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CME/CE Information
CME/CE Released: 08/26/2010; Valid for credit through 08/26/2011

Target Audience

This activity is intended for psychiatrists, primary care physicians, and advanced practice clinicians (nurse practitioners,
physician assistants) who work with patients treated for depression.

Goal

The goal of this activity is to explore the optimal management of medication side effects in the treatment of major
depressive disorder to improve adherence and subsequent outcomes in patients with depression.

Learning Objectives

Upon completion of this activity, participants will be able to:

1. Identify side effects of medications used to treat depression that may hinder adherence to treatment
2. Distinguish between treatment-related side effects and symptoms of poorly controlled depression
3. Describe interventions to ameliorate side effects or to optimize treatment when side effects occur, including dose
adjustment, patient education, add-on therapies, and switching to a new agent
4. Suggest strategies for communicating with and educating patients about side effects of antidepressant
medications and how to cope with them

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Author(s)

Ian A. Cook, MD

Joanne and George Miller and Family Chair in Depression Research; Director, UCLA Depression Research & Clinic
Program; Professor of Psychiatry, David Geffen School of Medicine at UCLA, and Semel Institute for Neuroscience and
Human Behavior at UCLA; Vice Chief of Staff, Resnick Neuropsychiatric Hospital at UCLA, Los Angeles, California

Disclosure: Ian A. Cook, MD, has disclosed the following relevant financial relationships:
Received grants for clinical research from: Aspect Medical Systems; Eli Lilly and Company; Neuronetics; Sepracor Inc.
Served as an advisor or consultant for: Bristol-Myers Squibb Company
Served as a speaker or a member of a speakers bureau for: Neuronetics; Wyeth Pharmaceuticals Inc.

Dr. Cook does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the
US Food and Drug Administration (FDA) for use in the United States.

Dr. Cook does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved
by the FDA for use in the United States.

Editor(s)

Priscilla Scherer, RN

Scientific Director, Medscape LLC

Disclosure: Priscilla Scherer has disclosed no relevant financial relationships.

CME Reviewer/Nurse Planner

Laurie E. Scudder, DNP, NP

Accreditation Coordinator, Continuing Professional Education Department, Medscape, LLC; Clinical Assistant Professor,
School of Nursing and Allied Health, George Washington University, Washington, DC; Nurse Practitioner, School-Based
Health Centers, Baltimore City Public Schools, Baltimore, Maryland

Disclosure: Laurie E. Scudder, DNP, NP, has disclosed no relevant financial relationships.

From MedscapeCME Psychiatry & Mental Health

Managing Side Effects of Depression Treatment CME/CE
Ian A. Cook, MD
CME/CE Released: 08/26/2010; Valid for credit through 08/26/2011

The following Test-and-Teach case is an educational activity modeled on the interactive grand rounds approach. The
questions within the activity are designed to test your current knowledge. After each question, you will be able to see
whether you answered correctly and will then read evidence-based information that supports the most appropriate
answer choice. Please note that these questions are designed to challenge you; you will not be penalized for
answering the questions incorrectly. At the end of the case, there will be a short post-test assessment based on
material covered in the activity.

Case Presentation

Ms. H is a 38-year-old woman who presents to her primary care practitioner (PCP) with
chief complaints of "trouble sleeping and keeping my mind from wandering." A brief
interview reveals that she has had "fitful" sleep over the past 9 months, beginning soon
after her husband was forced to accept a pay cut at his job with a state institution. The
patient becomes tearful and explains that, even with both their salaries (she is an
administrative assistant for a local merchant), she and her husband have barely been
able to make ends meet. With their eldest child now in college, the financial situation is
a major source of family stress. The patient volunteers that she has trouble focusing
her attention on her work during the day, she feels sad most days, her energy is low, she is anxious and keyed up virtually
every day, and she feels guilty that she took years off from working to raise their children. When asked whether she has
thoughts of harming herself or worse, she says, "I would never think of doing those things." However, she mentions that in
her late teens, she became depressed when she wasn't accepted by the college she wanted to attend. She briefly thought
about "ending it all," but never acted on these thoughts.
Her medical history and blood tests for anemia, thyroid function, vitamin B12 levels, and liver or kidney disease do not
support depression caused by a general medical condition. Based on her history and reported symptoms, the PCP
informs Ms. H. that she meets criteria for major depression and prescribes a generic selective serotonin reuptake inhibitor
(SSRI), at the minimum therapeutic dose each day, and asks her to follow up if her symptoms did not respond to
treatment within the next 3 to 4 weeks.

Which statement is true about antidepressant medications?

All antidepressants affect the reuptake of serotonin at synapses in the brain

The majority of patients will experience remission (abolition of nearly all symptoms) with the first
antidepressant medication prescribed
In the primary care setting, most patients refill their antidepressant prescriptions promptly
The majority of patients with major depression can experience remission, although most will need
to try more than one treatment before finding a successful regimen

Achieving Remission With Antidepressant Treatment

In the STAR*D trial,[1] 32.9% of patients overall achieved remission, as measured by improvements in the Quick Inventory
of Depressive Symptomatology - Self Report (QIDS-SR), with the first treatment, the SSRI citalopram. For patients who
had never received antidepressant treatment, 42.7% achieved remission with the first treatment. Moreover, STAR*D found
that response or remission did not occur until after 6 weeks in up to one half of patients, which is longer than most
treatment trials typically allow before assuming failure of a given agent.[2] The STAR*D investigators estimated that the
overall cumulative remission rate would approach 70% if all patients who continued to need treatment in the study stayed
on treatment through the fourth step, or 4 treatment trials,[1] but this may take as long as 1 year to achieve.[3]

A variety of antidepressant classes with different sites of action are available and effective for treating depression (Table
1). This provides several useful alternatives for patients who face either efficacy or tolerability problems with any given
antidepressant. According to guidelines from the American Psychiatric Association (APA),[4] response between and within
classes of antidepressants is generally comparable, and thus, potential or anticipated side effects play a major role in the
selection process for the individual patient. An early study assessing the duration of antidepressant treatment in primary
care compared prescription fill rates by patients receiving first-generation antidepressants (amitriptyline, imipramine, or
doxepin) and those of patients receiving newer antidepressants, with more favorable side effect profiles (nortriptyline,
desipramine, trazodone, and fluoxetine). Two thirds of the patients in this study did not refill antidepressant prescriptions at
all in the year after they received the prescription.[5] More recent studies have confirmed these basic findings.[6]

Table 1. Sites of Action of Commonly Used Antidepressants

Class of Agent Site of Action

SSRIs Selective inhibitors of serotonin reuptake; potentiate effect of serotonin (5-HT)

(eg, fluoxetine, sertraline,
escitalopram, citalopram,
paroxetine)
SNRIs
(eg, venlafaxine, duloxetine)
SRAs
(eg, nefazodone*, trazodone)
with little effect on other neurotransmitters
Selective inhibitors of serotonin and norepinephrine reuptake; potentiate activity
of these neurotransmitters
Block postsynaptic serotonin type-2 receptors and inhibit presynaptic serotonin
reuptake
TCAs Block the reuptake of various neurotransmitters, including norepinephrine and
(eg, amitriptyline, nortriptyline, serotonin; additionally, anticholinergic and histaminic activity
imipramine)
MAOIs Block the degradation of various amine neurotransmitters, including
(eg, phenelzine, selegiline) epinephrine, norepinephrine, dopamine, and serotonin, thus increasing levels of
neurotransmitter molecules
NDRIs Appears to act on noradrenergic and/or dopaminergic pathways; in animals,
(eg, bupropion) selectively reduces the firing rate of noradrenergic neurons
Tetracyclic antidepressants Multiple mechanisms; inverse agonist at 5HT2a and 2c receptors and at
(eg, mirtazapine) noradrenergic alpha2a and alpha2c receptors

MAOIs = monoamine oxidase inhibitors; NDRIs = norepinephrine and dopamine reuptake inhibitors; SNRIs =
serotonin-norepinephrine reuptake inhibitors; SRAs=serotonin receptor antagonist; SSRIs = selective serotonin
reuptake inhibitors; TCAs = tricyclic antidepressants
*Nefazodone is no longer available in the United States.

Case Continued

Ms. H returns for a follow-up visit a month later, still "feeling depressed." She explains that she took the antidepressant for
about 4 days, but stopped because it didn't seem to be making a difference, and she didn't like how she felt when she
was taking it.

The primary care provider might have been able to prevent Ms. H's abandonment of initial treatment by
all of the following except:

Telling her at their previous visit that, unlike most substances that affect the brain and mind (eg,
pain medications, alcohol, caffeine), antidepressants tend not to have an immediate effect, and the
symptomatic benefits may take weeks to become apparent
Educating her at the time of prescribing that many medication-related side effects may occur in
the first week of treatment and then become less severe with time, so persistence is key
Asking her at the time of diagnosis what she knew about antidepressants and how they are used
to relieve depression to address any questions or correct any misinformation she may have learned
from friends or the Internet
Avoiding a discussion of side effects, knowing that too much information at the initial visit can be
overwhelming and sometimes leads patients to expect problems that may not occur
Giving her explicit instructions to leave a voicemail message at the 1-week point to alert her
physician to any issues, questions, or concerns that may have developed

Adherence in Depression Treatment

Poor adherence is a major problem for patients receiving depression treatment, with discontinuation rates ranging from
roughly 30% in clinical trial settings to as much as 60% in clinical practice.[7,8] Antidepressant side effects appear to be a
major cause for withdrawal from treatment. Lin and colleagues[9] used automated pharmacy data and medical records to
identify 155 patients who were prescribed antidepressants. The investigators interviewed the participants 1 and 4 months
after they began treatment. Within the first month, roughly 28% of these patients had discontinued treatment, and by month
4, 51.2% had stopped their antidepressant medication; 62.2% of patients who stopped their medication within the first 30
days cited side effects as the primary reason, as did two thirds of those who discontinued treatment between day 31 and
day 90. A more recent 6-month study found similar results.[10] Moreover, of the 50% who prematurely discontinued
treatment, only about 11% informed the prescribing physician of their decision.
In the study by Lin and colleagues,[9] patients who received 5 specific directives were more likely to continue the
antidepressant through the first month of therapy:

Take the antidepressant daily;

Antidepressants must be taken for 2 to 4 weeks to realize a noticeable effect;
Continue to take the antidepressant even if you feel better;
Do not stop taking antidepressant without checking with the healthcare provider; and
What to do/who to call when questions arise about antidepressants.

Meta-analyses likewise have found that patient education regarding treatments is the most frequently recommended
intervention following randomized controlled trials and narrative reviews on adherence. Bollini and colleagues [8] conducted
a systematic analysis of narrative reviews about improving treatment adherence. They found the greatest evidence base
for the following interventions, in this order: patient education, patient-physician empathy/alliance, family education, clinical
management strategies, active management of side effects, simplicity of treatment, behavioral feedback, use of SSRIs,
training of providers (Table 2). The APA guidelines for treatment of major depression support these interventions.[4]

Table 2. Evidence-based Interventions to Improve Adherence to Depression Treatment[8]

Patient education Information about causes of depression, expected course of disease, treatment
effects, duration and side effects
Patient-provider Good relationship between patient and provider, with an emphasis on
empathy/alliance communication, consensus, and understanding
Family education Information for family members about causes of depression, expected course of
disease, treatment effects, duration, and side effects
Clinical management strategies Advice regarding a standardized approach to taking medications and compliance,
frequent follow-up visits, especially during initial phases of treatment
Simplicity of treatment Keep number of medications and doses per day to a minimum
Active management of side Inform patient about side effects, anticipate and check for their occurrence,
effects provide reassurance and treatment adjustments
Behavioral feedback Advise patients on ways to incorporate treatment into daily routine; modify
schedule to fit medication routine, behavioral reminders, pill boxes, easy-to-read
prescription labels
Preference for selective Related to fewer side effects relative to tricyclic antidepressants
serotonin reuptake inhibitors
Physician training Improve skills on how to effectively provide care for depressed patients and ways
to improve adherence

Case Continued

Ms. H elaborates that she stopped her medication because she felt worse rather than better. She thinks the
antidepressant made her stomach feel sour, and this sour stomach and nausea caused her to salivate excessively. She
also mentions that she had problems falling asleep, which seemed worse than the sleep difficulties she had before she
took the medication. As soon as her head hits the pillow, she says, she begins to worry about the next day's
responsibilities at work and whether she will be able to perform adequately enough to keep her job. She has gained weight
because she's a nervous eater, she says. Finally, she has no interest in having sexual relations with her husband; this has
persisted even after she stopped taking the SSRI.

Which of the following is not a common side effect of SSRIs?

Nausea or other gastrointestinal upset

Excessive salivation
 Dry mouth
Insomnia
Somnolence

Based on Ms. H's history and report of symptoms, which of the following is easily distinguished as a
medication-related side effect vs a feature of this patient's episode of depression that is not responding
to treatment?

Her sense that she's having more difficulty falling asleep now than before she took the
medications
Her sense that she feels especially anxious in the evening
Her recent weight gain of 5 pounds
These symptoms cannot be distinguished as medication vs depression related

Symptoms vs Side Effects

Ms. H's complaints could be related to either her depression or side effects of treatment. In this case, specifically,
difficulty falling asleep could have been part of her original pattern of "fitful" sleep or could have arisen from taking an
"activating" SSRI medication in the evening. Diurnal variation in symptoms could be part of depression, or her evening
anxiety could also be occurring because she is taking her medication in the evening. Weight loss or gain can be related to
depression or may be idiosyncratically associated with the use of antidepressant medications. However, without having
systematically evaluated and recorded her presenting symptoms using a scale, such as the Quick Inventory of Depressive
Symptomatology-Self Reported (QIDS-SR), the clinician cannot reliably distinguish between adverse events of treatment
and worsening (or persistence) of symptoms.

Although many clinicians may believe that rating scales are "for research use only," some investigations have found that
measurement-based care with systematic observations using scales can lead to improved clinical outcomes and are
practical in a clinical practice setting.[11] Furthermore, some health insurance companies now require clinicians to submit
rating scale data as evidence of treatment effectiveness to receive authorization for payment.

Case Continued

Ms. H admits that she felt discouraged by her initial treatment experience but insists that she is determined to get better
and asks about other options. She indicates a reluctance to try the first agent again, even though she had only taken it for a
few days. She is open to trying other medications.

She admits that her symptoms are "maybe 5%" worse than before, and at this visit, the clinician administers the Public
Health Questionnaire (PHQ-9). Ms. H scores a 19, consistent with moderately severe depression,[12] and the clinician
uses this to guide a more in-depth discussion of her symptoms.

Evidence-based guidelines from the APA and the Canadian Network for Mood and Anxiety Treatment
(CANMAT) would support any of the following as next steps except:

Try a different SSRI antidepressant

Try a serotonin norepinephrine reuptake inhibitor (SNRI) antidepressant, which inhibits reuptake
of both serotonin and norepinephrine
Try a combination of an SNRI and thyroid hormone
Try an antidepressant that is not a reuptake inhibitor (bupropion or mirtazapine)
Next Steps for Ms. H

Given Ms. H's brief exposure to the initial agent, it is probably reasonable to approach her second treatment trial as if it
were the first, albeit without using the initial agent. The second edition of the APA Practice Guideline for the Treatment of
Patients With Major Depressive Disorder [4] and guidelines from CANMAT[13] note that the choice of treatment depends
on the severity of the depression, the side effect profile of the various classes of antidepressants, and patient preference.
The APA guidelines further state that most patients with typical unipolar major depressive disorder (MDD) will respond to
most medications in the various classes of antidepressant drugs.

The STAR*D study found that the likelihood of disease remission with treatment drops considerably for
patients who have tried but not achieved remission with a third round of treatment compared with those
who have failed to receive benefit from 2 rounds of treatment. In considering Ms. H's history, should her
experience with the first medication "count" when assessing where she is along the treatment-
resistance spectrum?

Yes
No

According to the APA Practice Guideline, after prescribing a new antidepressant for treatment of major
depression, how long should the patient remain at a dose in the low end of the therapeutic range before
considering dose escalation if symptoms have not remitted?

1 week
2 weeks
4 weeks
6 weeks
12 weeks

Assessing Treatment Success or Failure

In psychopharmacology research settings, the Antidepressant Treatment History Form[14] is frequently used to quantify
formally the success or failure of each trial of an antidepressant, its duration, and the dose. A medication is generally not
counted as a "failure" for the patient if the exposure is too brief to allow a meaningful interpretation, generally considered
to mean anything less than 4 weeks at a therapeutic dose for that agent. Whether or not one makes a formal quantification
of the duration and dose of each treatment tried, abbreviated exposures such as this patient experienced are too brief to
yield information about whether the agent might hold potential for therapeutic success for her.

The APA guidelines for treatment of major depression urge reassessment and modification of the treatment plan at the
4-week mark and suggest that if a patient has not achieved at least moderate improvements within 4 to 8 weeks of
receiving a given medication or treatment modality, symptoms should be reassessed and an alternative should be
considered.[4]

When the clinician is advising Ms. H about additional options, she asks for a more complete discussion
about potential side effects. Which category of medication is most commonly linked to cardiac
 conduction changes?

SSRIs
SNRIs
Tricyclic antidepressants (TCAs)
MAOIs

Which category of medication is most commonly linked to hypertensive crisis with ingestion of tyramine-
containing foods?

SSRIs
SNRIs
TCAs
MAOIs

Which category of medication is most commonly linked to sexual dysfunction (arousal and/or orgasm)?

SSRIs
TCAs
MAOIs
Lithium

Which category of medication is most commonly linked to risk for metabolic syndrome within the first
year of treatment when added to an SSRI for augmentation, adjunctive, or combination use?

Lithium
Second-generation (atypical) antipsychotic agents
Thyroid hormone
Buproprion

Management of Antidepressant Side Effects

Fears of side effects may influence the acceptability of medications for treating depression. Although most of the second-
generation antidepressants (post-tricyclic era) are generally well tolerated, the likelihood that a patient will experience 1 or
more common adverse events associated with antidepressant medication treatment is high. In a meta-analysis of 80
head-to-head trials involving more than 17,000 patients, Gartlehner and colleagues [15] found no substantial differences in
efficacy or effect on quality of life among the various second-generation antidepressants, including SSRIs, SNRIs, and
others. However, roughly one fourth of patients in this population discontinued their antidepressant medication because of
treatment-related side effects. On average, 61% of patients in these trials reported at least 1 adverse event, and nausea
and vomiting were the side effects most frequently cited as the cause for subjects withdrawing from the studies. Table 3
lists side effects generally associated with the various antidepressants and approaches to ameliorating them.

Table 3. Adverse Effects of Commonly Used Antidepressants and Approaches to Treatment[4]

Side Effect Antidepressant(s) Associated Treatment

With Effect
Cardiovascular
Orthostatic hypotension Tricyclic antidepressants; Lower dose; discontinue medication;
trazodone; nefazodone*; MAOIs fludrocortisone; add salt to diet
Reduced cardiac output Tricyclic antidepressants Discontinue medication
Arrhythmias Tricyclic antidepressants Discontinue medication
Hypertension Venlafaxine Lower dose; discontinue medication
Hypertensive crisis MAOIs Discontinue medication; intravenous phentolamine
Increase in cholesterol Mirtazapine Lower dose; discontinue medication
Anticholinergic
Dry mouth Tricyclic antidepressants; Pilocarpine oral rinse; gum; candy
reboxetine*
Constipation Tricyclic antidepressants; Hydration; bulk laxatives
reboxetine*
Urinary hesitancy Tricyclic antidepressants; Bethanechol
reboxetine*
Visual changes Tricyclic antidepressants; Pilocarpine eye drops
reboxetine*
Delirium Tricyclic antidepressants Discontinue medication; antipsychotic medication
Sedation Tricyclic antidepressants; Bedtime dosing
trazodone; nefazodone*;
mirtazapine
Weight gain Tricyclic antidepressants; Lower dose; change to secondary amine (if tricyclic
mirtazapine; MAOIs antidepressant required); discontinue medication
Nausea, vomiting SSRIs; bupropion, sustained Lower dose; discontinue medication
release; venlafaxine, extended
release
Insomnia SSRIs; bupropion; reboxetine* Lower dose; discontinue medication; morning
dosing; trazodone at bedtime
Activation SSRIs; venlafaxine Lower dose; discontinue medication
Neurological

Myoclonus Tricyclic antidepressants; MAOIs Lower dose; discontinue medication; clonazepam

Extrapyramidal Amoxapine Lower dose; discontinue medication
symptoms; tardive
dyskinesia
Seizures Bupropion; amoxapine Lower dose; discontinue medication; antiepileptic
medication
Headaches SSRIs; bupropion Lower dose; discontinue medication
Sexual side effects
Arousal, erectile Paroxetine; venlafaxine Lower dose; discontinue medication; sildenafil;
dysfunction yohimbine; ginkgo; methylphenidate;
dextroamphetamine; pemoline
Tricyclic antidepressants; SSRIs Lower dose; discontinue medication; sildenafil;
yohimbine; ginkgo; bethanechol; neostigmine

*Nefazodone and reboxetine are no longer available in the United States.

MAOI = monoamine oxidase inhibitor; SNRI = serotonin norepinephrine reuptake inhibitor; SSRI = selective serotonin
reuptake inhibitor
Adapted with permission. Practice Guideline for the Treatment of Patients With Major Depressive Disorder.
Washington, DC:American Psychiatric Association; 2000.

Many antidepressant side effects can be minimized with gradual titration to a therapeutic dose. In addition, some side
effects will appear early after treatment initiation and then abate over time. A significant number of side effects may
persist, however. For example, Hu and colleagues [16] conducted phone interviews with 401 patients who had been taking
an SSRI for 75 to 105 days; 86% reported at least 1 side effect, 55% reported 1 side effect that was "bothersome," and
52% reported 3 or more side effects. Side effects included drowsiness, sexual dysfunction, dry mouth, headache,
dizziness, insomnia, anxiety, nausea, weight gain, tremors, diarrhea, constipation, rash or itching, weight loss, stomach
upset, blurred vision, and swelling. Although most side effects appeared within the first 2 weeks, most patients (and in
some cases, more patients) continued to report the same side effects even after 3 months of treatment. The rate of
persistence of side effects varied; 65.9% reported stomach upset within 2 weeks of treatment, but that percentage had
dropped to 28% by 3 months. On the other hand, 69.9% complained of sexual dysfunction after 2 weeks of treatment, but
by 3 months, that percentage had risen to 83.3%.

These investigators also surveyed the prescribing physicians. Roughly 54% reported discussing antidepressant side
effects with their patients. Overall, physicians significantly underestimated both the frequency of their patients' side effects
and the level of discomfort caused by them, with the exception of sexual dysfunction and drowsiness. Of the 15 side
effects reported, the distress related to blurred vision and constipation was the most underestimated by physicians.

Patient-provider communication is essential to improve adherence, and a discussion about side effects as part of the
initial visit as well as part of every follow-up visit often will help improve tolerability, particularly if the discussion includes
specific strategies for coping with these problems. The most effective way to discern the presence of side effects is to
ask about them specifically. Thus, more effective than asking, "Are you having any side effects?" is to say, "Some of my
patients have problems with nausea and loss of appetite. Has your appetite changed?" These direct queries about
specific side effects should make the patient feel more comfortable talking, especially about personal issues, will open up
a dialogue between patient and provider, and will highlight problems that the patient may not realize are medication-related.
For example, problems with sexual function are probably the most underreported antidepressant side effect. One survey
of 344 patients found that 14% spontaneously reported sexual dysfunction, but 58% reported it when specifically
questioned.[17]

Knowing the comparative side effects of various classes of antidepressants and the patient's priorities in that regard will
help with treatment choices (Table 3). For example, certain patients may be more concerned about sexual side effects,
whereas for others, nausea, sleep disturbances, or weight gain may be more distressing. Although the SSRIs are
generally well tolerated, the potential for sexual dysfunction (including problems with arousal, desire, and orgasm) is higher
with these agents when compared with the norepinephrine and dopamine reuptake inhibitor, bupropion[18] or the serotonin
receptor antagonist nefazodone.*[19] Nausea is fairly common across classes of antidepressant drugs, but using
controlled-release formulations of the SNRI venlafaxine and the SSRI paroxetine may result in less nausea than using the
immediate-release formulations.[20] Insomnia is likewise common across classes of antidepressants, but the incidence
appears to be lower with the SRAs, trazodone and nefazodone, and with the mixed-action agent, mirtazapine, than with the
SSRIs.[20] Compared with the SSRIs, rates of somnolence and fatigue are lower with bupropion but higher with
venlafaxine, duloxetine, and nefazodone.[20] Mirtazapine, venlafaxine, and the SSRIs are associated with weight gain in
relatively high percentages of patients (up to 26% for mirtazapine); bupropion and nefazodone are associated with weight
gain in lower percentages of patients (12%).[20]

Finally, the TCAs have well-documented adverse cardiovascular effects that include orthostatic hypotension, corrected
QT interval changes, and arrhythmias.[20-22] The SSRIs may be a better choice for patients with any history of heart
disease affecting cardiac conduction.[21] The potential of the MAOIs to affect the blood pressure and to cause drug and
food interactions are well documented.[4]

*Nefazodone is no longer available in the United States.

Case Continued

After discussing the various treatment options with Ms. H, she agrees to a trial of a different SSRI. By starting at a low,
subtherapeutic dose, she is able to tolerate the medication during the first 2 weeks, allowing the dose to be increased into
the therapeutic range without new side-effect issues. After 6 weeks at a therapeutic dose, she completes another PHQ-9
scale. Her score has dropped by 2 points, which is improved but still in the "moderately severe" range. She says that she
feels she's made more subtle improvements than are reflected in the choices for answers on the PHQ-9 questionnaire.
The clinician then administers the QIDS-SR 16-item questionnaire, which more precisely identifies the presence and
severity of Diagnostic and Statistical Manual of Mental Disorders target symptoms of depression. On this scale, Ms. H
scores a 12, which is also in the moderate range.

The PCP offers Ms. H a choice of adding an adjunctive medication or trying a new antidepressant to address her
symptoms. Having derived some benefit from this SSRI but still being symptomatic and having difficulty functioning in life,
she expresses an interest in adding something rather than giving up this medication and "starting over from scratch" with
something new.

Which of the following accurately reflects outcomes of augmentation strategies, based on findings from
the National Institute of Mental Health's STAR*D study?

Augmenting with lithium was superior to augmenting with thyroid hormone (triiodothyronine, T3)
The presence of anxiety (either symptoms or comorbid condition) was associated with a more
robust response to treatment whether or not augmentation was needed
There was no significant difference in remission rates between augmenting with bupropion vs
buspirone, although the former led to greater symptom reduction and had better tolerability
The addition of a second-generation antipsychotic led to remission in a significant number of
subjects

Antidepressant Augmentation Strategies

The STAR*D trial examined a number of augmentation strategies at several steps during the 37-month duration of the
study.[3] In Level 2, participants could choose to switch antidepressants and/or augment the existing or new drug. Those
who chose to switch to a new antidepressant (57% of the total) had experienced less improvement and more side effects
with the initial SSRI than those who chose to augment the initial SSRI. No difference in remission rates was seen in
participants who augmented with bupropion vs buspirone; however, bupropion led to greater symptom reduction and had
better tolerability than buspirone.

Level 3 of the study comprised patients who had experienced intolerance or suboptimal benefit of treatment with previous
strategies. The Level 3 augmentation arm compared lithium and T3 augmentation of one of the Level 2 switch options or
the initial SSRI. T3 augmentation was found to be numerically but not statistically superior to lithium augmentation, but
lithium was associated with more frequent side effects, and more participants who received lithium withdrew from
treatment because of intolerance.

STAR*D also found that greater chronicity of depression and number of comorbid psychiatric conditions, including anxiety,
were directly correlated with treatment resistance during the trial. None of the serial strategies in STAR*D involved the use
of second-generation antipsychotic medications, although other trials have examined second-generation antipsychotic
drugs in the context of antidepressant augmentation, and several of these drugs have been approved by the US Food and
Drug Administration (FDA) for that purpose (Table 4).

Table 4. Second-Generation Antipsychotics and Use With Antidepressants for Patients With MDD

Name of Common Adverse Effects Notes

Agent

Aripiprazole Restlessness and akathisia First SGA specifically approved by the FDA for adjunctive therapy with
antidepressants
 Olanzapine Sedation; increased Only approved by the FDA for use in combination with fluoxetine
appetite; weight gain
More recent clinical experience favors combinations with lower doses
of olanzapine (3 and 6 mg/day)

Early weight gain tends to predict longer-term risk for metabolic

Quetiapine Sedation; dry mouth;
XR increased appetite; weight
gain
Risperidone Extrapyramidal symptoms
Ziprasidone Sedation; insomnia;
orthostasis; akathisia
The FDA has imposed a black-box warning on these agents for risk of death in the elderly with dementia-
related psychosis.
complications
Recently approved by the FDA for adjunctive therapy with
antidepressants in MDD
Although there are 2 positive placebo control studies in the literature,
risperidone is not being developed for adjunctive use in MDD and has
no FDA-approved indication in MDD
The literature is mixed with both positive and negative trials for
ziprasidone augmentation in treatment-resistant depression, and it has
no FDA-approved indication in MDD

FDA = US Food and Drug Administration; MDD = major depressive disorder; SGA = second-generation
antipsychotics; XR = extended release

Case Continued

After an extended discussion, Ms. H agrees to augmentation of her SSRI with bupropion. Over the ensuing 12 weeks, her
SSRI and bupropion doses are pushed to maximum tolerable doses for a period of 8 weeks. Her score on the QIDS-SR
has improved slightly and she is feeling more positive and in control of her life. She is happy with her drug regimen,
although she is concerned that she continues to gain weight, nearly 15 pounds in all. She says that her stomach feels
queasy most of the time ("like morning sickness"), and she snacks frequently in an effort to control the queasiness. With
further questioning, she also admits that she and her husband aren't getting along. He is irritable with her and seems
almost unhappy that she isn't depressed any longer. He's worried about being laid off, defensive about earning less than
she does, and constantly reminds her that he's working just as hard as she is. When asked about sexual relations, she
says that they have sex about once a week, but with all the sniping back and forth, neither one of them seems to be
enjoying it as much as they used to.

She says that she is not interested in trying an alternative antidepressant agent at this point.

Of the following interventions, which would be the most appropriate next steps for Ms. H?

Gently persuade her to try a different SSRI and refer the couple for marriage counseling
Refer the couple for marriage counseling and suggest her husband seek psychoanalysis
Recommend exercise and cognitive-behavioral therapy (CBT), and refer for nutrition and
marriage counseling
Add a second-generation antipsychotic agent and refer the couple for marriage counseling

Nonpharmacologic Interventions

The APA's Practice Guideline for the Treatment of Patients With Major Depressive Disorder discusses several
psychosocial interventions for major depression. These can be used both as monotherapy in patients for whom
pharmacotherapy is contraindicated or who cannot tolerate antidepressants, and as adjunctive to pharmacotherapy.[4]
These interventions include CBT, behavior therapy, interpersonal therapy, psychodynamic psychotherapy, marital and/or
family therapy, and group therapy. In general, studies have found that these interventions can be effective for patients with
mild to moderate symptoms.[4]

CBT has probably been the most widely studied of these interventions, but results of studies comparing CBT with
pharmacotherapy have been mixed, with some comparisons finding CBT to be superior to pharmacotherapy and others
finding equal or less efficacy.[4] Some have suggested that these inconsistencies may relate to symptom severity as well
as to study design. Unemployment, male gender, comorbidity, and dysfunctional attitudes are among the factors that may
predispose to a poorer outcome with CBT.

Marital and family problems are common complaints for patients with MDD and can be a contributing factor or a result of
MDD. Marital and family therapy have been found to reduce depression symptoms and the risk for relapse in this
population.[4]

Finally, exercise may be a useful adjunct to antidepressant pharmacotherapy. A study comparing exercise alone,
medication, and combined exercise and medication for patients with MDD found that all 3 interventions were effective.[23]
Dunn and colleagues[24] demonstrated a dose-response effect for patients with MDD who participated in a program of
aerobic exercise. By the end of 12 weeks, those with the highest energy expenditure (the "public health dose" of exercise
recommended by the American College of Sports Medicine and consensus public health recommendations) had reduced
their Hamilton Rating Scale for Depression scores by 47% from baseline. Those in the lowest energy expenditure group
had symptom reductions comparable to those of patients taking placebo.

Case Continued

Through a program subsidized by her health insurance company, Ms. H joins a gym close to work and begins to work out
during her lunch hour. The gym also offers a weight loss program that provides nutritional counseling. After 8 weeks, she
has lost about 4 pounds and feels generally "okay" at work. Her husband has refused to participate in marriage counseling
but recently received assurances that there will be no lay-offs for the foreseeable future. Their relationship has improved,
with much less bickering about money, although she admits their life together still can be trying at times. She continues to
be disinterested in having sexual relations but feels that she can tolerate this. She does not want to change her
medications, saying that things feel more or less "in balance," has learned to cope with the side effects, and doesn't want
to risk upsetting that equilibrium. At this time, her QIDS-SR score is about the same as 8 weeks earlier.

Within the next 5 weeks, Ms. H makes several appointments, which she cancels because of "work issues." When she
finally keeps an appointment, she appears harried and is tearful. She continues to go to the gym but recently has started
feeling as though it doesn't really matter; she does not enjoy the exercise anymore and has recently cut back her time
there, fearing that her boss is unhappy that she takes a full hour for lunch. She says she's really not making a difference in
anyone's life and feels "useless" most of the time. Her relationship with her husband also seems to have deteriorated.
Even though his job is secure and she has cut back on most nonessential purchases, he is constantly complaining that
she spends too much money.

There is a large base of peer-reviewed evidence to consider for all of the available options except:

Augmenting the SSRI with a second- or third-generation antipsychotic agent

Switching from SSRI + bupropion to venlafaxine + mirtazapine
Waiting another 8 weeks at the current medication doses
Using a neuromodulation method such as electroconvulsive therapy

The use of which of the following second-generation antipsychotic drugs is most likely to result in weight
gain?

Aripiprazole
Olanzapine
 Risperidone

Augmenting Antidepressants to Improve Outcomes

STAR*D examined venlafaxine + mirtazapine as a third-step treatment (level 4), and found it to be useful in a subset of
individuals who had not had remission earlier in that study's treatment algorithm.[25] This step compared the venlafaxine +
mirtazapine combination with the MAOI tranylcypromine; more patients taking tranylcypromine withdrew from treatment
because of side effects and dietary restrictions.

Electroconvulsive therapy remains a useful intervention when a patient has been refractory to multiple medication trials or
when a rapid response is critical (eg, when weight loss becomes medically dangerous, when behaviors are influenced by
delusions in a psychotic depression).[4,26] It was not a treatment option in the STAR*D trial.

The FDA has approved antidepressant augmentation with the second-generation antipsychotic agents aripiprazole,
quetiapine XR, and olanzapine combined with fluoxetine. Other research studies support off-label use of other second-
generation antipsychotic agents in treatment-resistant depression with variable strengths of evidence. As noted in Table 4,
however, adding these agents not only augments antidepressant effects but also may increase side effects, and these
need to be carefully addressed when considering this strategy.

Post-Assessment: Measuring Educational Impact

Thank you for participating in the CME activity. Please take a few moments to read the following cases and complete the
questions that follow to help us assess the effectiveness of this medical education activity.

In your experience, which of the following is the most significant barrier to optimally managing
medication adherence in patients with major depressive disorder?

Insufficient time allotted for patient education

Lack of patient understanding and expectations of antidepressant medications
Medical comorbidities
Inadequate clinician monitoring and response to side effects

Case #1: Rhonda is 34-year-old single woman who presents to your office because she feels
"depressed." She reports that over the past several months she has had low energy, sleeplessness, and
crying spells. She reports that she has been under a lot of stress at work but cannot identify a single
stressor that has triggered her symptoms. She reports that she has felt "down" in the past, but never as
bad as she has recently. She states, "most days, I just feel like I don't want to get out of bed. I can't get
anything done at work." She states that she feels hopeless about the future. She denies any suicidality
but does state that some days she feels like she would be better off "not waking up." You decide to start
her on an SSRI.

What advice would you give this patient about her likely therapeutic response?

Her depressive symptoms should be largely resolved within 2 weeks

The first medication may not resolve all her symptoms, but you will work with her to find one that
does
She is less likely to notice improvement because she has never been on an antidepressant
before
She should expect to try at least 2 or 3 medications before finding one that works well
What instructions would you give her?

She should write down any concerns and present them to you at a future office visit
She should contact you if she cannot find the answers to her questions on Internet forums
She should call your office after taking the medication for 1 week to report any issues, questions,
and concerns
There is no need for her to follow up if she is doing well

What anticipatory guidance would you give this patient regarding medication side effects?

It is unlikely that she will experience any side effects on an SSRI

Most side effects will present in the first few weeks of treatment and often diminish over time
If she experiences a side effect, she should immediately discontinue the medication
If she experiences side effects, she will most likely need a new class of medication

Case #1 (cont.): Rhonda returns at 4 weeks and states that she feels better. However, she reports that
she is having some mild anxiety in the morning and has noticed mild weight gain. She also reports a
decreased sex drive. She is now ambivalent about staying on the medication.

What would you tell her regarding her symptoms?

Her symptoms are likely side effects from the medication

Her symptoms indicate worsening of her depression
Her symptoms may be related to depression or to antidepressant side effects
Regardless of the cause, she will need medication augmentation

Case #2: Raymond is a 45-year-old married man who has a history of depression. He has been treated
with SSRIs in the past with good results. He presents to your office stating that he has been
experiencing a return in his depressive symptoms. These include poor sleep with early morning
awakenings, anhedonia, poor concentration, and loss of appetite. You restart SSRI therapy, which he
previously responded well to and, over 4 weeks, titrate to the standard therapeutic dose. Six weeks
later, he reports that he still feels very depressed. He is particularly concerned because at higher doses
of the SSRI, he experiences sexual side effects including anorgasmia.

What would be your next treatment step?

Increase the dose of his current medication

Stop the medication treatment and consider a psychosocial intervention such as marriage
counseling
Switch to a tricyclic antidepressant
Switch to a serotonin norepinephrine reuptake inhibitor (SNRI)

If you decide to alter this patient's antidepressant regimen, when would you reassess his response?

1 week
2 weeks
4 weeks
6 weeks

Case #3: Marcus is a 62-year-old man who presents complaining of low energy, fatigue, poor
concentration, and anhedonia but no suicidal ideation. You conclude that he is having a major
depressive episode and recommend starting an SSRI.

What approach would you take to initiating therapy in this patient?

Start a low initial dose and gradually titrate upwards

Start a high dose to facilitate quick symptom remission and decrease
Start at the usual therapeutic dose to adhere to treatment guidelines
It is not advisable to start new medications in patients who are sensitive to side effects

What strategy would you use to monitor his therapeutic response?

Administer a baseline and follow-up self rating scale such as the QIDS-SR
Rely on your detailed clinical history alone to determine symptom improvement
Obtain collateral information from relatives or friends at baseline and at 4-6 weeks follow-up
Supplement your clinical assessment with neuropsychiatric evaluations, as needed

Case #3 (cont.): The patient reports modest symptomatic improvement with his new therapy but has not
achieved remission at 8 weeks. His SSRI dose is increased. After 6 weeks at the higher dose, the
patient's mood, energy, and concentration are markedly improved. However, he reports that he feels
"jittery" on the medication and has experienced some weight gain.

What therapeutic strategy would you recommend?

Increase the dose of the SSRI again

Lower the current SSRI dose and augment with another class of antidepressant
Switch to another antidepressant medication class
Continue present treatment and offer reassurance that side effects should improve with time

Which of the following established patients would be most likely to benefit from cognitive behavioral
therapy (CBT)?

A 65-year-old woman with a history of depression for 40 years with multiple treatment failures
and nonadherence
A 50-year-old diabetic man recently placed on dialysis for advanced renal disease
A 45-year-old woman in remission with an SSRI but with a difficult marriage and weight gain
A 40-year-old woman with 2 months of insomnia, weight loss, and now having suicidal ideations

Please indicate how relevant this CME activity is to your practice: Approximately how many patients do
you see each week with depression?

0
1-10
11-20
21-30
> 30
Supported by an independent educational grant from Bristol-Myers Squibb.

This article is a CME/CE certified activity. To earn credit for this activity visit:
http://cme.medscape.com/viewarticle/726498

References

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one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917. Abstract
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3. Warden D, Rush AJ, Trivedi MH, Fava M, Wisniewski SR. The STAR*D Project results: a comprehensive review of
findings. Curr Psychiatry Rep. 2007;9:449-459. Abstract
4. American Psychiatric Association Practice Group on Major Depressive Disorder.. Practice Guideline for the
Treatment of Patients With Major Depressive Disorder, Second Edition. Washington, DC: American Psychiatric
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7. Pampallona S, Bollini P, Tibaldi G, Kupelnick B, Munizza C. Patient adherence in the treatment of depression. Br J
Psychiatry. 2002;180:104-109. Abstract
8. Bollini P, Pampallona S, Kupelnick B, Tibaldi G, Munizza C. Improving compliance in depression: a systematic
review of narrative reviews. J Clin Pharm Ther. 2006;31:253-260. Abstract
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influence of antidepressant concerns and treatment preferences. Prim Care Companion J Clin Psychiatry.
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remission. J Clin Psychiatry. 2009;70 Suppl 6:26-31. Abstract
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2001;16:606-613. Abstract
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Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major
depressive disorder in adults. III. Pharmacotherapy. J Affect Disord. 2009;117 Suppl 1:S26-43. Abstract
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selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate. J Clin
Psychiatry. 2004;65:959-965. Abstract
17. Montejo-Gonzalez AL, Llorca G, Izquierdo JA, et al. SSRI-induced sexual dysfunction: fluoxetine, paroxetine,
sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital
Ther. 1997;23:176-194. Abstract
18. Thase ME, Haight BR, Richard N, et al. Remission rates following antidepressant therapy with bupropion or
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Psychiatry. 2005;66:974-981. Abstract
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Disclaimer

The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support educational programming on
www.medscapecme.com. These materials may discuss therapeutic products that have not been approved by the US Food and Drug
Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic
product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational
activity.

MedscapeCME Psychiatry & Mental Health © 2010 MedscapeCME

This article is a CME/CE certified activity. To earn credit for this activity visit:
http://cme.medscape.com/viewarticle/726498