|Outpatient Management of Depression
10 - Use of Antidepressants With Other Medications
The preceding chapters have focused on the antidepressant
alone; however, the majority of patients on an antidepressant
seen in primary-care settings are on other medications as
well (Table 10.1). In this chapter, the potential downside
of polydrug therapy will be discussed as a cautionary note.
In the next chapter, the upside of polydrug therapy will be
discussed; specifically, from the perspective of adding other
drugs to either treat tolerability problems or augment antidepressant
This chapter then will focus on the caution that should
be exercised when using polydrug therapy. It will discuss
the potential for adverse outcome resulting from an unintended
To understand the potential magnitude of this problem, consider
the percentage of patients on an antidepressant in different
practice settings who are on more than one other medication
and thus at risk for having a drug-drug interaction. In both
primary-care and general outpatient psychiatry, two thirds
of patients on an antidepressant are on at least one other
systemically taken, prescription medication. In fact, one
third of all patients on an antidepressant are on three or
more other systemically taken,
prescription medications (Table 10.1).
|TABLE 10.1 — Percentage
of Patients on Antidepressants Having the Potential to
Experience a Drug-Drug Interaction as a Function of Treatment
||Number of Patients
||Prescribed only an Antidepressant
||Prescribed at Least One Other
||Prescribed Three or More Other
|VA medical clinics
Veterans Administration; HIV, human immunodeficiency virus.
include a systemically taken, prescription drug from any
therapeutic class. Does not include over-the-counter medications,
topicals, or herbs.
|Adapted from: Preskorn
SH. J Prac Psych Behav Hlth. 1998;4:37-40.
These percentages are even higher in older and more medically
ill populations. That fact has three consequences:
- Elderly and more medically ill patients are at greater
risk for having a drug-drug interaction.
- Due to their fragile health, any adverse
outcome due to such an interaction is likely to be more
- Finally, the interaction is more likely to be erroneously
attributed to a worsening of their underlying health problems.
Such a misattribution will likely delay effective intervention
and can also increase health-care utilization (ie, increased
use of laboratory tests to determine the cause of the problem).
It can even increase the number of medications the patient
is taking since the clinician may add another medication
to treat what is, in fact, a drug-drug interaction.
The importance of this issue is further underscored by a
literature search that revealed that the annual number of
publications on drug-drug interactions increased five-fold
from 1970 through 1997. Potential reasons include:
- Increases in both the number and type of medications available.
- An increase in the use of maintenance drug therapy for
chronic conditions (eg, diabetes, hypertension, clinical
- Increased percentage of elderly in the US population
(these patients are likely to have one or more chronic illnesses
which require concomitant drug therapy).
Patients with clinical depression may be particularly at
risk for being on polydrug therapy for the following reasons:
- Patients with a variety of chronic medical illnesses have
a higher incidence of clinical depression than physically
healthy patients (Table 10.2). These patients will be on
medications for their chronic medical conditions as well
as on an antidepressant.
- Patients with clinical depression
have a higher utilization of medical services in comparison
to patients who are not depressed.
- Depressed patients often present with a variety of medical
complaints (eg, headaches, muscle aches) which can lead
to concomitant drug therapy.
- The clinician may use a second drug
to either treat an adverse effect caused by an antidepressant
or to boost its effectiveness (Chapter 11).
10.2 — Prevalence of Major Depression in Specific Medically
|Terminal solid tumors
to > 50%
|Data from: Evans
D. Am Soc Clin Psychopharm Progress Notes. 1995;6:22-25;
Robertson MM, Trimble MR. Epilepsia. 1983;24(suppl 2):S109-S116;
and Series HG. J Psychosom Res. 1992;36:1-16.
For all of these reasons, the prescriber must consider the
potential for a drug-drug interaction when selecting an antidepressant
for a depressed patient. There are two ways an antidepressant
can interact with a coprescribed drug:
- Through its mechanism of action (ie,
a pharmacodynamic interaction)
- Through its inhibition of a drug metabolizing CYP enzyme
(ie, a pharmacokinetic interaction).75,254
Twenty years ago, clinicians were acutely aware of the risk
of drug-drug interactions when prescribing antidepressants
because their only options were tricyclic antidepressants
(TCAs) and monoamine oxidase inhibitors (MAOIs). As outlined
in Chapters 6 through 8, the pharmacology of these older antidepressants
is such that they cause a number of different types of potentially
serious pharmacodynamic drug-drug interactions when used in
combination with other medications. For that reason, many
practitioners twenty years ago were reluctant to use these
antidepressants in elderly or medically ill patients.
In comparison to TCAs, most newer antidepressants have a
much more limited number of pharmacologic actions. As explained
in Chapter 6, that fact accounts for their better tolerability,
wider therapeutic index, and a reduced risk of interacting
pharmacodynamically with other coprescribed drugs. For these
reasons, clinicians may have been lulled into a false sense
of security. However, a number of the newer antidepressants
can cause pharmacokinetic drug-drug interactions by virtue
of their inhibition of drug-metabolizing cytochrome P450 (CYP)
enzymes (Table 6.10).
Cytochrome P450 enzyme-mediated interactions are probably
the most common type of pharmacokinetic drug-drug interaction.
They are also the most easily misinterpreted type of drug-drug
interaction because they can present in a myriad of ways,
- Dose-dependent toxicity
- Dose-dependent tolerability problems
- Decreased efficacy
- Withdrawal symptoms.
These interactions typically cause an increase or a decrease
in the concentration-dependent effects of the drug whose metabolism
was altered. Hence, the prescriber may attribute the adverse
outcome to a problem of "sensitivity" or "resistance"
on the part of the patient.168,174
Because our understanding of the mechanism underlying such
interactions (ie, the inhibition of CYP enzymes) has increased
dramatically over the last decade and because of their clinical
importance, the remainder of this chapter will be devoted
to some actual case examples that demonstrate the problems
CYP enzyme-mediated drug-drug interactions can cause.
This patient presented to his clinician with a recurrent
episode of major depression.187
He was otherwise physically healthy based on medical history
and physical examination. The patient stated he was in danger
of losing his job because of poor performance resulting from
his lack of energy and motivation.
His psychiatric history revealed that his depressive illness
began in his early twenties. The current episode was his fourth
and had begun approximately 3 months before he presented for
care. According to the patient's medical history, he had responded
to previous treatment with either a tertiary amine tricyclic
antidepressant (TATCA) alone or a serotonin selective reuptake
inhibitor (SSRI) alone, but the response had been incomplete
and had taken considerable time.
Due to concerns about his job, the patient
desperately wanted to feel better quickly. In response, his
prescriber used an augmentation strategy; the combined use
of a TCA and an SSRI (Chapter 11). He chose amitriptyline,
150 mg/day, and fluoxetine, 40 mg/day. The patient responded
quickly with his only adverse effect being a mild dry mouth.
However, several weeks later, the patient was found dead.
There was no evidence of foul play. An autopsy found no anatomical
cause of death. The results of the analyses of postmortem
blood samples revealed toxic levels of amitriptyline and its
active metabolite, nortriptyline. The coroner signed this
case out initially as a suicide.
Suicide is an understandable conclusion in this case for
several reasons. The high levels of amitriptyline and its
metabolites indicate a drug overdose. This patient had several
risk factors for suicide (Table 4.1). He had recurrent clinical
depression which leads to death by suicide in 15% of cases
and had been under considerable psychosocial stress.
However, there were also several factors against this interpretation
including the absence of a suicide note, no missing pills
from his amitriptyline prescription bottle, and no pill fragments
in his stomach.
The definitive answer about the cause of death came by examining
the relative ratio of amitriptyline to nortriptyline in the
gastric contents, blood, and tissue samples taken at autopsy.
Amitriptyline is converted into nortriptyline by CYP 2D6-mediated
oxidative drug metabolism. After taking amitriptyline on a
regular basis for a week or more, an equilibrium (steady-state)
is reached between the central compartment (the blood) and
deep compartments in the tissue. Once steady-state is reached,
the ratio of amitriptyline to nortriptyline is the same in
the deep tissue compartment as it is in the blood.
Since gastric fluid is produced from
the plasma, it reflects the ratio of drug in the plasma unless
it is distorted by what is consumed. In an acute overdose,
the amitriptyline in his stomach would dissolve into the gastric
fluid substantially distorting the amitriptyline to nortriptyline
ratio. In fact, patients typically die from an acute cardiac
arrest before all of the amitriptyline is absorbed. For these
reasons, in an acute amitriptyline overdose we would expect
that the highest ratio of amitriptyline to nortriptyline would
be in the stomach fluid, next highest in the blood, and lowest
in the deep compartments. In this case, the ratios in these
three compartments were the same, proving that this patient
did not die from an acute overdose.
When these facts were presented to the coroner years later,
the death certificate was corrected to show death occurred
as a result of a chronic, unintentional overdose of amitriptyline
consistent with fluoxetine-induced inhibition of CYP 2D6.
In fact, the functional dose of amitriptyline in this case
was closer to 900 mg/day than to the prescribed dose of 150
mg/day due to the fluoxetine-induced decrease in amitriptyline
A dose of 900 mg/day would be expected to produce toxic levels
in almost all patients. The time course from starting the
combined therapy to the patient's death is due to the fact
that it takes several weeks for fluoxetine to accumulate and
sufficiently inhibit the metabolism of amitriptyline. That
is the reason why the prescriber must consider the long half-life
of fluoxetine when starting or stopping fluoxetine.
This patient was in a nursing home for
cognitive impairment and delusions.136
The latter problem had been successfully treated with molindone,
an intermediate potency antipsychotic medication, which she
tolerated with only a mild, intermittent resting tremor. She
then developed a depressive episode and was treated with the
SSRI, paroxetine. Being aware of the issue of drug-drug interactions,
her prescriber reduced the dose of molindone from 30 mg/day
to 20 mg/day. Two weeks later, the patient had a prominent
3-cycle-per-second resting tremor, mask-like facies, cogwheel
rigidity, and was unable to walk or care for herself.
The clinician attributed these problems to the worsening
of underlying Parkinson's disease. As a result, he reduced
the dose of molindone to 10 mg/day and added L-dopa/carbidopa
and the anticholinergic drug, benztropine. Over the next several
days, the patient developed a superimposed delirium. All of
her medications were then discontinued and she gradually returned
to her baseline status over the next 2 weeks.
The metabolism of molindone has not been characterized;
however, this case suggests that CYP 2D6 plays a major role.
If that is correct, then the addition of paroxetine 20 mg/day
would be expected to substantially increase her molindone
levels. In other words, her clinician would have functionally
increased her dose of molindone conceivably well beyond 30
mg/day even though he thought he had reduced the dose to 20
An increased accumulation of molindone
would produce a greater degree of dopamine receptor blockade
in her brain which in turn would have caused the development
of marked parkinsonism. The failure to consider this possibility
led to the misdiagnosis and the addition of the antiparkinsonian
medications which caused her delirium. While benztropine is
another drug whose metabolism has not been characterized,
some authors have postulated a CYP 2D6 component on the basis
of cases of delirium occurring following the addition of fluoxetine
or paroxetine to patients on stable doses of benztropine.11,211
As in the first case, this example illustrates how "not
seeing" may simply mean "not recognizing."
It also shows how the adverse consequence of a drug-drug interaction
can be mistaken for another disease. The result can be both
poor patient outcome and increased health-care costs.
This patient had grand mal epilepsy and a triad of behavioral
problems (irritability, angry outbursts, and agitation) for
which he had been treated for some time with phenytoin, 400
mg/day, and carbamazepine, 600 mg/day.224
On this regimen, he improved in terms of both seizure control
and behavior. When he later presented with a major depressive
episode, his prescriber added the SSRI, fluoxetine 20 mg/day.
The depressive episode resolved. He also experienced a further
reduction in the frequency of seizures and behavioral problems.
After 1 year of successful maintenance therapy, the fluoxetine
was stopped since he had only one depressive episode. One
month after discontinuation of the fluoxetine, his phenytoin
level had fallen by 50% and was below the usually effective
threshold for seizure control. His carbamazepine levels had
also fallen, but only by approximately 15%.
Fortunately, a quality-control program detected the potential
problem. The alerted clinician rechecked the patient's phenytoin
and carbamazepine levels and increased their dose. If that
had not occurred, this patient was at risk for both an increase
in his seizure frequency and a worsening of his behavioral
In this case, the problem was a loss of the inhibitory effect
of fluoxetine on the clearance of the anticonvulsants. During
fluoxetine coadministration, the levels of the anticonvulsants
had risen which likely accounted for the better control of
his seizure disorder and behavioral problems during that time.
However, the prescriber did not understand that he needed
to increase the doses of the anticonvulsants when he stopped
fluoxetine if he wanted to maintain these higher levels.
This case demonstrates that loss of efficacy
can result from a CYP enzyme-mediated drug-drug interaction.
It also illustrates that a drug like fluoxetine can have different
effects on two CYP enzymes. CYP 2C9/10 mediates the metabolism
of phenytoin and is substantially inhibited by fluoxetine
20 mg/day, while CYP 3A mediates the metabolism of carbamazepine
and is only mildly inhibited by fluoxetine 20 mg/day (Tables
6.9 and 6.10).
Had this patient experienced a seizure, the clinician might
have erroneously concluded that the patient had not been compliant
when he found low anticonvulsant plasma levels on repeat therapeutic
This patient was a narcotic addict and had been successfully
treated for several years with methadone.24
He then developed a depressive episode that was in turn successfully
treated with the SSRI, fluvoxamine, 200 mg/day. After 3 months,
the clinician decided to stop the SSRI, feeling treatment
was adequate. Within several days, this patient experienced
abdominal cramps, loose stools, sweating, tremulousness, chills,
and a runny nose.
The patient was in narcotic withdrawal. The reason is that
fluvoxamine produces substantial inhibition of CYP 1A2 which
metabolizes methadone (Table 6.9). During the 3 months that
this patient was on fluvoxamine, his methadone levels had
risen as a result of decreased clearance and he had become
dependent on the higher methadone levels. When the fluvoxamine
was stopped, his methadone clearance increased and his methadone
levels fell precipitating withdrawal symptoms.
Had the clinician not thought of this possibility, he might
have thought the patient was drug seeking or that the symptoms
were due to an intercurrent medical problem. The latter interpretation
could have resulted in unnecessary medical testing while the
patient suffered needlessly.
The information reviewed in these case studies should help
demystify the issue of drug-drug interactions, particularly
those mediated by CYP enzymes. The cases illustrate that CYP
enzyme-mediated drug-drug interactions can present in myriad
ways from sudden and life-threatening toxicity to more subtle
but nevertheless clinically important problems. Such interactions
can result in poor patient outcome and increased health-care
costs, and frequently have the same consequence as would occur
with a comparable change in the dose of the affected (or "victim")
While this book is focused on antidepressant
pharmacotherapy, the basic concepts covered in this chapter
are relevant to all therapeutic classes of medications. By
understanding the mechanisms underlying such interactions,
clinicians can minimize the risk of such interactions by proper
drug selection. Fortunately, there are a number of newer antidepressant
options that generally do not produce clinically meaningful
inhibition of drug metabolizing enzymes and hence are not
at serious risk for causing such interactions (Table 6.10).