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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
ELIZABETH SHULTZ, DO DONALD A. MALONE, JR., MD 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 University, Cleveland, OH A practical approach to prescribing
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- ement of trial and error.
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 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- from each class of antidepressants.
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 We hope our recommendations will help 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.
treatment for your patients.
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 complete blood cell count • A complete metabolic panel • 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 with this effect. CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 80 • NUMBER 10 OCTOBER 2013 every 2 weeks based on tolerance and patient Drugs discussed this article
response. That said, each patient may respond Amitriptyline (Elavil) differently, requiring perhaps a lower starting Bupropion (Wellbutrin, Zyban) dose or a longer titration schedule. Buspirone (Buspar) Anticipate side effects. Most of the side ef-
Citalopram (Celexa) fects of an antidepressant drug can be explained Clomipramine (Anafranil) by its mechanism of action. Although side ef- Clonazepam (Klonopin) fects should certainly be considered when Desvenlafaxine (Pristiq) choosing an agent, patients can be reassured Doxepin (Sinequan) that most are transient and benign. A detailed Duloxetine (Cymbalta) Escitalopram (Lexapro) discussion of side effects of antidepressant drugs Fluoxetine (Prozac) is beyond the scope of this article, but a review Imipramine (Tofranil) by Khawam et al1 was published earlier in this Maprotiline (Deprilept, Ludiomil, Psymion) Milnacipran (Savella) Reassess. If after 4 to 6 weeks the patient
Mirtazapine (Remiron) has had little or no response, it is reasonable Nefazodone (Serzone) to switch agents. For a patient who was on Nortriptyline (Aventyl, Pamelor, Norpress) an SSRI, the change can be to another SSRI Paroxetine (Paxil) or to an SNRI. However, if two SSRIs have Phenelzine (Nardil) already failed, then choose an SNRI. Agents Selegiline (Eldepryl) are commonly cross-tapered during the switch Sertraline (Zoloft) Sildenafil (Viagra) to avoid abrupt cessation of one drug or the Tadalafil (Cialis) increased risk of adverse events such as cy- Tranycypromine (Parnate) tochrome P450 interactions, serotonin syn- Trazodone (Desyrel) drome, or hypertensive crisis (when switching Venlafaxine (Effexor) to an MAO inhibitor). 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- 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 able with an agent from each class, ie: 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- take inhibitor (SNRI) longation, as mentioned earlier.
• A tricyclic antidepressant (TCA) 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 discount lists at retail pharmacies. Symptoms should start to improve in about Class and examples Typical daily dose Maximum dose Cost a 2 weeks, and the optimal response should be achieved in 4 to 6 weeks of treatment. If this Tricyclic antidepressants (TCAs) does not occur, consider either adding an aug- 25–150 mg, b,c 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 has both conditions, the SNRIs and TCAs 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 headache and neuropathic pain.2 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 and other pain conditions.6–9 For TCAs and SNRIs, the effective dose range for chronic pain overlaps that for de- 25–200 mg for sleep b 600 mg pression. However, TCAs are often given at 150 mg for depression d lower doses to patients without depression. We recommend starting at a low dose and 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
Monoamine oxidase (MAO) inhibitors One of the more commonly reported side ef- fects of antidepressants is sexual dysfunction, generally in the form of delayed orgasm or de- Tranylcypromine 10–30 mg 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 sociated wth sexual dysfunction.
c Can be divided Both erectile dysfunction and priapism d In divided doses 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 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 may be greater at higher doses. 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 tially to these agents.
experiences this side effect, switching to bu- Bupropion tends to be more activating 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- ent manner from SSRIs and SNRIs. 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 sible, can be of value. patients with significant comorbid anxiety. Temporarily using a benzodiazepine such as ■ PATIENTS WITH ANXIETy
clonazepam may make the transition more 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 drome with SSRIs, SNRIs, or MAO inhibi- 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- relief in and of itself.
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 pram may be able to improve sleep.32 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 dementia and depression.38 as an adjunct to another antidepressant to en- hance sleep and mood. However, the TCAs also ■ DIABETIC PATIENTS
shorten the REM stage of sleep.33 Chronic pain
The previously mentioned drug interac- 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 known to cause weight gain. mg), but its sedating effects can be quite limiting Bupropion and nefazodone are the most 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 with other agents. susceptible to potential bradycardia caused by SSRIs and MAO inhibitors may improve SSRIs. The TCAs have the more worrisome 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 ■ 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, black-box warning.
since depression, if untreated, can increase the TCAs and MAO inhibitors can also cause 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 TCAs and tetracyclic agents have a ten- 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.
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ADDRESS: Donald A. Malone, Jr., MD, Department of Psychiatry and Psy-
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chology, P57, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; comorbidities in Alzheimer disease. Ann Pharmacother 2001; Visit WWW.CCJM.ORG Test your knowledge of clinical topics and earn Category I CME Credit CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 80 • NUMBER 10 OCTOBER 2013

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