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Only one-third of people with major depression achieve remission after trying one antidepressant. When the first medication doesn鈥檛 adequately relieve symptoms, next step options include taking a new drug along with the first, or switching to another drug. With time and persistence, nearly seven in 10 adults with major depression eventually find a .

Of course, that also means that the remaining one-third of people 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 published online this week in the suggests otherwise鈥攁nd the findings provide new insights into the nature of treatment-resistant depression.

Researchers at (MGH) and colleagues analyzed outcomes for roughly 4,000 participants in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which was conducted both in primary care and psychiatric settings in order to mimic real-world treatment of major depression. The STAR*D investigators had used a simple questionnaire to ask participants about symptoms characteristic of bipolar disorder (such as mania or hypomania) 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.

The MGH researchers did find that many participants in the STAR*D study had multiple symptoms associated with bipolar disorder rather than major depression. , however, these symptoms did not significantly worsen chances of attaining remission after taking antidepressants. Instead, the researchers found that participants who said they experienced one or more unusual beliefs or experiences in the past two weeks鈥攕ymptoms that can indicate psychosis鈥攚ere significantly less likely than other STAR*D participants to attain remission.

鈥淲e found that about one-third of participants in the STAR*D study reported strange or unusual experiences,鈥� explains , medical director of the at MGH and lead author of the paper. 鈥淭hat doesn鈥檛 mean that one in three participants were psychotic, but that unusual thinking is common in people with major depression. As such, it is important that clinicians are on the alert for these symptoms, because they are associated with poorer response to antidepressants.鈥�

In recent years, both scientific review papers 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 Dr. Perlis and others are growing concerned that bipolar disorder is now overdiagnosed as a result. 鈥淲e were seeing an increasing number of patients diagnosed with bipolar disorder, or bipolar spectrum disorder, simply because they had a family member with bipolar disorder or hadn鈥檛 responded well to antidepressants,鈥� says Dr. Perlis. (In a 2008 , researchers at estimated that more than half of bipolar diagnoses might be wrong鈥攑artly because clinicians attribute symptoms like agitation or racing thoughts to mania rather than to major depression.)

When people with major depression don鈥檛 benefit adequately from a first antidepressant, Dr. Perlis advises that it鈥檚 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. 鈥淚t鈥檚 critical to revisit the diagnosis any time a treatment isn鈥檛 working, and this should include consideration of bipolar disorder,鈥� Dr. Perlis explained. 鈥淩isk factors such as a family history of bipolar disorder certainly increase my concern, and cause me to look even more closely. On the other hand, treatment resistance does not automatically equal bipolar disorder.鈥�

Consider other illnesses. It鈥檚 also important to consider whether another medical illness, such as anemia or obstructive sleep apnea, might be causing fatigue and other symptoms of depression.

Consider comorbidities. Major depression frequently occurs in conjunction with other psychiatric disorders, such as anxiety or substance use disorders, which can also affect antidepressant responsiveness. In such cases, it鈥檚 important to treat the co-occurring mental health problem in addition to major depression.

Double-check dose. It鈥檚 always wise to double-check whether someone is taking the drug at the dose prescribed.

Give it more time. Although the standard advice for patients is to take an antidepressant for six weeks to see if symptoms improve, earlier findings from the STAR*D trial suggest that many people need more time to respond. The recommended that people with major depression take an antidepressant for at least eight weeks before considering another strategy.