Epilepsia, 43(Suppl.

2):3744, 2002
Blackwell Publishing, Inc.
International League Against Epilepsy

Clinical Significance of Pharmacokinetic Interactions Between

Antiepileptic and Psychotropic Drugs
*Edoardo Spina and Emilio Perucca
*Institute of Pharmacology, University of Messina, Messina; and Clinical Pharmacology Unit, Department of Internal
Medicine, University of Pavia, Pavia, ltaly

Summary: As antiepileptic drugs (AEDs) and psychotropic

agents are increasingly used in combination, the possibility of
pharmacokinetic interactions between these compounds is relatively common. Most pharmacokinetic interactions between
AEDs and psychoactive drugs occur at a metabolic level, and
usually involve changes in the activity of the cytochrome P450
mixed-function oxidases (CYP) involved in their biotransformation. As a consequence of CYP inhibition or induction,
plasma concentrations of a given drug may reach toxic or subtherapeutic levels, and dosage adjustments may be required to
avoid adverse effects or clinical failure. Enzyme-inducing
AEDs, such as carbamazepine (CBZ), phenytoin (PHT), and
barbiturates, stimulate the oxidative biotransformation of many
concurrently prescribed psychotropics. In particular, these
AEDs may decrease the plasma concentrations of tricyclic antidepressants, many antipsychotics, including traditional compounds, i.e., haloperidol and chlorpromazine, and newer
agents, i.e., clozapine, risperidone, olanzapine, quetiapine, and
ziprasidone, and some benzodiazepines. Conversely, new

AEDs appear to have a lower potential for interactions with all

psychotropic drugs. While antipsychotics and anxiolytics do
not significantly influence the pharmacokinetics of most AEDs,
some newer antidepressants, such as viloxazine, fluoxetine, and
fluvoxamine, may lead to higher serum levels of some AEDs,
namely CBZ and PHT, through inhibition of CYP enzymes. No
significant pharmacokinetic interactions have been documented
between AEDs and lithium. Information about CYP enzymes
responsible for the biotransformation of individual agents and
about the effects of these compounds on the activity of specific
CYP enzymes may help in predicting and avoiding clinically
significant interactions. Apart from careful clinical observation,
serum level monitoring of AEDs and psychotropic drugs can be
useful in determining the need for dosage adjustments, especially if there is any change in seizure control, or possible
toxicity. Key Words: AntiepilepticsAntidepressants
AntipsychoticsAnxiolyticsLithiumPharmacokinetic
interactionsCytochrome P450.

When two or more drugs are administered together,

clinically important interactions may occur, both at pharmacokinetic and at pharmacodynamic levels. Pharmacokinetic interactions consist of changes in the absorption,
distribution, or elimination or the affected drug and/or its
metabolites, whereas pharmacodynamic interactions involve alterations in drug effect(s) at the site of action.
Whereas this classification is useful for didactic purposes, it should be pointed out that many interactions are
multifactorial in nature. In general, pharmacokinetic interactions have been more extensively investigated,
largely because changes in drug concentrations are more
easily quantifiable than are changes in pharmacodynamic
response.
The purpose of this article is to provide a concise
overview of pharmacokinetic interactions between psy-

chotropic agents and antiepileptic drugs (AEDs). These

interactions are relatively common, for a number of reasons (1,2). First, the incidence of psychiatric disorders is
increased in patients with epilepsy, partly as a consequence of the underlying disease and partly as a result of
the adverse effects of some AEDs on mood and behavior.
Second, a number of AEDs, particularly carbamazepine
(CBZ), valproate (VPA), and lamotrigine (LTG), are increasingly used in the management of psychiatric disorders, generally as mood stabilizers and often in
combination with antidepressants, lithium, or antipsychotics. Finally, many AEDs and psychotropics exert a
major influence on the activity of the hepatic drugmetabolizing enzymes, leading to a wide variety of interactions with drugs eliminated by biotransformation.
In light of these considerations, it is no surprise that
most pharmacokinetic interactions between AEDs and
psychotropic drugs occur at metabolic level, and usually
involve changes in the activity of the cytochrome P-450
mixed-function oxidases (CYP) (3,4). This system con-

Address correspondence and reprint requests to Prof. E. Spina at

Institute of Pharmacology, University of Messina, Policlinico Universitario, Via Consolare Valeria, 98125 Messina, Italy. E-mail: espina@
www.unime.it

37

38

E. SPINA AND E. PERUCCA

sists of several isoenzymes divided into families (designated by a first arabic number) and subfamilies
(designated by a capital letter) on the basis of similarities
in their amino acid sequences, with individual isoenzymes being designated by a second arabic number (5).
The major CYP enzymes involved in drug metabolism
include CYPIA2, CYP2C9, CYP2C19, CYP2D6, and
CYP3A4. The activity of these isoenzymes is genetically
determined and may be influenced by environmental factors, such as concomitant administration of other drugs.
Over the past decade there have been great advances in
our understanding of this system, and the different substrates, inhibitors, and inducers of these isoenzymes have
been identified. As indicated in Table l, the majority of
commonly used AEDs and psychotropics are metabolized by CYP enzymes, and some of these also may act
as inhibitors or inducers of one or more of these isoenzymes (6). This knowledge may help the physician to
predict and eventually to avoid 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. If, as
a consequence of concomitant treatment with CYP inhibitors or inducers, plasma concentrations of a given
substrate reach toxic or subtherapeutic levels, dosage adjustments will be required to avoid adverse effects or
clinical failure. Obviously, the opposite will be true after
discontinuation of CYP inhibitors or inducers.
Not all theoretically possible interactions are clinically
relevant, and several factors must be considered when
evaluating the practical implications of a potential interaction (7): (a) the nature of interaction at the enzyme site
(substrate, inhibitor, or inducer); (b) the potency for inhibition/induction; (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; (f) the presence of active metabolites of the substrate; (g) the therapeutic window of the
substrate; (h) the inherent enzyme activity of the individual, and phenotyping/genotyping information; (i) the
risk level for each individual to experience adverse effects (e.g., the elderly); and (j) the probability of the
interacting drugs being used concurrently.
Of the many potential pharmacokinetic interactions
between AEDs and psychotropics, some are well documented, whereas others have been described only in anecdotal reports not confirmed by formal kinetic studies.
INTERACTIONS BETWEEN AEDS
AND ANTIDEPRESSANTS
Effects of AEDs on the pharmacokinetics
of antidepressants
Being potent inducers of hepatic drug-metabolizing
enzymes, particularly CYP3A4, CYP1A2, and CYP2C9,
CBZ, phenytoin (PHT), and barbiturates stimulate the
oxidative transformation of many concurrently prescribed antidepressants. In particular, these AEDs have
been found to decrease the plasma concentration of tricyclic antidepressants such as amitriptyline, nortriptyline, imipramine, desipramine, clomipramine,
desmethylclomipramine, protriptyline, and doxepin (8
16). Because the demethylation of tricyclic antidepressants is catalyzed by multiple isozymes, including
CYP1A2, CYP2C19, and CYP3A4, it is likely that induction of these isoforms is involved in at least some of
the reported interactions.
Another major enzyme contributing to the metabolism
of tricyclic antidepressants, CYP2D6 is generally regarded to be noninducible, even though in two formal

TABLE 1. Antiepileptic and psychotropic drugs as substrates, inhibitors, or inducers of CYP enzymes

Substrates

CYP1A2

CYP2C9

CYP2C19

Tricyclic antidepressants
(demethylation)
Fluvoxamine

Phenytoin
Phenobarbital

Tricyclic antidepressants
(demethylation)
Citalopram

Tricyclic antidepressants
(hydroxylation)
Fluoxetine
Paroxetine

Phenytoin
Diazepam

Venlafaxine
Mianserin

Felbamate

Thioridazine
Fluoxetine
Paroxetine

Clozapine
Olanzapine

Inhibitors

Fluvoxamine

Inducers

Carbamazepine
Phenytoin
Phenobarbital
Primidone

Fluoxetine
Valproate

CYP2D6

CYP3A4
Thioridazine
Perphenazine
Haloperidol
Clozapine
Olanzapine
Risperidone
Sertindole

Tricyclic antidepressants
(demethylation)
Sertraline
Nefazodone
Reboxetine
Diazepam
Alprazolam
Midazolam
Triazolam
Fluoxetine
Fluvoxamine
Nefazodone
Carbamazepine
Phenytoin
Phenobarbital
Primidone
Oxcarbazepinea
Topiramatea
Felbamatea

Oxcarbazepine, topiramate and felbamate are much weaker enzyme inducers compared with carbamazepine, phenytoin, and barbiturates.

Epilepsia, Vol. 43, Suppl. 2, 2002

Haloperidol
Clozapine
Risperidone
Quetiapine
Ziprasidone
Carbamazepine
Felbamate
Tiagabine
Zonisamide

INTERACTIONS OF AEDS AND PSYCHOTROPIC DRUGS

kinetic studies, the 2-hydroxylation of desipramine, a
reaction primarily catalyzed by CYP2D6, was found to
be accelerated by CBZ and PB (17,18). Irrespective of
the mechanism of the interaction, the decrease in plasma
concentrations of tricyclic antidepressants is likely to
have clinical implications, and patients receiving longterm treatment with enzyme-inducing AEDs may require
higher dosage for clinical efficacy to be achieved or
maintained (19).
Conflicting data exist on the possible interaction between VPA, a broad-spectrum inhibitor of drug metabolism, and tricyclic antidepressants. Two studies have
reported a 5060% elevation in plasma amitriptyline and
nortriptyline concentrations in patients comedicated with
VPA (20,21), and there also is evidence that the combination of VPA and clomipramine may result in increased
plasma levels of the antidepressant and its metabolites
with consequent risk for seizures in predisposed patients
(22). In contrast, another study reported an increase in
desipramine concentrations after discontinuation of VPA
(23).
Enzyme-inducing AEDs have been reported to decrease plasma concentrations of some second-generation
antidepressants, such as mianserin and nomifensine
(15,24), but not viloxazine (25). CBZ also has been
found to induce the biotransformation of bupropion, a
new antidepressant that inhibits the reuptake of noradrenaline and dopamine. CBZ decreased the area under
the plasma concentrationversustime curve (AUC) of
bupropion by 84% and increased the AUC of its metabolite hydroxybupropion by 50% (26). As hydroxybupropion may contribute to therapeutic or adverse effects, the
clinical significance of this interaction has not yet been
established.
With respect to the effect of AEDs on the pharmacokinetics of selective serotonin reuptake inhibitors (SSRIs),
there is evidence that phenobarbital (PB) and phenytoin
(PHT) decrease by 25% the plasma levels of paroxetine, probably as a result of accelerated metabolism
(27,28), whereas VPA may somewhat increase the
plasma paroxetine concentrations (28). These pharmacokinetic changes have not been found to be associated
with any obvious alterations in clinical effects.
Effects of antidepressants on the pharmacokinetics
of AEDs
Although AEDs can profoundly affect the plasma concentration of tricyclic antidepressants, there is little evidence that tricyclics can influence the pharmacokinetics
of AEDs. One study showed that nortriptyline coadministration produced a small increase in PHT levels (29),
whereas in another report, plasma PHT concentration
was found to increase in two patients during treatment
with imipramine and to return to baseline after its discontinuation (30).

39

As far as second-generation antidepressants are concerned, a clinically important interaction occurs between
viloxazine and CBZ. A mean 55% increase in plasma
CBZ concentration was observed in six patients with
epilepsy started on viloxazine, and this was associated
with symptoms typical of CBZ intoxication, such as fatigue, dizziness, and ataxia (Fig. 1) (31,32). Discontinuation of viloxazine resulted in remission of the symptoms
and return of CBZ concentrations to pretreatment values.
Viloxazine also was reported to increase the plasma concentration of PHT (33). In a recent case report, trazodone
was found to increase plasma CBZ levels by 30% (34).
With respect to interactions involving SSRIs, there are
several reports of plasma PHT concentrations increasing
to toxic levels after the addition of fluoxetine (3537),
probably because of inhibition of CYP2C9, a major isoenzyme contributing to the metabolism of PHT (38).
Fluoxetine and fluvoxamine are mild to moderate inhibitors of CYP3A4, the primary enzyme involved in the
metabolism of CBZ, but evidence for an interaction between these drugs is conflicting. There have been reports
of increased CBZ concentration and associated toxic effects after coadministration of fluoxetine (39,40) and,
likewise, six healthy volunteers had a significant increase
in the plasma AUC for CBZ (27%) and CBZ-10,11epoxide (31%) when fluoxetine, 20 mg/day for 7 days,
was added to CBZ, 400 mg/day (41). However, in another study, eight epilepsy patients with depressive
symptoms stabilized on CBZ showed no change in
steady-state CBZ and CBZ-10,11-epoxide concentrations when fluoxetine, 20 mg/day, was added for 3 weeks
(42). In a separate investigation, fluoxetine and norfluoxetine had no effect on CBZ clearance in perfused rat
liver, and inhibition of CBZ-10,11-epoxide formation in
human liver microsomes occurred only at concentrations
>20 times those found clinically (43).

FIG. 1. Changes in serum carbamazepine (CBZ) levels during

viloxazine (Vilox.) therapy. Values represent the mean SD in
seven patients. Reproduced from reference 31, with permission.

Epilepsia, Vol. 43, Suppl. 2, 2002

40

E. SPINA AND E. PERUCCA

As with fluoxetine, there are few reports of substantial

increases in plasma CBZ concentration and/or development of CBZ toxicity after the addition of fluvoxamine at
dosages of 100300 mg/day (4446). In contrast, a study
of seven epilepsy patients with depressive symptoms
started on fluvoxamine, 100 mg/day, failed to identify
any modification in CBZ or CBZ-10,11-epoxide concentrations (42). Two other SSRIs, paroxetine and sertraline,
do not seem to affect the plasma concentration of CBZ
(27,47), and paroxetine also was found not to modify the
plasma concentration of PHT and VPA (27). Conversely,
in a patient with bipolar depression treated with VPA, the
addition of sertraline (100 mg/day) resulted in a threefold
elevation in serum VPA concentrations associated with
signs of VPA intoxication (48). A clinically relevant
pharmacokinetic interaction also may occur between sertraline and LTG, a new AED predominantly metabolized
by glucuronide conjugation. A twofold increase in
plasma LTG concentration associated with symptoms of
toxicity was observed 6 weeks after the addition of a low
dose of sertraline, 25 mg/day (49).
INTERACTIONS BETWEEN AEDS
AND ANTIPSYCHOTICS
Effects of AEDs on the pharmacokinetics of
antipsychotic agents
CBZ is increasingly used in combination with antipsychotics both for prevention of seizures and for the treatment of schizoaffective or bipolar disorders. Because of
its potent inducing effects on different CYPs, including
CYPIA2 and CYP3A4, CBZ may cause a clinically significant reduction in the plasma concentrations of many
antipsychotic agents.
In a series of case reports and formal pharmacokinetic
studies, addition of CBZ to haloperidol was found to
decrease plasma haloperidol concentrations by between
20 and 80% (5054), and worsening of therapeutic response has been described in patients receiving moderate
doses of haloperidol (52), but not in those receiving
higher doses (50,51). Because haloperidol is metabolized
predominantly by CYP2D6 and CYP3A4, this interaction is likely to be primarily mediated by induction of
CYP3A4. CBZ also may decrease the plasma concentration of chlorpromazine (54) and mesoridazine, the active
metabolite of thioridazine, but not of thioridazine (55).
Finally, it is well established that CBZ decreases the
plasma concentration of clozapine, an atypical antipsychotic metabolized largely by CYPIA2 and CYP3A4. In
several case studies, addition of CBZ resulted in a mean
50% decrease in plasma clozapine concentrations (55,56)
and elevation of plasma clozapine levels after CBZ discontinuation was reported in two patients (57). Irrespective of the implications of the interaction, the view has
been expressed that the CBZclozapine combination
Epilepsia, Vol. 43, Suppl. 2, 2002

should be avoided because of concerns about potential

additive adverse hematologic effects (58).
With respect to interactions between CBZ and newer
antipsychotics, a formal study in healthy volunteers demonstrated that administration of CBZ for 2 weeks induces
a significant decrease in the peak concentrations, AUC,
and half-life of olanzapine, whereas plasma olanzapine
clearance increased by 46% (59). These effects may be
attributed to CYP1A2-mediated metabolism of olanzapine. A clinically significant interaction between CBZ and
risperidone has been described recently. Risperidone is a
relatively new antipsychotic primarily metabolized by
9-hydroxylation to the active metabolite 9-hydroxyrisperidone. This reaction is catalyzed predominantly by
CYP2D6, but CYP3A4 also plays an important role. In a
case study, addition of CBZ in a schizophrenic patient
stabilized with risperidone resulted in a marked decrease
in the plasma concentrations of both risperidone and its
9-hydroxy metabolite, the effect being associated with an
acute exacerbation of psychotic symptoms (60). A subsequent investigation found that total plasma risperidone
levels (risperidone plus 9-hydroxyrisperidone) were reduced by 70% in patients receiving risperidone and
CBZ compared with patients treated with risperidone
alone or in combination with VPA (Fig. 2) (61). In a
pharmacokinetic study in healthy volunteers, CBZ was
reported to decrease by 35% the AUC of ziprasidone,
presumably through induction of the CYP3A4-mediated
metabolism of this new antipsychotic (62).
PB and PHT also are broad-spectrum enzyme inducers
and would be expected to stimulate the metabolism of
antipsychotic agents similarly to CBZ. Indeed, studies
conducted in the mid-1970s found that coadministration
of PB resulted in lower plasma concentrations of chlorpromazine (6365). Likewise, Linnoila et al. (66) described a significant decrease in the plasma
concentrations of haloperidol and mesoridazine, the active metabo1ite of thioridazine, in patients treated with
PB and/or PHT, but the plasma levels of thioridazine

FIG. 2. Dose-normalized plasma concentrations of active moiety

(sum of concentrations of risperidone and 9-hydroxyrisperidone)
in 11 patients treated with risperidone and carbamazepine (RISP
+ CBZ), in 10 patients treated with risperidone and valproate
(RISP + VPA) and in 23 patients receiving risperidone alone
(RISP). Reproduced from reference 61, with permission.

INTERACTIONS OF AEDS AND PSYCHOTROPIC DRUGS

were not significantly affected by the interaction. Both
PB and PHT have been shown to decrease plasma levels
of clozapine (6769). There also is evidence that PHT
decreases plasma levels of quetiapine, a new antipsychotic whose biotransformation is dependent on
CYP3A4 (70).
Overall, the findings reviewed suggest that the activity
of some antipsychotics may be decreased in patients
treated with enzyme-inducing AEDs, and that larger
antipsychotic dosages may be required to achieve therapeutic efficacy. Conversely, discontinuation of enzymeinducing agents may result in increased antipsychotic
concentrations, with associated risk of toxicity.
Like CBZ, VPA is increasingly used in combination
with antipsychotics. In particular, it has been used as a
prophylactic agent to prevent seizures in patients already
receiving clozapine, or as a first-line agent in conjunction
with antipsychotics to treat bipolar affective disorders.
Controversial findings have been reported concerning
the effect of VPA on clozapine disposition. Although
VPA may act as a metabolic inhibitor and may increase
the plasma concentrations of many other drugs (71), two
reports suggested that the plasma concentrations of
clozapine and its metabolites may decrease after the addition of VPA (72,73). Conversely, other studies (74,75)
reported that patients comedicated with VPA had significantly higher concentrations of clozapine and slightly
lower concentrations of metabolically derived norclozapine compared with patients taking clozapine alone. As
mentioned earlier, a recent study in schizophrenic patients indicated that VPA does not modify total plasma
risperidone concentrations (61).
The interaction between topiramate (TPM), a newer
AED, and haloperidol was investigated in healthy volunteers (76). Twelve subjects received a single 2-mg
dose of haloperidol before (day 1) and during multiple
dosing with TPM (day 14). TPM dosing began on day 8
at 100 mg/day with titration to 150 mg/day on day 9 and
200 mg/day on days 1016. TPM slightly increased
plasma haloperidol concentrations: although differences
in AUC (but not Cmax) were significant, 90% confidence
intervals for the ratio of AUC means were within bioequivalence limits.
Effects of antipsychotic agents on the
pharmacokinetics of antiepileptic drugs
Antipsychotics of the phenothiazine class, thioridazine
and chlorpromazine, are potent inhibitors of CYP2D6
(77), but there is no evidence that this isozyme plays a
primary role in the metabolism of any major AED. There
are anecdotal reports that thioridazine and chlorpromazine may cause PHT intoxication (78,79), probably by
inhibiting its metabolism. In addition, thioridazine has
been reported to increase the plasma concentration of PB
(80). Many patients, however, tolerate the combination

41

of phenothiazines and AEDs without any apparent

change in the plasma levels of PB, PHT, or CBZ (66,81,
82). All new antipsychotics are only weak in vitro inhibitors of CYPs, and therefore these agents are not
expected to affect the metabolism of concurrently administered AEDs.
INTERACTIONS BETWEEN AEDS
AND LITHIUM
Many AEDs, including a number of newer agents, are
increasingly used in the management of bipolar disorder
and other conditions in which lithium also is indicated.
There is some evidence that the combination of lithium
and CBZ may lead to an increased incidence of neurotoxicity, but the mechanism of interaction appears to be
mainly pharmacodynamic (83,84). As far as potential
pharmacokinetic interactions between lithium and VPA
are concerned, a recent study in rats suggested that
lithium may decrease serum VPA levels, but the applicability of these data to the clinical setting remains to be
confirmed (85).
In one study conducted in 13 patients (86), gabapentin
(GBP) at a mean daily dosage of 3,646 mg had no significant influence on the pharmacokinetics of a single
dose of lithium (600 mg). In another study in 20 healthy
volunteers, LTG, 100 mg daily, also was found not to
influence steady-state lithium concentrations (87). Conversely, an investigation in 12 subjects showed that
TPM, at dosages 200 mg/day, slightly reduced serum
lithium concentrations at steady state (88). This effect
may be mediated by TPM-induced inhibition of carbonic
anhydrase, which transiently increases renal clearance of
monovalent cations, including lithium.
INTERACTIONS BETWEEN AEDS
AND ANXIOLYTICS
Most anxiolytic agents do not influence the disposition
of AEDs, but there is evidence that enzyme-inducing
AEDs may stimulate the biotransformation of many benzodiazepines (BZDs), compounds primarily metabolized
by CYP3A4. In general, given the wide therapeutic index
of these agents, the clinical significance of these interactions is limited. CBZ has been reported to induce the
conversion of clobazam (CLB) and diazepam (DZP) to
their active metabolites norclobazam and nordiazepam,
respectively (89,90). Because norclobazam and nordiazepam are pharmacologically active, these interactions
may not necessarily result in a decreased clinical response to these BZDs. CBZ also has been demonstrated
to enhance the clearance of clonazepam (CZP) and alprazolam (91,92). In a case study, CBZ-induced decrease
in plasma levels of alprazolam resulted in a worsening of
clinical symptoms (93). A clinically relevant interaction
also occurs between enzyme-inducing AEDs and midEpilepsia, Vol. 43, Suppl. 2, 2002

42

E. SPINA AND E. PERUCCA

6.
7.

8.
9.

10.

11.
FIG. 3. Serum midazolam concentration (mean SD) after a
single oral 15-mg dose in six patients with epilepsy () and seven
healthy individuals () in a control group. Five of the six patients
received carbamazepine [in combination with phenytoin (PHT) in
three cases], and one received PHT. Reproduced from reference
94, with permission.

12.

13.

14.

azolam (MDL), another substrate of CYP3A4 (94).

Plasma MDL concentrations after a single oral dose were
found to be reduced dramatically in patients treated with
CBZ and PHT, because of induction of CYP3A4mediated first-pass metabolism in the liver (Fig. 3).

15.

16.

CONCLUSIONS
Because concomitant administration of AEDs and
psychotropic drugs is relatively common, the possibility
of pharmacokinetic interactions between these drugs
must be considered. Information about CYP enzymes
responsible for the biotransformation of individual
agents and about the effects of these compounds on the
activity of specific CYP enzymes may help in predicting
and avoiding clinically significant interactions. Apart
from careful clinical observation, monitoring of plasma
concentrations of the relevant drugs may be useful in
determining the need for adjustments in individual cases.
Acknowledgment: Professor Trimble and the members of
The Commission for the Psychobiology of Epilepsy are very
grateful to the International League Against Epilepsy for their
financial support of the commission and for their help with the
publication of this supplement.

17.

18.
19.
20.

21.

22.

23.

24.
25.

REFERENCES
1. Perucca E, Manzo L, Crema A. Pharmacokinetic interactions between antiepileptic and psychotropic drugs. In: Trimble MR, ed.
The psychopharmacology of epilepsy. London: John Wiley &
Sons, 1985:95105.
2. Monaco F, Cicolin A. Interactions between anticonvulsant and
psychoactive drugs. Epilepsia 1999;40(suppl 10):716.
3. Gonzalez FJ. Human cytochrome P450: problem and prospects.
Trend Pharmacol Sci Rev 1992;13:34652.
4. Guengerich FP. Role of cytochrome P450 enzymes in drug-drug
interactions. Adv Pharmacol 1997;43:735.
5. Nelson DR, Kamataki T, Waxman DJ, et al. The P450 superfamily:

Epilepsia, Vol. 43, Suppl. 2, 2002

26.

27.

28.

29.

update on new sequences, gene mapping, accessum numbers, early

trivial names of enzymes and nomenclature. DNA Cell Biol
1993;12:151.
Levy RH, Thummel KE, Trager WF, et al., eds. Metabolic drug
interactions. Philadelphia: Lippincott Williams & Wilkins, 2000.
Sproule BA, Naranjo CA, Bremner KE, et al. Selective serotonin
reuptake inhibitors and CNS drug interactions: a critical review of
the evidence. Clin Pharmacokinet 1997;33:45471.
Burrows GD, Davies B. Antidepressants and barbiturates. Br Med
J 1971;4:113.
Braithwaite RA, Flanagan RA, Richens A. Steady-state plasma
nortriptyline concentrations in epileptic patients. Br J Clin Pharmacol 1975;2:46971.
Hewick DS, Sparks RG, Stevenson IH, et al. Induction of imipramine metabolism following barbiturate administration. Br J Clin
Pharmacol 1977;4:339.
Moody JP, Whyte SF, McDonald AJ, et al. Pharmacokinetic aspects of protriptyline plasma level. Eur J Clin Pharmacol
1977;11:516.
Traskman L, Asberg M, Bertilsson L, et al. Plasma levels of chlorimipramine and its desmethyl metabolite during treatment of depression. Clin Pharmacol Ther 1979;26:60010.
Baldessarini RJ, Teicher MH, Cassidy JW, et al. Anticonvulsant
cotreatment may increase toxic metabolites of antidepressants and
other psychotropic drugs. J Clin Psychopharmacol 1988;8:3812.
Brown CS, Wells BG, Cold JA, et al. Possible influence of carbamazepine on plasma imipramine concentration in children with
attention deficit hyperactivity. J Clin Psychopharmacol
1990;10:35962.
Leinonen E, Lillsunde P, Laukkanen V, et al. Effects of carbamazepine on serum antidepressant concentrations in psychiatric patients. J Clin Psychopharmacol 1991;11:3138.
Jerling M, Bertilsson L, Sjoqvist F. The use of therapeutic drug
monitoring data to document kinetic drug interactions: an example
with amitriptyline and nortriptyline. Ther Drug Monit 1994;16:1
12.
Spina E, Avenoso A, Campo GM, et al. The effect of carbamazepine on the 2-hydroxylation of desipramine. Psychopharmacology 1995;117:4136.
Spina E, Avenoso A, Campo GM, et al. Phenobarbital induces the
2-hydroxylation of desipramine. Ther Drug Monit 1996;18:604.
Brosen K, Kragh-Sorensen P. Concomitant intake of nortriptyline
and carbamazepine. Ther Drug Monit 1993;15:25860.
Vandel S, Bertschy G, Jounet JM, et al. Valpromide increases the
plasma concentrations of amitriptyline and its metabolite nortriptyline in depressive patients. Ther Drug Monit 1988;10:3869.
Bertschy G, Vandel S, Jounet JM, et al. Valpromide-amitriptyline
interaction: increase in the bioavailability of amitriptyline and nortriptyline caused by valpromide. Encephale 1990;16:435.
DeToledo JC, Haddad H, Ramsay RE. Status epilepticus associated with the combination of valproic acid and clomipramine. Ther
Drug Monit 1997;19:713.
Joseph AB, Wroblewsky BA. Potentially toxic serum concentrations of desipramine after discontinuation of valproic acid. Brain
Injury 1993;7:4635.
Nawishy S, Hathaway N, Turner P. Interaction of anticonvulsant
drugs with mianserin and nomifensine. Lancet 1981;2:8701.
Pisani F, Fazio A, Spina E, et al. Pharmacokinetics of the antidepressant drug viloxazine in normal subjects and in epileptic
patients receiving chronic anticonvulsant treatment. Psychopharmacology 1986;90:2958.
Ketter TA, Jenkins JB, Schroeder DH, et al. Carbamazepine but
not valproate induces bupropion metabolism. J Clin Psychopharmacol 1995;15:32733.
Greb WH, Buscher G, Dierdorf HD. The effect of liver enzyme
inhibition by cimetidine and enzyme induction by phenobarbitone
on the pharmacokinetics of paroxetine. Acta Psychiatr Scand
1989;80(suppl 350):958.
Andersen BB, Mikkelsen M, Vesterager A, et al. No influence of
the antidepressant paroxetine on carbamazepine valproate and phenytoin. Epilepsy Res 1991;10:2014.
Houghton GW, Richens A. Inhibition of phenytoin metabolism by

INTERACTIONS OF AEDS AND PSYCHOTROPIC DRUGS

30.
31.

32.

33.

34.
35.

36.
37.
38.
39.
40.
41.

42.

43.

44.
45.
46.

47.

48.
49.
50.

51.

52.

53.

54.

55.

56.

other drugs used in epilepsy. Int J Clin Pharmacol 1975;12:210

216.
Perucca E, Richens A. Interaction between phenytoin and imipramine. Br J Clin Pharmacol 1977;4:4856.
Pisani F, Narbone MC, Fazio A, et al. Increased serum carbamazepine levels by viloxazine in epileptic patients. Epilepsia
1984;25:4825.
Pisani F, Fazio A, Oteri G, et al. Carbamazepine-viloxazine interaction in patients with epilepsy. J Neurol Neurosurg Psychiatry
1986;49:11425.
Pisani F, Fazio A, Artesi C, et al. Elevation of plasma phenytoin by
viloxazine in epileptic patients: a clinically significant drug interaction. J Neurol Neurosurg Psychiatry 1992;55:1267.
Romero AS, Delgado RG, Pena MF. Interaction between trazodone and carbamazepine. Ann Pharmacother 1999;33:1370.
Jalil P. Toxic reaction following the combined administration of
fluoxetine and phenytoin: two case reports. J Neurol Neurosurg
Psychiatry 1992;55:4123.
Darley J. Interaction between phenytoin and fluoxetine. Seizure
1994;3:1512.
Woods DJ, Coulter DM, Pillans P. Interaction of phenytoin and
fluoxetine. N Z Med J 1994;107:19.
Shader RI, Greenblatt DJ, Von Moltke LL. Fluoxetine inhibition of
phenytoin metabolism. J Clin Psychopharmacol 1994;14:3756.
Pearson HJ. Interaction of fluoxetine with carbamazepine. J Clin
Psychiatry 1990;51:126.
Dursun SM, Mathew VM, Reveley MA. Toxic serotonin syndrome
after fluoxetine plus carbamazepine. Lancet 1993;342:4423.
Grimsley SR, Jann MW, Carter JG, et al. Increased carbamazepine
concentrations after fluoxetine coadministration. Clin Pharmacol
Ther 1991;50:105.
Spina E, Avenoso A, Pollicino M, et al. Carbamazepine coadministration with fluoxetine or fluvoxamine. Ther Drug Monit
1993;15:24750.
Gidal BE, Anderson GD, Seaton TL, et al. Evaluation of the effect
of fluoxetine on the formation carbamazepine epoxide. Ther Drug
Monit 1993;15:4059.
Fritze J, Unsorg B, Lanczik M. Interaction between carbamazepine
and fluvoxamine. Acta Psychiatr Scand 1991;84:5834.
Bonnet P, Vandel S, Nezeloff S, et al. Carbamazepine, fluoxetine:
is there a pharmacokinetic interaction? Therapie 1992;47:167.
Martinelli V, Bocchetta A, Plamas AM, et al. An interaction between carbamazepine and fluvoxamine. Br J Clin Pharmacol
1993;36:6156.
Rapeport WG, Williams SA, Muirhead DC, et al. Absence of a
sertraline-mediated effect on pharmacokinetics and pharmacodynamics of carbamazepine. J Clin Psychiatry 1996;57(suppl 1):
203.
Berigan TR, Harazin J. A sertraline/valproic acid drug interaction.
Int J Psychiatr Clin Pract 1999;3:2878.
Kaufman KR, Gerner R. Lamotrigine toxicity secondary to lasertraline. Seizure 1998;7:1635.
Kidron R, Avrebach I, Klein E, et al. Carbamazepine-induced reduction of blood levels of haloperidol in chronic schizophrenia.
Biol Psychiatry 1985;20:21922.
Jann MW, Ereshefsky L, Saklad SR, et al. Effects of carbamazepine on plasma haloperidol levels. J Clin Psychopharmacol
1985;5:1069.
Arana GW, Goff DC, Friedman H, et al. Does carbamazepine
induced reduction of plasma haloperidol levels worsen psychotic
symptoms? Am J Psychiatry 1986;143:6501.
Kahn EM, Schulz SC, Perel JM, et al. Change in haloperidol level
due to carbamazepine: a complicating factor in combined medication for schizophrenia. J Clin Psychopharmacol 1990;10:547.
Raitasuo V, Lehtovaara R, Huttonen MO. Effect of switching carbamazepine to oxcarbazepine on the plasma levels of neuroleptics.
Psychopharmacology 1994;116:1156.
Tiihonen J, Vartiainen H, Hakola P. Carbamazepine-induced
changes in plasma levels of neuroleptics. Pharmacopsychiatry
1995;28:268.
Jerling M, Lindstrom L, Bondesson U, et al. Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine:

57.
58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.
70.

71.
72.
73.

74.

75.

76.

77.

78.
79.
80.
81.

43

evidence from a therapeutic drug monitoring service. Ther Drug

Monit 1994;16:3684.
Raitasuo V, Lehtovaara R, Huttunen OM. Carbamazepine and
plasma levels of clozapine. Am J Psychiatry 1996;152:169.
Junghan U, Albers M, Woggon B. Increased risk of hematological
side-effects in psychiatric patients treated with clozapine and carbamazepine? Pharmacopsychiatry 1993;26:262.
Lucas RA, Gilfillan DJ, Bergstrom RF. A pharmacokinetic interaction between carbamazepine and olanzapine: observations on
possible mechanisms. Eur J Clin Pharmacol 1998;54:63943.
Spina E, Scordo MG, Avenoso A, et al. Adverse drug interaction
between risperidone and carbamazepine in a patient with chronic
schizophrenia and deficient CYP2D6 activity. J Clin Psychopharmacol 2001;21:1089.
Spina E, Avenoso A, Facciol G, et al. Plasma concentrations of
risperidone and 9-hydroxyrisperidone: effect of comedication with
carbamazepine or valproate. Ther Drug Monit 2000;22:4815.
Miceli JJ, Anziano RJ, Robarge L, et al. The effect of carbamazepine on the steady-state pharmacokinetics of ziprasidone in
healthy volunteers. Br J Clin Pharmacol 2000;49(suppl 1):65S
70S.
Forrest FM, Forrest IS, Serra MT. Modifications of chlorpromazine metabolism by some other drugs frequently administered to
psychiatric patients. Biol Psychiatry 1970;2:538.
Curry SH, Davis JM, Janowsky DS, et al. Factors affecting chlorpromazine plasma levels in psychiatric patients. Arch Gen Psychiatry 1970;22:20915.
Loga S, Curry S, Lader M. Interactions of orphenadrine and phenobarbitone with chlorpromazine plasma concentrations and effects in man. Br J Clin Pharmacol 1975;2:197208.
Linnoila M, Viukari M, Vaisanen K, et al. Effect of anticonvulsants on plasma haloperidol and thioridazine levels. Am J Psychiatry 1980;137:81921.
Facciol G, Avenoso A, Spina E, et al. Inducing effect of phenobarbital on clozapine metabolism in patients with chronic schizophrenia. Ther Drug Monit 1998;20:62830.
Cheng YF, Lundberg T, Bondesson U, et al. Clinical pharmacokinetics of clozapine in chronic schizophrenic patients. Eur J Clin
Pharmacol 1988;34:4459.
Miller DD. Effect of phenytoin on plasma clozapine concentrations
in two patients. J Clin Psychiatry 1991;52:235.
Wong YWJ, Yeh C, Thyrum P. The effects of concomitant phenytoin administration on the steady-state pharmacokinetics of
quetiapine. J Clin Psychopharmacol 2001;21:8993.
Bourgeois BFD. Pharmacological interactions between valproate
and other drugs. Am J Med 1988;84:2933.
Finley P, Warner D. Potential impact of valproic acid therapy on
clozapine disposition. Biol Psychiatry 1994;36:4878.
Longo LP, Salzman C. Valproic acid effects on serum concentrations of clozapine and norclozapine. Am J Psychiatry 1995;152:
650.
Centorrino F, Baldessarini RJ, Kando J, et al. Serum concentrations of clozapine and its metabolites: effects of cotreatment with
fluoxetine or valproate. Am J Psychiatry 1994;151:1235.
Facciol G, Avenoso A, Scordo GM, et al. Small effects of valproic acid on the plasma concentrations of clozapine and its major
metabolites in patients with schizophrenic or affective disorders.
Ther Drug Monit 1999;21:3415.
Doose DR, Kohl KA, Desai-Krieger D, et al. No clinically significant effect of topiramate on haloperidol plasma concentration. Eur
Neuropsychopharmacol 1999;9:S357.
Spina E, Martines C, Caputi AP, et al. Debrisoquine oxidation
phenotype during neuroleptic monotherapy. Eur J Clin Pharmacol
1991;41:46770.
Vincent FM. Phenothiazine-induced phenytoin intoxication. Ann
Intern Med 1980;93:567.
Kutt H. Interactions between anticonvulsants and other commonly
prescribed drugs. Epilepsia 1984;225(suppl 2):S11831.
Gay PE, Madsen JA. Interaction between phenobarbital and thioridazine. Neurology 1983;33:16312.
Sands CD, Robinson JD, Salem RB, et al. Effect of thioridazine on
phenytoin serum concentrations: a retrospective study. Drug Intell
Clin Pharmacol 1987;21:26772.

Epilepsia, Vol. 43, Suppl. 2, 2002

44

E. SPINA AND E. PERUCCA

82. Spina E, Amendola DAgostino AM, Ioculano MP, et al. No effect

of thioridazine on plasma concentrations of carbamazepine and its
active metabolite carbamazepine-10,11-epoxide. Ther Drug Monit
1990;12:5113.
83. Chaudhry RP, Waters BG. Lithium and carbamazepine interaction:
possible neurotoxicity. J Clin Psychiatry 1983;44:301.
84. Marcoux AW. Carbamazepine-lithium interaction. Ann Pharmacother 1996;30:547.
85. Yoshioka H, Ida S, Yokota M, et al. Effects of lithium on the
pharmacokinetics of valproate in rats. J Pharm Pharmacol
2000;52:297301.
86. Fye MA, Kimbrell TA, Dunn RT, et al. Gabapentin does not alter
single-dose lithium pharmacokinetics. J Clin Psychopharmacol
1998;18:4614.
87. Chen C, Veronese L, Yin Y. The effects of lamotrigine on the
pharmacokinetics of lithium. Br J Clin Pharmacol 2000;50:1935.
88. Doose DR, Kohl KA, Desai-Krieger D, et al. No significant effect
of topiramate on lithium serum concentration. Presented at the XI
World Congress of Psychiatry, Hamburg, Germany.

Epilepsia, Vol. 43, Suppl. 2, 2002

89. Levy RH, Lane EA, Guyot M, et al. Analysis of parent drugmetabolite relationship in the presence of an inducer: application to
the carbamazepine-clobazam interaction in normal man. Drug
Metab Dispos 1983;11:28692.
90. Dhillon S, Richens A. Pharmacokinetics of diazepam in epileptic
patients and normal volunteers following intravenous administration. Br J Clin Pharmacol 1981;12:8414.
91. Lai AA, Levy RH, Cutler RE. Time-course of interaction between
carbamazepine and clonazepam in normal man. Clin Pharmacol
Ther 1978;24:31623.
92. Furukori H, Otani K, Yasui N, et al. Effect of carbamazepine on
the single oral dose pharmacokinetics of alprazolam. Neuropsychopharmacology 1998;18:3649.
93. Arana GW, Epstein S, Molloy M, et al. Carbamazepine-induced
reduction of plasma alprazolam concentrations: a clinical case report. J Clin Psychiatry 1988;49:488.
94. Backman TJ, Olkkola KT, Ojala M, et al. Concentrations and
effects of oral midazolam are greatly reduced in patients on carbamazepine or phenytoin. Epilepsia 1996;37:2537.