CURRENT DRUG THERAPY EDUCATIONAL OBJECTIVE: Readers will prescribe antidepressant drugs more confidently on the basis CREDIT of the characteristics of the patient and the various drugs
Department of Psychiatry and Psychology,
Chair, Department of Psychiatry and Psychology,
Cleveland Clinic; Clinical Instructor, Cleveland Cleveland Clinic; Professor, Cleveland Clinic Lerner
Clinic Lerner College of Medicine of Case
College of Medicine of Case Western Reserve
Western Reserve University, Cleveland, OH
A practical approach to prescribing antidepressants
■■ABSTRACT With the variety of drugs available for
treating depression, choosing one can be
Although antidepressant drugs do not differ much in their daunting. Different agents have characteristics
efficacy rates, the particular characteristics of one drug
that may make them a better choice for dif-
may make it a better choice in a given patient. This article ferent types of patients, but even so, treating
provides insight into the art of prescribing antidepres-
any kind of mental illness often requires an el-
sants in primary care, with recommendations for prescrib-
ing for patients with chronic pain, sexual dysfunction,
Primary care providers are on the frontline
of treating mental illness, often evaluating pa-
anxiety, chronic fatigue syndrome, fibromyalgia, severe
tients before they are seen by a psychiatrist.
insomnia, old age, diabetes, and heart problems.
The purpose of this article is to provide insight
■■KEY POINTS
into the art of prescribing antidepressants in the
primary care setting. We will discuss common
We suggest that clinicians become familiar with one drug patient presentations, including depressed pa-
tients without other medical comorbidities as
well as those with common comorbidities, with
our recommendations for first-line treatment.
Many antidepressants are also approved for conditions
other than depression, and for patients who have both
you to navigate the uncertainty more confi-
depression and one or more of these comcomitant condi-
dently, resulting in more efficient and tailored
tions, these drugs can have a “two-for-one” benefit.
Adverse effects of an antidepressant are usually predict-
■ BASELINE TESTING
able on the basis of the drug’s mechanism of action.
When starting a patient on antidepressant
drug therapy, we recommend obtaining a set
of baseline laboratory tests to rule out underly-
ing medical conditions that may be contrib-
uting to the patient’s depression or that may
preclude the use of a given drug. (For example,
elevation of liver enzymes may preclude the
use of duloxetine.) Tests should include:
• A thyroid-stimulating hormone level.
Electrocardiography may also be useful, as
some antidepressants can prolong the QT in-
terval or elevate the blood levels of other drugs
CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 80 • NUMBER 10 OCTOBER 2013
PRESCRIBING ANTIDEPRESSANTS
every 2 weeks based on tolerance and patient
Drugs discussed this article
response. That said, each patient may respond
differently, requiring perhaps a lower starting
Anticipate side effects. Most of the side ef-
fects of an antidepressant drug can be explained
by its mechanism of action. Although side ef-
fects should certainly be considered when
choosing an agent, patients can be reassured
that most are transient and benign. A detailed
discussion of side effects of antidepressant drugs
is beyond the scope of this article, but a review
by Khawam et al1 was published earlier in this
Maprotiline (Deprilept, Ludiomil, Psymion)
Reassess. If after 4 to 6 weeks the patient
has had little or no response, it is reasonable
to switch agents. For a patient who was on
Nortriptyline (Aventyl, Pamelor, Norpress)
an SSRI, the change can be to another SSRI
or to an SNRI. However, if two SSRIs have
already failed, then choose an SNRI. Agents
are commonly cross-tapered during the switch
to avoid abrupt cessation of one drug or the
increased risk of adverse events such as cy-
tochrome P450 interactions, serotonin syn-
drome, or hypertensive crisis (when switching
Beware of interactions. All SSRIs and
SNRIs are metabolized through the P450 sys-
■ GENERAL TREATMENT CONSIDERATIONS
tem in the liver and therefore have the poten-
antidepressants
tial for drug-drug interactions. Care must be
at half the
There are several classes of antidepressants, taken when giving these agents together with
normal dose,
and each class has a number of agents. Re-
drugs whose metabolism can be altered by
search has found little difference in efficacy
P450 inhibition. For TCAs, blood levels can
and titrate
among agents. So to simplify choosing which
be checked if there is concern about toxicity;
one to use, we recommend becoming comfort-
however, dosing is not strictly based on this
level. Great care should be taken if a TCA is
as tolerated
• A selective serotonin reuptake inhibitor given together with an SNRI or an SSRI, as
about every
the TCA blood level can become significantly
• A selective serotonin-norepinephrine reup-
elevated. This may result in QT interval pro-
Refer. Referral to a psychiatrist is appropri-
• A monoamine oxidase (MAO) inhibitor.
ate for patients for whom multiple classes have
Each class includes generic agents, many of
failed, for patients who have another psychiat-
which are on the discount lists of retail phar-
ric comorbidity (such as psychosis, hypomania,
macies. TABLE 1 shows representative drugs from
or mania), or for patients who may need hos-
each class, with their relative costs.
pitalization. Referral is also appropriate if the
Start low and go slow. In general, when
physician is concerned about suicide risk.
starting an antidepressant, consider starting at
half the normal dose, titrating upward as toler-
■ PATIENTS WITH MAJOR DEPRESSION ONLy
ated about every 14 days. This approach can
minimize side effects. For example, if prescrib-
For a patient presenting with depression but
ing fluoxetine, start with 10 mg and titrate no other significant medical comorbidity, the
626 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 80 • NUMBER 10 OCTOBER 2013
SHULTZ AND MALONE
first-line therapy is often an SSRI. Several ge-
neric SSRIs are available, and some are on the
Representative antidepressants
Symptoms should start to improve in about
2 weeks, and the optimal response should be
achieved in 4 to 6 weeks of treatment. If this
does not occur, consider either adding an aug-
menting agent or switching to a different anti-
■ PATIENTS WITH CHRONIC PAIN
Chronic pain and depression often go hand
in hand and can potentiate each other. When
Selective serotonin reuptake inhibitors (SSRIs)
considering an antidepressant in a patient who
are typically preferred. Some SNRIs, namely
duloxetine and milnacipran, are approved
for certain chronic pain conditions, such as
fibromyalgia. SNRIs are frequently used off-
label for other chronic pain conditions such as
TCAs such as amitriptyline, nortriptyline,
Serotonin-norepinephrine reuptake inhibitors (SNRIs)
and doxepin are also often used in patients
with chronic pain. These agents, like the
SNRIs, inhibit the reuptake of serotonin and
norepinephrine and are used off-label for neu-
ropathic pain,3,4 migraine, interstitial cystitis,5
range for chronic pain overlaps that for de-
pression. However, TCAs are often given at
lower doses to patients without depression.
Dopamine-norepenphrine reuptake inhibitor
slowly titrating upward to an effective dose.
SNRIs are often preferred over TCAs because
they do not have anticholinergic side effects
and because an overdose is much less likely to
■ PATIENTS WITH SEXUAL DySFUNCTION
One of the more commonly reported side ef-
fects of antidepressants is sexual dysfunction,
generally in the form of delayed orgasm or de-
creased libido.10 Typically, these complaints
are attributed to SSRIs and SNRIs; however,
a $ = on discount list ($4 or less for 30-day supply), $$ = generic available or relatively
TCAs and MAO inhibitors have also been as-
low-cost brand name, $$$ = no generic available b At bedtime
have been linked to certain antidepressants.
e Depending on formulation f Selegiline transdermal system (Emsam patch)
In particular, trazodone is a known cause of
CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 80 • NUMBER 10 OCTOBER 2013
PRESCRIBING ANTIDEPRESSANTS
priapism. Even if using low doses for sleep, ful for nighttime anxiety, as they can aid sleep.
male patients should be made aware of this Of note, the anxiolytic effect of mirtazapine
Switching from one agent to another in MAO inhibitors often go unused because
the same class is not likely to improve sexual
of the dietary and medication restrictions in-
side effects. In particular, all the SSRIs are volved. However, very refractory cases of cer-
similar in their likelihood of causing sexual tain anxiety disorders may respond preferen-
dysfunction. In a patient taking an SSRI who
experiences this side effect, switching to bu-
propion11 or mirtazapine12 can be quite useful.
than other antidepressants, so is often avoided
Bupropion acts primarily on dopamine and in anxious patients. However, some research
norepinephrine, whereas mirtazapine acts on
suggests this is not always necessary.20 If the
serotonin and norepinephrine but in a differ-
anxiety is secondary to depression, it will of-
ten improve significantly with this agent.
Adjunctive treatment such as a choliner-
When starting or increasing the dose of an
gic agonist, yohimbine (contraindicated with
antidepressant, patients may experience in-
MAO inhibitors), a serotonergic agent (eg, creased anxiety or feel “jittery.” This feeling
buspirone), or a drug that acts on nitric oxide
usually passes within the first week of treat-
(eg, sildenafil, tadalafil) may have some utility
ment, and it is important to inform patients
but is often ineffective. Dose reduction, if pos-
about this effect. “Start low and go slow” in
patients with significant comorbid anxiety.
Temporarily using a benzodiazepine such as
■ PATIENTS WITH ANXIETy
Many antidepressants are also approved for
anxiety disorders, and still more are used off-
■ PATIENTS WITH CHRONIC FATIGUE
label for this purpose. Anxiety and depression
SyNDROME OR FIBROMyALGIA Depressive
often occur together, so being able to treat
both conditions with one drug can be quite
Increasing recognition of both chronic fa-
symptoms
useful.13 In general, the antidepressant effects
tigue syndrome and fibromyalgia has led to
should start
are seen at lower doses of SSRIs and SNRIs,
more proactive treatment for these disorders.
to improve
whereas more of the anxiolytic effects are seen
Depression can go hand in hand with these
at higher doses, particularly for obsessive-
disorders, and certain antidepressants, namely
about 2 weeks compulsive disorder.14
the SNRIs, can be useful in this population.
after treatment First-line treatment would be an SSRI or More data exist for the treatment of fibro-
SNRI. Most anxiety disorders respond to ei-
myalgia. Both duloxetine and milnacipran are
ther class, but there are some more-specific approved by the US Food and Drug Adminis-
recommendations. SSRIs are best studied in
tration (FDA) for the treatment of fibromyal-
panic disorder, generalized anxiety disorder, gia.21 Venlafaxine is also used off-label for this
social anxiety disorder, posttraumatic stress purpose. SSRIs such as fluoxetine and citalo-
disorder, and obsessive-compulsive disorder. pram have had mixed results.21–23 TCAs have
Fluoxetine, citalopram, escitalopram, and been used with some success; however, their
sertraline15 can all be effective in both major
side effects and lethal potential are often lim-
depressive disorder and generalized anxiety iting.21,24,25 A recent study in Spain also sug-
disorder. Panic disorder also tends to respond
gested there may be benefit from using MAO
well to SSRIs. SNRIs have been evaluated pri-
inhibitors for fibromyalgia, but data are quite
marily in generalized anxiety disorder but may
also be useful in many of the other conditions.
The data for treating chronic fatigue syn-
Additionally, mirtazapine (used off-label)12
and the TCAs16–18 can help treat anxiety. Clo-
tors are conflicting.27–29 However, managing
mipramine is used to treat obsessive-compul-
the co-existing depression may provide some
sive disorder.19 These drugs are especially use-
628 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 80 • NUMBER 10 OCTOBER 2013
SHULTZ AND MALONE
■ PATIENTS WITH FREQUENT INSOMNIA
SSRIs, bupropion, and the SNRIs tend not
to affect cognition. Escitalopram and dulox-
Insomnia can be a symptom of depression, but
etine have been suggested to be particularly
it can also be a side effect of certain antide-
effective in the elderly.35,36 A study from the
pressants. The SSRIs and SNRIs can disrupt
Netherlands linked SSRIs with increased risk
sleep patterns in some patients by shortening
of falling in geriatric patients with dementia.37
the rapid-eye-movement (REM) stage.30,31
Constipation, which could lead to ileus, is in-
In patients with severe insomnia, it may be
creased with TCAs and certain other agents
best to first recommend taking the antidepres-
(ie, paroxetine) in the geriatric population.
sant in the morning if they notice worsening
Mirtazapine is often very useful in elderly
sleep after initiating treatment. Patients can
patients for many reasons: it treats both anxi-
be told with any antidepressant, “If it makes
ety and depression, stimulates appetite and
you tired, take it at night, and if it wakes you
weight gain, can help with nausea, and is an
up, take it in the morning.” Of note, a recent
effective sleep aid. Concerns about weight,
South African study suggested that escitalo-
appetite, and sleep are particularly common
in the elderly, whereas younger patients can
If that does not solve the problem, there are
be less tolerant of drugs that make them gain
other options. For instance, mirtazapine, par-
weight and sleep more. Normal age-related
ticularly in doses of 15 mg or 30 mg, aids depres-
changes to the sleep cycle contribute to de-
sion and insomnia. At higher doses (45 mg), the
creased satisfaction with sleep as we age. In
sleep-aiding effect may be reduced. Low doses
addition, depression often further impairs
of TCAs, particularly doxepin, maprotiline sleep. So, in the elderly, optimizing sleep is
(technically speaking, a tetracyclic antidepres-
key. Research has also shown mirtazapine to
sant), amitriptyline, and nortriptyline can be be effective in patients with both Alzheimer
effective sleep aids. These agents may be used
as an adjunct to another antidepressant to en-
hance sleep and mood. However, the TCAs also
■ DIABETIC PATIENTS Chronic pain
One of the more worrisome side effects of psy- and depression
tions with SSRIs and SNRIs also need to be
chiatric medications in diabetic patients is
considered. Caution should be used when dis-
weight gain. Certain antidepressants have a often go
continuing these medications, as patients may
greater propensity for weight gain and should hand in hand
experience rebound symptoms in the form of
likely be avoided as first-line treatments in and can
much more vivid dreams. MAO inhibitors this population.12 Typically, these agents in-
may worsen insomnia because they suppress clude those that have more antihistamine ac- potentiate
tion such as paroxetine and the TCAs. These each other
Trazodone is another agent that at lower dos-
agents also may lead to constipation, which
es (25–150 mg) can be an effective, nonaddict-
could potentially worsen gastroparesis. Mir-
ing sleep aid. When used as an antidepressant, it
tazapine and the MAO inhibitors are also
is generally prescribed at higher doses (300–400
mg), but its sedating effects can be quite limiting
at these levels. It is important to remember the
weight-neutral of all antidepressants. Nefazo-
possibility of priapism in male patients.
done has fallen out of favor because of its po-
tential to cause fulminant liver failure in rare
■ GERIATRIC PATIENTS
cases. However, it remains a reasonable op-
tion for patients with comorbid anxiety and
Old age brings its own set of concerns when
depression who have significant weight gain
treating depression. Elderly patients are more
susceptible to potential bradycardia caused by
or be neutral toward glucose metabolism, and
cardiac side effect of QTc prolongation. TCAs
some data suggest that SNRIs may impair this
can slow cognitive function, whereas the process.39
CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 80 • NUMBER 10 OCTOBER 2013
PRESCRIBING ANTIDEPRESSANTS
■ PATIENTS WITH CARDIAC CONDITIONS
lopram at doses greater than 40 mg in adult
patients43; however, research has suggested
Major depression often coexists with cardiac citalopram is effective in treating depression
conditions. In particular, many patients develop
in cardiac patients.44 Research has not shown
depression after suffering a myocardial infarc-
an increase in efficacy at doses greater than
tion, and increasingly they are being treated for
40 mg daily, so we recommend following the
it.40 Treatment in this situation is appropriate,
since depression, if untreated, can increase the
risk of recurrence of myocardial infarction.41
orthostatic hypotension. On the other hand,
However, there are many concerns that consuming large amounts of tyramine, in
accompany treating depression in cardiac foods such as aged cheese, can precipitate a
patients. Therefore, a baseline electrocardio-
hypertensive crisis in patients taking MAO
gram should be obtained before starting an inhibitors.
Which antidepressants tend to be safer in
cardiac patients? Sertraline has been shown to
dency to prolong the QTc interval and po-
be safe in congestive heart failure and coro-
tentiate ventricular arrhythmias,42 so it may nary artery disease,45–47 but the SSRIs are typi-
be prudent to avoid these in patients at risk.
cally safe. Fluoxetine has shown efficacy in
These agents can also significantly increase patients who have had a myocardial infarc-
the pulse rate. This tachycardia increases the
tion.48 Mirtazapine has also been shown to be
risk of angina or myocardial infarction from
efficacious in cardiac patients.49 Nefazodone,
the anticholinergic effects of these drugs.
mirtazapine, bupropion, SSRIs, and SNRIs
In February 2013, the FDA issued a warn-
have little or no tendency toward orthostatic
ing about possible arrhythmias with cita-
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Measuring the Quality of Surgical Care:Structure, Process, or Outcomes?John D Birkmeyer, MD, FACS, Justin B Dimick, MD, Nancy JO Birkmeyer, PhDWith widespread recognition that surgical outcomesstandard in cardiac surgery and in hospitals of the De-vary by providersurgeons and hospitals are increas-ingly being asked to provide evidence of the quality ofIn this article, we consider the relativ