephalon,
Eli Lilly, GSK, Grunenthal, Lundbeck, Organon,
Pharmacia, Pierre Fabre, Pfizer, Roche, Servier,
Sumitomo, and Wyeth and holds or has held research
grants (on behalf of his employer) from Cephalon, Eli
Lilly, GSK, Lundbeck, Organon, Pfizer, Pharmacia,
Roche, and Wyeth.
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