CME Article

Catastrophic Drug-Drug Interactions in

Psychopharmacology
Andrew D. Carlo, MD; and Jonathan E. Alpert, MD, PhD

© Shutterstock
ABSTRACT actions involving psychotropic medica- catastrophic. The focus of this review is on
Drug interactions may reflect pharma- tions are ubiquitous; they typically result in the principal mechanisms of drug interac-
cokinetic processes, pharmacodynamic changes in drug levels and/or drug effects. tions and on potentially serious and life-
processes, or both. Some interactions are Fortunately, most drug interactions in psy- threatening adverse consequences (eg,
classified as idiosyncratic, as their mecha- chiatry do not result in serious harm. Some serotonin syndrome, hypertensive crises,
nisms are not yet understood. Drug inter- drug interactions, however, are potentially arrhythmias, anticholinergic toxicity, sei-
zures, dermatologic emergencies, bleeding,
Andrew D. Carlo, MD, is a Postgraduate Year-4 Resident, Massachusetts General Hospital/ respiratory depression) of drug interactions
McLean Hospital Adult Psychiatry Residency Program; and a Clinical Fellow in Psychiatry, Har- in psychiatry. Patients with refractory psy-
vard Medical School. Jonathan E. Alpert, MD, PhD, is an Associate Chief of Psychiatry and the chiatric disorders, as well as medical comor-
Director, Depression Clinical and Research Program, Department of Psychiatry, Massachusetts bidity, often require treatment with com-
General Hospital; and the Joyce R. Tedlow Associate Professor of Psychiatry, Harvard Medical plex drug regimens. The risk of catastrophic
School. drug interactions involving psychotropic
Address correspondence to Andrew D. Carlo, MD, Massachusetts General Hospital, WACC 812, medications may be minimized by knowl-
15 Parkman Street, Boston, MA 02114; email: acarlo@partners.org. edge of the mechanisms of drug interac-
Disclosure: Jonathan E. Alpert discloses consultant fees from Luye Pharmaceuticals and a roy- tions and by familiarity with the rare, yet po-
alty from Belvoir Publications Inc. The remaining author has no relevant financial relationships tentially life-threatening drug interactions
to disclose. that involve psychotropic medications.
doi: 10.3928/00485713-20160623-01 [Psychiatr Ann. 2016;46(8):439-447.]

PSYCHIATRIC ANNALS • Vol. 46, No. 8, 2016 439


D
rug-drug interactions refer to
alterations in drug levels or
drug effects (or both) related
to the administration of two or more
prescribed, recreational, or over-the-
counter medications taken in close
temporal proximity.1 These interactions
can occur via multiple mechanisms,
specifically involving alterations in
(1) pharmacokinetics (absorption, dis-
tribution, metabolism, and excretion),
(2) pharmacodynamics (interactions at
the receptor level), or (3) both phar-
macokinetics and pharmacodynamics
(mixed interactions). Some sporadi-
cally occurring interactions are classi-
fied as “idiosyncratic” in the absence
of definitive information about their
underlying mechanisms. Although drug
interactions involving psychotropic
medications are ubiquitous, most are
not associated with serious adverse ef-
fects and, indeed, some are therapeutic,
as when naltrexone blocks the effects of
an opiate overdose. On the other hand,
some drug interactions involving psy-
chotropic medications can lead to po-
tentially catastrophic outcomes, such
as serotonin syndrome, hypertensive
crisis, QTc prolongation (leading to ar-
rhythmia), anticholinergic toxicity, sei-
zures, and dermatologic reactions (such
as Stevens-Johnson syndrome [SJS]).
This article focuses on the uncommon,
but potentially catastrophic, drug-drug
interactions related to psychopharma-
cologic practice.
ABSORPTION
Pharmacokinetic processes (includ-
ing absorption, distribution, metabo-
lism, and excretion) can potentially lead
to drug-drug interactions, specifically
those that produce changes in plasma
levels or tissue concentrations of one
or more drugs. Absorption, which re-
fers to the movement of a drug into the
blood, can be affected by changes in
gastric emptying, gut motility, stomach
pH, and the activity of gastrointestinal
440 Copyright © SLACK Incorporated
CME Article
(GI) tract enzymes. Orally administered
drugs are affected to the greatest degree
(as opposed to those that are parenter-
ally administered) because their overall
rate and extent of absorption is affected
by fluctuations in absorption through
the GI tract.1 Drugs that speed gastric
Pharmacokinetic processes
(including absorption,
distribution, metabolism, and
excretion) can potentially lead
to drug-drug interactions.
emptying (such as metoclopramide)
can increase the rate of drug delivery to
the small intestine (the primary site of
absorption of many drugs) and escalate
the speed of absorption of substances,
such as cyclosporine.2 Motility through
the GI tract can also have a significant
impact on drug absorption. Rapid rates
of motility lessen contact time of the
drug with the intestinal epithelium and
may lead to a reduction in the oppor-
tunity for absorption. Slower rates of
motility, on the other hand, can either
(1) increase the time of contact of a
drug with the gastric mucosa, poten-
tially leading to increased serum con-
centrations (as with opiates or mari-
juana) or (2) prolong the exposure of
the drug to gut metabolism, thereby
reducing the amount of drug available
for absorption (as in drugs with signifi-
cant anticholinergic activity).1,3 Agents
that reduce GI acidity (eg, proton pump
inhibitors and histamine H2 receptor
antagonists) can affect the absorption
of drugs with pH-dependent absorption
rates.3 The binding of a drug to another
substance in the stomach (such as ant-
acids, charcoal, kaolin-pectin, chole-
styramine, calcium, magnesium, or
iron-containing compounds) may cause
the formation of a complex that passes
unabsorbed through the GI lumen.1,3
Lastly, the local action of enzymes in
the GI tract (eg, monoamine oxidase
and cytochrome [CYP] 450 3A4) may
be responsible for metabolism of a drug
before absorption, which is relevant to
certain pressor amines such as tyra-
mine.1
DISTRIBUTION
Drug distribution refers to the move-
ment of the absorbed drug through the
bloodstream to its site of action.2 The
amount of drug ultimately reaching
receptor sites in tissues is determined
by a variety of factors, including the
concentration of free (unbound) drug
in plasma, regional blood flow, and
physiochemical properties of the drug
(eg, lipophilicity or structural charac-
teristics).1 Psychotropic medications
must cross the lipophilic blood-brain
barrier to enter the central nervous sys-
tem (CNS). Lipophilic (or fat-soluble)
drugs (such as benzodiazepines, neuro-
leptics, and cyclic antidepressants) are
able to penetrate the blood-brain barrier
and circulate more widely in the body
than hydrophilic (or water-soluble)
drugs (eg, lithium), which move
through a smaller volume of distribu-
tion.1 Lastly, drug-transport proteins
(such as P-glycoproteins) play a cru-
cial role in regulating permeability of
intestinal epithelia, lymphocytes, renal
tubules, the biliary tract, and the blood-
brain barrier. These transport proteins
are thought to account for the develop-
ment of certain forms of drug resistance
and tolerance and are increasingly seen
as important components of many drug-
drug interactions.1,4 P-glycoproteins,
for example, are induced by St. John’s
wort and are inhibited by haloperidol
and methadone.5
In general, psychotropics have
relatively high affinities for plasma
proteins (some to albumin but others,
such as antidepressants, to alpha 1-acid

glycoproteins and lipoproteins). Most
psychotropic drugs are more than 80%
protein-bound.1 Because drugs are ac-
tive in their free (nonprotein-bound)
form, the unbound fraction of a drug
accounts for its pharmacologic activity
in the body. Protein-binding drug-drug
interactions occur when a substance
displaces another drug from its bind-
ing protein, leading to an increase in
the availability of free (unbound) drug
(eg, diazepam can displace phenytoin,
and salicylates can displace methotrex-
ate and warfarin).3 Fluoxetine, aripip-
razole, and diazepam are examples
of the many psychotropic drugs that
are highly protein-bound (and that are
most susceptible to drug-drug interac-
tions related to protein binding). In
contrast, venlafaxine, lithium, topi-
ramate, zonisamide, gabapentin, pre-
gabalin, milnacipran, and memantine
are examples of drugs with minimal
protein-binding.1 It is noteworthy that,
in most instances of drug-drug inter-
actions related to protein-binding, the
net changes in plasma concentrations
of active drugs are quite small because
the unbound drug is susceptible to re-
distribution, metabolism, and excretion
processes, thereby off-setting the initial
temporary rise in plasma levels.1
METABOLISM
Drug metabolism refers to the bio-
transformation of a drug to a less ac-
tive or inactive form, a process that is
usually mediated by enzymes in the
liver or the small intestine.1,2 Many
psychotropic drug interactions of clini-
cal significance are based on interfer-
ence with one or more phases of this
biotransformational progression. Meta-
bolic processes are catalyzed by vari-
ous enzyme systems and include phase
I (oxidation, reduction, and hydrolysis)
and phase II (conjugation of the drug
or its phase I metabolite with endog-
enous compounds such as glucuronate,
sulphate, glutathione, or acetate) reac-
PSYCHIATRIC ANNALS • Vol. 46, No. 8, 2016 441
CME Article
tions.2 The principle outcome of phase
II conjugation reactions is the enhance-
ment of a drug’s hydrophilic proper-
ties for eventual renal excretion. Most
psychotropics undergo both phase I and
phase II metabolic reactions; notable
exceptions include valproic acid and
a subset of benzodiazepines (includ-
ing oxazepam, temazepam, and loraz-
epam), which skip phase I metabolism
and undergo phase II reactions only.
These agents (oxazepam, temazepam,
and lorazepam) can be re-called by
use of the mnemonic, “OTL” (outside
the liver). In addition, certain medica-
tions (eg, lithium, gabapentin) do not
undergo any hepatic biotransformation
before excretion by the kidneys.1
The synthesis or activity of hepatic
microsomal enzymes is affected by
metabolic inhibitors and inducers, as
well as by distinct genetic polymor-
phisms (stably inherited traits).1 By
influencing the activity of hepatic en-
zymes (via induction, inhibition, or
both), drugs can increase or decrease
their own serum levels or those of other
substances. Specific drug-enzyme in-
teractions will be discussed in a subse-
quent section.
The CYP450 isoenzymes represent
a family of more than 30 related heme-
containing enzymes, largely located in
the endoplasmic reticulum of hepato-
cytes (but also present elsewhere, eg, the
gut and the brain), that mediate oxidative
metabolism of a wide variety of drugs,
as well as endogenous substances (in-
cluding prostaglandins, fatty acids, and
steroids).1 Although the CYP450 iso-
enzymes represent only one of the nu-
merous enzyme systems responsible for
drug metabolism, they are responsible
for metabolizing, at least in part, over
80% of all prescribed drugs.1 CYP450
1A2 (CYP1A2), CYP2C9, CYP2C19,
CYP2D6, and CYP3A4 are the most
important P450s catalyzing the biotrans-
formation of psychotropic drugs.6 A pa-
tient’s baseline CYP450 enzyme activity
can be classified as poor, intermediate,
extensive (normal), or ultra-rapid de-
pending on their genetic predisposition.
Poor metabolizers are relatively im-
pervious to drug interactions involving
inhibition of the particular isoenzyme
system for which they are already defi-
cient.1 Table 1 describes common sub-
strates, inducers, and inhibitors for the
CYP450 isoenzymes most relevant to
psychotropic medications.
There are important distinctions be-
tween the mechanisms of inhibition and
induction of CYP450 isoenzymes. En-
zyme inhibition tends to occur rapidly
and can cause a swift increase in the
serum levels of drugs metabolized by
that particular enzyme. The inhibitory
process can occur via competitive inhi-
bition (displacement of substrate), co-
valent binding (conformational change
of enzyme), or enzyme destruction (for
example, phytochemicals of grape-
fruit juice may destroy CYP3A4).1,7,8
Enzyme induction, on the other hand,
occurs more slowly and has a more
gradual impact on serum drug levels.
The process occurs by increasing the
production of a particular CYP450 iso-
enzyme. For example, carbamazepine
is a CYP3A4 inducer and will slowly
lead to an increase in the body’s pro-
duction of CYP3A4. Co-administration
of carbamazepine with risperidone,
which is a substrate of CYP3A4, can
result in decreased plasma risperidone
levels and possibly loss of its clinical
efficacy.7
It is noteworthy that multiple criti-
cal medications can be rendered largely
ineffective by changes in CYP450 iso-
enzyme activity. Tamoxifen, for exam-
ple, requires CYP2D6 for conversion
of a prodrug to an active drug. There-
fore, medications that inhibit CYP2D6
(eg, fluoxetine, duloxetine, bupropion)
can drastically reduce levels of active
tamoxifen. On the other hand, CYP3A4
inducers (eg, carbamazepine, phenobar-
bital, rifampin) can lead to reduced se-
 CME Article

TABLE 1.

Important CYP450 Substrates, Inducers, and Inhibitors

Enzyme Substrate Inhibitors Inducers

CYP1A2 Antipsychotics: asenapine, fluphenazine, Fluvoxamine,b ciprofloxacin Ritonavir,b cigarette smoking, armodafinil,
perphenazine, thioridazine, haloperidol,a chlor- (fluoroquinolones),b erythro- modafinil, omeprazole, insulin, tobacco
promazine, clozapine, risperidone, olanzapine, mycin, caffeine, cimetidine,
aripiprazole, iloperidone amiodarone
Antidepressants: citalopram, escitalopram, fluox-
etine, paroxetine, fluvoxamine, amitriptyline,
nortriptyline, clomipramine, desipramine, imip-
ramine, mirtazapine, venlafaxine, duloxetine
Stimulants: caffeine
Other: theophylline, aminophylline, warfarin,
mexiletine, verapamil, acetaminophen, estra-
diol, ondansetron, cyclobenzaprine, riluzole,
ropinirole, tacrine, zolmitriptan

CYP2C9 Antidepressants: sertraline Fluvoxamine,b valproic acid, Barbiturates,b rifampin,b ritonavir,b carbam-
Mood stabilizers: valproic acid fluoxetine, fluconazone, azepine,
Other: tamoxifen, warfarin, carvedilol, verapamil, ginkgo biloba, modafinil, St. John’s wort
sertraline, vilazodone
losartan, ibuprofen, naproxen, phenobarbital

CYP2C19 Antipsychotics: clozapinea
 Fluvoxamine,b fluoxetine,b Barbiturates,b rifampin,b

Antidepressants: citalopram, escitalopram, carbamazepine, topiramate, carbamazepine, prednisone
clomipramine, imipramine, amitriptyline oxcarbazepine, fluconazole, ci-
metidine, modafinil, sertraline,
Anxiolytics: diazepam
vilazodone
Mood stabilizers: valproic acid
Other: primidone, warfarin, phenytoin

CYP2D6 Antipsychotics: aripiprazole, brexpiprazole, Bupropion,b quinidine Dexamethasone, rifampin

fluphenazine, perphenazine, thioridazine, (antimalarials),b duloxetine,b
haloperidol, chlorpromazine, clozapine,a risperi- paroxetine,b fluoxetine,b
done, olanzapine,a aripiprazole, iloperidone tricyclic antidepressants,
Antidepressants: citalopram, escitalopram, fluox- hydroxyzine, methadone,
etine, paroxetine, fluvoxamine, amitriptyline, metoclopramide, cimetidine,
nortriptyline, clomipramine, desipramine, imip- ritonavir, sertraline, citalopram,
ramine, mirtazapine, venlafaxine, duloxetine, vilazodone, desvenlafaxine,
bupropion, nefazodone, vortioxetine venlafaxine, amiodarone,
mibefradil, nelfinavir, terbin-
Stimulants: amphetamine, atomoxetine
afine
Other: tamoxifen, codeine, lidocaine, hydro-
codone, metoprolol, propranolol, carvedilol,
nebivolol, mexiletine, dextromethorphan,
diltiazem, donepezil, flecanide, galantamine,
hydroxycodone, oxycodone, metoclopramide,
mexilitene, nifedepine, ondansetron, propafe-
none, tramadol, trazodone

442 Copyright © SLACK Incorporated

 CME Article

TABLE 1. (continued)

Important CYP450 Substrates, Inducers, and Inhibitors

Enzyme Substrate Inhibitors Inducers

CYP2E1 Other: acetaminophen, ethanol Ethanol, isoniazid Rifampin,b barbiturates

CYP3A4 Antipsychotics: haloperidol, pimozide, clozapine,a Nefazodone,b ketoconazole Carbamazepine,b rifampin,b

risperidone,a quetiapine, ziprasidone, aripipra- (antifungals),b fluvoxamine,b phenobarbital (barbiturates),b pioglitazone,
zole, iloperidone, lurasidone, brexpiprazole ritonavir,b indinavir, fosampre- troglitazone, glucocorticoids, nevirapine,
Antidepressants: citalopram, escitalopram, ami- navir, nelfinavir, cimetidine, oxcarbazepine, modafinil, armodafinil, efavi-
triptyline, clomipramine, imipramine, mirtazap- erythromycin (macrolide renz, phenytoin, ritonavir, St. John’s wort
ine, sertraline, venlafaxine, trazodone, nefazo- antibiotics), diltiazem (calcium-
done, levomilnacipran, vilazodone channel blockers), fluoxetine,
ciprofloxacin (fluoroquino-
Anxiolytics: alprazolam, clonazepam, diazepam,
lones), sertraline, efavirenz
buspirone
Sedatives/hypnotics: zolpidem, zaleplon, eszopi-
clone, flurazepam, triazolam, chlordiazepoxide,
suvorexant, alfentanil, midazolam, fentanyl
Mood stabilizers: carbamazepine, topiramate
Other: methadone, tamoxifen, metoprolol,
warfarin, verapamil (calcium channel blockers),
losartan, dextromethorphan, prednisone, rito-
navir, ketoconazole, erythromycin, amiodarone,
bromocriptine, caffeine, cocaine, cyclosporine,
efavirenz, estradiol, progesterone, testosterone,
guanfacine, indinavir, HMG-CoA reductase
inhibitors (lovastatin and simvastatin), lidocaine,
loratadine, methadone, propafenone, quinidine,
ramelteon, sildenafil, tacrolimus, vardenafil,
vinblastine

Abbreviations: CYP, cytochrome; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A.

a
Nonprimary metabolizing enzymes.
b
Potent inhibitor/inducer.
Adapted from Alpert1,8 and Adis Medical Writers.3

rum levels and consequent diminished
efficacy of cyclosporine, oral contra-
ceptives, and other crucial substrates.1
EXCRETION
Drug excretion encompasses the
series of processes that result in the
elimination of a substance from the
body. Many psychotropic medications
(eg, antidepressants, anxiolytics, anti-
psychotics) are mostly eliminated by
hepatic metabolism and are not as af-
fected by alterations in renal excretion
as are medications such as lithium, ga-
bapentin, and pregabalin (which are, to
a large extent, eliminated unchanged
by the kidneys).1,3 In patients with a
baseline reduced glomerular filtration
rate, relatively small reductions in renal
elimination can result in disproportion-
ate increases in drug toxicity of medi-
cations that are predominately excreted
unchanged by the kidneys.3 Conditions
that cause sodium deficiency such as
dehydration and use of thiazide diuret-
ics may result in increased proximal
tubular reabsorption of lithium, which
can lead to increased serum levels and
to toxicity, given lithium’s narrow ther-
apeutic range.1 Perhaps the most com-
monly used medications that interact
with lithium are the nonsteroidal anti-
inflammatory agents (NSAIDs). By
inhibiting the cyclooxygenase enzyme
system, NSAIDs reduce prostaglandin
synthesis and consequently diminish
sodium excretion in the kidneys, there-
by decreasing lithium clearance and in-
creasing the chance for lithium toxicity
when administered at high prescription-
strength doses.9 Lastly, certain drugs
can alter the pH of the urine and lead
to increases or decreases in the rates of
excretion for specific substances. For
example, acidification of the urine by

PSYCHIATRIC ANNALS • Vol. 46, No. 8, 2016 443


ascorbic acid, ammonium chloride, or
methenamine mandelate increases the
rate of excretion of weak bases (such
as the amphetamines and phencycli-
dine). Conversely, alkalinization of the
urine by administration of sodium bi-
carbonate or acetazolamide may hasten
the excretion of weak acids (including
long-acting barbiturates, such as phe-
nobarbital).1
CATASTROPHIC DRUG
INTERACTIONS
Serotonin Syndrome
Serotonin syndrome is a potentially
life-threatening, drug-induced syn-
drome characterized by a cluster of
dose-related adverse effects that are
due to increased serotonin concentra-
tions in the CNS.10 The syndrome is
diagnosed clinically; it often devel-
ops within hours and shows no unique
laboratory findings (unlike neuroleptic
malignant syndrome).1 Most often, a
clinical triad arises: neuromuscular
excitation (clonus, hyperreflexia, my-
oclonus, rigidity), autonomic excita-
tion (hyperthermia, tachycardia), and
altered mental status (agitation, con-
fusion).10 Several criteria have been
advanced for the serotonin syndrome,
most notably the Sternbach criteria,
which examine a wide range of clinical
signs and symptoms (with a particular
focus on the mental status) and, more
recently, the Hunter criteria, which
focus on a smaller number of well-
defined clinical features.11,12 Serotonin
syndrome most often occurs in the set-
ting of starting or increasing the dose
of a potent serotonergic drug, in tan-
dem with an overdose, or shortly after
a second serotonergic agent is added,
leading to a drug interaction.10 Sero-
tonin syndrome is particularly likely
when 1 of 2 serotonergic drugs is a
monoamine oxidase inhibitor (MAOI).
However, the drug that is combined
with the MAOI does not necessarily
have to be a drug that functions princi-
444 Copyright © SLACK Incorporated
CME Article
pally to increase serum serotonin, such
as a selective serotonin reuptake inhib-
itor (SSRI) or a tricyclic antidepressant
(TCA). Many illicit drugs (cathinones,
other synthetic stimulants, ecstasy, am-
phetamines, cocaine), herbal medicines
(St. John’s wort, ginseng, tryptophan),
Many psychotropic medications
have the potential to cause
electrocardiogram changes
that increase the likelihood
of fatal arrhythmias.
and analgesics (meperidine) are known
to have significant serotonergic activ-
ity. Other commonly used medications,
such as tramadol, fentanyl, linezolid,
methylene blue, and dextrometho-
rphan, have noteworthy serotonergic
activity.10,13 The principal treatments
for serotonin syndrome are stopping
the offending agents and providing
supportive care. For severe serotonin
toxicity, intravenous (IV) chlorproma-
zine has been used, but IV fluid load-
ing is essential to prevent hypotension.
Oral cyproheptadine has also been
used to treat moderate serotonin toxic-
ity, and oral diazepam may be effective
for agitation.10 There are no clinical tri-
als or other strong evidence to support
these treatments, but recovery is usual
and mortality is low (<1%) when such
approaches have been applied along
with intensive supportive treatment.10
Hypertensive Crisis
Although it is widely appreciated
that MAOIs may cause a hypertensive
crisis via interaction with tyramine-
containing foods, it is important to keep
in mind that drug-drug interactions can
also produce a hypertensive crisis. Al-
though MAOIs potentiate norepineph-
rine in the serum, they have generally
not been shown (apart from anecdotal
reports) to cause hypertension without
other coadministered medications. In
fact, when administered alone without
other medications MAOIs are more
likely to cause orthostatic hypotension
than hypertension.14 However, when
drugs that have sympathomimetic ac-
tivity are combined with an MAOI, par-
ticularly in patients with pre-existing
and poorly controlled hypertension, a
dangerous hypertensive crisis can de-
velop.13 Alpha-1 agonists such as phen-
ylephrine and oxymetazoline, which
are commercially available as over-
the-counter decongestants, can be dan-
gerous when administered with MAOIs
in at-risk patients. Antihistamines are
the preferred over-the-counter agents
for people taking MAOIs with cold or
allergy symptoms.13 The sudden addi-
tion of a medication that inhibits the
reuptake of norepinephrine such as a
serotonin-norepinephrine reuptake in-
hibitor (SNRI) or TCA can lead to a
hypertensive crisis. Psychostimulants
such as amphetamine salts and meth-
ylphenidate have been used safely in
compelling clinical situations such as
severe treatment-resistant depression,
although they should be used with ex-
ceptional caution (with a slow titration
starting at a low dose).13,15 Other drugs
with noradrenergic activity, such as
nonamphetamine stimulants (atomox-
etine), appetite suppressants (sibutra-
mine), and analgesics (tramadol)
should generally be avoided in com-
bination with an MAOI unless deemed
to be essential by an experienced pro-
vider.13
Arrhythmia/QTc Prolongation
Many psychotropic medications
have the potential to cause electro-
cardiogram changes that increase the
likelihood of fatal arrhythmias, such
as torsades de pointes (TdP), a form

of polymorphic ventricular tachycar-
dia.16 Specifically, medications such
as SSRIs, TCAs, antipsychotics, and
methadone can lead to prolongation of
the QTc interval, which is indicative of
the time (in milliseconds) from the be-
ginning of ventricular depolarization to
the end of repolarization.
All TCAs are known to prolong the
QTc interval by blockade of both sodi-
um and calcium channels (a mechanism
that is similar to the antiarrhythmic
quinidine), with the risk being greatest
in those with pre-existing cardiac dis-
ease.1,16 A systematic review in 2004
suggested that amitriptyline and ma-
protiline (a tetracyclic antidepressant)
were the most likely to be implicated
in TdP, whereas clomipramine was the
least likely.16-18 Although SSRIs are
typically thought to convey a lower
risk of QTc prolongation and TdP than
TCAs, case reports have linked all
SSRIs (except paroxetine) with QTc
prolongation. However, it is notewor-
thy that a 2013 systematic review of
more than 38,000 patients identified
a dose-response QTc prolongation for
only citalopram and escitalopram.19 To
date, the US Food and Drug Adminis-
tration maintains a black-box warning
(regarding QTc prolongation among
SSRIs) solely for citalopram.19 There
is little evidence to suggest significant
QTc prolongation with other antide-
pressants, such as venlafaxine, dulox-
etine, mirtazapine, and bupropion.16
Trazodone has been associated with
mild QTc prolongation, but this has
mostly been observed in the setting of
overdose.16 Lastly, antipsychotic medi-
cations have well-described effects on
the QTc interval. In a randomized, pro-
spective study evaluating the effects on
the QTc interval in medically healthy
people with psychotic disorders, thio-
ridazine showed the greatest prolonga-
tion of the QTc interval compared with
ziprasidone, risperidone, olanzapine,
quetiapine, or haloperidol.16,20 In gen-
PSYCHIATRIC ANNALS • Vol. 46, No. 8, 2016 445
CME Article
eral, low-potency typical antipsychot-
ics are thought to carry a greater risk
than are high-potency agents, and this
risk is thought to be dose-related.16
However, some high-potency typical
antipsychotics, such as pimozide, lead
to a particularly high risk for QTc pro-
longation. The route of administration
has also been shown to be influential,
with IV haloperidol causing a more
substantial QTc interval prolongation
than both the intramuscular and oral
formulations. Among the atypical an-
tipsychotics, ziprasidone causes the
greatest mean QTc prolongation, com-
pared with olanzapine, risperidone, and
quetiapine.16 Anticonvulsant mood-sta-
bilizing agents, including valproate, la-
motrigine, carbamazepine, and oxcar-
bazepine, have not been found to cause
QTc prolongation. Lithium (in concen-
trations >1.2 mmol/L) can prolong the
QTc interval, but no cases of TdP have
been reported with its use.16
Anticholinergic Toxicity
When multiple medications having
significant anticholinergic activity are
combined, there is an increased risk
of anticholinergic side effects, such as
urinary retention, dry mouth, constipa-
tion, blurred vision, impaired memory,
reduced ability to concentrate, and in-
creased intraocular pressure in the set-
ting of narrow-angle glaucoma, related
to their shared pharmacodynamic ac-
tivity at the muscarinic receptor. In the
setting of overdose, a severe anticho-
linergic syndrome can develop, which
includes signs and symptoms of de-
lirium, paralytic ileus, tachycardia, and
dysrhythmias.1 The elderly are at high-
est risk for these severe and, in some
cases life-threatening, adverse events.
Of the antipsychotics, the lower-poten-
cy first- and second-generation agents,
including chlorpromazine, olanzap-
ine, and clozapine, generally have the
greatest anticholinergic effects.1 As a
result, caution should be taken when
combining these medications with oth-
er highly anticholinergic agents, such
as benztropine, diphenhydramine, hy-
droxyzine, and TCAs. The high-poten-
cy agents such as haloperidol and non-
anticholinergic atypical agents such
as risperidone are recommended in
clinical scenarios where there is con-
cern for anticholinergic toxicity.1 The
SSRIs as a class are largely thought to
share similar pharmacologic activity
and to have minimal anticholinergic
effects. However, recent studies have
shown that paroxetine has a uniquely
increased affinity for the muscarinic
acetylcholine receptor, which may be
comparable to that of the TCAs.21,22
SNRIs such as venlafaxine, desven-
lafaxine, and duloxetine appear to
have minimal anticholinergic activ-
ity. MAOIs, although largely devoid
of anticholinergic activity, have been
shown to indirectly potentiate the anti-
cholinergic properties of medications,
such as atropine and scopolamine.1
TCAs have well-described anticho-
linergic effects that are explained, in
part, by their structural similarities to
low-potency typical antipsychotics. As
stated previously, care should be taken
when combining TCAs with other an-
ticholinergic medications. Studies have
shown that, among the TCAs, amitrip-
tyline and clomipramine have the high-
est anticholinergic activity, whereas
desipramine and nortriptyline have the
lowest activity.23
Seizures
Numerous psychotropic medica-
tions, including antipsychotics, bupro-
pion, clomipramine, maprotiline, and
others, are known to reduce the seizure
threshold and consequently to increase
the chance for seizure induction. With
respect to the first-generation antipsy-
chotics, chlorpromazine has been as-
sociated with the greatest risk of sei-
zure provocation (although others have
been similarly linked).24 Conversely,

haloperidol, fluphenazine, and trifluo-
perazine have been shown to lower the
risk of seizures.24 Of the second-gen-
eration antipsychotics, clozapine has
been associated with the highest risk
of seizures, with risperidone appearing
to confer a relatively low risk.24 Other
factors, such as a history of seizure ac-
tivity, CNS lesions, metabolic distur-
bances, concurrent use of other drugs
that lower the seizure threshold, rapid
dose titration, and slow drug metabo-
lism, appear to increase the chances
of an antipsychotic medication induc-
ing seizure activity.24 Bupropion also
leads to a well-documented reduction
in the seizure threshold. Specifically, it
has been associated with a dose-related
risk for seizure of 0.1% (at doses up to
300 mg/day with the sustained-release
formulation) and 0.4% (at doses up to
450 mg/day with the immediate-release
formulation).25 Lastly, in people with
neurologic disorders, the combination
of clonazepam and valproate has been
shown to increase the chance of an ab-
sence of seizures.1
Stevens-Johnson Syndrome/Toxic
Epidermal Necrolysis
SJS and toxic epidermal necrolysis
(TEN) are severe cutaneous adverse
reactions that occur mostly as a result
of medications; they occur on a con-
tinuum and are characterized by ex-
tensive detachment of epidermis and
by erosions of mucous membranes.26
Based on a large, multinational study
from Europe between 1997 and 2001,
carbamazepine, lamotrigine, and phe-
nobarbital are the psychotropics most
likely to cause SJS/TEN.26 For all three
of these medications, the risk of devel-
oping SJS/TEN is substantially higher
in the first 8 weeks of treatment. This
is illustrated by carbamazepine, which
has a reported relative risk of >32 for
the first 8 weeks, with that number fall-
ing to 2 in subsequent weeks.26 Conse-
quently, it follows that a delay of 4 to
446 Copyright © SLACK Incorporated
CME Article
28 days between the beginning of drug
use and the onset of the adverse reac-
tion is the most suggestive timing sup-
porting drug causality in SJS/TEN.26 It
is noteworthy that, in the same study,
sertraline had an overall relative risk of
Many psychotropic medications
have CNS-depressant effects that,
among other complications, can
lead to significant respiratory
depression.
4.8, although none of the other SSRIs
had a significant risk. Although valpro-
ic acid has not been shown to increase
the risk of SJS/TEN when prescribed
as monotherapy, it can increase serum
levels of lamotrigine several fold by
inhibiting glucuronidation, thereby in-
creasing the risk of seizures.1,26 As a re-
sult, the Physicians’ Desk Reference27
provides guidelines for more gradual
dose titration of lamotrigine and lower
target doses when introduced in a pa-
tient already taking valproate. When
valproate is added to lamotrigine, the
dose of the latter should typically be
reduced by one-half to two-thirds.1
SSRI Medications and Bleeding
Risk
Current evidence indicates that use
of SSRIs may play a causal role in
upper GI bleeding and that the risk is
most significant when these medica-
tions are coadministered with others
that increase the risk of bleeding, such
as NSAIDs, corticosteroids, antico-
agulants, or low-dose aspirin. Patients
at particular risk include those with
previous ulcers or GI bleeding, the el-
derly, those with certain concurrent ill-
nesses (eg, malignancy, alcoholism, or
bleeding disorders), and patients taking
high-risk, coadministered medications.
Suggested strategies to reduce the risk
of bleeding in people who are high-
risk include (1) alternatives to SSRI
use, (2) prescribing a less gastrotoxic
NSAID (ibuprofen or diclofenac),28
or (3) coprescribing a gastroprotective
agent (such as misoprostol, a proton
pump inhibitor, or high doses of a his-
tamine H2 receptor antagonist).29,30
Respiratory Depression and
Psychotropic Medications
Many psychotropic medications
have CNS-depressant effects that,
among other complications, can lead
to significant respiratory depression.
This potentially catastrophic outcome
is most likely to occur when multiple
CNS depressants, such as benzodi-
azepines, barbiturates, narcotics, or
ethanol, are coadministered, leading to
additive effects. It is also noteworthy
that alterations in drug metabolism (via
CYP450 isoenzyme inhibition or other
pharmacokinetic mechanisms) can lead
to similar outcomes by increasing se-
rum levels of CNS depressant agents.
When benzodiazepines are the underly-
ing cause of respiratory depression or
general toxicity, the specific benzodi-
azepine antagonist, flumazenil, is most
commonly used in management.1
CONCLUSION
Drug interactions can occur via
pharmacokinetic or pharmacodynamic
mechanisms or both. Knowledge of
catastrophic drug interactions, such as
serotonin syndrome, hypertensive cri-
sis, QTc prolongation, anticholinergic
toxicity, seizures, and dermatologic
reactions (SJS/TEN) can allow clini-
cians to avoid critical pitfalls in clinical
practice.
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