DRUG INTERACTIONS Clin. Pharmacokinet.

1997 Dec; 33 (6): 454-471

0312-5963/97/0012-0454/$09.00/0

© Adis International Limited. All rights reserved.

Selective Serotonin Reuptake

Inhibitors and CNS Drug Interactions
A Critical Review of the Evidence
Beth A. Sproule,1,2,3 Claudio A. Naranjo,1,3,4,5 Karen E. Bremner1,4 and Paul C. Hassan1
1 Psychopharmacology Research Program, Sunnybrook Health Science Centre, Toronto,
Ontario, Canada
2 Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
3 Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
4 Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
5 Department of Medicine, University of Toronto, Toronto, Ontario, Canada

Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
1. Cytochromes P450 and Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
2. Selective Serotonin Reuptake Inhibitors (SSRIs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459
3. SSRI-Antipsychotic Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460
3.1 Citalopram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460
3.2 Fluoxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460
3.3 Fluvoxamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
3.4 Paroxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
3.5 Sertraline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
3.6 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
4. SSRI-Tricyclic Antidepressant Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
4.1 Citalopram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
4.2 Fluoxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
4.3 Fluvoxamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
4.4 Paroxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
4.5 Sertraline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
4.6 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
5. SSRI-Benzodiazepine Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
5.1 Citalopram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
5.2 Fluoxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
5.3 Fluvoxamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
5.4 Paroxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
5.5 Sertraline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
5.6 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
6. SSRI-Mood Stabilisers Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
6.1 Citalopram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
6.2 Fluoxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
6.3 Fluvoxamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
6.4 Paroxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
6.5 Sertraline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
6.6 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
7. SSRIs With Other CNS Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
SSRIs and CNS Drug Interactions 455

8. Clinical Management of SSRI-CNS Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . 468

9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468

Summary The potential for drug-drug interactions in psychiatric patients is very high as
combination psychopharmacotherapy is used to treat comorbid psychiatric dis-
orders, to treat the adverse effects of a medication, to augment a medication effect
or to treat concomitant medical illnesses. Interactions can be pharmacodynamic
or pharmacokinetic in nature. This paper focuses on the metabolic kinetic inter-
actions between selective serotonin reuptake inhibitors (SSRIs) and other central
nervous system (CNS) drugs. The evidence for and clinical significance of these
interactions are reviewed, with special emphasis on antipsychotics, tricyclic anti-
depressants and benzodiazepines.
Many psychotropic medications have an affinity for the cytochrome P450
(CYP) enzymes which promote elimination by transforming lipid soluble sub-
stances into more polar compounds. SSRIs serve both as substrates and inhibitors
of these enzymes. In vitro studies provide a screening method for evaluating drug
affinities for substrates, inhibitors or inducers of CYP enzymes. Although in vitro
data are important as a starting point for predicting these metabolic kinetic drug
interactions, case reports and controlled experimental studies in humans are re-
quired to fully evaluate their clinical significance. Several factors must be con-
sidered when evaluating the clinical significance of a potential interaction
including: (a) the nature of each drugs’ activity at an enzyme site (substrate,
inhibitor or inducer); (b) the potency estimations for the inhibitor/inducer; (c) the
concentration of the inhibitor/inducer at the enzyme site; (d) the saturability of
the enzyme; (e) the extent of metabolism of the substrate through this enzyme
(versus alternative metabolic routes); (f) the presence of active metabolites of the
substrate; (g) the therapeutic window of the substrate; (h) the inherent enzyme
activity of the individual, phenotyping/genotyping information; (i) the level of
risk of the individual experiencing adverse effects (e.g. the elderly) and (j) from
an epidemiological perspective, the probability of concurrent use.
This paper systematically reviews both the in vitro and in vivo evidence for
drug interactions between SSRIs and other CNS drugs. As potent inhibitors of
CYP2D6, both paroxetine and fluoxetine have the potential to increase the plasma
concentrations of antipsychotic medications metabolised through this enzyme,
including perphenazine, haloperidol, thioridazine and risperidone in patients who
are CYP2D6 extensive metabolisers. Controlled studies have demonstrated this
for perphenazine with paroxetine and haloperidol with fluoxetine. Fluvoxamine,
as a potent inhibitor of CYP1A2, can inhibit the metabolism of clozapine, result-
ing in higher plasma concentrations.
Drug interactions between the SSRIs and tricyclic antidepressants (TCAs) can
occur. Fluoxetine and paroxetine, as potent inhibitors of CYP2D6, can increase
the plasma concentrations of secondary and tertiary tricyclic antidepressants.
Sertraline and citalopram are less likely to have this effect. Fluvoxamine can
increase the plasma concentrations of tertiary TCAs.
Fluvoxamine inhibits, via CYP3A, CYP2C19 and CYP1A2, the metabolism
of several benzodiazepines, including alprazolam, bromazepam and diazepam.
Fluoxetine increases the plasma concentrations of alprazolam and diazepam by
inhibiting CYP3A and CYP2C19, respectively. The clinical importance of the

© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 1997 Dec; 33 (6)
456 Sproule et al.

interaction with diazepam is attenuated by the presence of its active metabolite.

Sertraline inhibits these enzymes only mildly to moderately at usual therapeutic
doses. Therefore the potential for interactions is less; however, the in vivo evi-
dence is minimal. Paroxetine and citalopram are unlikely to cause interactions
with benzodiazepines.
The evidence is conflicting for an interaction between carbamazepine and the
SSRIs fluoxetine and fluvoxamine. These combinations should be used cautious-
ly, and be accompanied by monitoring for adverse events and carbamazepine
plasma concentrations. A lack of interaction between paroxetine or sertraline and
carbamazepine has been documented.
The SSRIs are not equivalent in their potential for drug interactions when
combined with other CNS medications. Each combination must be assessed in-
dividually. Several factors must be considered when predicting the outcome of a
potential interaction based on in vitro data (e.g. active metabolites and concen-
tration ranges). In vivo studies are required to evaluate their clinical significance.
Generally, sertraline and citalopram at the lower therapeutic dosage range appear
to have less propensity for interactions. Anticipated pharmacokinetic interactions
can usually be managed with careful monitoring and appropriate adjustments in
dosage and titration.

Psychiatric patients usually take more than one
medication. Combination psychopharmacotherapy
is used to treat comorbid psychiatric disorders (e.g.
schizophrenia and depression), to treat the adverse
effects of a medication (e.g. a neuroleptic and anti-
Parkinsonian agents), to augment a medication
effect (e.g. lithium augmentation of a tricyclic anti-
depressant) or to treat concomitant medical
illnesses. Comorbid psychiatric disorders are also
common in patients with substance use disor-
ders.[1] In addition, 2 or more drugs may be present
in the body when a patient is switched from one
medication to another without an adequate wash-
out period.[2] Therefore, the potential for drug-drug
interactions in psychiatric patients is very high.
Drug interactions can be pharmacokinetic or
pharmacodynamic in nature. Pharmacodynamic
interactions occur at biologically active sites (i.e.
receptors) and change the pharmacological activity
of a drug without necessarily altering the kinetics
of either agent. In contrast, in a pharmacokinetic
interaction, one drug specifically affects the
plasma concentration of another drug by altering
its kinetics (absorption, distribution, metabolism
or excretion).[2]
Currently, 5 selective serotonin reuptake inhib-
itors (SSRIs) are available worldwide: citalopram,
fluoxetine, fluvoxamine, paroxetine and sertraline.
They were developed as antidepressants, with the
goal of producing a medication which would spe-
cifically inhibit the neuronal uptake pump for se-
rotonin with little effect on other neurotransmit-
ters, such as histamine and acetylcholine.[3] To this
extent they have a different, and generally better
tolerated, adverse effect profile from the tricyclic
antidepressants (TCAs), with equivalent anti-
depressant efficacy.[4] Additionally, some SSRIs
are indicated for obsessive-compulsive, panic and
anxiety disorders.[5] Therefore, SSRIs are currently
widely prescribed medications.
In this paper, the mechanisms of metabolic ki-
netic interactions between SSRIs and other central
nervous system (CNS) drugs, as well as the evi-
dence for and clinical significance of these interac-
tions will be reviewed, with special emphasis on
antipsychotics, TCAs and benzodiazepines.
1. Cytochromes P450 and
Drug Interactions
Many psychotropic medications have an affin-

© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 1997 Dec; 33 (6)
SSRIs and CNS Drug Interactions 457

Table I. Features of selected cytochromes P450 (CYP)[8-13]

Feature CYP2D6 CYP1A2 CYP3A CYP2C19
General features Polymorphic: Caucasians Widely studied in Broad substrate specificity Polymorphic: Caucasians
5 to 10% PM; Orientals 1% carcinogen activation; with 10- to 40-fold variation <5% PM; Orientals and
PM; small proportion of EM trimodal polymorphism: in activity in individuals; also Blacks 20% PM
are very rapid metabolisers; 12 to 13% PM active in intestine;
saturable polymorphism not
demonstrated
In vitro test Dextromethorphan, Phenacetin O-deethylation Alprazolam α and S-mephenytoin,
reactions examples O-demethylation, 4-hydroxylation, erythromycin 4′-hydroxylation
debrisoquine N-demethylation
4-hydroxylation,
sparteine oxidation
In vivo Dextromethorphan, Caffeine, phenacetin Erythromycin Mephenytoin, omeprazole
phenotyping probe debrisoquine, sparteine
drugs

Substrate examples
CNS drugs Paroxetine, fluoxetine,
haloperidol, thioridazine,
perphenazine, clozapine,
risperidone, desipramine,
nortriptyline, clomipramine,
amitriptyline, codeine
Others Propranolol, timolol,
propafenone, encainide,
mexiletine
Clozapine, diazepam, Sertraline, carbamazepine, Citalopram, diazepam
imipramine, desipramine, triazolam, midazolam,
amitriptyline, clomipramine alprazolam
Acetaminophen, tacrine, Terfenadine, astemizole, Omeprazole, lansoprazole
theophylline, caffeine erythromycin,
dihydropyridines, cyclosporin,
testosterone, estradiol

Inhibitor examples
Potent Paroxetine, fluoxetine, Fluvoxamine, cimetidine Ketoconazole, erythromycin Ketoconazole, omeprazole
quinidine
Moderate Fluvoxamine Fluvoxamine, fluoxetine
Weak Sertraline, citalopram Sertraline, fluoxetine Sertraline, paroxetine?

Inducer examples
Polycyclic aromatic Barbiturates, Rifampicin
compounds (smoking), dexamethasone,
phenytoin, omeprazole rifampicin (rifampin),
phenytoin, carbamazepine
Abbreviations: EM = extensive metabolisers; PM = poor metabolisers.

ity for the drug metabolising oxidative enzymes
known as the cytochromes P450 (CYP) since their
purpose is to promote elimination by transforming
lipid soluble substances into more polar com-
pounds. Medications may be substrates for the
enzymes and/or they may alter the activity of the
enzyme through inhibition or induction. It is these
actions which originate the potential for CYP
mediated drug interactions amongst SSRIs and
other CNS drugs.
Detailed reviews of CYP enzyme function and
nomenclature are available.[6] CYP enzymes are
named using the root CYP followed by a number
representing the family, a letter for the subfamily
and a number for the individual enzyme. The fam-
ilies primarily involved in drug metabolism are
CYP1, CYP2 and CYP3.[7] This paper focuses in
particular on CYP1A2, CYP2C19, CYP2D6 and
the CYP3A subfamilies of enzymes, usually re-
ferred to as isozymes, which have been shown to
be important in the metabolism of psychotropic
medications (table 1).
The activity of these enzymes varies amongst
individuals and ethnic groups. A number of genes

© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 1997 Dec; 33 (6)
458
coding for CYP enzymes have variant alleles re-
sulting from mutation. The existence of these al-
leles in at least 1% of the population is referred to
as genetic polymorphism.[12] Specific gene muta-
tions (i.e. genotypes) can be identified through
DNA analysis. Genetic polymorphisms may result
in the formation of enzymes that are functionally,
normal, abnormal or inactive.
The activity of CYP enzymes can be evaluated
through both in vitro and in vivo techniques. In
vitro studies provide a screening method for eval-
uating drug affinities as substrates, inhibitors or in-
ducers of CYP enzymes. For example, one tech-
nique uses human liver microsomes incubated
under physiological conditions. The inhibitory po-
tential of a drug may be determined by evaluating
its effect on a known drug metabolic reaction
which has been established for a specific en-
zyme.[13]
The activity of CYP enzymes can be measured
in vivo through the use of standardised phenotyp-
ing procedures. Phenotyping involves administer-
ing a probe drug to an individual, collecting and
analysing blood or urine samples and calculating
an index of enzyme activity based on the ratio of
parent drug to the metabolites biotransformed by
the specific isozyme. Standardised procedures
have been validated for particular enzymes includ-
ing the choice of probe drug, dose regimen, route
of administration and sample collection periods.
Dextromethorphan has been used as a probe
drug for phenotyping CYP2D6 activity.[14-16] For
example, in this procedure, the individual ingests
dextromethorphan 30mg and then their urine is col-
lected for the next 8 hours.[16] The percentage of
dose excreted as unchanged dextromethorphan and
metabolites is expressed as the O-demethylation
metabolic ratio (ODMR) [i.e. the ratio of non-O-
demethylated compounds to O-demethylated me-
tabolites]. The ability to measure the function of
the enzyme in this manner is important since it in-
dicates current activity and can be used to detect
changes over time (i.e. secondary to an inhibitory
medication). For example, phenotyping before and
after administration of an inducer or inhibitor in a
© Adis International Limited. All rights reserved.
Sproule et al.
drug interaction study is critical in elucidating the
mechanism of the observed interaction.
Drug-drug interactions are initially studied in
vitro in order to predict the potential importance
in vivo. Several approaches have been used to
correlate in vitro data to in vivo drug interac-
tions.[8,13,17,18] There are many factors which may
limit the ability to make in vivo predictions.[8] For
example, in vitro experimental conditions may
limit the extrapolation to in vivo since the milieu of
the reaction varies (e.g. pH, protein and phos-
pholipid content) and they do not take into account
the presence of enzymes outside of the liver. The
inhibitory values reported from in vitro studies
must be considered as relative estimations within
an experimental condition and cannot be compared
across studies.
The clinical significance of a potential interac-
tion must be further evaluated by considering sev-
eral factors (table II).
• The likelihood that the drug concentrations
achieved at the enzyme site are sufficient to af-
fect the enzyme.[17]
• The saturability of the enzyme.
• The extent of metabolism of the substrate
through this enzyme. Since most drugs have
several metabolic pathways, the inhibition of 1
isozyme may have limited impact on the overall
disposition of the parent drug since another iso-
zyme system may provide sufficient secondary
metabolic pathways.
• The presence of active metabolites. If the meta-
bolite of the substrate is also pharmacologically
active then the impact of an inhibitor or inducer
may be reduced. This may vary again depend-
ing on the metabolites’ subsequent metabo-
lism.
• The therapeutic window of the substrate. Those
medications with a wide therapeutic window are
less likely to have clinically significant conse-
quences from altered concentrations.
• The inherent enzyme activity of the individual.
The consequences of adding an inhibitor to the
regimen of patients stabilised on a medication
which has been titrated to clinical effect may be
Clin. Pharmacokinet. 1997 Dec; 33 (6)
SSRIs and CNS Drug Interactions
Table II. Evaluating the clinical significance of a potential metabolic kinetic drug interaction
Factors
Pharmacokinetic factors
Nature of activity at enzyme
In vitro potency of inhibitor/inducer
Concentration of inhibitor/inducer at enzyme site
Saturability of enzyme
Alternative pathways for substrate
Pharmacodynamic factors
Presence of active metabolites
Therapeutic window for substrate
Patient factors
Inherent enzyme activity
Level of risk for toxicity
Epidemiological factor
Probability of concurrent use
very different. For example, it may be more
important for those taking a higher dose because
of extensive metabolism compared with those
taking a low dose due to low inherent enzyme
activity.
• The individual’s level of risk of experiencing
adverse effects. For example, the elderly may
be at increased risk for experiencing psycho-
motor or cognitive impairment from enhanced
benzodiazepine effects, extrapyramidal effects
from antipsychotics, or anticholinergic effects
from TCAs.
• The probability of concurrent use. From an epi-
demiological perspective, the frequency of a
drug-drug interaction is increased with the pre-
valence of concurrent use of the drugs.
Therefore, although in vitro data are an impor-
tant starting point for predicting metabolic kinetic
drug interactions, case reports and controlled ex-
perimental studies in humans are required to fully
evaluate their mechanisms and clinical impor-
tance. This paper systematically reviews both the
in vitro and in vivo evidence for drug interactions
between SSRIs and other CNS drugs.
© Adis International Limited. All rights reserved.
459
Consider
Substrate/substrate, substrate/inhibitor, or substrate/inducer combinations for the
same enzyme
Evidence for potency compared to known inhibitors/inducers
Likelihood that concentration required for inhibition or induction is achieved clinically
Likelihood of saturation of enzyme by substrate or inhibitor and, therefore,
unavailability to another substrate
Extent of metabolism of substrate through the specific enzyme
Impact of increasing or reducing presence of an active metabolite
Change in substrate concentration required to be clinically important
Impact of inhibitor or inducer based on individual inherent enzyme activity (e.g.
extensive versus poor metabolisers)
Impact of enhanced substrate effects in specific individuals (e.g. the elderly)
Importance from a population perspective based on how likely the combination will
be used
2. Selective Serotonin Reuptake
Inhibitors (SSRIs)
As a class, the SSRIs have similar efficacy and
safety at their usual effective therapeutic doses.[19]
However, the SSRIs differ in their kinetic parame-
ters (table III). Fluoxetine is unique in its long half-
life (t1⁄2) and its active metabolite with a longer t1⁄2,
norfluoxetine, which is also potent in inhibiting
both serotonin reuptake and CYP2D6.[29,30] The
metabolite of sertraline, desmethylsertraline, has
no important effects on the serotonin uptake
pump[20] but is equipotent to sertraline itself as an
inhibitor of CYP2D6 enzymes[31] and has a longer
t1⁄2, thus prolonging the effect.
Neither fluvoxamine nor paroxetine have meta-
bolites which are active in terms of inhibition of
serotonin reuptake but the M2 metabolite of paro-
xetine is a potent CYP inhibitor.[32] The metabo-
lites of citalopram, desmethylcitalopram and di-
desmethycitalopram, are less potent serotonin
reuptake inhibitors than citalopram and since their
plasma concentrations are low they are not thought
to contribute to its therapeutic efficacy.[20] The
clinically relevant pharmacology of SSRIs has re-
cently been reviewed.[21] Figures 1 to 4 illustrate
Clin. Pharmacokinet. 1997 Dec; 33 (6)
460 Sproule et al.

Table III. Relevant features of SSRIs for metabolic pharmacokinetic interactions

Features Usually effective t1⁄2β fm fe Metabolic Therapeutically active Metabolites contributing
dosage (%) (%) pathway metabolites to CYP inhibition
(depression)
Citalopram 20-60 mg/day 33h ? ≈ 25 at 12 CYP2C19 >
[9,12,20-23]
least CYP2D6
Fluoxetine 20-80 mg/day 2-4 days ≥90 2.5-10 CYP2D6 (≈60) Norfluoxetine (also Norfluoxetine (CYP2D6)
[8,9,12,21,24,25]
metabolised via
CYP2D6, t1⁄2 7-15 days)
Fluvoxamine 100-300 mg/day 19-22h >90 2 CYP2D6 >
[8,9,12,21,26]
CYP1A2 >> NAT
Paroxetine 20-50 mg/day 24h >90 <2 CYP2D6 (≥ 80) M2 paroxetine
[8,9,12,21,27]
> COMT (minor) (CYP2D6)
Sertraline 50-200 mg/day 26h >90 <1 CYP3A > others Desmethylsertraline
[8,9,12,21,28]
(CYP2D6)
Abbreviations: COMT = catechol O-methyltransferase; CYP = cytochrome P450; fm = fraction of drug metabolised; fe = fraction of the
systemically available drug execreted into the urine; h = hours; NAT = N-acetyltransferase; t1⁄2 = half-life; t1⁄2β = elimination half-life.

in vitro inhibitory data for the SSRIs and enyzmes
of interest.
3. SSRI-Antipsychotic Interactions
SSRIs and antipsychotic medications are likely
to be used concurrently because of the high preva-
lence of comorbid psychotic and depressive symp-
toms.[38,39] Many antipsychotic medications are
metabolised by CYP2D6;[40-44] therefore, the po-
tential for interactions with the SSRIs, particularly
paroxetine and fluoxetine, exists (see table I). The
clinical effects of increased antipsychotic plasma
concentrations (i.e. extrapyramidal effects, im-
paired cognitive function and sedation) resulting
from these interactions may be significant. Unlike
other antipsychotics, clozapine is primarily meta-
bolised by CYP1A2.[45]
3.1 Citalopram
There are no reports of citalopram causing in-
creased antipsychotic plasma concentrations. One
study showed no increase in plasma concentrations
of halperidol, chlorpromazine, zuclopenithixol,
levomepramazine, thioridazine or perphenazine in
patients after adding citalopram 40 mg/day to their
treatment regimen.[46] Conversely, antipsychotics
have been implicated in altering citalopram phar-
macokinetics. The steady-state plasma concentra-
tions of citalopram increased by 36% during
coadministration of the phenothiazines levome-
promazine and alimemazine.[47] A single dose of
levomepromazine had no effect on the pharmaco-
kinetics of citalopram, however, levomepromazine
increased citalopram metabolite by 20%.[48] In an-
other study,[49] levomepromazine and trimeprazine
increased citalopram trough concentrations by
30%. These alterations are unlikely to be clinically
significant.
3.2 Fluoxetine
Haloperidol has a complex metabolism. The ox-
idation of reduced haloperidol to haloperidol is de-
pendent upon CYP2D6[50] but it is not known if the
metabolism of haloperidol involves this en-
zyme.[51] Higher plasma concentrations of haloper-
idol have been observed in poor metabolisers of
CYP2D6.[52] In a pharmacokinetic study in 8 pa-
tients receiving stable doses of haloperidol, the ad-
ministration of fluoxetine 20 mg/day for 7 to 10
days resulted in a 20% increase in mean haloperi-
dol serum concentration.[53] However, only 3 of the
patients had substantial increases in serum haloper-
idol, and they had low initial haloperidol concen-
trations and appeared to be rapid metabolisers.
In the other 5 patients who were slow metabo-
lisers of haloperidol, serum concentrations were
unaffected.[53,54] There are case reports of patients
on neuroleptics (haloperidol, pimozide and flu-

© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 1997 Dec; 33 (6)
SSRIs and CNS Drug Interactions 461

phenazine deconate), who experienced increased 100

extrapyramidal symptoms when fluoxetine 20 or
40 mg/day was added.[55,56] Another patient devel-

Log IC50 (μmol/L)

10
oped muscular stiffness after fluoxetine 20 mg/day
was added to haloperidol 1 mg/day.[57] No blood
concentrations of haloperidol were taken when the 1
symptoms occurred.
Clozapine is metabolised through CYP2D6 as a
secondary pathway. The potential for interaction 0

am

am
between clozapine and fluoxetine was studied in 6

in

in

in

tin

in
am

et

al

et

pr

pr
xe
rtr
x

ox

lo

lo
patients with psychosis receiving mean daily doses

ro

uo
ox

Se

ita

ita
flu
Pa
uv

Fl

lc
or
Fl

hy
of fluoxetine 36mg and clozapine 346mg for at

et
m
es
least 1 week compared with 17 patients who re-

D
ceived clozapine alone. Clozapine concentrations
Fig. 2. Log IC50 values (μmol/L) of selective serotonin reuptake
in patients also taking fluoxetine were 76% higher inhibitors (SSRIs) for microsomal CYP1A2 activity using para-
(p ≤ 0.05) than the control patient group, even cetamol (acetaminophen) as a probe.[35] Abbreviation: IC50 = the
when corrections were made for bodyweight and concentration of the inhibitor which reduced the formation of a
metabolite by 50% where lower values indicate higher inhibitory
dose variations.[58] potency.

3.3 Fluvoxamine range of 2 to 6mg) were administered fluvoxamine

150 to 300 mg/day for 7 weeks, serum haloperidol
Fluvoxamine has been shown to increase serum concentrations increased to 38 μg/L (from 9 μg/L
concentrations of haloperidol in a small study. pre-fluovoxamine) and to 56 μg/L (from 19
When 2 patients with schizophrenia receiving μg/L).[59] In a third patient who received fluvox-
maintenance haloperidol therapy (mean daily dose amine 50 mg/day for only 2 weeks, serum haloper-
of 33.8mg with a range of 15 to 60mg) and idol concentration increased to 16 μg/L, from 9
benztropine (mean daily dose of 3.5mg with a μg/L pre-fluvoxamine. Word recall and psychomo-
tor test performance diminished and both negative
7 and positive symptoms of schizophrenia increased
6 during combination pharmacotherapy. The meta-
5 bolic pathways for haloperidol have not been fully
Ki (μmol/L)

4
elucidated, however, the authors postulate fluvox-
3
amine inhibition of CYP1A2 as the possible mech-
anism for this interaction, although another possi-
2
bility could be CYP3A inhibition.
1
Clozapine is primarily metabolised through
0
CYP1A2. The addition of fluvoxamine 50 to 200
e

am
tin

tin

in

in

in

a
et

al

pr

pr

mg/day to clozapine therapy in 4 patients resulted

xe

xe

rtr
ox

xa

lo

lo
ro

uo

Se

ita

ita
flu

o
Pa

Fl

uv

in high serum clozapine concentrations in all 4 pa-

C

lc
or

hy
Fl
N

et

tients, however only 2 patients had data both with

m
es
D

and without fluvoxamine.[60] In 1 patient serum

Fig. 1. Apparent Ki values (μmol/L) of selective serotonin clozapine increased from 394 μg/L to 446 μg/L; in
reuptake inhibitors (SSRIs) for microsomal CYP2D6 activity us- the other, serum clozapine increased from 481
ing dextromethorphan as a probe.[33,34] Abbreviation: Ki = the in
vitro competitive inhibition constant where lower values indicate μg/L while taking 700 mg/day clozapine, to 3781
higher inhibitory potency. μg/L, while taking 550 mg/day clozapine and

© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 1997 Dec; 33 (6)
462 Sproule et al.

90 symptoms and impairment of psychomotor perfor-

80
mance and memory.[62]
70
No significant pharmacodynamic interactions
60
Ki (μmol/L)

50
between paroxetine and haloperidol were observed
40 in healthy volunteers.[63]
30
20 3.5 Sertraline
10
0 As a mild inhibitor of CYP2D6, sertraline is un-
e

e
likely to significantly increase the concentrations
in

in

in

in

in
m

et

al

et
xe
rtr
xa

ox

ox
ro

of antipsychotics metabolised through this en-

Se
vo

flu

u
Pa

Fl
u

or
Fl

zyme. In a double-blind, randomised, placebo-

Fig. 3. Ki values (μmol/L) of selective serotonin reuptake inhib-
itors (SSRIs) for microsomal cytochrome P450 (CYP) 3A activity
using alprazolam as a probe.[17,36] Abbreviation: Ki = the in vitro
competitive inhibition constant where lower values indicate
higher inhibitory potency.
fluvoxamine 150 mg/day, resulting in sedation and
urinary incontinence which resolved when clozap-
ine was reduced to 50 mg/day and fluvoxamine
to 50 mg/day (serum clozapine decreased to 163
μg/L). With careful monitoring of serum clozapine
concentrations, the authors suggested this interac-
tion could be used advantageously.
A patient’s positive symptoms of schizophrenia
were in control with clozapine, but the negative
symptoms remained and adverse reactions limited
the clozapine dose. When fluvoxamine was added,
the negative symptoms improved with no adverse
effects; the combination of clozapine 150 mg/day
and fluvoxamine 50 mg/day resulted in serum
clozapine concentrations within the target range of
controlled study in 24 healthy males, a single dose
of haloperidol 2mg produced impairment in cogni-
tive function and psychomotor performance which
was not altered by steady-state sertraline 200
mg/day.[64] Sertraline has not been shown to have
a significant effect on CYP1A2; therefore it is un-
likely to affect the metabolism of clozapine.
3.6 Summary Points
As potent inhibitors of CYP2D6, both paroxet-
ine and fluoxetine have the potential to increase the
plasma concentrations of antipsychotic medica-
tions metabolised through this enzyme, including
perphenazine, haloperidol, thioridazine and ris-
peridone in patients who are CYP2D6 extensive
90
80
70
60
Ki (μmol/L)

350 to 500 μg/L.[61] 50

40
30
3.4 Paroxetine 20
10
0
There has been 1 controlled study evaluating the
e

am

m
in

lin

tin

tin

ra

effect of paroxetine on the pharmacokinetics of

et

pr
a

xe

xe

p
rtr
ox

lo

lo
uo

ro
Se

ita

ita
flu

perphenazine.[62] Paroxetine 20mg administered

Pa
Fl

lc

C
or

hy
N

et

for 10 days to 8 extensive metabolisers of CYP2D6

m
es

caused a 2- to 13-fold increase (p < 0.001) in single

D

dose perphenazine peak plasma concentrations due
to inhibition of CYP2D6 activity. This was associ-
ated with increased CNS adverse effects of per-
phenazine including oversedation, extrapyramidal
Fig. 4. Ki values (μmol/L) of selective serotonin reuptake inhibi-
tors (SSRIs) for microsomal cytochrome P450 (CYP) 2C19 ac-
tivity using S-mephenytoin as a probe.[37] Abbreviation: Ki = the
in vitro competitive inhibition constant where lower values indi-
cate higher inhibitory potency.

© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 1997 Dec; 33 (6)
SSRIs and CNS Drug Interactions 463

Table IV. Summary of in vivo evidence for selective serotonin reuptake inhibitors (SSRI)-central nervous system (CNS) drug interactions
Citalopram Fluoxetine Fluvoxamine Paroxetine Sertraline
Evidence for clinically Nortriptyline, Amitriptyline, Desipramine
significant interactiona desipramine, clomipramine,
imipramine imipramine
Alprazolam Alprazolam, Perphenazine
diazepam,
bromazepam
Haloperidol, clozapine
Evidence for minor Desipramine Haloperidol, Desipramine,
interaction clozapine imipramine,
diazepam
Diazepam
Conflicting evidence: Triazolam Carbamazepine
potential for interaction
Carbamazepine
Evidence for no interaction Clonazepam Diazepam, oxazepam Haloperidol
Carbamazepine
Carbamazepine
a SSRI produced a clinically significant change in plasma concentration of interacting drug. If used concomitantly titrate to effect and
monitor for adverse effects.

metabolisers. Controlled studies have demonstr-
ated this effect for perphenazine with paroxetine
and haloperidol with fluoxetine. Fluvoxamine, as
a potent inhibitor of CYP1A2, can inhibit the me-
tabolism of clozapine, resulting in higher plasma
concentrations (table IV).
norfluoxetine and paroxetine are potent inhibitors
of CYP2D6 and fluvoxamine inhibits CYP1A2,
the potential exists for interactions amongst these
agents.
4.1 Citalopram

The addition of citalopram 40 to 60 mg/day did

4. SSRI-Tricyclic
Antidepressant Interactions
The combined use of an SSRI and a TCA may
be effective in patients refractory to TCAs
alone.[65] Interactions could also arise if there is
insufficient time given for the washout of an SSRI
before treatment with a TCA begins. The metabo-
lism of tertiary TCAs (e.g. imipramine, amitripty-
line and clomipramine) and secondary TCAs (e.g.
desipramine and nortriptyline) is important in un-
derstanding SSRI-TCA interactions. For example,
the demethylation of imipramine to desipramine is
mediated by CYP2C19, CYP3A3/4 and CYP1A2.
Hydroxylation of both imipramine and desipra-
mine appear to be mediated by CYP2D6. Similarly,
amitriptyline is metabolised by CYP2D6, CYP-
2C19 and CYP3A and its metabolite, nortriptyline,
is also metabolised by CYP2D6. Since fluoxetine,
not affect plasma concentrations of amitriptyline,
clomipramine or maprotiline in 5 case studies.[66]
Plasma concentrations of all medications indicated
compliance with treatment. In a controlled study,
citalopram increased the concentrations of the me-
tabolite of imipramine (desipramine) by 50% with
no change in imipramine and a modest decrease in
2-hydroxy desipramine.[48] The usual therapeutic
dose of citalopram is 20mg, thus the potential for
interaction is low.
4.2 Fluoxetine
There are case reports of 28 patients in whom
the combination of fluoxetine and a TCA resulted
in increased plasma TCA concentrations and ad-
verse effects.[67] For example, the plasma nortrip-
tyline concentrations of a 31-year-old woman be-
ing treated with nortriptyline 125 and 175 mg/day

© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 1997 Dec; 33 (6)
464
were 77 and 88 μg/L, respectively. When the nor-
triptyline dose was reduced to 100 mg/day and
fluoxetine 20 mg/day was added, she experienced
decreased energy, psychomotor retardation and
sedation, and her plasma nortriptyline concentra-
tions was 162 μg/L (above the therapeutic range)
10 days later. Nortriptyline was discontinued and
the patient was much improved on fluoxetine 20
mg/day alone.[68]
Similarly, there are 2 case reports of patients
taking desipramine 150 or 300 mg/day with fluo-
xetine 20 mg/day or 40 mg/day, in whom desipra-
mine plasma concentrations were 2 to 18 times
higher with fluoxetine than without.[69,70] One of
these patients, a 75-year-old woman, experienced
a worsening of depression, which had been partially
alleviated with desipramine alone.[70] In another
case, a 33-year-old man experienced improvement
in his depressive symptomatology on the combina-
tion pharmacotherapy but the adverse effects (dry
mouth, tinnitus and memory loss) were severe.[69]
In a pharmacokinetic study, 12 healthy volun-
teers were given single doses of desipramine 50mg
(n = 6) or imipramine 50mg (n = 6) alone, after a
single dose of fluoxetine 60mg and after 8 days of
fluoxetine 60mg.[71] Fluoxetine, single and multi-
ple doses, significantly reduced the oral clearance
of desipramine and imipramine and significantly
increased their t1⁄2 and plasma concentrations.
Fluoxetine 20 mg/day coadministered with desi-
pramine 50 mg/day for 4 weeks resulted in 4-fold
increases in peak plasma desipramine concentra-
tion.[72] Because of the long t1⁄2 of norfluoxetine,
desipramine concentration remained elevated for
approximately 3 weeks after fluoxetine discontin-
uation.
Two patients experienced grand mal seizures
when on fluoxetine and a TCA; 1 patient was tak-
ing imipramine 300 mg/day and fluoxetine 20
mg/day, and the other was taking doxepin 300
mg/day with fluoxetine 40 mg/day.[73]
4.3 Fluvoxamine
Fluvoxamine is a potent inhibitor of CYP1A2,
a moderate inhibitor of CYP3A4 but only a weak
© Adis International Limited. All rights reserved.
Sproule et al.
inhibitor of CYP2D6. Therefore, the metabolic
elimination of tertiary, but not secondary, TCAs is
impaired by fluvoxamine.[74] Fluvoxamine has been
observed to increase serum concentrations of con-
comitantly administered imipramine,[75-77] clomipra-
mine and amitriptyline.[78]
The effects of fluvoxamine on imipramine and
desipramine were determined in 2 different para-
digms. The administration of fluvoxamine 100
mg/day for 10 days in patients with depression re-
ceiving imipramine or desipramine resulted in in-
creased imipramine, but not desipramine, plasma
concentrations.[76] In healthy volunteers, the same
fluoxetine regimen increased the elimination t 1⁄2
and decreased the clearance of a single dose of imi-
pramine, but not desipramine.[77] These results in-
dicate that fluvoxamine inhibits imipramine de-
methylation by means of CYP1A2 but has a
minimal effect on the hydroxylation of desipra-
mine by means of CYP2D6.[51]
Fluvoxamine increased plasma concentrations
of TCAs in patients being treated with amitripty-
line and clomipramine.[78]
4.4 Paroxetine
Paroxetine, a potent inhibitor of CYP2D6, has
the potential to interact with TCAs. In pharmaco-
kinetic studies of healthy volunteers, plasma con-
centrations and the t1⁄2 of desipramine increased
1- to 3-fold during steady-state paroxetine 20
mg/day.[79-81]
4.5 Sertraline
In vitro data indicate that sertraline and des-
methylsertraline mildly inhibit CYP2D6.[31] In
case reports, plasma concentrations of desipramine
increased by 50 to 250% when sertraline 50 mg/day
was added to TCA maintenance therapy. The clin-
ical consequences were improved antidepressant
efficacy[82] or adverse effects of tremor, anxiety
and dysphoria.[83] In a controlled study, the area
under the concentration-time curve (AUC)0-24 of
desipramine was increased by only 23% in volun-
teers taking sertraline. In another pharmacokinetic
study, desipramine plasma concentrations in-
Clin. Pharmacokinet. 1997 Dec; 33 (6)
SSRIs and CNS Drug Interactions
creased by up to 3-fold following 29 days of ad-
ministration of sertraline 150 mg/day, with the
largest increases in patients with the highest
steady-state plasma concentrations of sertraline
and N-desmethylsertraline.[84]
In a third study, sertraline 150 mg/day for 8 days
increased the AUC of desipramine and imipramine
by 54 and 68%, respectively.[85] Similar results
were obtained in another recent study, where desi-
pramine AUC increased by 37% in healthy volun-
teers during coadministration of sertaline 50
mg/day.[81]
4.6 Summary Points
There is potential for drug interactions between
the SSRIs and TCAs. Fluoxetine and paroxetine,
as potent inhibitors of CYP2D6, can increase the
plasma concentrations of secondary and tertiary
tricyclic antidepressants. Sertraline and citalopram
are less likely to have this effect. Fluvoxamine can
increase the plasma concentrations of tertiary
TCAs (table IV).
5. SSRI-Benzodiazepine Interactions
Combination therapy with a benzodiazepine
and an SSRI is likely in cases of comorbid anxiety
and depression as well as during treatment initia-
tion with an SSRI where the benzodiazepine re-
lieves adverse effects, such as insomnia and anxi-
ety.[86-88] Some benzodiazepines are oxidatively
metabolised (alprazolam, bromazepam, diazepam,
midazolam and triazolam) and, therefore, may po-
tentially interact with SSRIs, while others are
directly conjugated (lorazepam, oxazepam and
temazepam) or nitro-reduced (clonazepam and
nitrazepam) and are less likely to have metabolic
pharmacokinetic interactions with SSRIs.
5.1 Citalopram
There are no reports of interactions between
citalopram and benzodiazepines.
© Adis International Limited. All rights reserved.
465
5.2 Fluoxetine
Potential interactions between fluoxetine and
benzodiazepines have been extensively studied. In
vitro evidence from human liver microsomes indi-
cates that norfluoxetine (Ki = 11.1 μmol/L) is a far
more potent inhibitor of alprazolam metabolism
than fluoxetine (Ki = 83.3 μmol/L).[17] In vivo, sig-
nificant increases in single dose alprazolam 1mg
t1⁄2 and AUC were observed following 3 to 7 days
of fluoxetine 20mg twice daily.[88] In a multiple
dose administration study, increases in plasma al-
prazolam concentrations and corresponding de-
creases in psychomotor performance were ob-
served following coadministration of alprazolam
1mg 4 times daily and fluoxetine 60 mg/day for 4
days.[87] Though the results of these studies are
conclusive and consistent with the known ability
of fluoxetine to inhibit CYP3A isozymes, the mag-
nitude of the interaction may be underestimated
since norfluoxetine requires at least 5 weeks to
reach steady-state concentrations.
Similar results would be expected for other
triazolobenzodiazepines such as midazolam and
triazolam. Yet, an in vitro study[94] predicts mini-
mal inhibition of midazolam 1′-hydroxylation by
fluoxetine and norfluoxetine, while an in vivo
study[86] found no pharmacokinetic interaction be-
tween a single dose of triazolam 0.25mg and
fluoxetine 60 mg/day for 8 days in healthy volun-
teers (n = 24). The results of the in vitro study may
be attributable to the use of only 1 liver specimen,
but the results of the in vivo study remain unex-
plained and inconsistent with significant CYP3A
inhibition by fluoxetine and with the results of the
alprazolam-fluoxetine studies.
The effect of fluoxetine on diazepam is less con-
troversial. One controlled study found that al-
though fluoxetine 60 mg/day coadministration for
8 days (n = 6) significantly increased the AUC and
t1⁄2 of diazepam while significantly decreasing
plasma clearance, there was a corresponding de-
crease in the AUC of N-desmethyldiazepam.[95]
Since both diazepam and its metabolite possess ap-
proximately equal pharmacological activity, it was
not surprising to observe little change in the psy-
Clin. Pharmacokinet. 1997 Dec; 33 (6)
466
chomotor performance of individuals receiving the
combination (n = 6).
In another study, a single dose of fluoxetine
60mg in combination with a single dose of diaze-
pam 5mg did not impair subject performance com-
pared with diazepam alone.[96] The diazepam
plasma concentrations were not reported.
The effects of fluoxetine on clonazepam were
also investigated. Since clonazepam is metabolised
mainly by nitro-reduction rather than oxidation, no
interaction was expected. This was confirmed in a
study of clonazepam 1mg single dose with fluoxet-
ine 40 mg/day though the results indicated that
fluoxetine significantly increased the rate of ab-
sorption of clonazepam.[88]
5.3 Fluvoxamine
Interactions with fluvoxamine are common be-
cause of its potent inhibition of CYP1A2 and mod-
erate inhibition of CYP3A and CYP2C isozymes.
Both in vitro and in vivo evidence support an inter-
action with alprazolam, which is primarily metabo-
lised by CYP3A. In vitro fluvoxamine was equipo-
tent to norfluoxetine in the inhibition of 4-hydroxy
and α-hydroxy alprazolam formation in human
liver microsomes.[36] An in vivo study found signif-
icant increases in alprazolam AUC, peak plasma
drug concentration (Cmax) and t1⁄2 when fluvox-
amine 100 mg/day was coadministered with al-
prazolam 1mg 4 times daily in healthy males
(n = 20).[89] Corresponding decreases in psycho-
motor performance and memory function were also
observed. A similar effect was demonstrated when
fluvoxamine 100 mg/day was coadministered with
a single dose of bromazepam 12mg.[90] Both
bromazepam AUC and t1⁄2 were significantly in-
creased. Triazolam and midazolam are also pri-
marily metabolised by CYP3A, and, therefore,
similar interactions may occur.
Diazepam, at high concentrations, is also a
CYP3A substrate but, at lower concentrations, it is
mainly a substrate of CYP2C19.[91,92] A kinetic
study in healthy volunteers (n = 8) demonstrated
significant increases in diazepam t1⁄2 and AUC as
well as the time to reach peak concentration follow-
© Adis International Limited. All rights reserved.
Sproule et al.
ing drug administration (tmax) and AUC of N-
desmethyldiazepam following a 3-day upward
titration of fluvoxamine. [93] Though significant
results were obtained, this study may underesti-
mate the impact of pretreatment with fluvoxamine
since insufficient time was allowed for steady-state
concentrations to be reached. Nevertheless, the
data emphasise the potential for fluvoxamine to
inhibit CYP2C19 and may further reflect a simul-
taneous inhibition of CYP3A.
5.4 Paroxetine
In vitro, the effects of paroxetine on the meta-
bolism of alprazolam have been investigated. Con-
sistent with a low inhibitory potential at CYP3A
isozymes, paroxetine was found not to signifi-
cantly inhibit the formation of 4-hydroxy alpra-
zolam (Ki = 39.4 μmol/L) or α-hydroxy alprazolam
(Ki = 36.7 μmol/L).[36]
In vivo, the interaction between paroxetine 30
mg/day and diazepam 5mg 3 times daily was as-
sessed in 12 healthy males.[97] No significant phar-
macokinetic interaction was observed and no ad-
verse effects were reported. These findings are
consistent with a low inhibitory potential for
paroxetine at both CYP2C19 and CYP3A. The ef-
fects of paroxetine on psychomotor inhibition by
oxazepam have also been investigated. No poten-
tiation of the sedative effects of oxazepam (after a
single dose of 30mg) were observed following pre-
treatment with paroxetine 30 mg/day for 10
days.[63] This finding is consistent with the elimin-
ation of oxazepam primarily by conjugation rather
than oxidative metabolism.
5.5 Sertraline
Interactions with sertraline and alprazolam have
been investigated in vitro in human liver micro-
somes. Neither sertraline nor desmethylsertraline
was found to significantly inhibit alprazolam me-
tabolism (Ki = 24 and 20 μmol/L, respectively)
though moderate inhibition was observed.[17] Sim-
ilarly, for in vitro 1′-hydroxy midazolam forma-
tion, inhibition by sertraline (Ki = 64.4 μmol/L)
and desmethylsertraline (Ki = 48.1 μmol/L) was
Clin. Pharmacokinet. 1997 Dec; 33 (6)
SSRIs and CNS Drug Interactions
found not to be significant, though the study was
based on only one liver sample.[94] Together, these
findings are consistent with a mild to moderate in-
hibitory potential for sertraline and desmethyl-
sertraline at CYP3A isozymes.
In vivo, only the interaction between sertraline
and diazepam has been investigated. The study ob-
served statistically significant reductions (21%) in
systemic clearance of diazepam (a single intrave-
nous dose of 10mg) following a 21-day upward
titration of sertraline from 50 mg/day to 200
mg/day (n = 10).[98] When compared with the 19%
decrease in diazepam clearance in the placebo
group, the difference was not considered to be
meaningful. No effect on maximal or overall expo-
sure to N-desmethyldiazepam was observed. These
findings could reflect a moderate inhibition of N-
desmethyldiazepam formation via CYP2C19 (at
low diazepam concentrations) and/or CYP3A iso-
zymes (at high diazepam concentrations) with a
simultaneous inhibition of N-desmethyldiazepam
metabolism.
5.6 Summary Points
Fluvoxamine inhibits, via CYP3A, CYP2C19
and CYP1A2, the metabolism of several benzo-
diazepines, including alprazolam, bromazepam
and diazepam. Fluoxetine significantly increases
the plasma concentrations of alprazolam and diaz-
epam by inhibiting CYP3A and CYP2C19. The
clinical significance of the interaction with diaze-
pam is attenuated by the presence of its active
metabolite. Sertraline inhibits these enzymes only
mildly to moderately; therefore, the potential for
interactions is less. However, in vivo evidence, par-
ticularly for doses greater than or equal to 100mg,
is not available. Paroxetine and citalopram are
unlikely to cause significant interactions with
benzodiazepines (table IV).
6. SSRI-Mood Stabilisers Interactions
Combination therapy with mood stabilisers and
antidepressants is often necessary in the treatment
of patients with bipolar mood disorder. Mood
stabilisers include lithium, carbamazepine, val-
© Adis International Limited. All rights reserved.
467
proic acid (valproate sodium), and more recently,
lamotrigine and gabapentin. Carbamazepine is a
well known inducer of CYP3A4 and is also a sub-
strate for this enzyme. Valproic acid has compli-
cated metabolism where less than 20% involves
CYP enyzmes. Lamotrigine is extensively metabo-
lised predominantly through glucuronyltransfer-
ase. Lithium and gabapentin do not undergo meta-
bolism. Therefore, it is primarily carbamazepine
which has been implicated in drug interactions
with the SSRIs.
6.1 Citalopram
There are no reports of an interaction between
citalopram and the mood stabilisers.
6.2 Fluoxetine
Fluoxetine, as an inhibitor of CYP3A4, may be
expected to interact with carbamazepine. There is
conflicting evidence for this interaction however.
There has been a report of 2 cases in which carba-
mazepine concentrations were elevated in associa-
tion with toxicity symptoms in 2 patients when
fluoxetine was added to their regimens.[99] Like-
wise, 6 healthy volunteers experienced a signifi-
cant increase in the AUC of carbamazepine (27%)
and carbamazepine-10,11-epoxide (31%) when
fluoxetine 20 mg/day for 7 days was added to
carbamazepine 400 mg/day.[100] Conversely, in an-
other study 8 epileptic patients with depressive
symptoms stabilised on carbamazepine had no
change in their steady-state carbamazepine or
carbamazepine-10,11-epoxide concentrations when
fluoxetine 20 mg/day was added for 3 weeks.[101]
6.3 Fluvoxamine
Similarly, the evidence for an interaction be-
tween fluvoxamine and carbamazepine is conflict-
ing. In a series of 3 cases, substantial increases in
carbamazepine concentrations, associated with
symptoms of toxicity, followed the addition of
fluvoxamine in these patients.[102] There have been
7 cases of fluvoxamine causing increased carbam-
azepine concentrations (ranging from 1.4- to 2.5-
Clin. Pharmacokinet. 1997 Dec; 33 (6)
468
fold increases) reported in the manufacturer’s
global fluvoxamine database.[103] Conversely, in a
study of 7 epileptic patients with depressive symp-
toms started on fluvoxamine no change in carbam-
azepine or carbamazepine-10,11-epoxide concen-
trations was observed.[101]
6.4 Paroxetine
In 6 patients stabilised on carbamazepine, the
addition of paroxetine did not affect the steady-
state carbamazepine concentrations.[104]
6.5 Sertraline
In a randomised, double-blind, placebo-control-
led trial in 14 healthy volunteers, sertraline did not
affect the pharmacokinetics of carbamazepine.[105]
6.6 Summary Points
The evidence is conflicting for an interaction
between carbamazepine and the SSRIs fluoxetine
and fluvoxamine. These combinations should be
used cautiously, monitoring for adverse events and
carbamazepine plasma concentrations. The evi-
dence suggests that there is no interaction be-
tween paroxetine or sertraline and carbamazepine
(table IV).
7. SSRIs With Other CNS Drugs
There is very little documentation of SSRI me-
tabolic pharmacokinetic drug interactions with
other CNS drugs. The potential exists for an inter-
action between SSRIs which inhibit CYP2D6 and
opiate medications which are metabolised through
CYP2D6, e.g. codeine, hydrocodone and oxyco-
done. This interaction may lead to a decrease in
analgesic efficacy since they are metabolised
through CYP2D6 to more active metabolites. De-
creased codeine effects have been demonstrated in
CYP2D6 poor metabolisers compared with exten-
sive metabolisers.[106] However, no studies have
been published which evaluated the potential in-
teraction between SSRIs and these opiates.
© Adis International Limited. All rights reserved.
Sproule et al.
8. Clinical Management of SSRI-CNS
Drug Interactions
The safe clinical management of SSRI-CNS
drug interactions begins with a knowledge and
understanding of their mechanisms and potential
for occurance so that drug combinations can be as-
sessed on an individual basis.[2] Coadministration
is not necessarily contraindicated. Information from
case reports may be useful and should be taken into
account, but ideally data from controlled pharma-
cokinetic/pharmacodynamic studies should be
considered.
Anticipated pharmacokinetic interactions can
usually be managed with careful monitoring and
appropriate adjustments in dosage and titration. If
there is evidence that the clearance of a second drug
may be decreased by an SSRI, then the second drug
should be introduced at a lower dosage than usual
and titrated until the desired therapeutic effect is
achieved and as long as no adverse effects occur.
Plasma concentration of the second drug should be
monitored if possible. Similarly, if an SSRI is
added to an ongoing regimen with another CNS
drug, the dosage of that drug should be decreased
and the SSRI added at a lower dose than might
otherwise be used. Then both drugs should be titr-
ated until the desired therapeutic effect is achieved.
Careful monitoring of adverse effects and determi-
nation of plasma drug concentrations will avoid
adverse interactions. The final medication regimen
is usually administration of the usual clinical dose
of the SSRI and reduced dose of the other CNS
drug.
9. Conclusions
The SSRIs are not equivalent in their potential
for drug interactions when combined with other
CNS medications. Each combination must be as-
sessed individually. Several factors must be con-
sidered when predicting the outcome of a potential
interaction based on in vitro data. In vivo studies
are required to evaluate their clinical significance.
Generally, citalopram and sertraline appear to have
less propensity for important interactions.
Clin. Pharmacokinet. 1997 Dec; 33 (6)
SSRIs and CNS Drug Interactions
Anticipated pharmacokinetic interactions can
usually be managed with careful monitoring and
appropriate adjustments in dosage and titration.
Our knowledge of CYP isozymes continues to in-
crease, in terms of the discovery, identification and
classification of new isoforms and their roles in the
metabolism of drugs and in the susceptibility to
interactions. This knowledge should impact on the
practices required for safe clinical management of
SSRI-CNS drug interactions and, therefore, should
be well known to all clinicians who prescribe these
medications.
References
1. Ross HE, Glaser FB, Germanson T. The prevalence of psychi-
atric disorders in patients with alcohol and other drug prob-
lems. Arch Gen Psychiatry 1988; 45: 1023-31
2. Rosenbaum JF. Managing selective serotonin reuptake inhibi-
tor-drug interactions in clinical practice. Clin Pharmacokinet
1995; 29 Suppl. 1: 53-9
3. Wong DT, Bymaster FT, Reid LR, et al. Fluoxetine and two
other serotonin uptake inhibitors without affinity for neuronal
receptors. Biochem Pharmacol 1983; 32: 1287-93
4. Kasper S, Heiden A. Do SSRIs differ in their antidepressant
efficacy. Hum Psychopharmacol Clin Exp Ther 1995; 10
Suppl. 3: S163-72
5. den Boer JA, Westenberg HGM. Serotonergic compounds in
panic disorder, obsessive-compulsive disorder and anxious
depression: a concise review. Hum Psychopharmacol Clin
Exp Ther 1995; 10 Suppl. 3: S173-83
6. Nelson DR, Koymans L, Kamataki T, et al. P450 superfamily:
update on new sequences, gene mapping, accession numbers
and nomenclature. Pharmacogenetics 1996; 6 (1): 1-42
7. Gonzalez FJ, Jeffrey RI. Pharmacogenetic phenotyping and
genotyping: present status and future potential. Clin Phar-
macokinet 1994; 26 (1): 59-70
8. Bertz RJ, Granneman GR. Use of in vitro and in vivo data to
estimate the likelihood of metabolic pharmacokinetic inter-
actions. Clin Pharmacokinet 1997; 32 (3): 210-58
9. Shen WW. Cytochrome P450 monooxygenases and interac-
tions of psychotropic drugs: a five-year update. Int J Psychi-
atry Med 1995; 25 (3): 277-90
10. Daly AK, Cholerton S, Gregory W, et al. Metabolic polymor-
phisms. Pharmacol Ther 1993; 57: 129-60
11. Ketter TA, Flockhart DA, Post RM, et al. The emerging role of
cytochrome P450 3A in psychopharmacology. J Clin Psy-
chopharmacol 1995; 15 (6): 387-98
12. De Vane CL. Pharmacogenetics and drug metabolism of newer
antidepressant agents. J Clin Psychiatry 1994; 55 Suppl. 12:
38-45
13. Schmider J, Greenblatt DJ, von Moltke LL, et al. Relationship
of in vitro data on drug metabolism to in vivo pharmacoki-
netics and drug interactions: implications for diazepam dis-
position in humans. J Clin Psychopharmacol 1996; 16 (4):
267-72
14. Schmid B, Bircher J, Preisig R, et al. Polymorphic dextrometh-
orphan metabolism: co-segregation of oxidative O-demethyl-
ation with debrisoquin hydroxylation. Clin Pharmacol Ther
1985; 38: 618-24
© Adis International Limited. All rights reserved.
469
15. Chen ZR, Somogyi AA, Bochner F. Polymorphic O-demethyl-
ation of codeine. Lancet 1988; II: 914-5
16. Wu D, Otton SV, Sproule BA, et al. Inhibition of human cyto-
chrome P450 2D6 (CYP2D6) by methadone. Br J Clin Phar-
macol 1993; 35: 30-4
17. von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, et al. In-
hibitors of alprazolam metabolism in vitro: effect of seroto-
nin-reuptake-inhibitor antidepressants, ketoconazole and
quinidine. Br J Clin Pharmacol 1994; 38: 23-31
18. Shader RI, von Moltke LL, Schmider J, et al. The clinician and
drug interactions: an update. J Clin Psychopharmacol 1996;
16 (3): 197-201
19. Preskorn SH. Clinical pharmacology of selective serotonin
reuptake inhibitors. 1st ed. Caddo (OK): Professional Com-
munications Inc., 1996
20. van Harten J. Clinical pharmacokinetics of selective serotonin
reuptake inhibitors. Clin Pharmacokinet 1993; 24 (3): 203-20
21. Preskorn SH. Clinically relevant pharmacology of selective se-
rotonin reuptake inhibitors. Clin Pharmacokinet 1997; 32
Suppl. 1: 1-21
22. Jeppesen U, Gram LF, Vistisen K, et al. Dose-dependent inhi-
bition of CYP1A2, CYP2C19 and CYP2D6 by citalopram,
fluoxetine, fluvoxamine and paroxetine. Eur J Clin Phar-
macol 1996; 51: 73-8
23. Sindrup SH, Brosen K, Hansen MGJ, et al. Pharmacokinetics
of citalopram in relation to the sparteine and the mephenytoin
oxidation polymorphisms. Ther Drug Monit 1993; 15 (1): 11-7
24. Altamura AC, Moro AR, Percudani M. Clinical pharmacokinet-
ics of fluoxetine. Clin Pharmacokinet 1994; 26 (3): 201-14
25. Benfield P, Heel RC, Lewis SP. Fluoxetine: a review of its phar-
macodynamic and pharmacokinetic properties, and therapeu-
tic efficacy in depressive illness. Drugs 1986; 32: 481-508
26. Fluvoxamine in perspective: a decade of experience. Chester
(UK): Adis International, 1995
27. Dechant KL, Clissold SP. Paroxetine: a review of its pharma-
codynamic and pharmacokinetic properties, and therapeutic
potential in depressive illness. Drugs 1991; 41 (2): 225-53
28. Murdoch D, McTavish D. Sertraline: a review of its pharmaco-
dynamic and pharmacokinetic properties, and therapeutic po-
tential in depression and obsessive-compulsive disorder.
Drugs 1992; 44 (4): 604-24
29. Lemberger L, Rowe H, Carmichael R, et al. Fluoxetine, a se-
lective serotonin uptake inhibitor. Clin Pharmacol Ther 1978;
23: 421-9
30. Brøsen K, Skjelbo E. Fluoxetine and norfluoxetine are potent
inhibitors of P450IID6: the source of the sparteine/debrisoqu-
ine oxidation polymorphism. Br J Clin Pharmacol 1991; 32:
136-7
31. von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, et al. Inhi-
bition of desipramine hydroxylation in vitro by serotonin-
reuptake-inhibitor antidepressants, and by quinidine and
ketoconazole: a model system to predict drug interactions in
vivo. J Pharmacol Exp Ther 1994; 268 (3): 1278-83
32. Crewe HK, Lennard MS, Tucker GT, et al. The effect of selec-
tive serotonin re-uptake inhibitors on cytochrome P4502D6
(CYP2D6) activity in human liver microsomes. Br J Clin
Pharmacol 1992; 34: 262-5
33. Otton SV, Wu D, Joffe RT, et al. Inhibition by fluoxetine of
cytochrome P450 2D6 activity. Clin Pharmacol Ther 1993;
53: 401-9
34. Otton SV, Ball SE, Cheung SW, et al. Venlafaxine oxidation in
vitro is catalysed by CYP2D6. Br J Clin Pharmacol 1996; 41
(2): 149-56
Clin. Pharmacokinet. 1997 Dec; 33 (6)
470
35. Brøsen K, Skjelbo E, Rasmussen JGC, et al. Fluvoxamine is a
potent inhibitor of cytochrome P4501A2. Biochemical Phar-
macology 1993; 45 (6): 1211-4
36. von Moltke LL, Greenblatt DJ, Court MH, et al. Inhibition of
alprazolam and desipramine hydroxylation in vitro by
paroxetine and fluvoxamine: comparison with other selective
serotonin reuptake inhibitor antidepressants. J Clin Psy-
chopharmacol 1995; 15: 125-31
37. Kobayashi K, Yamamoto T, Chiba K, et al. The effects of selec-
tive serotonin reuptake inhibitors and their metabolites on
S-mephenytoin 4’-hydroxylase activity in human liver
microsomes. Br J Clin Pharmacol 1995; 40 Suppl. 5: 481-5
38. Dubovsky SL, Thomas M. Psychotic depression: advances in
conceptualization and treatment. Hosp Community Psychia-
try 1992; 43: 1189-98
39. Plasky P. Antidepressant usage in schizophrenia. Schizophr Bull
1991; 17: 649-57
40. Dahl-Puustinen M, Liden A, Alm C, et al. Disposition of per-
phenazine is related to polymorphic debrisoquine hydroxyla-
tion in human beings. Clin Pharmacol Ther 1989; 46: 78-81
41. von Bahr C, Movin G, Nordin C, et al. Plasma levels of thiorid-
azine and metabolites are influenced by the debrisoquine hy-
droxylation phenotype. Clin Pharmacol Ther 1991; 49:
234-40
42. Llerena A, Alm C, Dahl ML, et al. Haloperidol disposition is
dependent on the debrisoquine hydroxylation phenotype.
Ther Drug Monit 1992; 14: 92-7
43. Huang ML, van Peer A, Woestenborghs R, et al. Pharmacoki-
netics of novel antipsychotic agent risperidone and the pro-
lactin response in healthy subjects. Clin Pharmacol Ther
1993; 54: 257-68
44. Jerling M, Dahl ML, Aberg-Wistedt A, et al. The CYP2D6 ge-
notype predicts the oral clearance of the neuroleptic agents
perphenazine and zuclopenthixol. Clin Pharmacol Ther 1996;
59: 423-8
45. Bertilsson L, Carrillo JA, Dahl ML, et al. Clozapine disposition
covaries with CYP1A2 activity determined by a caffeine test.
Br J Clin Pharmacol 1994; 38: 471-3
46. Syvalahti EK, Taiminen T, Saarijarvi S, et al. Citalopram causes
no significant alterations in plasma neuroleptic levels in schiz-
ophrenic patients. J Int Med Res 1997; 25 (1): 24-32
47. Milne RJ, Goa KL. Citalopram: a review of its pharmacody-
namic and pharmacokinetic properties and therapeutic poten-
tial in depressive illness. Drugs 1991; 41: 450-77
48. Gram LF, Hansen MGJ, Sindrup SH, et al. Citalopram: interac-
tion studies with levomepromazine, imipramine and lithium.
Ther Drug Monit 1993; 15: 18-24
49. Øyehaug E. Effect of phenothiazines on citalopram steady-state
kinetics in psychiatric patients. Nor Pharm Acta 1982; 46:
37-46
50. Tyndale R, Kalow W, Inaba T. Oxidation of reduced haloperidol
to haloperidol: involvement of human P450IID6 (sparte-
ine/debrisoquine monoxygenase). Br J Clin Pharmacol 1991;
31: 655-60
51. Nemeroff CB, DeVane CL, Pollock BG. Newer antidepressants
and the cytochrome P450 system. Am J Psychiatry 1996; 153
(3): 311-20
52. Llerena A, Dahl ML, Ekqvist B, et al. Haloperidol disposition
is dependent on the debrisquine hydroxylation phenotype: in-
creased plasma levels of the reduced metabolite in poor me-
tabolizers. Ther Drug Monit 1992; 14: 261-4
53. Goff DC, Midha KK, Brotman AW, et al. Elevation of plasma
concentrations of haloperidol after the addition of fluoxetine.
Am J Psychiatry 1991; 148: 790-2
© Adis International Limited. All rights reserved.
Sproule et al.
54. Nelson MR, Dunner DL. Treatment resistance in unipolar de-
pression and other disorders: diagnostic concerns and treat-
ment possibilities. Psychiatr Clin North Am 1993; 16 (3):
541-66
55. Tate JL. Extrapyramidal symptoms in a patient taking haloperidol
and fluoxetine [letter]. Am J Psychiatry 1989; 146: 399-400
56. Bouchard RH, Pourcher E, Vincent P. Fluoxetine and ex-
trapyramidal side effects [letter]. Am J Psychiatry 1989; 146:
1352-3
57. Brod TM. Fluoxetine and extrapyramidal side effects [letter].
Am J Psychiatry 1989; 146: 1353
58. Centorrino F, Baldessarini RJ, Kando J, et al. Serum concentra-
tions of clozapine and its major metabolites: effects of cotreat-
ment with fluoxetine or valproate. Am J Psychiatry 1994; 151
(1): 123-5
59. Daniel DG, Randolph C, Jaskiw G, et al. Coadministration of
fluvoxamine increases serum concentrations of haloperidol. J
Clin Psychopharmacol 1994; 14 (5): 340-3
60. Jerling M, Lindstrom L, Bondesson U, et al. Fluvoxamine inhi-
bition and carbamazepine induction of the metabolism of
clozapine: evidence from a therapeutic drug monitoring ser-
vice. Ther Drug Monit 1994; 16 (4): 368-74
61. Szegedi A, Wiesner J, Hiemke C. Improved efficacy and fewer
side effects under clozapine treatment after addition of
fluvoxamine. J Clin Psychopharmacol 1995; 15 (2): 141-3
62. Özdemir V, Naranjo CA, Herrmann N, et al. Paroxetine poten-
tiates CNS side effects of perphenazine: contribution of cyto-
chrome P450 2D6 inhibition in vivo. Clin Pharmacol Ther. In
press
63. Cooper SM, Jackson D, Loudon JM, et al. The psychomotor
effects of paroxetine alone and in combination with haloper-
idol, amylobarbitone, oxazepam or alcohol. Acta Psychiatr
Scand 1989; 80 Suppl. 350: 53-5
64. Williams SA, Wesnes K, Oliver SD, et al. Absence of effect of
sertraline on time-based sensitization of cognitive impairment
with haloperidol. J Clin Psychiatry 1996; 57 Suppl. 1: 7-11
65. Weilberg JB, Rosenbaum JF, Meltzer-Brody S. Tricyclic aug-
mentation of fluoxetine. Ann Clin Psychiatry 1991; 3: 209-14
66. Baettig D, Bondolfi G, Montaldi S, et al. Tricyclic antidepres-
sant plasma levels after augmentation with citalopram: a case
study. Eur J Clin Pharmacol 1993; 44: 403-5
67. Taylor D. Selective serotonin reuptake inhibitors and tricyclic
antidepressants in combination: interactions and therapeutic
uses. Br J Psychiatry 1995; 167: 575-80
68. Vaughan DA. Interaction of fluoxetine with tricyclic antidepres-
sants [letter]. Am J Psychiatry 1988; 145: 1478
69. Goodnick PJ. Influence of fluoxetine on plasma levels of desi-
pramine. Am J Psychiatry 1989; 146: 552
70. Bell IR, Cole JR. Fluoxetine induces elevation of desipramine
levels and exacerbation of geriatric non-psychotic depression.
J Clin Psychopharmacol 1988; 8: 447-8
71. Bergstrom RF, Peyton AL, Lemberger L. Qualification and
mechanism of the fluoxetine and tricyclic antidepressant in-
teraction. Clin Pharmacol Ther 1992; 51: 239-48
72. Preskorn SH, Alderman J, Chung M, et al. Pharmacokinetics of
desipramine coadministered with sertraline and fluoxetine. J
Clin Psychopharmacol 1994; 14: 90-8
73. Preskorn SH, Beber JH, Faul JC, et al. Serious adverse effects
of combining fluoxetine and tricyclic antidepressants. Am J
Psychiatry 1990; 147: 532
74. van Harten J. Overview of the pharmacokinetics of fluvoxam-
ine. Clin Pharmacokinet 1995; 29 Suppl. 1: 1-9
Clin. Pharmacokinet. 1997 Dec; 33 (6)
SSRIs and CNS Drug Interactions
75. Maskall DD, Lam RW. Increased plasma concentration of imip-
ramine following augmentation with fluvoxamine [letter].
Am J Psychiatry 1993; 150: 1566
76. Spina E, Pollicino AM, Avenoso A, et al. Fluvoxamine-induced
alterations in plasma concentrations of imipramine and desi-
pramine in depressed patients. Int J Clin Pharmacol Res 1993;
13: 167-71
77. Spina E, Pollicino AM, Avenoso A, et al. Effect of fluvoxamine
on the pharmacokinetics of imipramine and desipramine in
healthy subjects. Ther Drug Monit 1993; 15: 243-6
78. Bertschy G, Vandel S, Vandel R, et al. Fluvoxamine-tricyclic
antidepressant interaction: an accidental finding. Eur J Clin
Pharmacol 1991; 40: 119-20
79. Brøsen K, Hansen JG, Nielson KK, et al. Inhibition by paroxet-
ine of desipramine metabolism in extensive but not in poor
metabolizers of sparteine. Eur J Clin Pharmacol 1993; 44:
349-55
80. Preskorn SH. Pharmacokinetics of antidepressants: why and
how they are relevant to treatment. J Clin Psychiatry 1993;
54 Suppl. Sep: 14-34
81. Alderman J, Preskorn SH, Greenblatt DJ, et al. Desipramine
pharmacokinetics when coadministered with paroxetine or
sertaline in extensive metabolizers. J Clin Psychopharmacol
1997; 17 (4): 284-91
82. Lydiard RB, Anton RF, Cunningham T. Interactions between
sertraline and tricyclic antidepressants [letter]. Am J Psychi-
atry 1993; 150: 1125-6
83. Barros J, Asnis G. An interaction of sertraline and desipramine.
Am J Psychiatry 1993; 150: 1751
84. Zussmann BD, Davie CC, Fowles SE, et al. Sertraline, like
other SSRIs, is a significant inhibitor of desipramine metabo-
lism in vivo [abstract]. Br J Clin Pharmacol 1995; 39: 550-1
85. Kurtz DL, Bergstrom RF, Goldberg MJ, et al. The effect of
sertaline on the pharmacokinetics of desipramine and imipra-
mine. Clin Pharmacol Ther 1998; 62: 145-56
86. Wright CE, Lasher-Sisson TA, Steenwyk RC, et al. A pharma-
cokinetic evaluation of the combined administration of triaz-
olam and fluoxetine. Pharmacotherapy 1992; 12 (2): 103-6
87. Lasher TA, Fleishaker JC, Steenwyk RC, et al. Pharmacokinetic
pharmacodynamic evaluation of the combined administration
of alprazolam and fluoxetine. Psychopharmacology 1991;
104: 323-7
88. Greenblatt DJ, Preskorn SH, Cotreau MM, et al. Fluoxetine
impairs clearance of alprazolam but not of clonazepam. Clin
Pharmacol Ther 1992; 52: 479-86
89. Fleishaker JC, Hulst LK. A pharmacokinetic and pharmacody-
namic evaluation of the combined administration of alprazo-
lam and fluvoxamine. Eur J Clin Pharmacol 1994; 46: 35-9
90. van Harten J, Holland RL, Wesnes K. Influence of multiple-
dose administration of fluvoxamine on the pharmacokinetics
of the benzodiazepine bromazepam and lorazepam: a random-
ized, cross-over study [abstract]. Eur Neuropsychopharmacol
1992; 2: 381
91. Yasumori T, Nagata K, Yang S, et al. Cytochrome P450 mediated
metabolism of diazepam in human and rat: involvement of
human CYP2C in N-demethylation in the substrate concentra-
tion-dependent manner. Pharmacogenetics 1993; 3: 291-301
© Adis International Limited. All rights reserved.
471
92. Andersson T, Miners JO, Birkett DJ, et al. Diazepam metabo-
lism by human liver microsomes is mediated by both S-
mephenytion hydroxylase and CYP3A isoforms [abstract].
Clin Pharmacol Ther 1994; 55: 138
93. Perucca E, Gatti G, Cipolla G, et al. Inhibition of diazepam
metabolism by fluvoxamine: a pharmacokinetic study in nor-
mal volunteers. Clin Pharmacol Ther 1994; 56: 471-6
94. Ring BJ, Binkley SN, Roskos L, et al. Effect of fluoxetine,
norfluoxetine, sertraline and desmethylsertraline on human
CYP3A catalyzed 1′-hydroxy midazolam formation in vitro.
J Pharmacol Exp Ther 1995; 275: 1131-5
95. Lemberger L, Rowe H, Bosomworth JC, et al. The effect of
fluoxetine on the pharmacokinetics and psychomotor re-
sponses of diazepam. Clin Pharmacol Ther 1988; 43: 412-9
96. Moskowitz H, Burns M. The effects on performance of two anti-
depressants, alone and in combination with diazepam. Prog
Neuropsychopharmacol Biol Psychiatry 1988; 12: 783-92
97. Bannister SJ, Houser VP, Hulse JD, et al. Evaluation of the
potential for interactions of paroxetine with diazepam, cimet-
idine, warfarin, and digoxin. Acta Psychiatr Scand 1989; 80
Suppl. 350: 102-6
98. Gardner MJ, Baris BA, Wilner KD, et al. Effect of sertraline on
the pharmacokinetics and protein binding of diazepam in
healthy volunteers. Clin Pharmacokinet 1997; 32 Suppl. 1: 43-9
99. Pearson HJ. Interaction of fluoxetine with carbamazepine [let-
ter]. J Clin Psychiatry 1990; 51 (3): 126
100. Grimsley SR, Jann MW, Carter JG, et al. Increased carbamaz-
epine plasma concentrations after fluoxetine coadministra-
tion. Clin Pharmacol Ther 1991; 50: 10-5
101. Spina E, Avenoso A, Pollocino AM, et al. Carbamazepine
coadministration with fluoxetine or fluvoxamine. Ther Drug
Monit 1993; 15: 247-50
102. Fritze J, Unsorg B, Lanczik M. Interaction between carbamaz-
epine and fluvoxamine. Acta Psychiatr Scand 1991; 84: 583-4
103. Wagner W, Vause EW. Fluvoxamine: a review of global drug-
drug interaction data. Clin Pharmacokinet 1995; 29 Suppl. 1:
26-32
104. Andersen BB, Mikkelsen M, Vesterager A, et al. No influence
of the antidepressant paroxetine on carbamazepine, valproate
and phenytoin. Epilepsy Res 1991; 10 (2-3): 201
105. Rapeport WG, Williams SA, Muirhead DC, et al. Absence of a
sertaline-mediated effect on pharmacokinetics and pharma-
codynamics of carbamazepine. J Clin Psychiatry 1996; 57
Suppl. 1: 20-3
106. Caraco Y, Sheller J, Wood AJJ. Pharmacogenetic determination
of the effects of codeine and prediction of drug interactions.
J Pharmacol Exp Ther 1996; 278 (3): 1165-74
Correspondence and reprints: Dr Claudio A. Naranjo, Uni-
versity of Toronto, Sunnybrook Health Science Centre, Psy-
chopharmacology Research Program, 2075 Bayview Ave,
Rm F327, Toronto, Ontario M4N 3M5, Canada.
e-mail: naranjo@owl.sunnybrook.utoronto.ca
Clin. Pharmacokinet. 1997 Dec; 33 (6)