John, age 13, performs poorly at school, engages in loud, reckless behavior, cannot concentrate, and ruins social relationships. Does he have an adolescent adjustment disorder?

Mary, age 70, complains of fatigue, memory loss, weight loss, 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. Like many psychological conditions, however, depression is a complex, befuddling disorder.

A Common Disorder with Severe Consequences

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

The most catastrophic impact of depression is suicide: approximately 15% of those with depression commit suicide, with disproportionately higher rates among the youngest and the oldest.3-5 Additionally, depression is linked with early mortality. For example, among patients who experience a myocardial infarction, those with untreated MDD have a 5-fold increase in mortality.6 The Figure highlights the staggering economic impact of depression.7



Diagnosing depression often is a multistage process: accurately interpreting behaviors and thoughts as clinical signs of depression, and examining contributory factors such as medication side effects, thyroid functioning, and co-occurring illnesses. Table 18 lists diagnostic criteria for MDD. Table 24,5,9 describes atypical presentations frequently observed in elders and youths that can mimic other disorders.



Gender differences also exist. Women frequently present with guilt, sadness, and worthlessness. Men may present with physical symptoms, irritability, anger, sexual inappropriateness, substance abuse, and loss of interest in everyday pleasures.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 oxidase inhibitors and tricyclic antidepressants (TCAs) was believed to cause most treatment failures. Researchers thought that enhanced adherence would reduce the suicide rate. Improved antidepressants have been available for 2 decades, and the number of prescriptions written for patients with depression has grown significantly. The suicide rate has declined, perhaps due to better antidepressants or more vigorous outpatient care, albeit not as significantly as had been hoped.11

Most health care providers are unaware of depression relapse statistics: After 1 episode of depression, the likelihood of relapse is 50%. The likelihood increases to more than 70% after 2 episodes and exceeds 90% after 3 episodes.12 Relapse is more costly and more difficult to treat (ie, it is refractory). Early, sufficient treatment is essential. Even after they are prescribed treatment, at least 20% of patients never fill their prescriptions. Additionally, patients often remain on a prescribed antidepressant for just 6 to 8 weeks. Patients with first-episode MDD need medication treatment for at least 6 to 9 months.13

Who treats MDD may make a difference. Not everyone who has MDD is treated by a psychiatrist. Psychiatrists dose-escalate quickly. Primary care physicians, however, may be unaware that higher doses of many antidepressants increase the likelihood of treatment success and require 2 to 4 weeks to provide significant symptom relief.14-17 Up to 45% of treated patients respond only partially, if at all.13 Undertreatment and poor response lead to taxing outcomes.

Whereas suboptimal treatment outcomes are common, some people may be more inclined to commit suicide during the 2 weeks after appropriate treatment initiation, even with rapid-dose escalation and perfect adherence. Although energy, sleep, and appetite improve relatively quickly, feelings of helplessness and hopelessness can linger for weeks to months. Increased energy may allow patients with MDD to act on residual suicidal ideations.

In response to concern over the increased risk for suicide ideation in children and adolescents being treated with antidepressants, the FDA recently ruled that the entire category of antidepressant medications must include a "black box" warning. Manufacturers must add this warning to the health professional labeling. It will describe the risk and note the importance of close patient monitoring. In addition, the FDA has directed that pharmacists distribute a Patient Medication Guide (MedGuide) to all patients when they pick up their drugs. Finally, the FDA will work with manufacturers to develop "unit of use" packaging for all antidepressants to ensure that patients receive a MedGuide with each prescription. In a "unit of use" package, the medication is prepared in an original container, sealed, and prelabeled by the manufacturer.

Internal Workings

Serotonin and norepinephrine have defined functional domains. Insufficient norepinephrine leads to vigilance and motivation disorders. Patients who lack motivation or energy and who communicate poorly may be good candidates for a medication such as bupropion (which stimulates dopamine and norepinephrine). Patients with problems with impulse control, aggression, appetite, and sexual functioning may respond to a serotonin-enhancing medication (ie, a selective serotonin reuptake inhibitor [SSRI]).12,18-20

The TCAs and venlafaxine possess dual action and may lead to faster remission. Their many limitations, however, are well known. TCAs can lead to cardiotoxicity, orthostasis, anticholinergic effects, weight gain, and sedation.

Venlafaxine can produce cardiovascular concerns, including hypertension at higher doses. These drugs can cause systemic changes, falls and fractures, and nonadherence as well. Bedtime dosing can address some, but not all, of these concerns. Venlafaxine requires doses of at least 150 mg daily (and often more) for effectiveness. A pivotal venlafaxine study found that the incidence of clinical hypertension was 3% with 75 mg venlafaxine extended release (ER) daily, compared with 2% for placebo. At 150 mg of venlafaxine ER daily, the incidence increased to approximately 5%, and at more than 225 mg daily it reached 8% to 13%. Blood pressure monitoring is essential.21

Counseling Patients and Prescribers

Acknowledging that adherence with antidepressants is notoriously poor, pharmacists must encourage patients to adhere to their treatment plan. Open discussion also ameliorates the stigma associated with depression and makes patients feel engaged and worthy.

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

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

Depression often is comorbid with other diseases. Up to 50% of patients with Parkinson's disease experience depression. Yet, few guidelines exist for co-occurring depression with neurologic disorders. Some clinicians suspect that the SSRIs may exacerbate Parkinson's disease symptoms, but studies have failed to find significant effects. Among the TCAs, nortriptyline causes fewer anticholinergic effects and might be considered for Parkinson's disease patients who are unresponsive to SSRIs.22 The side effects of TCAs can at times be beneficial. In amyotrophic lateral sclerosis patients, TCAs may relieve depression and concurrently ameliorate drooling and weight loss.23,24


The prevalence and mixed manifestations of depression have prompted judicious providers to screen routinely for depression. Once the disorder is accurately diagnosed, treatment decisions leave the realm of routine. Keeping abreast of pharmacotherapy for depression is critical for all pharmacists.

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

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