Published in UAB Insight, Fall 2006
ABSTRACT: Depression is a treatable disease that requires accurate diagnosis and expertise in managing medications and other therapies to achieve optimal outcomes.
CME OBJECTIVE: The reader will appreciate the importance of accurate diagnosis for depression and the need to alter therapy in patients who fail to respond initially.
F. Cleveland Kinney, PhD, MD, honoria: Pfizer, Novartis
Ten percent of adult women and 4% of men currently take antidepressants, a number that has tripled since 1988. Major depressive disorder affects up to 15% of the US population, yet some studies estimate nearly one third of patients fail to respond to antidepressant therapy, while many have only partial responses.
“Patients’ initial response to a single antidepressant may not be ideal, but newer research reveals switching or adding antidepressants or combining medication and psychotherapy improves outcomes in patients with recurring major depression,” says UAB psychiatrist F. Cleveland Kinney, PhD, MD, who directs the Division of Geriatric Psychiatry.
Findings from the National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies support Kinney’s recommendations. Data from STAR*D’s Level 2 study showed 1 in 3 patients who did not get relief with an initial antidepressant became symptom free after adding another therapy, and 1 in 4 achieved remission after switching to a different antidepressant (N Engl J Med. 2006;354;1231-1242).
Steps to Relieve Symptoms
During the 7-year STAR*D trial, investigators at 23 psychiatric and 18 primary care treatment sites recruited more than 4000 participants for the largest and longest trial evaluating therapies for depression. STAR*D employed a “switch” strategy, allowing patients at specific points to try alternate or additional therapies. At Level 1, participants began treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram. One third achieved remission with citalopram alone. Participants who did not achieve satisfactory outcomes could enter study Level 2, which offered 7 options: 4 allowed patients to switch citalopram for a new medication and 3 options augmented citalopram by adding a new medication or talk therapy.
During Level 2, investigators asked participants if it would be equally acceptable to switch or augment therapies, or if they preferred a specific approach. “This strategy mimics a real-world setting,” Kinney says. “Only 21 participants agreed to complete randomization; more than 1400 chose to limit treatment options — more than half of whom switched to a different medication.” Unlike many antidepressant trials, which exclude people with signifi-cant comorbidities, STAR*D featured broad inclusion and limited exclusion criteria. “Consequently, this cohort better reflects patients clinicians see in practice,” he says.
Level 2 switch medications included sertraline, an SSRI targeting serotonin; venlafaxine extended release, which targets serotonin and norepinephrine; and the non-SSRI bupropion. Within 14 weeks, 25% of those who switched medications became symptom free. Despite different mechanisms of action among switch medications, no significant differences in drug efficacy, safety, or tolerability were reported among treatment groups, lending credence to the authors’ assertion that lack of efficacy with one antidepressant does not predict results with another.
Augmenting Therapy
The 565 participants who chose augmented therapies continued with citalopram and were randomized to either bupropion sustained release (SR) or buspirone, an agent that enhances serotonin action. Again, within 14 weeks, patients in both groups reported improvements, with about one third achieving remission. However, those taking bupropion-SR experienced fewer symptoms, better symptom relief, and fewer adverse effects compared with those adding buspirone.
Investigators encouraged the 235 participants who had an inadequate response with Level 2 interventions to move on to Level 3, which compared 2 14-week switch strategies (mirtazapine or nortriptyline) and 2 augmentation options (lithium or T3 thyroid hormone). Only 1 in 5 people achieved remission with mirtazapine or nortriptyline, with no statistical differences between the 2 drugs (Am J Psychiatry. 2006;163:1161-1172). Study authors note that although Level 3 switch medications have different mechanisms of action than antidepressants used in Levels 1 and 2, patients achieved only modest remission rates, significantly lower than rates of 27% to 50% reported in previous efficacy trials.
Certain factors predicted antidepressant response in Level 3 participants. Well-educated, employed, married, white women with few comorbidities fared better than people who had concurrent anxiety, substance abuse history, physical disorders, and self-reported diminished quality of life. Investigators will publish analysis of Level 3 augmentation options and the fourth and final STAR*D level later in 2006.
Diagnosing Depression
Depressive symptoms include hopelessness, low self-esteem, impaired memory, difficulty concentrating, an-hedonia, altered eating patterns, anxiety, preoccupation with negative thoughts, and thoughts of suicide, as well as fatigue, sleep problems, loss of libido, headaches, backaches, and gastrointestinal difficulties. One study of depressed patients found 69% presented to their primary care providers with somatic symptoms as a chief complaint (N Engl J Med. 1999;34[18]:1329-1335).
To identify depression, the US Preventive Service Task Force recommends routine screening in adult primary care patients (Ann Inter Med. 2002;136:760-764). Task force guidelines suggest asking patients 2 questions: if, within the past 2 weeks, they have felt down, depressed, or hopeless or if they have lost interest or pleasure in normal social activities. The task force found these questions may be as effective as more extensive screening tools. An affirmative response to these questions should prompt in-depth diagnostic testing.
“For patients with major depression, we perform MRI scans to detect any damage to the central nervous system and SPECT scans to check for decreased blood flow to the frontal lobes,” Kinney says. Some studies show diminished regional cerebral blood flow in people with depression returns to normal following appropriate treatment.
“Depression is a complex neurophysiologic illness caused by altered neurochemistry,” he says. “SSRIs are frequently prescribed with great success, but venlafaxine and mirtazapine, which also inhibit norepinephrine reuptake, may enhance remission in some patients. Typically, combining medications and psychotherapy is better than either strategy alone. Patients with refractory major depression or who suffer from psychotic features may benefit from electroconvulsive therapy.”
Reassurance and Referrals
The inability to directly compare outcomes in participants who augmented therapy with participants who switched medications is an inherent limitation of STAR*D, authors say, noting their findings highlight the chronic, recurrent, treatment-resistant nature of major depression.
“Clinicians should refer patients with major depression to a psychiatrist as soon as possible, if they are willing to seek such assistance,” Kinney says, adding that studies confirm substantial savings for patients and reduced health care costs when patients are referred early in the course of their illness.
He also reminds physicians that depressive and bipolar disorders are associated with a 10- to 15-fold increased suicide rate compared with the general population, and the elderly, particularly men, are disproportionately likely to take their own lives. The highest suicide rates in the country are among white men 85 years and older. “Identifying patients at risk of suicide saves lives,” Kinney says, noting up to 75% of elderly suicide victims visit their primary care physicians within a month of their deaths.
Soliciting feedback about symptom relief and potential adverse effects in the early stages of initiating an antidepressant medication is key to patient compliance. Clinicians must evaluate side effects, such as headache, diarrhea, anxiety, insomnia, weight changes, and interruptions in sexual performance, and balance them against severity of depressive symptoms.
“When the clinical situation permits, advise patients to continue medication for at least 1 month before altering dose, switching, or augmenting,” Kinney says. “If symptoms are not relieved, or if unpleasant side effects make compliance difficult after the initial trial, switching or augmenting the therapies may be appropriate.”
For more information
Dr. F. Cleveland Kinney
1.800.UAB.MIST
mist@uabmc.edu