The American Psychiatric Association (1983) reports that recurrent episodes occur in at least 50% of patients who seek treatment for major depressive disorder (MDD). Most studies, though, have examined only single occurrences. To help describe the episodic nature of MDD, the National Institute of Mental Health initiated the Collaborative Program on the Psychobiology of Depression, a prospective, naturalistic, longitudinal investigation. This program’s early research found the cumulative probability of recurrence was nearly 30% six months after recovery from an index episode of unipolar major depression.

Since the 1983 report, many of the original study subjects have experienced multiple recurrences of major depressive disorder (MDD). In a study published in the Feb. issue of The American Journal of Psychiatry, David A. Solomon, M.D., and colleagues prospectively focused on the time to recurrence of MDD across multiple episodes. They predicted that the risk of recurrence would decrease as time of recovery increased. They also predicted that each recurrence would increase the risk of a subsequent recurrence.

The original collaborative depression group had a total of 955 patients. Of those, 318 recovered from their intake episode of major depression and were at risk of recurrence during the 10-year follow-up period. The study group for the Solomon et al. analysis consisted of these 318 subjects. Recovery was defined as at least eight consecutive weeks “with either no symptoms of major depressive disorder or only one or two symptoms at a mild level of severity”. Recurrence, which could occur only after recovery from the preceding depressive episode, was defined as the reappearance of major depressive disorder (MDD) meeting the full criteria for at least two consecutive weeks, beginning with the first of these two weeks. Episodes meeting criteria for minor depression and chronic intermittent depression were not included.

For the first five years of the follow-up study, patients were assessed every six months, and annually after that, using the Longitudinal Interval Follow-Up Evaluation. The analyses encompass data for up to 520 weeks of follow-up. As an observational study, treatment was not randomized or in any way controlled by anyone connected to the study.

Of the 318 subjects, 263 (83%) were followed for at least five years, and 208 (65%) were followed for the entire 10-year period. During those 10 years, 481 recurrences were observed. The mean number of episodes of major depressive disorder (MDD) per year of follow-up was 0.21 (SD=0.24).

Once the first eight-week recovery period was completed for the 318 subjects, 202 suffered a recurrence. Of those subjects, 172 recovered and remained healthy for the following eight-week period. A second recurrence was suffered by 115 of those patients. The median time to recurrence for the first episode was 150 weeks; for the second, 83 weeks; and for the third 77 weeks. These intervals were significantly longer than the time to recurrence for subsequent recurrences.

The investigators were also interested in the probability of a well patient experiencing a recurrence during a six-month period (the patient having began that period still well). They found the mean probability for recurrence during the first six months after recovery was 20% (SD=6) across the five prospectively observed recurrences. They wrote, “This indicates that, on average, of the subjects at risk for recurrence, 20% had a recurrence in the first 6 months after the onset of recovery from the preceding depressive episode”.

They found that rate of recurrence decreased in subsequent six-month intervals. In the second six months the probability of recurrence was 19% (SD=7), in the third six months it was 15% (SD=6), in the fourth six months it was 13% (SD=3), in the fifth six months it was 11% (SD=3). In the final six months after the onset of recovery from the preceding depressive episode the probability of recurrence was 9% (SD=6).

Solomon et al. found that the risk for recurrence increased by 16% for each successive episode of major depression. The number of lifetime episodes of major depressive disorder (MDD) was significantly associated with recurrence during this 10-year follow-up period. Analysis showed that there was very little consistency in the time to recurrence within the subject group.

When the researchers looked at treatment of these subjects, they called the low level of maintenance pharmacotherapy during any of the four weeks immediately preceding any of the prospectively observed recurrences striking. Up to 47% to 50% of subjects received no pharmacotherapy during the four weeks immediately preceding the first three recurrences. One-third received no pharmacotherapy in the four weeks immediately preceding the fourth and fifth recurrences. During any of the preceding four-week periods, only 33% to 45% of subjects received at least 100 mg/d of imipramine (Tofranil) or its equivalent. Only 18% to 30% of subjects received at least 200 mg/d of imipramine or its equivalent during the same time period prior to any of the five prospectively observed recurrences.

Solomon et al. wrote that, as predicted, “as the duration of recovery increases, the risk of recurrences decreases or decays.” Also as predicted, “With each successive recurrence, the risk of a subsequent recurrence increases by 16%.” Consistency in time to recurrence, however, was highly variable among this group, indicating that time to recurrence is also highly variable for any individual.

Limitations of this study, the researchers pointed out, included the progressively smaller group size following each recurrence. They speculate that this caused the data analyses to underestimate rates of recurrence over a patient lifetime. Another limitation was the exclusion of minor or intermittent depression, causing a possible underreporting of the extent of psychopathology in the subject group. Finally, the researchers suggest that variability in treatment may have influenced the findings. Patients may have discontinued treatment following recovery, putting themselves at greater risk of recurrence. Recurrence may have caused other patients to discontinue treatment due to discouragement, putting these patients at risk for further recurrence as well. Solomon et al. found the lack of maintenance pharmacotherapy unfortunate, given its role in preventing recurrences