Depression: A Common but Complex Disorder

Pharmacy Times
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John, age 13, performs poorly at school, engages inloud, reckless behavior, cannot concentrate, and ruinssocial relationships. Does he have an adolescentadjustment disorder?

Mary, age 70, complains of fatigue, memory loss, weightloss, and insomnia. Is she showing early signs of dementia?

John and Mary actually share the same diagnosis: depression.This term is used daily in flippant and naive ways. Likemany psychological conditions, however, depression is acomplex, befuddling disorder.

A Common Disorder with Severe Consequences

The World Health Organization estimates that 340 millionpeople worldwide will undergo a major depressive disorder(MDD) in their lifetime.1 Approximately 11 millionAmericans experience depression in any given year,2 withwomen affected twice as often as men.3 By age, 2.3% of childrenand 8.3% of adolescents suffer from depression, and,among the oldest Americans, up to 18.5% (6.5 million) areclinically depressed.2 Yet, clinicians underrecognize andundertreat MDD, often dismissing symptoms summarily.Fewer than half of its victims seek treatment, confusingtheir symptoms with other conditions or fearing providerindifference.3

The most catastrophic impact of depression is suicide:approximately 15% of those with depression commit suicide,with disproportionately higher rates among theyoungest and the oldest.3-5 Additionally, depression is linkedwith early mortality. For example, among patients whoexperience a myocardial infarction, those with untreatedMDD have a 5-fold increase in mortality.6 The Figure highlightsthe staggering economic impact of depression.7


Diagnosing depression often is a multistage process: accuratelyinterpreting behaviors and thoughts as clinical signsof depression, and examining contributory factors such asmedication side effects, thyroid functioning, and co-occurring illnesses. Table 18 lists diagnostic criteria for MDD. Table24,5,9 describes atypical presentations frequently observed inelders and youths that can mimic other disorders.

Gender differences also exist. Women frequently presentwith guilt, sadness, and worthlessness. Men may presentwith physical symptoms, irritability, anger, sexual inappropriateness,substance abuse, and loss of interest in everydaypleasures.10 Depression can occur without sadness and hopelessness,a paradox that contributes to misdiagnosis.

Treatment Considerations

Depression is surely, if slowly, responsive to medication,and its most tragic outcome?suicide?can be avoided.Historically, poor adherence to monoamine oxidaseinhibitors and tricyclic antidepressants (TCAs) wasbelieved to cause most treatment failures. Researchersthought that enhanced adherence would reduce the suiciderate. Improved antidepressants have been available for2 decades, and the number of prescriptions written forpatients with depression has grown significantly. The suiciderate has declined, perhaps due to better antidepressantsor more vigorous outpatient care, albeit not as significantlyas had been hoped.11

Most health care providers are unaware of depressionrelapse statistics: After 1 episode of depression, the likelihoodof relapse is 50%. The likelihood increases to more than 70%after 2 episodes and exceeds 90% after 3 episodes.12 Relapse ismore costly and more difficult to treat (ie, it is refractory).Early, sufficient treatment is essential. Even after they are prescribedtreatment, at least 20% of patients never fill their prescriptions.Additionally, patients often remain on a prescribedantidepressant for just 6 to 8 weeks. Patients withfirst-episode MDD need medication treatment for at least 6 to9 months.13

Who treats MDD may make a difference. Not everyonewho has MDD is treated by a psychiatrist. Psychiatristsdose-escalate quickly. Primary care physicians, however,may be unaware that higher doses of many antidepressantsincrease the likelihood of treatment success and require 2 to4 weeks to provide significant symptom relief.14-17 Up to 45%of treated patients respond only partially, if at all.13 Undertreatmentand poor response lead to taxing outcomes.

Whereas suboptimal treatment outcomesare common, some people maybe more inclined to commit suicideduring the 2 weeks after appropriatetreatment initiation, even with rapid-doseescalation and perfect adherence.Although energy, sleep, and appetiteimprove relatively quickly, feelings ofhelplessness and hopelessness canlinger for weeks to months. Increasedenergy may allow patients with MDDto act on residual suicidal ideations.

In response to concern over theincreased risk for suicide ideation in children and adolescentsbeing treated with antidepressants, the FDA recentlyruled that the entire category of antidepressant medicationsmust include a "black box" warning. Manufacturers mustadd this warning to the health professional labeling. It willdescribe the risk and note the importance of close patientmonitoring. In addition, the FDA has directed that pharmacistsdistribute a Patient Medication Guide (MedGuide)to all patients when they pick up their drugs. Finally, theFDA will work with manufacturers to develop "unit of use"packaging for all antidepressants to ensure that patientsreceive a MedGuide with each prescription. In a "unit ofuse" package, the medication is prepared in an original container,sealed, and prelabeled by the manufacturer.

Internal Workings

Serotonin and norepinephrine havedefined functional domains.Insufficient norepinephrine leads tovigilance and motivation disorders.Patients who lack motivation or energyand who communicate poorly may begood candidates for a medication suchas bupropion (which stimulatesdopamine and norepinephrine).Patients with problems with impulsecontrol, aggression, appetite, and sexualfunctioning may respond to a serotonin-enhancing medication (ie, aselective serotonin reuptake inhibitor[SSRI]).12,18-20

The TCAs and venlafaxine possessdual action and may lead to fasterremission. Their many limitations,however, are well known. TCAs canlead to cardiotoxicity,orthostasis, anticholinergiceffects, weight gain, and sedation.

Venlafaxine can producecardiovascular concerns,including hypertension athigher doses. These drugs cancause systemic changes, fallsand fractures, and nonadherenceas well. Bedtime dosingcan address some, but not all,of these concerns.Venlafaxine requires dosesof at least 150 mg daily (andoften more) for effectiveness.A pivotal venlafaxine studyfound that the incidence ofclinical hypertension was 3%with 75 mg venlafaxineextended release (ER) daily,compared with 2% for placebo.At 150 mg of venlafaxineER daily, the incidenceincreased to approximately5%, and at more than 225mg daily it reached 8% to13%. Blood pressure monitoringis essential.21

Counseling Patients and Prescribers

Acknowledging that adherence with antidepressants isnotoriously poor, pharmacists must encourage patients toadhere to their treatment plan. Open discussion also amelioratesthe stigma associated with depression and makespatients feel engaged and worthy.

As in the past, pharmacists can help clinicians balanceside-effect burden with effectiveness. With older drugs,weight gain, sexual dysfunction, and sedation are issues.With newer agents, insomnia, agitation, and some cardiacissues are more significant.

Assessing drug?drug interactions?and coaching cliniciansand patients when a switch in drugs is needed?is an areawhere pharmacist input often is welcome. For some treatment-refractory patients, combined therapy with more than 1drug or perhaps an anticonvulsant or anxiolytic is necessary.

Depression often is comorbid with other diseases. Up to50% of patients with Parkinson's disease experience depression.Yet, few guidelines exist for co-occurring depressionwith neurologic disorders. Some clinicians suspect that theSSRIs may exacerbate Parkinson's disease symptoms, butstudies have failed to find significant effects. Among theTCAs, nortriptyline causes fewer anticholinergic effects andmight be considered for Parkinson's disease patients who areunresponsive to SSRIs.22 The side effects of TCAs can at timesbe beneficial. In amyotrophic lateral sclerosis patients, TCAsmay relieve depression and concurrently ameliorate droolingand weight loss.23,24


The prevalence and mixed manifestations of depression haveprompted judicious providers to screen routinely for depression.Once the disorder is accurately diagnosed, treatment decisionsleave the realm of routine. Keeping abreast of pharmacotherapyfor depression is critical for all pharmacists.

Dr. Zanni is a health-systems consultant and a former commissionerof mental health for the District of Columbia. Ms. Yeznach Wick is asenior clinical research pharmacist at the National Cancer Institute,National Institutes of Health. The opinions expressed are those of theauthors and not necessarily those of any government agency.

For a list of references, send a stamped, self-addressed envelope to:References Department, Attn. A. Stahl, Pharmacy Times,241 Forsgate Drive, Jamesburg, NJ 08831;or send an e-mail request to:

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