Antidepressants Linked to Increased Mania Risk

Nancy A. Melville

December 17, 2015

Treatment of unipolar depression with selective serotonin reuptake inhibitors (SSRIs) or venlafaxine (multiple brands) is associated with a significantly increased risk for subsequent diagnoses of manic or bipolar disorder, new research shows. However, theories to account for the association weigh heavily on the side of undiagnosed bipolar depression.

"Although our findings do not demonstrate any causal link between antidepressant therapy and bipolar disorder, 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," the authors write in their study, which was published online December 14 in BMJ Open.

It is known that treatment of bipolar disorder with antidepressants can trigger episodes of mania by further offsetting already unstable moods and behaviors, but questions have remained as to the role of the drugs in increasing the risk for mania or bipolar symptoms in patients who are not bipolar and only have unipolar depression.

To investigate the issue, Rashmi Patel, MD, and colleagues at King's College London's Institute of Psychiatry evaluated data on 21,012 adults who were diagnosed and treated for unipolar depression between 2006 and 2013 in the South London and Maudsley National Health Service (NHS) Trust, in the United Kingdom.

They found that the overall annual risk for a new diagnosis of subsequent mania or bipolar disorder in the cohort was 1.1%.

Previous treatment with antidepressants was associated with an increased incidence of subsequent mania or bipolar disorder, ranging from 1.3% to 1.9% (hazard ratio [HR], 1.11 - 1.47).

A multivariate analysis that was controlled for age and sex showed that the strongest association was between use of SSRIs (HR, 1.34; 95% confidence interval [CI], 1.18 - 1.52; P < .001) and venlafaxine (HR, 1.35; 95% CI, 1.07 -1.70; P = .01) and development of mania or bipolar disorder.

Consistent with previous findings, the incidence of manic or bipolar disorder was higher in patients aged 26 to 35 years.

The factors that could explain the increased rates of mania or bipolar disorder are unclear, Dr Patel told Medscape Medical News.

"We do not know exactly why antidepressant therapy is associated with higher rates of mania or bipolar disorder," Dr Patel said. "It is thought that a family history of bipolar disorder, a depressive episode with psychotic symptoms, young age at first diagnosis of depression, and depression that is unresponsive to treatment may be linked to an increased risk of developing mania with antidepressant treatment."

Dr Patel noted that previous studies have shown much stronger associations between the use of antidepressants and mania, with one meta-analysis estimating rates of mania to be as high as 12.5% among patients with major depressive disorder and bipolar disorder who were treated with antidepressants. There was little protection from mood stabilizers.

Dr Patel said the lower rates in the current study were unexpected.

"It was a surprise," he said. "One explanation for this finding is that we investigated data from patients presenting to specialist mental health care services. However, in the UK, antidepressants are commonly prescribed by GPs [general practitioners], and it could be that some patients developed mania after being prescribed antidepressants by their GP but before presenting to specialist mental healthcare services."

The findings underscore the need to consider the potential for the presence of mania or bipolar disorder when treating depression, Dr Patel said.

"When prescribing antidepressants, it is important to consider whether someone could be at risk of developing bipolar disorder and to look out for symptoms, such as elevated mood or mood instability, which could be associated with an emerging episode of hypomania or mania."

Philip Muskin, MD, professor of psychiatry and chief of service in consultation-liaison psychiatry at New York-Presbyterian Hospital/Columbia University Medical Center, New York City, speculated that those measures were likely not followed by practitioners in the study and that many of the patients may have already had undiagnosed bipolar disorder.

"A problem with this study is we don't know if a good history on risk factors for mania or bipolar disease was obtained, so I don't think it proves anything beyond the fact that we don't know if these patients weren't misdiagnosed," Dr Muskin told Medscape Medical News.

For the majority of patients with bipolar disorder, the index episode will be depression, he explained, and if practitioners are not aware of that or of the need to ask questions about potential signs of bipolar disorder, they may only find out when the patient is treated with antidepressants and subsequently experiences manic episodes, he explained.

"The administration of the antidepressant in a sense can correctly expose the patient's bipolar vulnerability and may have nothing to do with the idea that these drugs can make unipolar depressed patients become bipolar."

He seconded the recommendation that patients presenting with depression be questioned on whether they or their family members have experienced any mood instability or manic behaviors.

"Patients certainly may not be forthcoming with that information, so it's very important to ask," Dr Muskin said. "If the patient does have this in their history, then treatment should instead focus on options such as a mood stabilizer or a second-generation antipsychotic."

Dr Patel has disclosed no relevant financial relationships. Coauthors of the study have received research funding from Roche, Pfizer, Johnson & Johnson, Janssen, Sunovion, Bristol-Myers Squibb, and Otsuka.

BMJ Open. Published online December 14, 2015. Full text

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