Introduction

Antipsychotics are widely used and often in combination with other drugs, thereby frequently subjected to drug-drug interactions. This review will provide a summary of potential pharmacokinetic (PK) and pharmacodynamic (PD) drug interactions associated with antipsychotic drugs.

Methods

A literature search was conducted for clinically significant drug interactions with antipsychotics.

Results

Most common PK drug interactions take place via the cytochrome P450 (CYP) system. PK profiles of first generation antipsychotics are inadequately studied; nevertheless most common drug interactions involve changes to their metabolic processes. Interactions with second generation antipsychotics are somewhat well-established, documented, and give some guidance for therapeutic treatment interventions. PD interactions occurring at the receptor level result in additive, synergistic, or antagonistic effects.

Discussion

This review summarizes a collection of relevant literature of significant PK and PD interactions occurring with antipsychotics. The involvement of multiple CYP enzymes makes it more difficult to predict the extent of the interaction and clinicians should take into consideration the timeline when evaluating potential interactions.

Antipsychotics are widely used in patients who suffer from schizophrenia, bipolar disorder, and other psychiatric illnesses, often long term as these conditions are chronic, treatment resistant, or lifelong. As a disease worsens, antipsychotics are often used in combination with other psychotropic medications.1 Thus, the likelihood of drug interactions increases and may result in complex and unpredictable outcomes. Clinicians should have a good understanding of these drug interactions to maximize the therapeutic benefit and minimize side effects. The aim of this article is to review significant pharmacokinetic (PK) and pharmacodynamic (PD) interactions with antipsychotics.

The potential combination or removal of other drugs may affect the way an antipsychotic or its metabolites are handled in the body, resulting in changes to the antipsychotic or its active by-products by altering its absorption, distribution, metabolism, or excretion.1 From a clinical perspective, these PK interactions help explain or predict bioavailability, onset, duration of activity, and interactions between drugs that alter their metabolism and excretion.2 It is beyond the scope of this article to review every PK interaction reported. Thus, the focus will be limited to drug-drug interactions with oral antipsychotics that may have a substantial influence in the clinical setting.

Pharmacokinetic profiles of first-generation antipsychotics (FGAs) are not well described in the literature. Many of their potential metabolites remain undiscovered or their physiological activity inadequately studied. Nonetheless, general statements can be made when comparing the conventional antipsychotics as a group. All FGAs are well absorbed, with peak concentrations obtained 1 to 4 hours after oral administration. They attain clinical efficacy of improving illness symptoms of schizophrenia as rapidly as 15 minutes.3 Most FGAs are highly protein bound (85%-90%), and although changes in protein binding can have an influence on individual PK parameters, those changes caused by drug-drug interactions will usually not influence the clinical exposure of a patient, and no routine adjustments in dosing regimen are necessary.3,4 

Oral formulations undergo extensive liver metabolic transformations including glucuronidation, oxidation, reduction, and methylation. Most FGAs are metabolized by the cytochrome P450 (CYP) system, and most common PK drug-drug interactions involve effects on metabolism via the CYP system as listed in Table 1. Because of the many active metabolites and biological variability, there exist differences of the clinical response among FGAs and significant difficulty in predicting those interactions most likely to cause harm if not detected. The elimination half-lives of FGAs vary from 18 to 40 hours, and steady-state levels of oral drugs are reached in approximately 3 to 8 days. Numerous factors such as genetically determined metabolic rates, age, and co-administration of other hepatically metabolized drugs affect the half-life to such a degree that plasma levels may vary among individuals by 10- to 20-fold. The major routes of excretion are through urine and feces by way of bile, with minor pathways of excretion via sweat, saliva, tears, and breast milk.2,3 

TABLE 1:

First-generation antipsychotic metabolism and the potential for drug interactions5,-11 

First-generation antipsychotic metabolism and the potential for drug interactions5-11
First-generation antipsychotic metabolism and the potential for drug interactions5-11

Most PK interactions with second-generation antipsychotics (SGAs) arise at the stage of drug metabolism and usually involve changes to drug-metabolizing enzymes when other psychotropic agents or medications in the treatment of concomitant medical illness are added.12 A summary of PK drug interactions related to metabolism is presented in Table 2. In addition to drug-drug interactions related to the metabolism of SGA discussed in Table 2, it is important to take into consideration PK interactions consisting of changes in the absorption, distribution, or elimination of the antipsychotic that may result after the addition of another chemical agent.

TABLE 2:

Second-generation antipsychotic metabolism and the potential for drug interactions1,3,5,12,-14 

Second-generation antipsychotic metabolism and the potential for drug interactions13512-14
Second-generation antipsychotic metabolism and the potential for drug interactions13512-14

In theory, studies of PK interactions conducted during the drug-development stage in a controlled environment in animal models, and thereafter in healthy volunteers using population PK modeling, are unambiguous; however, in reality, it is prudent to keep in mind that the interactions may be multifactorial. For example, formulation and drug-molecule differences, food-dependent absorption, lipophilicity resulting in high volume of distributions, and competition for protein binding leading to subsequent displacement interactions interfere with PK. In addition, the state of the hepatic portal system and a patient's genetic variability, which in turn may affect the drug's hepatic and renal clearance, play important roles, resulting in clinically significant drug interactions.1 

Pharmacodynamic drug-drug interactions occur when drugs being added to the antipsychotic compete at the receptor level, interfering with the therapeutic efficacy or perhaps contributing to an adverse effect. For example, when levodopa, a drug used for Parkinsonism with agonistic action at dopamine D2 receptor is added, the antipsychotic through its dopamine antagonism can oppose the effects of levodopa. The result may culminate in worsening motor function, a relapse of psychosis or a combination thereof.2  Table 3 lists several examples of PD interactions resulting in antagonistic, additive, or synergistic effects most often leading to adverse effects but, at times, rarely and deliberately augmented to obtain a favorable effect.

TABLE 3:

Pharmacodynamic interactions with antipsychotics1,13,15,-18 

Pharmacodynamic interactions with antipsychotics11315-18
Pharmacodynamic interactions with antipsychotics11315-18

Nondrug patient factors (such as age, sex, concomitant diseases, genetic polymorphisms, caffeine and drug intake habits, and use of herbal medications) as well as drug-related factors (such as formulation, dose, and route of administration) contributing to antipsychotic drug interactions are beyond the scope of this review; nevertheless, these factors should be taken into consideration when assessing PK- and PD-drug interactions comprehensively. Some studies find proposed PK principles lacking a significant impact on the plasma levels of the antipsychotic, suggesting that theoretical drug interactions may not always occur as anticipated. In addition, researchers suggest that multiple CYP enzyme involvement in an antipsychotic metabolism will make it more difficult to predict the extent of the drug interaction because at low doses one type of CYP metabolism may predominate, while at higher doses another CYP enzyme interaction may possibly be prominent.1 

During this review, it is also noted that newer antipsychotics introduced in recent years have more-specific, standardized PK information and recommendations in their product labeling compared with those agents marketed decades ago. However, there is little information on monitoring of plasma concentration levels to gauge the response of a drug interaction. The blood-brain distribution of the antipsychotic drugs or their potentially active metabolites may or may not contribute to varying plasma concentrations among individuals, suggesting that plasma levels may not be a useful measure in evaluating PK and PD interactions. Moreover, the time course of the drug interactions are rarely mentioned in literature, but clinicians should take into consideration the timeline (eg, half-life, time for steady state) when evaluating potential PK and PD interactions especially in patients on multiple and long-term drug treatment. Lastly, avoidance of unnecessary polypharmacy, knowledge of drug-interaction profiles, experience, and good clinical judgement are essential in preventing significant and potentially adverse PK- and PD-drug interactions in patients receiving antipsychotics.

1
Kennedy
WK
,
Jann
MW
,
Kutscher
EC.
Clinically significant drug interactions with atypical antipsychotics
.
CNS Drugs
.
2013
;
27
(
12
):
1021
-
48
. DOI: .
2
Bleakley
S.
Identifying and reducing the risk of antipsychotic drug interactions
.
Prog Neurol Psychiatry
.
2012
;
16
(
2
):
20
-
4
. DOI: .
3
Schatzberg
AF
,
Nemeroff
CB.
Essentials of clinical psychopharmacology. 3rd ed
.
Arlington (VA)
:
American Psychiatric Publishing;
2013
.
4
Benet
L.
Changes in plasma protein binding have little clinical relevance
.
Clin Pharmacol Ther
.
2002
;
71
(
3
):
115
-
21
. DOI: .
5
American Pharmacists Association
.
Drug information handbook with international trade names index. 21st ed
.
Hudson (OH)
:
Lexi-Comp;
2012
.
6
Sanofi-aventis, New Zealand Ltd
.
Largactil (chlorpromazine hydrochloride)
.
[rev 2013 Feb; cited 2014 Dec 21]
.
7
Mylan Pharmaceuticals Inc
.
Fluphenazine hydrochloride
.
[rev 2010 Feb; cited 2014 Dec 21]
.
8
Kudo
S
,
Ishizaki
T.
Pharmacokinetics of haloperidol: an update
.
Clin Pharmacokinet
.
1999
;
37
(
6
):
435
-
56
. DOI: .
9
Sandoz Inc
.
Perphenazine
.
[rev 2013 Dec; cited 2014 Dec 21]
.
10
Teva Select Brands
.
ORAP (Pimozide)
.
[rev 2014 Oct; cited 2014 Dec 21]
.
11
Remedyrepack Inc
.
Thioridazine hydrochloride
.
[rev 2011 Apr; cited 2014 Dec 21]
.
12
Spina
E
,
de Leon
J.
Metabolic drug interactions with newer antipsychotics: A comparative review
.
Basic Clin Pharmacol Toxicol
.
2007
;
100
(
1
):
4
-
22
. DOI: . PubMed PMID: 17214606.
13
Bazire
S.
Psychotropic drug directory 2014
.
Warwickshire, UK
:
Lloyd-Reinhold Communications LLP;
2014
.
14
Stockley's Drug Interactions
[Internet]
.
The Pharmaceutical Press
;
MedicinesComplete c2015; Royal Pharmaceutical Society [updated 2015 Feb; cited 2015 May 9]
.
15
Letsas
KP
,
Efremidis
M
,
Filippatos
GS
,
Sideris
AM.
Drug-induced long QT syndrome
.
Hellenic J Cardiol
.
2007
;
48
:
296
-
9
.
PubMed PMID: 17966685
.
16
Coates
TD.
Drug-induced neutropenia and agranulocytosis
.
In
:
Boxer
LA
,
ed
.
UpToDate [Internet]
.
2014
.
17
Beach
SR
,
Celano
CM
,
Noseworthy
PA
,
Januzzi
JL
,
Huffman
JC.
QTc prolongation, torsades de pointes, and psychotropic medications
.
Psychosomatics
.
2013
;
54
(
1
):
1
-
13
. DOI: .
18
Taylor
D
,
Paton
C
,
Kapur
S
,
editors
.
The Maudsley prescribing guidelines in psychiatry
.
11th ed
.
West
Sussex
,
UK
:
John Wiley & Sons;
2012
.

Competing Interests

Disclosures: The author has no conflicts of interest to disclose.