Pharmacological Research 106 (2016) 72–86

Contents lists available at ScienceDirect

Pharmacological Research
journal homepage: www.elsevier.com/locate/yphrs

Review

Clinically significant pharmacokinetic drug interactions of

antiepileptic drugs with new antidepressants and new antipsychotics
Edoardo Spina a,∗ , Francesco Pisani a , Jose de Leon b,c,d
a
Department of Clinical and Experimental Medicine, University of Messina, Italy
b
University of Kentucky Mental Health Research Center at Eastern State Hospital, Lexington, KY, United States
c
Psychiatry and Neurosciences Research Group (CTS-549), Institute of Neurosciences, University of Granada, Granada, Spain
d
Biomedical Research Centre in Mental Health Net (CIBERSAM), Santiago Apostol Hospital, University of the Basque Country, Vitoria, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Antiepileptic drugs (AEDs) are frequently co-prescribed with new antidepressants (ADs) or new antipsy-
Received 21 January 2016 chotics (APs). A PubMed search with no time limit was used to update the review of the clinically
Received in revised form 8 February 2016 significant pharmacokinetic (PK) drug interactions DIs (DIs) between AEDs with new ADs and APs. Our
Accepted 11 February 2016
best interpretation of what to expect regarding dosing changes in the average patient after combining
Available online 16 February 2016
AEDs with new ADs or new APs is summarized on updated tables that integrate the information on
in vitro metabolism studies, therapeutic drug monitoring (TDM) studies, case report/series and prospec-
Keywords:
tive studies. There will be a need to periodically update these dose correction factors as new knowledge
Antiepileptics
Antidepressants becomes available. These tables will provide some orientation to clinicians with no TDM access and
Antipsychotics may also encourage clinicians to further study TDM. The clinical relevance of the inductive proper-
Drug interactions ties of carbamazepine, phenytoin, phenobarbital and primidone on new ADs and new APs and the
Pharmacodynamics inhibitory properties of valproic acid and some new ADs, are relatively well understood. On the other
Pharmacokinetics hand, PK DI studies combining new AEDs with weak inductive properties (particularly oxcarbazepine
doses ≥ 1200 mg/day), topiramate doses ≥ 400 mg/day, clobazam, eslicarbazepine, and rufinamide), with
new ADs and new APs are needed. Valproic acid may be 1) an inhibitor and/or inducer of clozapine and
olanzapine with potential for clinically relevant DIs, 2) an inhibitor of paliperidone, and 3) a weak inducer
of aripiprazole. Fluoxetine and fluvoxamine are relevant inhibitors of phenytoin and valproic acid and
possibly of clobazam, lacosamide, phenobarbital, or primidone.
© 2016 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
2. Basic mechanisms of DIs between AEDs and new psychotropic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
2.1. PK DIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
2.2. PD DIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
3. DIs between AEDs and new ADs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
3.1. Effect of AEDs on the PKs of new ADs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
3.1.1. Enzyme-inducing AEDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
3.1.2. Valproic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
3.1.3. Newer AEDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
3.2. Effect of new ADs on the PKs of AEDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
3.2.1. SSRIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
3.2.2. SNRIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

∗ Corresponding author at: Department of Clinical and Experimental Medicine,

University of Messina, Policlinico Universitario, Via Consolare Valeria, 98125
Messina, Italy.
E-mail address: espina@unime.it (E. Spina).

http://dx.doi.org/10.1016/j.phrs.2016.02.014
1043-6618/© 2016 Elsevier Ltd. All rights reserved.
 E. Spina et al. / Pharmacological Research 106 (2016) 72–86 73

3.2.3. Other newer antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

4. DIs between AEDs and new APs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
4.1. Effect of AEDs on the PKs of new APs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
4.1.1. Carbamazepine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
4.1.2. Phenobarbital/phenytoin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
4.1.3. Valproic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
4.1.4. Lamotrigine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
4.1.5. Oxcarbazepine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
4.1.6. Topiramate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
4.1.7. Other newer AEDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
4.2. Effect of new APs on the PKs of AEDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

1. Introduction sive disorder, psychosis and behavioral disorders in dementia,

psychosis associated with Parkinson’s disease, resistant obsessive-
When polypharmacotherapy is used, there is a potential risk of compulsive disorder, aggressive behavior and irritability in autism
drug interactions (DIs) [1]. A clinically relevant DI occurs when the spectrum disorders [5].
efficacy or safety of a drug is altered by the concomitant administra- Considering the frequent co-prescription of AEDs with new psy-
tion of another medication. In a few cases DIs may prove beneficial, chotropic agents, it is essential for clinicians to be aware of the
resulting in an increased efficacy or reduced risk of adverse drug potential DIs between these compounds. In recent years, a number
reactions, and therefore certain drug combinations may be used of comprehensive reviews of clinically relevant pharmacokinetic
advantageously in clinical practice. However, more often, DIs are DIs involving AEDs [2,6–11], new ADs [12,13], new APs [14,15],
harmful, leading to diminished efficacy or increased toxicity of one or combinations [3,16–20] have been published. The purpose of
or more of the administered medications. this article is to provide an updated review of clinically significant
DIs represent a frequent complication associated with the use of pharmacokinetic DIs between AEDs and new ADs and APs.
antiepileptic drugs (AEDs) [2]. AEDs are generally administered for Articles for this review were obtained from a PubMed search
prolonged periods, often for a lifetime, increasing the probability with no time limit. Searches were conducted for each of the AEDs,
of co-medication with other AEDs or drugs used for the manage- new ADs or new APs. Only articles published in peer-reviewed
ment of associated disorders. In this respect, AEDs are increasingly journals were included, while meeting abstracts were excluded.
prescribed in combination with psychotropic agents for a variety of Information was also obtained from the individual product inserts
reasons [3]. Firstly, there is a relatively high incidence of psychiatric of each AED, new AD or new AP. Additional DI information was also
disorders in patients with epilepsy. Secondly, a number of AEDs, obtained from citations of the articles that were retrieved during
notably carbamazepine, valproic acid and lamotrigine, are increas- our search, and these were also included in our review. This search
ingly used in the management of psychiatric disorders, generally was beyond the articles previously found and listed in the authors’
as mood stabilizers, and may be co-administered with psychoac- published literature reviews and DI studies.
tive medications. Thirdly, AEDs are extensively prescribed for the
management of various non-epileptic conditions (i.e., neuropathic 2. Basic mechanisms of DIs between AEDs and new
pain, migraine), further enhancing the possibility of combination psychotropic agents
therapy.
In recent years, new psychotropic drugs, in particular antide- Based on their mechanisms, DIs can be classified as either phar-
pressants (ADs) and antipsychotics (APs), have been introduced macokinetic (PK) or pharmacodynamic (PD).
into clinical practice. In addition to older or traditional ADs,
such as tricyclic antidepressants (TCAs) and monoamine oxi- 2.1. PK DIs
dase inhibitors (MAOIs), newer ADs including selective serotonin
reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake PK DIs consist of changes in the absorption, distribution,
inhibitors (SNRIs) and other ADs with varying mechanisms of action metabolism or excretion of a drug and/or its metabolite(s) after the
are currently available [4]. Some of these agents, notably SSRIs, addition of another drug. These DIs are associated with a modifica-
have progressively replaced older compounds for the treatment of tion in plasma concentration of either the drug or its metabolite(s)
depressive disorders, mainly because of their improved tolerability and usually are easily verified by therapeutic drug monitoring
and safety profile. New ADs are also widely used for the treatment of (TDM). PK parameters of AEDs, newer ADs and newer APs are sum-
other psychiatric conditions including anxiety disorders, obsessive- marized in Tables 1– , respectively.
compulsive disorder, eating disorders, and various forms of chronic The majority of clinically important PK DIs between AEDs and
pain such as diabetic neuropathic pain and fibromyalgia [4]. Con- new psychotropic agents occur at a metabolic level and usu-
cerning APs, over the past two decades, second-generation APs ally involve the hepatic cytochrome P450 (CYP) system and, to
(amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, a lesser extent, the uridine diphosphate glucuronosyltransferase
clozapine, iloperidone, lurasidone, olanzapine, paliperidone, que- (UGT) system [21]. In recent years, the in vitro characterization of
tiapine,risperidone, and ziprasidone) have become the drugs of the major drug-metabolizing enzymes with identification of sub-
choice for the management of psychotic disorders due to better strates, inhibitors and inducers of different CYP isoforms has greatly
safety profiles for reversible extrapyramidal symptoms and tar- improved the prediction of metabolic DIs, providing an invaluable
dive dyskinesia as compared to first-generation APs [5]. Moreover, resource in helping to anticipate and avoid potential DIs [21]. In
new APs are increasingly prescribed not only for schizophrenia principle, concomitant treatment with drugs metabolized by the
and bipolar disorder, but for adjuvant treatment of major depres- same enzyme or co-administration of a drug with another medica-
Table 1
PK parameters of AEDs. Based on [1,10,19].

74
Bioavail-ability (%) Protein binding (%) Half-life (h) Most important Other ways of Active metabolites Induction or inhibition of metabolic enzymes
way of eliminationa elimination

FIRST-GENERATION AEDs
Carbamazepine 75−85 75 5−26 CYP3A4b CYP2C8, CYP1A2, Carbamazepine Induction of CYP1A2, CYP2A6, CYP2B6,
UGT2B7, epoxide epoxide CYP2C9, CYP2C19, CYP3A4, UGT1A1, UGT2B7,
hydrolase UGT2B15, epoxide hydrolase
Ethosuximide 90−100 <10 25−70 CYP3A4b CYP2E1, renal
Phenytoin 90 90 7−80 CYP2C9b CYP2C19 (less Induction of CYP1A2, CYP2B6, CYP2C8, CYP2C9,
important: CYP2C19, CYP3A4, UGTs, epoxide hydrolase
CYP2C18, CYP3A4)
Phenobarbital >95 45−60 70−130 CYP2C9b CYP2C19, CYP2E1, Induction of CYP1A2, CYP2B6, CYP2C8,
N-glucosidation, CYP2C9, CYP2C19, CYP2E1, CYP3A4, UGT,
renal epoxide hydrolase
Primidone >90 10 5−20 CYP2C9b Renal, CYP2C19, Phenobarbital Induction of CYP1A2, CYP2B6, CYP2C8,
CYP2E1, CYP2C9, CYP2C19, CYP2E1, CYP3A4, UGT,
N-glucosidation, epoxide hydrolase
Valproic acid >90 70−95 8−16 Several UGTs ␤-oxidation, Inhibition of CYP2C9, UGT1A4, UGT2B7,
CYP2C9 (other epoxide hydrolase, N-glucosidation.
CYPs are minor) Mild auto-induction3
and mild induction of other drugsc

E. Spina et al. / Pharmacological Research 106 (2016) 72–86

SECOND-GENERATION AEDs
Clobazam ∼100 80−90 36−42 CYP3A4b CYP2C19d N- Mild induction of CYP3A4
desmethylclobazam Mild inhibition of CYP2C19 and CYP2D6
Eslicarbazepine ∼100 30 13−20 UGTs e
Renal S-licarbazepine Mild induction of CYP3A4, UGTs.
Mild inhibition of CYP2C9, CYP2C19
Felbamate 90 20−25 11−25 CYP3A4b Renal, CYP2E1, Mild induction of CYP3A4
UGTs Inhibition of CYP2C19, ␤-oxidation
Gabapentin <65 0 5−9 Renal
Lacosamide ∼100 <15 12−16 CYP2C19b Renal
Lamotrigine >95 55 25 UGT1A4 Mild induction of UGTs.
Levetiracetam 100 <10 6−8 Renal Esterase hydrolysis
in blood
Oxcarbazepine ∼100 40 7−12 Renal UGTs MHD Mild induction of CYP3A4, UGTs
(monohydroxy Mild inhibition of CYP2C19.
derivate)f
Perampanel ∼100 95 52−129 CYP3A4 UGTs Mild induction of CYP3A4
Pregabalin >90 0 5−7 Renal
Retigabine 60 80 8−10 Arylamine N-acetyl UGTs
(ezogabine) transferase-2
Rufinamide 85 30 8−12 Carboxyles-terases Mild induction of CYP3A4, UGTs
Mild inhibition of CYP2E1.
Stiripentol ≥70 99 4.5−13 CYP1A2, CYP2C19, Inhibition of CYP1A2, CYP2C19, CYP2D6,
CYP3A4, UGTsg CYP3A4.
Tiagabine ∼100 96 5−9 CYP3A4b
Topiramate ∼100 13−17 10−30 Renal CYP Mild induction of CYP3A4, ␤-oxidation,
UGT1A4.
Mild inhibition of CYP2C19.
Vigabatrin ≥50 0 4−7 Renal CYP (only 10%) Mild induction of CYP2C9.
Zonisamide ∼100 50 50−70 CYP3A4b N-acetylation
transferase, renal

AED: antiepileptic drugs; CYP: cytochrome P450; PK: pharmacokinetics; UGT: uridine diphosphate glucuronosyltransferase.
a
This refers to normal metabolism. Some subjects may not have this enzyme or have it inhibited. Other enzymes may become more important during induction.
b
Any substrate competes with others for the corresponding enzyme and inhibits it (competitive inhibition). There is data in the literature that competitive inhibition may occur at CYP1Ab, CYPbC9, CYPbC19, CYPbD6, and
CYP3A4. UGTs tend to have overlapping substrates and it is not clear that they can be subject to competitive inhibition. A good example of competitive inhibition is phenytoin in high serum concentrations (>20 mcg/ml) which
may saturate its metabolic enzymes, CYPbC9 and CYPbC19, completely or almost completely.
c
Valproic acid has been demonstrated to have mild auto-induction properties by inducing ␤-oxidation. Valproate may be an inducer of the metabolism of other medications including aripiprazole, clozapine, irinotecan and
olanzapine, but the induced enzymes are not established.
d
N-Desmethlyclobazam is mainly metabolized by CYP2C19.
e
Eslicarbazepine is a pro-drug that is activated by hepatic esterases to S-licarbazepine. S-licarbazepine is eliminated by UGTs and by the kidney (unchanged).
f
MHD is also called licarbazepine. Oxcarbazepine is a pro-drug and is activated by a cytosolic arylketone reductase that converts it to MHD, the active drug.
g
There are four metabolic pathways. No specific enzyme can be considered a major enzyme.
Table 2
PK parameters of new ADs. Based on [20].

Bioavail-ability (%) Protein binding (%) Half-life (h) Most important Other ways of Active metabolites Inhibitory effect on
way of eliminationa elimination CYP isoenzymes

SSRI
Citalopram 95 82 23−45 CYP2C19b CYP3A4, CYP2D6 CYP2D6 (weak)
Escitalopram 80 56 27 CYP2C19b CYP3A4, CYP2D6 CYP2D6 (weak)
Fluoxetine 80 95 2–4 days CYP2D6b CYP2C9, CYP2C19, Norfluoxetine CYP2D6 (potent)
CYP3A4 CYP2C9 (moderate)
CYP2C19 and
CYP3A4 (weak to
moderate)
CYP1A2 (weak)
Fluvoxamine <53 77 15−22 CYP1A2, CYP2D6 CYP1A2 and
CYP2C19 (potent)
CYP2C9 and
CYP3A4 (moderate)

E. Spina et al. / Pharmacological Research 106 (2016) 72–86

CYP2D6 (weak)
Paroxetine >64 93 10−21 CYP2D6b CYP3A4 CYP2D6 (potent)
CYP1A2, CYP2C9,
CYP2C19, CYP3A4
(weak)
Sertraline >44 98 22−36 CYP2B6 CYP2C19, CYP2C9, CYP2D6 (weak to
CYP2D6, CYP3A4 moderate)
CYP1A2, CYP2C9,
CYP2C19 and
CYP3A4 (weak)
SNRI
Desvenlafaxine 80 30 9−15 Renal UGT, CYP3A4
Duloxetine 50 >90 10−12 CYP1A2b CYP2D6 CYP2D6
(moderate)
Levomilnacipran 92 22 12 Renal UGT, CYP3A4
Milnacipran 85 13 8−10 Renal UGT, CYP3A4 CYP3A4 (weak)
Venlafaxine 92 27 5 CYP2D6b CYP3A4 Desvenlafaxine
Other newer ADs
Agomelatine <5 95 1−2 CYP1A2b CYP2C9
Bupropion 90 84 20 CYP2B6 Hydroxybupropion CYP2D6
Threohydrobupropion (moderate)
Erythrohydrobupropion
Mirtazapine 50 85 20−40 CYP2D6, CYP3A4 CYP1A2, UGTs
Reboxetine >60 97 12−16 CYP3A4b
Trazodone 65 89−95 5−9 CYP3A4b m-
chlorophenylpiperazine
(mCPP)
Vilazodone 72c 96−99 20−24 CYP3A4b CYP2C19, CYP2D6, CYP2C8 (?)
Carboxylesterase
Vortioxetine 75 98 57−66 CYP2D6b CYP3A4, CYP2C19,
CYP2C9, CYP2A6,
CYP2C8, CYP2B6

AD; antidepressant; CYP: cytochrome P450; PK: pharmacokinetics; SNRI: Serotonin and noradrenaline reuptake inhibitor; SSRI: Selective serotonin reuptake inhibitor; UGT: Uridine diphosphate glucuronosyltransferase.
a
This refers to normal metabolism. Some subjects may not have this enzyme or the enzyme is inhibited. Other enzymes may become more important during induction.
b
Any substrate competes with others for the corresponding enzyme and inhibits it (competitive inhibition). Data in the literature shows that competitive inhibition may occur at CYP1Ai, CYPiC9, CYPiC19, CYPiD6, and CYP3A4.
UGTs tend to have overlapping substrates and it is not clear that they can be subject to competitive inhibition. For example,venlafaxine can behave as a CYPiD6 competitive inhibitor.
c
Absorption is decreased when not administered with food.

75
76 E. Spina et al. / Pharmacological Research 106 (2016) 72–86

Table 3
PK parameters of new APs. Based on [19].

Bioavail-ability Protein binding Half-life (h) Most important Other ways of Active Induction or
(%) (%) ways of elimination metabolites inhibition of
eliminationa metabolic
enzymes

Amisulpride 43−48 17 12 Renal excretion Minimal

hepatic
metabolism
Aripiprazole 87 99 48−68 CYP2D6,b Dehydroaripiprazoled
CYP3A4b
Asenapine 35 95 1−2 UGT1A4,b CYP2D6 (weak)
CYP1A2b
Brexpiprazole 95 >90 91 CYP2D6,b
CYP3A4b
Cariprazine High (exact 91−97 2–4 days CYP3A4b CYP2D6 Didesmethylcaripirazine
values are not (parent drug),
reported) 2-3 weeks
(metabolite)
Clozapine 12−81 95 6−33 CYP1A2b CYP2C19, Norclozapinee
CYP3A4,
CYP2D6
Iloperidone 96 93 20−24 CYP2D6b CYP3A4 P88,f P95
Lurasidonec 9−19 99 18 CYP3A4b ID-14823
Olanzapine 60−80 93 20−70 CYP1A2,b CYP2D6, FMO
UGT1A4b
Paliperidone 28 30 24 Renal excretion Minimal
hepatic
metabolism
Quetiapine NA 83 5−8 CYP3A4b Norquetiapineg
Risperidone 68 90 3−24 CYP2D6,b CYP3A4b 9-
hydroxyrisperidone
Ziprasidone 60c 99 4−10 Aldehyde CYP3A4
oxidase

AP; antipsychotic; CYP: cytochrome P450; PK: pharmacokinetics; UGT: Uridine diphosphate glucuronosyltransferase.
a
This refers to normal metabolism. Some subjects may not have this enzyme or the enzyme is inhibited. Other enzymes may become more important during induction.
b
Any substrate competes with others for the corresponding enzyme and inhibits it (competitive inhibition). Data in the literature shows that competitive inhibition may
occur at CYP1Al, CYPlC9, CYPlC19, CYPlD6, and CYP3A4. UGTs tend to have overlapping substrates and it is not clear that they can be subject to competitive inhibition. For
example, quetiapine can behave as a CYP3A4 competitive inhibitor.
c
Absorption is decreased when not administered with food.
d
It is not definitively established in the literature how much dehydroaripiprazole contributes to antipsychotic efficacy or adverse drug reactions of aripiprazole.
e
Norclozapine does not appear to have antipsychotic efficacy but it may contribute to anticholinergic effects and hypersalivation.
f
It does not cross the blood-brain barrier. It may contribute to peripheral adverse drug reactions.
g
Some authors suggest that norquetiapine may contribute to quetiapine antidepressant properties but at this time this is only a hypothesis.

tion acting as an inhibitor or inducer involves a DI risk. A number
of drug-related (i.e., potency and concentration/dose ratio of the
inhibitor/inducer, therapeutic index of the substrate, extent of
metabolism of the substrate through the affected enzyme, presence
of active metabolites), patient-related (i.e., age, genetic predisposi-
tion) and environmental factors (i.e., smoking) will then influence
the potential occurrence, magnitude, and clinical significance of a
metabolic DI [1]. As shown in Tables 1–3, most AEDs, new ADs and
new APs are extensively metabolized via CYPs or UGTs. As many
compounds of these therapeutic classes share common metabolic
pathways, potential DIs may be anticipated. Furthermore, AEDs
may be involved in metabolically-based DIs because they act
as inhibitors or inducers of various drug-metabolizing systems
(Table 1). Among first-generation AEDs, carbamazepine, phenytoin,
phenobarbital and primidone (enzyme-inducing AEDs) induce the
activity of CYP1A2, CYP2C9, CYP2C19 and CYP3A4, as well as UGTs
and epoxide hydrolase. Valproic acid is a broad-spectrum inhibitor
of various drug-metabolizing enzymes including CYP2C9 and UGTs
and, recently, some inductive effects have been demonstrated.
The newer AEDs are associated with limited enzyme-inducing
potential compared with older-generation compounds. How-
ever, clobazam, eslicarbazepine, felbamate, oxcarbazepine (at
dosages ≥ 1200 mg/day), perampanel, rufinamide and topiramate
(at dosages ≥ 400 mg/day) can induce the activity of CYP3A4 and,
possibly, some UGTs. Some of the newer AEDs may at times act
as enzyme inhibitors. In this respect, eslicarbazepine, felbamate,
oxcarbazepine and topiramate are weak inhibitors of CYP2C19,
while stiripentol is a potent inhibitor of CYP1A2, CYP2C19, CYP2D6
and CYP3A4. Some newer ADs including fluoxetine, fluvoxamine,
paroxetine, duloxetine and bupropion, act as potent or moderate
inhibitors of various CYPs and may therefore impair the elimination
of AEDs metabolized via these isoforms (Table 2). Conversely, most
second-generation APs appear to be neither inhibitors nor inducers
of the major drug-metabolizing enzymes and only asenapine may
have weak CYP2D6 inhibitory properties (Table 3).
Other PK mechanisms are unlikely to mediate clinically impor-
tant DIs between AEDs and new psychotropic agents. To our
knowledge, no clinically significant DI has been described so far
during at the absorption phase or at protein binding between com-
pounds of these drug classes [19,20]. DIs at the level of renal
excretion are rare and probably not clinically relevant as most
AEDs and new psychotropic drugs are mainly eliminated by hep-
atic metabolism. In theory, DIs during the excretion phase can
be expected to occur only with those AEDs (i.e., gabapentin,
pregabalin, vigabatrin, levetiracetam and topiramate), new ADs
(i.e.,desvenlafaxine, levominalcipran and milnacipran) and second-
generation APs (i.e., amisulpride and paliperidone) which are
eliminated predominantly through the kidneys [19,20]. PK DIs
between AEDs and new ADs or APs may also involve drug
transporters, in particular P-glycoprotein (P-gp), which plays an
important role in the absorption, distribution and excretion of a
wide variety of therapeutic agents [22]. P-gp is a multidrug efflux
transporter highly expressed in the small intestine, brain, liver and
kidney that acts as a natural defense mechanism against several
 E. Spina et al. / Pharmacological Research 106 (2016) 72–86
drugs by limiting their absorption from the gut and penetration
into the brain and promoting their elimination in the bile and urine.
As some AEDs, ADs and APs may act as substrates, inducers or
inhibitors of P-gp [23–25], it cannot be excluded that some PK DIs
between these agents, currently believed to be CYP-mediated, may
also be explained by modulation of multidrug-transporters [26].
2.2. PD DIs
PD DIs take place directly at the site of action of a drug or indi-
rectly by interfering with other physiological mechanisms. They
result in a modification of the pharmacological action of a drug
without any change in the plasma concentration and are more dif-
ficult to identify and measure than pharmacokinetic DIs. These DIs
can be additive (i.e., equal to the sum of the effects of the indi-
vidual drugs), synergistic (i.e., combined effects are greater than
expected from the sum of individual effects) or antagonistic (i.e.,
combined effects are less than additive) [1]. They can be associ-
ated with positive effects (increased efficacy and safety) or negative
effects (decreased efficacy and/or safety). They will not be further
reviewed in this article but interested readers can look at two prior
review articles; one article described the PD DIs between AEDs and
ADs [20] and the other between AEDs and APs [19].
3. DIs between AEDs and new ADs
AEDs and new ADs are often prescribed together in patients with
different clinical conditions [20]. As the incidence of depressive
disorders in epileptic patients is estimated to be 30%–70% in their
lifetime, ADs are frequently administered to patients with epilepsy
[27,28]. Some AEDs, notably valproic acid, carbamazepine and lam-
otrigine, are also used as mood stabilizers and, therefore, may be
given in combination with ADs for the management of bipolar dis-
order [29]. Pregabalin is also approved in Europe for the treatment
of generalized anxiety disorder and may be added to SSRI or SNRI
treatment in patients with partial response [30]. Combined treat-
ment of the new AEDs, pregabalin or gabapentin, and ADs of the
SNRI class may be a useful strategy for the management of neuro-
pathic pain [31,32].
3.1. Effect of AEDs on the PKs of new ADs
3.1.1. Enzyme-inducing AEDs
The traditional AEDs carbamazepine, phenytoin, phenobarbital
and primidone are potent inducers of several drug-metabolizing
enzymes including CYPs, specifically CYP1A2, CYP2A6, CYP2B6,
CYP2C9, CYP2C19, CYP3A4, as well as UGTs such as UGT1A1,
UGT2B7, and UGT2B15 [1]. Case reports and formal PK studies in
patients or healthy subjects have repeatedly documented that con-
comitant treatment with enzyme-inducing AEDs may produce a
potentially clinically significant decrease in drug concentrations of
most new ADs.
Concerning SSRIs, earlier PK investigations showed that phe-
nobarbital, phenytoin and carbamazepine caused a decrease by
about 25% in the plasma levels of paroxetine, probably as a result of
induced metabolism [33,34]. Administration of carbamazepine was
reported to cause a marked decrease in plasma sertraline concen-
trations in two patients, resulting in lack of AD efficacy [35] and
in a case-control study phenytoin or carbamazepine were asso-
ciated with a sertraline C/D ratio 3 times lower [36]. In an open
pilot study involving 6 patients with major depression stabilized
on citalopram (40–60 mg/day), augmentation treatment with rel-
atively low doses of carbamazepine (200–400 mg/day) for 4 weeks
was associated with a significant decrease in plasma concentra-
tions of S-citalopram and R-citalopram by 27% and 31% (both,
77
p< 0.05), respectively [37]. This effect is presumably related to non-
stereoselective induction of CYP3A4-mediated N-demethylation of
citalopram by carbamazepine.
In a study of healthy subjects, co-administration with carba-
mazepine, 200 mg twice a day for 32 days, was found to decrease
by approximately 20% plasma concentrations of milnacipran, an
SNRI antidepressant whose metabolism is partly dependent on
CYP3A4 [38]. Two PK investigations evaluated the reciprocal DI
between the new AD mirtazapine (30 mg/day) and carbamazepine
(400 mg/day) or phenytoin (200 mg/day) in healthy volunteers
under steady-state conditions [39,40]. In the first study, the addi-
tion of carbamazepine in 24 healthy subjects resulted in a mean
decrease of 39% in the peak plasma concentration (Cmax ) of mirtaza-
pine and of 61% in the area under the plasma concentration-time
curve (AUC) [39]. Similarly, co-administration with phenytoin in 17
healthy male volunteers was associated with a mean reduction of
the Cmax and the AUC of mirtazapine by 33% and 47%, respectively
[40]. Induction of CYP3A4-mediated metabolism of mirtazapine
by carbamazepine and phenytoin may explain the observed PK
changes.
A clinically relevant PK DI may occur between carbamazepine
and bupropion. In a study involving 12 patients with mood dis-
orders given a single 150-mg dose of bupropion, addition of
carbamazepine, at a mean dose of 942 mg/day, was found to
decrease the Cmax of bupropion by 87% (p < 0.001) and its AUC by
90% (p < 0.001) [41]. On the other hand, carbamazepine increased
the AUC of its pharmacologically active metabolite hydroxybupro-
pion by 50% (p < 0.05). This DI is presumably due to the inducing
effect of carbamazepine on CYP2B6, the major isoform responsible
for the metabolism of bupropion.
Reboxetine, trazodone and vilazodone, which are mainly metab-
olized by CYP3A4, may be particularly sensitive to induction by
enzyme-inducing AEDs. In this respect, a case report described two
patients with low serum concentrations of reboxetine in relation to
the dose during carbamazepine or phenobarbital treatment, possi-
bly mediated by induction of CYP3A4 [42].
3.1.2. Valproic acid
Valproic acid has traditionally been considered a broad-
spectrum inhibitor of various drug-metabolizing enzymes as
it inhibits different CYPs including CYP2C9 and, to a lesser
extent,CYP2C19 and CYP3A4, some UGTs, probably UGT1A4
andUGT2B7, and epoxide hydrolase [1]. Moreover, recent in vitro
and in vivo evidence indicates that valproic acid may behave as a
mild inducer when administered at high doses [43]. A study based
on a retrospective analysis of venlafaxine TDM data examined the
potential DI between valproic acid and venlafaxine, an SNRI antide-
pressant mainly metabolized by CYP2D6 and, to a lesser extent, by
CYP2C9 and CYP3A4 [44]. The mean dose-corrected serum concen-
trations of venlafaxine plus O-desmethylvenlafaxine in 41 patients
receiving valproic acid co-medication did not differ significantly
from those of matched controls on venlafaxine monotherapy.
However, the dose-corrected serum concentrations of the active
metabolite O-desmethylvenlafaxine were significantly higher (by
27%, p < 0.02) in patients treated with the combination of valproic
acid with venlafaxine. To explain the elevation of serum concen-
trations of O-desmethylvenlafaxine, the authors speculate that the
inhibition of the CYP2C9-mediated N-demethylation of venlafax-
ine by valproate may lead to a stronger O-demethylation and, as
a consequence, to higher serum levels of O-desmethylvenlafaxine.
Differently from carbamazepine, valproic acid did not affect the
metabolism of bupropion in patients with depression [41].
3.1.3. Newer AEDs
Unlike first-generation agents, newer AEDs have a lower
propensity to cause PK DIs [1]. Although some of the newer AEDs
78 E. Spina et al. / Pharmacological Research 106 (2016) 72–86
may act as inhibitors or inducers of specific drug-metabolizing
enzymes (see previous section) and may theoretically affect AD
disposition, to our knowledge, no systematic study so far has inves-
tigated the effect of any of these AEDs on the PKs of newer ADs.
3.2. Effect of new ADs on the PKs of AEDs
Some new ADs act as inhibitors of various CYPs and may there-
fore impair the biotransformation of various AEDs [12,13].
3.2.1. SSRIs
Fluoxetine and its metabolite norfluoxetine are potent
inhibitors of CYP2D6 and moderate inhibitors of CYP2C9, while
they mildly to moderately decrease the activity of CYP2C19 and
CYP3A4 [12]. Early case reports described concomitant use of flu-
oxetine and phenytoin as associated with significantly increased
phenytoin serum levels along with signs of toxicity [45–47]. This
DI can be attributed to the inhibitory effect of fluoxetine on the
CYP2C9-mediated biotransformation of phenytoin. A number of
case reports indicated that the addition of fluoxetine to an ongo-
ing treatment with valproic acid may increase steady-state plasma
concentrations of valproic acid, possibly associated with toxic
effects [48–50]. The most plausible explanation for the raised val-
proic acid levels is inhibition of CYP2C9 by fluoxetine. There is
conflicting evidence for a PK DI between fluoxetine and carba-
mazepine. Although case reports have documented that fluoxetine
increased carbamazepine levels [51,52], no changes in steady-state
concentrations of carbamazepine were observed in eight epileptic
patients stabilized on carbamazepine (800–1600 mg/day) after a
3-week co-administration with fluoxetine, 20 mg/day [53]. It can
be speculated that inhibition of CYP3A4-mediated carbamazepine
metabolism might occur only at higher fluoxetine doses or require
more than 3 weeks to manifest, due to the long half-life of norfluox-
etine. Retrospective analysis of a large lamotrigine TDM database
revealed that dose-normalized serum concentrations of lamotrig-
ine were 39% lower inpatients co-prescribed fluoxetine (n = 15) as
compared to patients receiving lamotrigine monotherapy (n = 614)
[54]. As fluoxetine is not known as an enzyme inducer, it is difficult
to explain the observed effect on lamotrigine.
Paroxetine is a potent inhibitor of CYP2D6, while it only min-
imally affects other CYPs [12]. As CYP2D6 plays a minor role in
the biotransformation of AEDs, paroxetine is not expected to cause
clinically-relevant DIs with these agents. Consistent with this, a
single-blind, placebo-controlled, cross-over study of 20 patients
with epilepsy, stabilized on phenytoin, carbamazepine or valproic
acid, showed that addition of paroxetine, 10–30 mg/day for 16 days,
did not affect significantly plasma concentrations of these AEDs
[34].
Fluvoxamine is a potent inhibitor of CYP1A2 and CYP2C19,
a moderate inhibitor of CYP2C9 and CYP3A4, and only a weak
inhibitor of CYP2D6 [12]. Being an inhibitor of different CYP iso-
forms, fluvoxamine may theoretically impair the elimination of
various AEDs. The possibility of a clinically relevant DI between
fluvoxamine and carbamazepine was suggested by case reports
describing increased carbamazepine levels with associated symp-
toms of toxicity following the addition of fluvoxamine [55,56].
However, a study of seven epileptic patients on a chronic treatment
with carbamazepine (800–1600 mg/day) found no modifications in
carbamazepine levels after three weeks of co-administration with
fluvoxamine, 100 mg/day [53]. A case report documented a 3-fold
increase in serum concentrations of phenytoin after administra-
tion of fluvoxamine [57]. This PK change was explained as a result
of inhibition of both CYP2C9 and CYP2C19 by fluvoxamine.
Sertraline is a mild to moderate in vitro inhibitor of CYP2D6
and a weak inhibitor of the other CYP isoenzymes [12]. Two for-
mal PK studies in healthy volunteers documented that sertraline,
at a dose of 200 mg/day for 17 days, did not affect the pharma-
cokinetics of carbamazepine (400 mg/day for 32 days; n = 14) and
phenytoin (300 mg/day for 24 days; n = 30), substrates for CYP3A4
and CYP2C9, respectively [58,59]. The possibility of a DI between
sertraline and valproic acid was suspected on the basis of a report
describing the case of a patient with bipolar depression treated
with valproic acid who developed signs of toxicity, associated with
a 3-fold elevation in serum concentration of valproic acid, after the
addition of sertraline (100 mg/day) [60]. A clinically-significant DI
may also occur between sertraline and lamotrigine. In two epilep-
tic patients treated with lamotrigine the addition of a low dose of
sertraline, 25 mg/day, resulted in a two-fold elevation in plasma
lamotrigine concentration associated with symptoms of toxicity,
such as fatigue, sedation, confusion and decreased cognition [61].
Inhibition of lamotrigine glucuronidation by sertraline has been
proposed to explain this DI. A subsequent study, based on a ret-
rospective analysis of lamotrigine plasma concentrations, did not
confirm the severity of the DI [62]. Dose-corrected concentrations
of lamotrigine were only slightly, but not significantly, higher (by
18%) in 7 patients treated with both drugs in combination than in
the 44 patients receiving lamotrigine without sertraline.
Citalopram and escitalopram are weak in vitro inhibitors of
CYP2D6 and negligible inhibitors of CYP1A2, CYP2C9, CYP2C19 and
CYP3A4 [12,13]. Due to their minimal effect on drug-metabolizing
enzymes, citalopram and escitalopram are not expected to cause
clinically relevant DIs with AEDs. Consistent with this, in an
open-label investigation in 12 healthy volunteers, the addition of
citalopram, 40 mg/day for 14 days, to carbamazepine, administered
at the dose of 400 mg/day for 35 days, did not alter the steady-state
PK parameters of carbamazepine and its active epoxide metabolite
[63].
3.2.2. SNRIs
Among SNRIs, venlafaxine, desvenlafaxine, milnacipran and
levomilnacipran are negligible inhibitors of CYP isoforms (or min-
imally affect the activity of CYPs), while duloxetine is a moderate
inhibitor of CYP2D6 [13]. To date, there have been no reports that
these ADs affect the PKs of AEDs.
3.2.3. Other newer antidepressants
Mirtazapine has minimal inhibitory effects on the various CYP
isoforms in vitro [13]. In agreement with this, two PK studies
in healthy subjects showed that mirtazapine (30 mg/day) had
no effect on the disposition of both carbamazepine and pheny-
toin [39,40]. Trazodone, a CYP3A4 substrate, has no significant
inhibitory effect on the activity of CYP isoforms. The addition of tra-
zodone in a patient receiving a chronic treatment of carbamazepine
was associated with symptoms of carbamazepine toxicity, accom-
panied by an increase in its serum concentration [64]. After the
discontinuation of trazodone, toxic symptoms lessened and carba-
mazepine concentrations progressively decreased, suggesting the
possibility of a PKDI between the two drugs. Competitive inhibition
of CYP3A4 may provide a possible explanation for this case.
Anecdotal evidence indicates that bupropion may inhibit the
metabolism of phenytoin and valproate [65]. On the other hand, in
a randomized, open-label, two-way crossover study in 12 healthy
subjects, PK parameters of a single oral dose of 100 mg lamotrig-
ine were not affected by steady-state bupropion, 150 mg twice/day
[66].
Other newer ADs, such as agomelatine, vortioxetine, or vila-
zodone, are only weak inhibitors or are not inhibitors of CYP
isoforms at usual therapeutic concentrations and are not expected
to affect thedisposition of concomitantly administered AEDs.
 E. Spina et al. / Pharmacological Research 106 (2016) 72–86
4. DIs between AEDs and new APs
AEDs and new APs may be used in combination for a number of
reasons [17,19]: (a) there is a high prevalence of psychotic disorders
in patients with epilepsy; (b) some AEDs, particularly those with
mood-stabilizing properties (i.e., carbamazepine, valproic acid and
lamotrigine), are increasingly used in the management of bipolar
disorder; (c) autism spectrum disorders are associated with very
high risk of epilepsy and some second-generation APs are approved
for the treatment of irritability in children with these disorders; (d)
AEDs may be used to treat dosage-related seizures associated with
some new APs such as clozapine; (e) AEDs may be used to treat non-
epileptic conditions (e.g., neuropathic pain and migraine) which
may occur in psychotic patients.
4.1. Effect of AEDs on the PKs of new APs
4.1.1. Carbamazepine
Being a powerful inducer of several drug-metabolizing enzymes,
carbamazepine has been reported to cause a clinically significant
decrease in plasma concentrations of many second-generation APs.
4.1.1.1. Clozapine. In a study based on a clozapine TDM database,
patients co-treated with carbamazepine had a mean 50% lower
concentration-to-dose (C/D) ratio of clozapine than the monother-
apy group [67]. Moreover, in a study of 12 patients stabilized on
clozapine therapy, serum concentrations of clozapine were 47%
lower in patients also treated with carbamazepine than in those
receiving oxcarbazepine [68]. The inducing effect of carbamazepine
on CYP1A2- and CYP3A4-mediated clozapine metabolism probably
explains these results.
4.1.1.2. Olanzapine. The pharmacokinetics of a single 10-mg olan-
zapine dose were investigated in 11 healthy volunteers before and
after administration of carbamazepine 400 mg/day for 18 days [69].
Carbamazepine caused a 46% increase in olanzapine clearance and a
34% decrease in its AUC. A number of subsequent TDM studies doc-
umented that the median C/D ratio of olanzapine was 36–71% lower
in carbamazepine patients than in those on olanzapine monother-
apy [70–74]. In their study, Linnet and Olesen [71] measured
both free and glucuronidated olanzapine and found that carba-
mazepine lowered free olanzapine concentration by increasing
glucuronidation metabolism. All of these studies clearly indicated
that carbamazepine increases olanzapine metabolism by CYP1A2-
and UGT-induction.
4.1.1.3. Quetiapine. In a PK study of 18 psychiatric patients, car-
bamazepine (600 mg/day) decreased quetiapine Cmax by 80% and
AUC by 87% and causeda 7.5-fold increase in its oral clearance [75].
Retrospective evaluation of quetiapine TDM databases provided
similar results [76–79]. In particular, in a large TDM study, co-
administration with carbamazepine (n = 39) was associated with
a significant decrease by 86% (p < 0.001) in quetiapine C/D ratio as
compared to quetiapine monotherapy (n = 1123) [77]. The clinical
implications of this DI were demonstrated in three patients tak-
ing carbamazepine 400–800 mg/day in which serum quetiapine
concentrations could not be detected (<25 ng/mL) despite taking
700 mg/day [80]. These massive PK changes are explained by the
potent inducing effect of carbamazepine on CYP3A4-mediated que-
tiapine metabolism. Appropriate dosage adjustment of quetiapine
is obviously needed if the two drugs are given concurrently.
4.1.1.4. Risperidone. Two case reports suggested the possibility
of a clinically relevant PK interaction between carbamazepine
and risperidone, presumably due to an inducing effect of carba-
mazepine on CYP3A4-partly dependent risperidone metabolism
79
[81,82]. A subsequent study showed that risperidone active moi-
ety (sum of plasma concentrations of risperidone and its active
9-hydroxyrisperidone metabolite) was approximately 1.4 times
lower in 11 carbamazepine patients versus 23 patients on risperi-
done alone [83]. In 5 patients assessed on and off carbamazepine
co-medication, risperidone active moiety was 1.5 times lower on
carbamazepine [83]; in 11 other patients it was 1.8 times lower
[84].
4.1.1.5. Paliperidone. The new AP paliperidone is predominantly
excreted unchanged through the kidney and undergoes limited
hepatic metabolism. Based on this, CYP inhibitors or inducers
are not expected to have a significant influence on paliperi-
done pharmacokinetics. In a study of six schizophrenic patients
initially treated with a 6–12 mg/d dose of paliperidone alone,
coadministration with carbamazepine, 600 mg/day for 2–4 weeks,
was associated with an average reduction in plasma paliperi-
done concentrations by 66% [85]. This effect may be attributed
to carbamazepine induction of drug-metabolizing enzymes, i.e.,
CYP3A4, and/or drug transporters, i.e., renal P-glycoprotein. In
a PK investigation in healthy subjects, sub-therapeutic doses
of carbamazepine,400 mg/day, for 3 weeks decreased the mean
steady-state serum peak concentration (Cmax ) and the AUC of
paliperidone by approximately 37%, due to a 35% increase in the
renal clearance of paliperidone [86].
4.1.1.6. Ziprasidone. In a study of 19 healthy volunteers receiving
40 mg/day of ziprasidone, carbamazepine (400 mg/day) lowered
ziprasidone mean Cmax by 27% and mean AUC0-12h by 36% [87].
These changes are probably due to an inducing effect of carba-
mazepine on CYP3A4-mediated metabolism of ziprasidone.
4.1.1.7. Aripiprazole. Co-administration of carbamazepine for 4–6
weeks in 9 patients with schizophrenia or schizoaffective disorder
given aripiprazole monotherapy (30 mg/day) caused a significant
decrease in the AUC of aripiprazole and dehydroaripiprazole serum
concentrations by 71% and 69%(both, p< 0.001), respectively, [88].
Similarly, in a study of 18 schizophrenia patients treated with arip-
iprazole (12 or 24 mg/day), a 1-week addition of carbamazepine,
400 mg/day, significantly decreased plasma concentrations of both
aripiprazole and dehydroaripiprazole by 64% and 68% (p< 0.001),
respectively [89]. Consistent with these findings, a routine TDM
study indicated that carbamazepine lowered dose-adjusted con-
centrations of aripiprazole by 88% [90].
4.1.1.8. Other new APs. Carbamazepine is expected to induce the
metabolism of other recently commercialized APs such as lurasi-
done and cariprazine, mainly metabolized by CYP3A4, iloperidone
and brexpiprazole, partially metabolized by CYP3A4, and asenap-
ine, substrate for CYP1A2 and UGT1A4. To date, no study has
investigated the effect of carbamazepine on the PKs of these new
medications.
4.1.2. Phenobarbital/phenytoin
Like carbamazepine, phenobarbital and phenytoin are consid-
ered powerful inducers of CYPs, (including CYP1A2, CYP2C, and
CYP3A4) as well as UGTs.
Phenobarbital and phenytoin may cause a clinically relevant
induction of clozapine metabolism. Addition of phenytoin to a
stable clozapine treatment resulted in a psychotic exacerbation
associated with decreased clozapine levels by 65–85% [91]. A
remarkable elevation of clozapine concentrations was described
in a patient 2 weeks after phenobarbital discontinuation [92].
In a study of patients with schizophrenia, serum clozapine con-
centrations were significantly lower in 7 phenobarbital-treated
80 E. Spina et al. / Pharmacological Research 106 (2016) 72–86
patients as compared to 15 patients on clozapine monotherapy
(232 ± 104 ng/ml versus 356 ± 13 ng/ml) [93].
A clinically significant PK DI has been reported to occur
between phenytoin and quetiapine. In a study of 10 patients
treated with quetiapine, 750 mg/day, co-administration of pheny-
toin, 300 mg/day, decreased plasma quetiapine concentrations by
approximately 80%, reflecting a potent inducing effect of phenytoin
on CYP3A4-mediated quetiapine biotransformation [94].
4.1.3. Valproic acid
As valproic acid is increasingly used in the treatment of bipolar
disorder, in recent years several studies investigated its effect on
the PKs of different second-generation APs.
4.1.3.1. Clozapine. Four studies reported a slight increase in cloza-
pine concentrations following co-administration of valproic acid,
suggesting that valproic acid may inhibit clozapine conversion to
norclozapine via CYP1A2 or CYP3A4 [95–98]. Conversely, in a case
series of four patients, clozapine concentrations were reported to
decrease by a mean 41% when valproic acid was administered
[99]. By using a statistical mixed model that estimated the effect
sizes of co-medications on clozapine levels after correcting for
confounding variables, Diaz et al. [100] found that valproic acid
appeared to act as a clozapine inhibitor in non-smokers and as
an inducer in smokers. These findings may account for the con-
troversial results of the earlier observations. A replication with
the same statistical model in another sample, verify mild induc-
tive effects of valproic acid on clozapine [101]. A case report in
a smoker suggests that on rare occasions valproic acid can have
major inductive effects on clozapine, similar to those of potent AED
inducers that may be dose-related [102]. Similarly, case reports and
case-control studies suggest that the inhibitory effects of valproic
acid on clozapine metabolism may have relevance by accelerating
already rapid clozapine titrations and contributing to clozapine-
induced myocarditis by a mechanism analogous to the contribution
of valproic acid to lamotrigine-induced Stevens-Johnson syndrome
[103].
4.1.3.2. Olanzapine. A PK interaction may theoretically occur
between valproic acid and olanzapine, as both compounds are
metabolized, at least partially, by UGT1A4. Initial TDM studies
found no significant effect of valproic acid on plasma olanzapine
concentrations [73,104]. However, in four patients stabilized on
olanzapine, valproic acid (1000–2700 mg/day) decreased olanza-
pine levels by 50% with a psychiatric deterioration in three of them
[105].A subsequent study investigated the effect of valproic acid on
the steady-state plasma concentrations of olanzapine in 18 patients
with bipolar or schizoaffective disorder [106]. After 4 weeks of
valproic acid co-administration (600–2000 mg/day), mean serum
olanzapine concentrations were decreased by 18%, but no patient
showed a worsening of psychopathological condition. The use of
a statistical model helped to clarify the clinical relevance of the
results of this prospective study in spite of their complexity [43].
The changes on olanzapine concentration varied with time (from
2 to 4 weeks) and with valproic acid concentrations, and could
be best interpreted as valproic acid being both an inducer and a
competitive inhibitor of olanzapine metabolism. The model could
be used to predict the effects of any olanzapine dose at 2 and
4 weeks. If we focus on 10 mg/day of olanzapine at 4 weeks as
an example: 1) in nonsmokers, valproate was an net inhibitor at
concentrations <42 ␮g/mL since the competitive inhibition over-
come the inductive effects; and 2) in smokers valproate was an
net inhibitor only at concentrations <13 ␮g/mL, beyond this low
valproate concentrations the inductive effects were greater than
the effects of the competitive inhibition. In a more recent TDM
study [74], serum concentrations of olanzapine were significantly
lower (−32%, p < 0.001) in patients co-medicated with valproic acid
(n = 92), compared with controls taking olanzapine alone (n = 205).
These changes are likely to be explained by valproic acid induction
on olanzapine metabolism by CYPs or UGTs with the possibility of
added competitive inhibition. The mechanisms and clinical rele-
vance of this DI need to be better investigated.
4.1.3.3. Quetiapine. Studies on the effect of valproic acid on que-
tiapine PKs provided inconsistent results. A TDM study found that
quetiapine C/D ratios were 77% higher (p = 0.016) in patients co-
medicated with valproic acid as compared to those not receiving
valproic acid [107]. Based on this finding, the authors suggested a
CYP3A4-mediated inhibition of quetiapine metabolism by valproic
acid. However, co-administration with valproic acid was associated
with no relevant changes in quetiapine concentrations accord-
ing to two other routine TDM studies [77,78] and a formal PK
study in 34 psychotic patients taking 300 mg/day of quetiapine and
1000 mg/day of divalproex sodium [108].
4.1.3.4. Risperidone. No major changes in risperidone moiety
were found in a PK study comparing 23 patients on risperi-
done monotherapy vs 10 on valproic acid co-medication
(1200–1500 mg/day) [83], and in another PK investigation of 22
bipolar patients taking valproic acid (1000 mg/day) in which half
were randomized to placebo or risperidone up to 4 mg/day [109].
This is consistent with the absence of an inhibitory effect of val-
proic acid on CYP2D6 or CYP3A4, the major isoforms involved in
risperidone metabolism.
4.1.3.5. Aripiprazole. In a PKstudy of 10 patients with schizophre-
nia, valproic acid co-administration resulted in decreases in the
Cmax and AUC of aripiprazole by 26% and 24%, respectively, with
minimal effects on PK parameters of the active metabolite dehy-
droaripiprazole [110]. Similarly, in a TDM study, aripiprazole C/D
ratio was 24% lower in 7 patients co-medicated with valproic acid
than in 23 on aripiprazole monotherapy [90]. As aripiprazole is a
CYP3A4 and P-gp substrate, these effects may be explained by a
mild induction of valproic acid on CYP3A4 and/or P-gp.
4.1.3.6. Asenapine. The metabolism of asenapine is predominantly
mediated by UGT1A4 and CYP1A2. In an open-label, randomized, 2-
way crossover study in 24 healthy male volunteers receiving 5 mg
of asenapine alone or under steady-state valproate (1000 mg/day
for 9 days), valproic acid substantially reduced the formation of
the N-glucuronide (AUC reduced 7.4-fold) and moderately reduced
that of N-desmethyl-asenapine (AUC reduced 30%) but did not
affect asenapine AUC [111]. The authors concluded that low-dose
valproic acid, although almost completely inhibiting asenapine glu-
curonidation, did not affect the PKs of asenapine itself.
4.1.4. Lamotrigine
Lamotrigine is a weak UGT inducer, while it does not appear
to be a CYP inhibitor or inducer [1]. In view of the frequent com-
bination of lamotrigine with second-generation APs, a number of
studies have examined the possibility of a PKDI between these
compounds.
4.1.4.1. Clozapine. A case report described the occurrence of symp-
toms of clozapine toxicity associated with a 3-fold increase in
serum clozapine concentrations in a patient after the addition of
lamotrigine [112]. However two subsequent studies, the first in 34
hospitalized treatment-resistant patients [113] and the second in
11 patients stabilized on clozapine [114], found no serum cloza-
pine concentration changes during lamotrigine treatment up to
200 mg/day.
 E. Spina et al. / Pharmacological Research 106 (2016) 72–86 81

Table 4
Provisional new AD dose correction factors after adding AEDs and AED dose correction factors after adding new ADs based on the limited available information.

AEDs ADs Outcome Action to take

Powerful inducers
carbamazepine,
phenobarbital
phenytoin, primidone
High dose mild inducers:
oxcarbazepine (≥1200 mg/day) or
topiramate (≥400 mg/day). And
probably high doses of clobazam,
eslicarbazepine, felbamate or
rufinamide.
Phenytoin, valproic acid
Not studied but likely to be relevant:
clobazam, lacosamide, phenobarbital,
primidone
Not studied; but possible relevant:
carbamazepine, felbamate, tiagabine,
zonisamide
Phenytoin, valproic acid
Not studied at steady state; but likely
relevant: clobazam, lacosamide,
phenobarbital, primidone
Not studied at steady state; but
possible relevant: carbamazepine,
felbamate, tiagabine, zonisamide
Bupropion
Sertraline
Mirtazapine
Citalopram, milnacipran, paroxetine
Trazadone, reboxetine, vilazodone
Agomelatine, duloxetine
Desvenlafaxine, escitalopram,
fluoxetine, fluvoxamine,
levomilnacipran,
venlafaxine,vortioxetine
Possibly relevant for: bupropion,
mirtazapine, reboxetine, sertraline,
trazadone, vilazodone
Inhibitor: Fluvoxamine
Inhibitor: Fluoxetine
↓ AD level 2–4 weeks
after adding inducer
↑ AD level 2–4 weeks
after D/C inducer
Mild ↓ ADlevel weeks after adding
mild inducer
Mild ↑ AD level weeks after D/C mild
inducer
↑ AED level after adding fluvoxamine
↓ AED level after D/C fluvoxamine
↑ AED level 2–3 months after adding
fluoxetine in average patient (some
may take longer)
↓ AED level 2–3 months after adding
fluoxetine in average patient (some
may take longer)
In the absence of TDM, use correction
factor:a
Avoid: correction factor is 10
Correction factor: 3 (up to 5 in case
reports)
Correction factor: 2–3
Correction factor is only 1.3. If this
correction factor is correct, it may not
be clinically relevant.
Be careful; induction of these ADs that
are dependent on CYP3A4 for their
metabolism may require high
correction factors: ≥5.
Not studied but likely to be clinically
relevant according to CYP involved in
AD metabolism
Not studied but unlikely to be relevant
according to CYP involved in AD
metabolism
Monitor for ↓ efficacy after adding mild
inducer.
Monitor for ADRs after discontinuing
mild inducer.
It is safer to select another AD.
Use AED TDM if you decide to add
fluvoxamine.
It is safer to select another AD.
Use AED TDM if you decide to add
fluoxetine.

AD: antidepressant; AED: antiepileptic drug; D/C: discontinuing; DI: drug–drug interaction; TDM: therapeutic drug monitoring.
a
Reviewed PK DI studies were used to estimate correction factors, which are >1 in inducers and <1 in inhibitors. A correction factor of 2 indicates that you need to double
the dose for the same effect. A correction factor of 0.5 indicates that you need to halve the dose for the same effect. The further the correction factor is from r, the more
relevant the DI may be. The therapeutic window or index also determines the clinical relevance of correction factors.

4.1.4.2. Olanzapine. Although UGT1A4 metabolizes both lamot-
rigine and olanzapine, two studies of healthy volunteers using
low lamotrigine doses (50 and 200 mg/day) found no effects on
olanzapine PKs [115,116]. A subsequent study of 14 patients
taking olanzapine (10–20 mg/day) showed that lamotrigine at
a dosage of 100 mg/day did not modify the PKs of olanzapine,
while mean plasma olanzapine concentrations increased by 16%
at a lamotrigine dosage of 200 mg/day [114]. By using a mixed
model, Botts et al. confirmed that lamotrigine behaved as an
olanzapine inhibitor in smokers, increasing the C/D ratio by 35%,
whereas lamotrigine produced a mild non-significant decrease in
olanzapine C/D ratio in nonsmokers [73]. However, in a retro-
spective analysis of olanzapine TDM data, serum concentration
of olanzapine did not differ between patients treated with lam-
otrigine (n = 110) and the control group on olanzapine alone
(n = 205) [74].
ine enhances the metabolism of quetiapine, probably via an action
on UGT1A4 glucuronidation.
4.1.4.4. Risperidone. A case report described the occurrence of
risperidone adverse effects associated with a 5–6-fold elevation
in risperidone levels after adding lamotrigine [118]. However, a
prospective study of 10 psychotic patients stabilized on risperi-
done (3–6 mg/day), demonstrated that lamotrigine, titrated up to
a final dosage of 200 mg/day over 8 weeks, did not affect serum
risperidone active moiety [114].
4.1.4.5. Aripiprazole. Analysis from an aripiprazole TDM database
found no significant differences in serum concentrations of arip-
iprazole and dehydroaripiprazole in patients who were prescribed
lamotrigine concomitantly as compared to those on aripiprazole
alone [119].

4.1.4.3. Quetiapine. A large TDM study reported a slight (17%) but
significant decrease in quetiapine C/D ratio in 147 lamotrigine
patients when 1123 were on quetiapine monotherapy [77].Analysis
of data from a subsequent quetiapine TDM database found that
mean plasma quetiapine C/D ratios were 57% lower in 22 patients
who were on concomitant lamotrigine, compared with matched
controls who were not [117]. The authors concluded that lamotrig-
4.1.5. Oxcarbazepine
Oxcarbazepine, a keto-analog of carbamazepine, is a weak
inducer of CYP3A4 and glucuronidation enzymes [1]. Concomitant
treatment with oxcarbazepine (900–1200 mg/day) for 5 weeks
in psychotic patients stabilized on risperidone (2–6 mg/day;
n = 12) or olanzapine (5–20 mg/day; n = 13) was associated with
minimal and not significant changes in serum concentration
82 E. Spina et al. / Pharmacological Research 106 (2016) 72–86

Table 5
Provisional new AP dose correction factors during PK DIs with AEDs with inhibitory and inducing properties based on the limited available information.

APs AEDs (inducers or inhibitors) Outcome Actions to takea

CYP1A2 APs Potent inducers: ↓ AP level 2–4 weeks after adding 1) Correction dose factor:
Clozapine carbamazepine, phenytoin or phenobarbital. inducer Clozapine: 1.5–2. Olanzapine:
Olanzapine ↑ AP level 2–4 weeks after D/C 2–3
inducer 2) TDM is strongly
recommended.
3) In some countries
carbamazepine is not
recommended since it is also
associated with
agranulocytosis.
High dose mild inducers: oxcarbazepine Mild ↓ AP level weeks after adding 1) Not well studied.
(≥1200 mg/day) or topiramate (≥400 mg/day) mild inducer 2) TDM is strongly
And probably highdoses of clobazam, Mild ↑ AP level weeks after D/C recommended.
eslicarbazepine, felbamate or rufinamide. mild inducer
Valproic acid: possible mild inhibitor and/or Mild ↑ or ↓ AP level after adding 1) Not well studied.
mild inducer. valproic acid 2)TDM is strongly
Mild ↓or ↑ AP level after D/C recommended.
valproic acid
CYP3A4 APs Potent inducers: carbamazepine, phenytoin or Severe ↓ AP level 2–4 weeks after Do not use (Correction factor
Cariprazine phenobarbital. adding inducer ≥5).
Lurasidone High dose mild inducers: oxcarbazepine Unknown ↓ AP level weeks after Do not use unless access to
Quetiapine (≥1200 mg/day) or topiramate (≥400 mg/day). adding mild inducer TDM is available.
And probably high doses of clobazam, Unknown ↑ AP level weeks after
eslicarbazepine, felbamate or rufinamide. D/C mild inducer
CYP2D6/CYP3A Potent inducers: carbamazepine, phenytoin or ↓ AP level 2–4 weeks after adding 1) Correction dose factor: 2.0
APs phenobarbital. inducer 2) Use TDM if available.
Aripiprazole ↑ AP level 2–4 weeks after D/C
Brexpiprazole inducer
Iloperiodone High dose mild inducers: oxcarbazepine Mild ↓ AP level weeks after adding 1) Not well studied.
Risperidone (≥1200 mg/day) or topiramate (≥400 mg/day). mild inducer 2) Use TDM if available.
And probably high doses of clobazam, Mild ↑ AP level weeks after D/C
eslicarbazepine, felbamate or rufinamide. mild inducer
Only Aripiprazole Valproic acid: possible inducer Mild ↓ aripiprazole after adding 1) Correction dose factor: 1.25.
valproic acid 2) Consider TDM.
Mild ↑ aripiprazolelevel after D/C
valproic acid
Aldehyde oxidase Potent inducers: carbamazepine, phenytoin or Mild ↓ AP level 2–4 weeks after 1)No need for dose change
(CYP3A4) phenobarbital. adding inducer (very small correction factor
Ziprasidone Mild ↑ AP level 2–4 weeks after 1.33)
D/C inducer 2)TDM can help to verify that.
UGT1A4 & CYP1A2 Potent inducers: carbamazepine, phenytoin or Unknown 1) Not well studied.
Asenapine phenobarbital. 2)TDM is strongly
recommended.
High dose mild inducers: oxcarbazepine Unknown 1) Not well studied.
(≥1200 mg/day) or topiramate (≥400 mg/day). 2) Consider TDM.
And possibly high doses of clobazam,
eslicarbazepine, felbamate or rufinamide.
Valproic acid: possible inhibitor. Unknown 1) Not well studied. 2)
Consider TDM.
Renally excreted Potent inducers: carbamazepine, phenytoin or Not relevant 1)No need for dose change.
Amisulpride phenobarbital. 2)TDM can help to verify that.
Renally excreted & P-gp or Potent inducers: carbamazepine, phenytoin or ↓ AP level 2–4 weeks after adding 1) Correction dose factor: 3.
CYP3A4b Paliperidone phenobarbital. inducer 2)TDM is strongly
↑ AP level 2–4 weeks after D/C recommended.
inducer
High dose mild inducers: oxcarbazepine Unknown ↓ AP level weeks after 1) Not well studied.
(≥1200 mg/day) or topiramate (≥400 mg/day). adding mild inducer 2)TDM is strongly
And possibly high-doses of clobazam, Unknown ↑ AP level weeks after recommended.
eslicarbazepine, felbamate or rufinamide. D/C mild inducer
Valproic acid: possible inhibitor ↑ AP level after adding valproic acid 1) Correction factor 0.50.
↓ AP level after D/C valproic acid 2) Consider TDM.

ADRs: Adverse dug reaction; AED: antiepileptic drug; AP: antipsychotic; CYP: cytochrome P450; D/C: discontinuing; DI: drug–drug interaction; TDM: therapeutic drug
monitoring.
a
Reviewed PK DI studies were used to estimate correction factors, which are >1 in inducers and <1 in inhibitors. A correction factor of 2 indicates that you need to double
the dose for the same effect. A correction factor of 0.5 indicates that you need to halve the dose for the same effect. The further the correction factor is from s, the more
relevant the DI may be. The therapeutic window or index also determines the clinical relevance of correction factors.
b
During induction there is a major increase in the percentage of paliperidone metabolized. It is currently unclear whether this is due to P-gp, CYP3A4, or another CYP.

of these APs [120]. A recent case report suggested that long- (≥1200 mg/day) prescribed for months are needed to defini-
term treatment with a high dose oxcarbazepine (900 mg/day tively establish the effects of oxcarbazepine in second-genera-
in an 8-year-old child) can reduce quetiapine C/D ratio by tion APs.
70% [121]. Prospective studies using high oxcarbazepine doses
 E. Spina et al. / Pharmacological Research 106 (2016) 72–86
4.1.6. Topiramate
Topiramate is a weak inhibitor of CYP2C19 and a weak
inducer of CYP3A4 [1].An open-label study of 12 healthy sub-
jects investigated the effect of topiramate (100 mg twice daily)
on the PKsof single-dose risperidone (2 mg) [122]. Topiramate
increased mean risperidone clearancevalues by 51% and decreased
mean plasma risperidone AUC values by 23%. Mean plasma 9-
hydroxyrisperidone(the pharmacologically active metabolite of
risperidone) AUC values were concurrently decreased by 8%. On
the other hand, in a study involving 38 outpatients with psy-
chotic disorders, steady-state plasma concentrations of clozapine
(10 patients), olanzapine (12 patients), risperidone (9 patients), or
quetiapine (7 patients) were not significantly affected after 8 weeks
of concomitant treatment with therapeutic doses of topiramate
(up to 200 mg/day) [123]. Prospective studies using high topira-
mate doses (≥400 mg/day) prescribed for months are needed to
definitively establish the effects of topiramate in new APs.
4.1.7. Other newer AEDs
To date, no clinically significant PK DI involving other new AEDs
and second-generation APs have been reported.
4.2. Effect of new APs on the PKs of AEDs
Few studies have investigated the effect of new APs on the PKs
of AEDs.
Two weeks after the addition of risperidone (1 mg/day) the
mean steady-state carbamazepine concentrations mildly increased
by 19% in 8 epileptic patients [124], probably due to competitive
inhibition of CYP3A4. Adding quetiapine to carbamazepine led to a
pharmacokinetic drug interaction and adverse effects in 2 patients
[125], probably due to the competitive inhibition of CYP3A4. In a
study involving 28 healthy volunteers, the addition of aripiprazole
30 mg/day to valproic acid (500 mg every 12 h) had no effect on
valproic acid PKs [126]. According to a TDM study, PK parameters
of lamotrigine were not significantly modifiedby clozapine, risperi-
done orolanzapine co-prescription [127]. Likewise, in a study of 18
patients, aripiprazole (30 mg/day at steady state), did not affect sig-
nificantly lamotrigine PKs (100–400 mg/day at steady state) [128].
In summary, new APs are not considered clinically relevant
except asenapine, which is a weak inhibitor of CYP2D6, a metabolic
enzyme not relevant for AEDs. In most circumstances new APs are
not expected to influence serum AED concentrations in a clinically
relevant way. On the other hand, clinicians need to know that in
rare circumstances, new APs may be clinically relevant inhibitors of
AEDs, particularly in situations of polypharmacotherapy, possibly
due to the saturation of several CYPs by competitive inhibition.
5. Conclusion
It is not easy to conduct PK DI studies using clinically relevant
doses of inducers or inhibitors. To get approval for the marketing
of their drugs, pharmaceutical companies tend to invest in simple
PK DI studies in volunteers, frequently using single dosing, but this
type of PK study rarely reflects clinical practice [129]. The DI mate-
rial in prescribing information (or package inserts) is usually not
designed to provide easy helps for clinicians to correct PK DIs with
dose changes [129].
To fill the need to orient clinicians, we have updated prior
tables [19,20] that integrate the information on in vitro metabolism
studies, TDM studies, case report/series and prospective studies to
provide our best interpretation of what to expect regarding dosing
changes in the average patient after combining AEDs with new ADs
(Table 4), combining new ADs with AEDs (Table 4) and combining
AEDs with new APs (Table 5). These tables will provide some ori-
83
entation to clinicians with no TDM access and may also encourage
clinicians to further study TDM.
Tables 4 and 5 provide correction factors calculated using the
available studies, assuming that the average patient represents the
population well. However, there is extensive PK variability among
patients, and TDM measurements should be advised for optimal
titration of the dosage in each individual. There will be a need
to periodically update these dose correction factors provided by
Tables 4 and 5 as new knowledge becomes available. These limited
correction factors are useful because: (i) many clinicians have no
access to TDM; (ii) there is limited clinical data on TDM for new
compounds; and (iii) having the correction factor helps clinicians
make decisions to select safer drugs, with less risk of PK DDIs.
There is relatively well understanding of the pharmacological
mechanisms and clinical relevance associated with the inductive
properties of carbamazepine, phenytoin, phenobarbital and prim-
idone on new ADs and new APs, and of the inhibitory properties
of valproic acid on some new ADs. On the other hand, PK DI stud-
ies combining new AEDs, particularly those with mild inductive
properties, with new ADs and new APs are needed. It appears safer
to overcaution clinicians about the potential risks of losing efficacy
when adding inducers or of increased ADRs when adding inhibitors,
as well as the risks of ADRs when discontinuing inducers or losing
efficacy when discontinuing inhibitors. Clinicians cannot afford to
wait for definitive studies, which are not likely to happen once the
new drugs are already marketed.
Using the limited available information, the authors believe
that in high doses oxcarbazepine (≥1200 mg/day) and topiramate
(≥400 mg/day) may be clinically relevant CYP3A4 inducers and
possibly inducers of some UGTs. It is possible that clobazam, esli-
carbazepine, and rufinamide may also be dose-dependent CYP3A4
inducers. Two other mild inducers, felbamate and vigabatrin, are
rarely prescribed AEDs. More problematic is the case of valproic
acid, a drug traditionally considered a potential inhibitor, which
may also be a dose-dependent mild inducer of some new APs.
The metabolic enzymes and/or transporters influenced by valproic
acid induction are not known. These metabolic enzymes and/or
transporters may also be subject to competitive inhibition by val-
proic acid. Regarding valproic acid, clinicians need to be aware that
it is: (1) definitely an inhibitor and/or inducer of clozapine and
olanzapine with potential for clinically relevant DIs, (2) possibly
an inhibitor of paliperidone, and (3) a possible weak inducer of
aripiprazole. Studies by independent investigators not associated
with the pharmaceutical company are needed for determining the
effects of potent inducers and valproic acid on asenapine. More DI
quetiapine studies are needed to establish the potential of lamot-
rigine to induce quetiapine and of valproic acid to inhibit quetiapine
metabolism. These possible effects are not described in Table 4 until
more definitive quetiapine DI studies are published. Quetiapine
TDM studies are complicated by the short half-life of this com-
pound with extreme variability within a day and between troughs
and peaks, making it difficult to eliminate variability due to time
differences in collectingsamples. Stiripentol is a clinically relevant
inhibitor of several CYPs with potential to decrease the metabolism
of several new APs and new ADs, but it is not likely to be combined
with them and there are no DI studies.
Fluoxetine and fluvoxamine are relevant inhibitors of phenytoin
and valproic acid, but the literature does not provide informa-
tion on calculating dose correction factors. Therefore, fluoxetine
and fluvoxamine should not be added or discontinued from
patients taking phenytoin or valproic acid without close monitor-
ing of the antiepileptic TDM. Other not-well-studied AEDs likely
to be influenced by the inhibitory effects of fluoxetine or flu-
voxamine are those dependent on CYP2C9 or CYP2C19 for their
metabolism, including clobazam, lacosamide, phenobarbital, or
primidone. Fluvoxamine may have also moderate inhibitory effects
84 E. Spina et al. / Pharmacological Research 106 (2016) 72–86
on AEDs dependent on CYP3A4 for their metabolism, such as car-
bamazepine, felbamate, tiagabine, or zonisamide. Fluoxetine may
take up to 2–3 months in an average patient (or even up to 6 months
in unusual patients) to reach maximal inhibitory effects on CYP3A4
due to the long half-life of norfluoxetine, so it may be important to
remember that when co-prescribing fluoxetine with AEDs depen-
dent on CYP3A4 such as carbamazepine, felbamate, tiagabine, or
zonisamide. Table 4 shows that it may be safer to select ADs other
than fluoxetine or fluvoxamine when taking any of these AEDs.
Isolated cases have suggested that fluoxetine and sertraline may
influence lamotrigine TDM. Before we highlight these DIs for clin-
icians, more definitive studies using high doses should establish
that sertraline inhibits lamotrigine metabolism or that fluoxetine
induces lamotrigine metabolism.
Conflict of interest
This work was not supported by any funding source.
In the past few years, Dr. Spina has participated in speak-
ers/advisory boards and lectured supported by AstraZeneca,
Bristol-Myers, Eli Lilly & Co, Janssen Pharmaceuticals, Lundbeck and
Pfizer.
In the past few years, Dr. Pisani has participated as speaker and
member of advisory boards supported by UCB Pharma, Eisai, Shire.
Dr. de Leon personally develops his presentations for lecturing,
has never lectured using any pharmaceutical or pharmacogenetic
company presentations, and has never been a consultant for phar-
macogenetic or pharmaceutical companies. In the past, Dr. de
Leon received researcher-initiated grants from Eli Lilly (one ended
in 2003 and the other, as co-investigator, ended in 2007); from
Roche Molecular Systems, Inc. (ended in 2007); and, in a collabo-
ration with Genomas, Inc., from the NIH Small Business Innovation
Research program (ended in 2010). He has been on the advisory
boards of Bristol-Myers Squibb (2003/04) and AstraZeneca (2003).
Roche Molecular Systems supported one of his educational presen-
tations, which was published in a peer-reviewed journal (2005). His
lectures were supported once by Sandoz (1997), twice by Lundbeck
(1999 and 1999), twice by Pfizer (2001 and 2001), three times by
Eli Lilly (2003, 2006, and 2006), twice by Janssen (2000 and 2006),
once by Bristol-Myers Squibb (2006), and seven times by Roche
Molecular Systems, Inc. (once in 2005 and six times in 2006).
Acknowledgment
The authors acknowledge Lorraine Maw, M.A., at the Mental
Health Research Center at Eastern State Hospital, Lexington, KY,
who helped in editing the article.
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