Depression: When Initial Therapy Fails

Among patients with MDD, almost 90% have moderate to very severe depression.¹ Kessler et al¹ reported that almost half of patients who experienced a depressive episode received no health care treatment during a 1-year follow-up, and of those who did, nearly 60% received inadequate treatment. Unfortunately, even among patients being treated adequately, response (ie, symptom reduction ≥ 50%)⁷ without remission is common; the STAR*D study⁸ found that initial treatment led to remission in only one-third of patients. Further, relapse occurred in 34% of patients who reached remission after 1 treatment step and 50% of patients who required 4 treatment steps to reach remission.

The impact of MDD on quality of life can be as great as or greater than that of chronic medical diseases such as diabetes.^9,10 Depending on depression severity, an average of 59% of patients with MDD report severe or very severe role impairment in at least 1 of the following domains: work, home, relationship, and social roles (AV 2).¹

Suicidality is also associated with MDD. Patients with affective disorders have a 2.2% lifetime risk of suicide compared with less than 0.05% for those without affective disorders.¹¹

Impact of MDD on Medical Illness

The presence of MDD is associated with an increased incidence of a number of medical conditions, including diabetes,¹² hypertension,¹³ and stroke.¹⁴ In patients who have existing medical conditions, the presence of MDD is associated with increased morbidity/mortality. For example, patients with stable coronary artery disease¹⁵ or with unstable angina¹⁶ are more likely to experience fatal or nonfatal cardiac events (eg, myocardial infarction) if they have comorbid depression. Survival after myocardial infarction appears to be reduced among patients with depression, especially those with first-episode depression.¹⁷ Among patients with congestive heart failure, the risk of death after 30-month follow-up is 8 times greater in depressed patients than in those without depression.¹⁸

The presence of depression appears to increase the risk of rehospitalization among patients with general medical conditions. A study¹⁹ of inpatients with a history of at least 1 prior admission within the previous 6 months found that those who screened positive for depression were 3 times more likely to be rehospitalized within 90 days.

Impact of MDD on Neuropathology

Depression may have a significant impact on brain physiology. A 3-year study²⁰ found a decrease in gray matter density in depressed patients relative to control subjects in areas of the brain associated with higher cognitive functioning, executive functioning, and emotional functioning, including the hippocampus, the anterior cingulum, the right dorsomedial prefrontal cortex, and the left amygdala. Patients who achieved remission during the prospective study had less decrease in gray matter density than patients who were not able to achieve remission. Hippocampal volume, which is involved in memory processing and the use of memory in terms of our response to the world, decreases as the number of episodes of depressive illness increases.²¹

A number of individuals experience major depression as a component of Alzheimer’s disease, but MDD also increases the risk of dementia. A 30-year study²² found that individuals with 3 or more depression episodes that led to hospital admission had a greater incidence of subsequent dementia compared with those who had had 1 or 2 hospitalizations for depression (AV 2). A postmortem study²³ of patients with Alzheimer’s disease showed that MDD was associated with a significant increase in both neuritic plaques (P<.005) and neurofibrillary tangles (P<.002)—the hallmark pathologies of Alzheimer’s disease—compared with patients without MDD. Among the patients with Alzheimer’s disease, those with a history of depression had had faster cognitive decline than those without depression (P<.004).

Burden of Treatment-Resistant MDD

A subset of patients with MDD has treatment-resistant depression,²⁴ defined as depression that has not responded to at least 2 different antidepressants administered at an adequate dose for an adequate duration.²⁵ Treatment-resistant depression leads to increased health care utilization and incurs higher costs than nonresistant depression. A study²⁶ found that patients with treatment-resistant depression were hospitalized at least twice as often and, on average, had total medical costs that were 6 times greater than patients whose depression was not resistant. Additionally, among outpatients with treatment-resistant depression, more than half of patients reported suicidal ideation and prominent hopelessness.²⁷

Treatment-resistant depression is associated not only with decreased quality of life but also with increased mortality.²⁸ In patients with coronary heart disease, especially those who have had acute coronary syndrome, cardiac morbidity and mortality are greater among those with treatment-resistant depression.²⁹ One 7-year follow-up study³⁰ found a doubling of cardiac mortality among patients whose depression failed to improve during the 6 months following acute coronary syndrome. Treatment-resistant depression is also associated with about a 2-fold increase in mortality in patients with stable COPD³¹ and, in patients with diabetes, about a 2-fold increase in the likelihood of poor adherence to medications for diabetes, dyslipidemia, and hypertension.³²

Conclusion

The burden of MDD on individuals includes impaired role functioning, decreased quality of life, the development of medical conditions, increased morbidity and mortality, and increased health care services utilization and cost. The burden is increased across all areas for individuals not achieving remission and especially for those with treatment-resistant depression. Low rates of remission and high rates of relapse and recurrence demonstrate the inadequacy of available treatment options. However, as many patients receive no treatment or suboptimal treatment for MDD, outcomes for many patients may still be improved while more effective treatments are being developed. For information about implementing up-to-date practice recommendations for MDD screening and treatment so as to minimize the burden of MDD on individuals and the health care system, see the rest of this series on “Depression: When Initial Therapy Fails.”

For Clinical Use

• To reduce the burden of depression, provide adequate treatment to improve the chances of full remission
• Screen patients with MDD, especially those with treatment resistance, for medical sequelae

Drug Names

No drugs were mentioned in this activity

Abbreviations

COPD = chronic obstructive pulmonary disease, MDD = major depressive disorder, QIDS-SR = Quick Inventory of Depressive Symptomatology Self-Report, SDS = Sheehan Disability Scale, STAR*D = Sequenced Treatment Alternatives to Relieve Depression

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