Antidepressants Don’t Cause Rapid Cycling, Study Finds

The use of antidepressants in combination with lithium for patients with bipolar disorder does not appear to be associated with the onset or exacerbation of rapid cycling, according to recent analysis of data from the National Institutes of Mental Health Collaborative Depression Study.

The same study also shows that bipolar patients with rapid cycling suffer substantial depressive morbidity and are at high risk for serious suicide attempts, said study author William Coryell, M.D., a professor of psychiatry at the University of Iowa School of Medicine.

A second study, appearing with it in the September edition of the Archives of General Psychiatry, also implicates rapid “switching” of mood—fluctuations of affective state over the course of a few weeks, days, or even hours that do not meet duration criteria for a manic or depressive episode—in a more complex clinical course of bipolar disorder. That study suggests that such rapid switching could be central to a range of affective phenomena in bipolar disorder representing distinct genetic phenomena.

Faulty Assumptions Made

Coryell told Psychiatric News that the link between rapid cycling and use of antidepressants made by earlier studies may be the result of a faulty assumption of cause and effect. He added that previous studies support the view that depression may naturally precede rapid cycling in bipolar patients, and that episodes that do begin with depression are more likely to develop a rapid-cycling course.

Consequently, he explained, patients who enter treatment in the depressive phase of the illness are likely to receive antidepressants; when rapid cycling begins, the assumption has been to attribute the onset to the antidepressant use, rather than the precipitating depression.

“There has been a tendency to assume some causality that may not be there,” Coryell told Psychiatric News.

In the study by Coryell and colleagues, 89 patients who exhibited rapid cycling were identified out of 345 with bipolar I or bipolar II disorder in the National Institute of Mental Health Collaborative Depression Study. The 89 subjects were compared with the remaining bipolar patients on the basis of demographics, overall affective morbidity, morbidity during specific treatment conditions, and the likelihood of suicidal behavior.

According to the analysis, use of antidepressants was not more likely in the weeks preceding shifts from depression to mania or hypomania. And resolution of rapid cycling—which occurred within two years of onset in 4 of 5 patients—was not associated with decreases in tricyclic antidepressant use. Throughout the follow-up, patients prone to rapid cycling experienced more depressive morbidity than other bipolar patients, especially when lithium was being used without tricyclic antidepressants, according to the study.

Patients with rapid cycling were significantly more likely to have experienced their first episode of bipolar disorder before 17 years of age and were more likely to make serious suicide attempts.

“People that manifest rapid cycling seem to have more morbidity over time,” Coryell said. “They may not rapid-cycle year in and year out, but they tend at any point to have more symptoms.”

Coryell said the significance of the finding is primarily of prognostic value. “It bears on what psychiatrists and their patients should expect over time,” he said. “A rapid-cycling pattern is not likely to persist for more than one or two years but is predictive of higher symptom levels in the long term, and medical management may be more challenging.”

Rapid Switching: Separate Entity?

A second study explored the phenomenon of rapid shifting of affective states that may not meet the durational criteria in the DSM-IV for a depressive or manic episode. (The DSM-IV definition of rapid cycling entails four discrete episodes of mania or depression in a single year demarcated by clear periods of remission or switches to episodes of opposite polarity.)

Study author Dean MacKinnon, M.D., told Psychiatric News that he believes such rapid switching may be central to a range of affective phenomena that is not accounted for using the narrower DSM-IV definition of rapid cycling, and that may represent a subtype of the disorder.

“If a clinician wants to know something about the course of illness and risk, he could ask about how many episodes a patient has had,” MacKinnon said. “But it may be difficult to get a picture of what is happening because the duration of episodes may not meet the criteria. Rapid switching may be better at differentiating people with a high risk of suicide and comorbidity.”

He is an assistant professor of psychiatry at Johns Hopkins University School of Medicine in Baltimore.

The Archives study used data on rapid switching from the National Institute of Mental Health Bipolar Disorder Genetics Initiative, a multisite bipolar disorder linkage study. (Requirements for entry were a proband with bipolar I disorder and at least one other first-degree relative with the disorder.)

During the interview, individuals were asked, “Have you ever switched back and forth quickly between feeling high to feeling normal or depressed?” Those who responded in the affirmative were then asked whether the switches had occurred every few hours, days, or weeks.

Sufficient information was given by 603 individuals, 44 percent of whom reported rapid switching. Forty percent of this group reported that switching occurred over the course of every few hours, and 41 percent switched every few days. The remainder switched over the course of weeks.

The researchers found that rapid switching was associated with early age of onset of bipolar disorder, higher risk of anxiety and substance abuse or dependence comorbidity, suicide attempts, antidepressant drug use, and having a relative with rapid switching.

“It demonstrates that rapid mood switching is common in families with more than one member with bipolar disorder and is associated with other clinical features,” MacKinnon said.

In a separate study published in the September American Journal of Psychiatry using the same data set, MacKinnon found that panic and the diagnosis of panic disorder in a family with bipolar disorder increased the risk for rapid mood switching.

MacKinnon believes that panic and rapid switching may represent a bipolar subtype with a genetic cause. “Anxiety is an abrupt-onset mood state,” he told Psychiatric News. “If you think of anxiety as an affect, as many researchers do, it is possible that the similarity between rapid switching and panic may be genetic because they are found in the same family. There appears to be a trait that confers vulnerability to both kinds of phenomena.”

An abstract of “The Long-Term Course of Rapid-Cycling Bipolar Disorder” is posted on the Web at http://archpsyc.ama-assn.org/cgi/content/abstract/60/9/914. An abstract of “Rapid Switching of Mood in Families With Multiple Cases of Bipolar Disorder” is posted at http://archpsyc.ama-assn.org/cgi/content/abstract/60/9/921. The AJP study, “Association of Rapid Mood Switching With Panic Disorder and Familial Panic Risk in Familial Bipolar Disorder,” is posted at http://ajp.psychiatryonline.org/cgi/content/full/160/9/1696. ▪

Arch Gen Psychiatry 2003 60 914

Arch Gen Psychiatry 2003 60 921

Am J Psychiatry 2003 160 1696