New Insights into Treatment-Resistant Depression

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Psychotic symptoms, rather than unrecognized bipolar disorder, may underlie poor response.

Only one-third of patients with major depression achieve remission after trying one antidepressant. When the first medication doesn't adequately relieve symptoms, next-step options include adding a new drug to the first or switching to another drug. With time and persistence, nearly seven in 10 adult patients with major depression eventually find a treatment that works.

Of course, that also means that the remaining one-third of patients with major depression cannot achieve remission even after trying multiple options. Experts are hunting for ways to understand the cause of persistent symptoms. In recent years, one theory in particular has gained traction — that many people with hard-to-treat major depression actually suffer from bipolar disorder. However, a paper suggests otherwise, and the findings provide new insights into the nature of treatment-resistant depression.

Researchers at Massachusetts General Hospital (MGH) and colleagues analyzed outcomes for roughly 4,000 patients who participated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which was conducted in multiple primary care and psychiatric settings around the country in order to mimic real-world treatment of major depression. The STAR*D investigators used a simple questionnaire to ask participants about symptoms characteristic of bipolar disorder (such as sleeplessness or high energy) as well as those suggesting psychosis (the inability to recognize reality, such as false beliefs or false perceptions). All participants initially received the antidepressant citalopram (Celexa), followed by up to three additional treatments as necessary.

Using a combination of self-reported symptoms and clinical screening instruments, the MGH researchers did find that many participants in the STAR*D study had multiple symptoms associated with bipolar disorder rather than major depression. Contrary to common wisdom, however, these symptoms did not significantly worsen chances of attaining remission after taking antidepressants. Instead, the researchers found that participants who said they had experienced one or more unusual beliefs or experiences in the past two weeks — symptoms that can indicate psychosis — were significantly less likely than other STAR*D participants to attain remission.

The MGH researchers found that about one-third of participants in the STAR*D study reported strange or unusual experiences. That doesn't mean that one in three patients was psychotic, but that unusual thinking is common in patients with major depression. As such, Dr. Roy H. Perlis, medical director of the Bipolar Clinic and Research Program at MGH and lead author of the paper, says it is important for clinicians to be on the alert for these symptoms, because they are associated with poorer response to antidepressants.

In recent years, both scientific reviews and continuing medical education courses have advised clinicians to re-evaluate a diagnosis of major depression and instead consider bipolar disorder when a patient does not respond to multiple antidepressants. But concern is growing that bipolar disorder is now overdiagnosed as a result. In 2008, researchers at Brown University estimated that more than half of bipolar diagnoses might be wrong — partly because clinicians attribute symptoms like agitation or racing thoughts to mania rather than to major depression.

When patients with major depression don't benefit adequately from a first antidepressant, it's wise to take several steps before deciding on the next treatment.

Review the diagnosis. Major depression can be difficult to diagnose because symptoms vary from one person to the next. If clinicians suspect bipolar disorder, it's important to do a careful symptom assessment for manic or hypomanic episodes rather than to rely solely on family history of bipolar disorder or on a screening tool that simply assesses individual symptoms. Risk factors such as a family history of bipolar disorder certainly raise the possibility that a patient may have this disorder as well, but such reports can be unreliable and do not automatically confirm that diagnosis.

Last Review Date: Mar 1, 2011

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