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Treatment with certain antidepressants was associated with new-onset manic episodes in patients thought to have unipolar depression, a British registry study found.

In the analysis of data from patients treated at a mental health service in the U.K., taking either selective serotonin reuptake inhibitors (SSRIs) or venlafaxine (Effexor) was associated with a significantly increased incidence of mania, , of King's College London, and colleagues .

"Although our findings do not demonstrate any causal link between antidepressant therapy and bipolar disorder," they wrote, "the association of antidepressant therapy with mania in people being treated for depression reinforces the importance of considering risk factors for mania or hypomania in people who present with an episode of depression."

Earlier work had found associations between acute episodes of mania and treatment with tricyclic antidepressants and venlafaxine, but it's hasn't been clear whether the drugs cause this excitatory state, or if they trigger the expression of an underlying bipolar disorder -- or whether the association resulted from confounding.

To look at the issue further, Patel and colleagues assessed electronic health records of 21,012 patients treated for depression at South London and Maudsley NHS Trust (SLaM), a large provider of inpatient and community mental healthcare in the U.K., from April 1, 2006 to March 31, 2013.

They found the overall rate of mania/bipolar in this group was 10.9 per 1,000 person-years -- a rate that was lower than seen in previous studies, but that could be due to the fact that these patients presented to a secondary mental health services provider, they said.

That means these patients may already have developed symptoms of mania while being treated with antidepressants in primary care and had already received a diagnosis of bipolar, the researchers wrote.

The peak incidence rate of mania/bipolar disorder in this population was seen in those ages 26 to 35, at 12.3 per 1,000 person-years, they reported.

Prior antidepressant treatment was associated with an increased incidence of mania/bipolar disorder, ranging from 13.1 to 19.1 per 1,000 person-years, they found.

Multivariate analysis revealed a significant association between incidence of mania and both SSRIs (HR 1.34, 95% CI 1.18 to 1.52) and venlafaxine (HR 1.35, 95% CI 1.07 to 1.70), Patel and colleagues reported.

Venlafaxine is recommended as a second-line therapy for unipolar depression, so it's possible that this association is confounded by resistance to antidepressant therapy, they noted.

There was no association, contrary to the earlier evidence, between mania and treatment with tricyclics. But the researchers noted that their study was limited because it was based on observational data, and because patients were treated in a secondary, not primary, care setting, so the results may not be generalizable.

Still, they concluded that the findings "highlight the importance of considering whether an individual who presents with depression could be at risk of future episodes of mania," noting that it's generally recommended to evaluate depressed patients who have manic episodes while taking antidepressants for bipolar disorder.

"Future research should not only focus on which classes of antidepressants are most associated with mania, but also on other associated factors in order to guide clinicians on the risk of mania in people with depression prior to prescribing antidepressant therapy," they wrote.

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