31 January 2012. Desperate times may call for desperate measures, and in the awful world of treatment-resistant depression, one such measure—inserting two electrodes deep into the brain and running electricity through them—appears safe and effective, according to a study published online January 2 in the Archives of General Psychiatry. Over the course of two years, deep brain stimulation (DBS) to the subcallosal cingulate relieved depression in 92 percent of patients with either major depressive disorder or bipolar 2 disorder, with minimal adverse effects. Unlike other antidepressant treatments, chronic DBS did not promote manic episodes in the bipolar patients.
Led by Paul Holtzheimer of Dartmouth Medical School in Lebanon, New Hampshire, and Helen Mayberg of Emory University in Atlanta, Georgia, the study explored a treatment option for the substantial 10-30 percent of depressed individuals who do not respond to available treatments. Earlier pilot studies found an antidepressant effect for DBS targeted to the axon tracts leading to the subcallosal cingulate, a regulator of negative mood that is hyperactive in depressed individuals (Mayberg et al., 2005; Lozano et al., 2008). The new study provides a longer-term and independent replication of DBS at this site in 17 individuals, including seven with bipolar 2 disorder, a variant of "manic-depressive" disease where the elevated moods never reach full manic proportions. The findings may help parse the brain circuitry involved in depression and mania. Extreme mania can resemble the psychosis seen in schizophrenia.
Holtzheimer and colleagues enrolled men and women, aged 18 to 70, who were moderately to severely depressed, despite trying four or more antidepressant treatments. The study was conducted in several phases, with depression symptoms and functioning assessed at baseline, immediately after electrode implantation, after a four-week sham stimulation period, after six months and up to two years of active stimulation that constantly delivered electrical pulses at 130 Hz, and during a discontinuation phase when the electrodes were turned off.
After implantation, the patients were told that their stimulating electrodes might or might not be turned on, depending on whether they were put into a sham stimulation group. DBS in this area does not produce a sensation, so patients couldn’t tell whether their electrodes were activated. In reality, the electrodes remained off for everyone during this time. Still, a modest sham effect emerged after four weeks, with a 14 percent decrease in depression ratings compared to baseline. However, there was no significant difference between sham stimulation and postoperative depression ratings, suggesting some other surgery-related antidepressant effect. In fact, 14 out of 17 patients guessed that they had been placed in the sham group because they could not detect a change in their depression during this time.
In contrast, after six months of active stimulation, average depression scores fell by 43.6 percent compared to baseline, with seven patients responding (as defined by at least a 50 percent change in score on the Hamilton Depression Rating Scale, or HDRS) and three in remission (as defined by a score less than 8 on the HDRS). During this time, pre-operative medication and psychotherapy schedules were held the same. When stimulation was turned off in three patients who were told they would be randomized to either active or sham stimulation groups, full relapse of depression occurred within two weeks. Though this argues for DBS efficacy, this discontinuation phase was not carried out for the remaining patients due to ethical concerns.
Two years later…
The researchers then followed the patients up to two years, during which DBS continued, but medication and psychotherapy treatments could change. At one year, the depression scores decreased by 43 percent of baseline—similar to the decrease measured after six months. At two years, however, the scores fell by 70.1 percent of baseline, with 11 patients responding and seven in remission. At this point, none of the patients scored as moderately or severely depressed. Depression scores also fell with similar trajectories in major depressive disorder and bipolar disorder. Notably, none of the bipolar patients experienced manic symptoms, which have emerged in studies of DBS to other targets (Malone et al., 2009).
During these two years, only a few adverse events transpired, such as an infection in one patient and nausea in another. Though two suicide attempts occurred during this time, they did not seem related to the electrodes. DBS maintained its efficacy over this time, too, as reflected by the fact that none of the patients who had gone into remission from depression experienced a relapse while the electrodes were on.
Though two years is a long time to wait for remission—let alone have a small stimulator in one's brain—DBS might be a viable option for those with treatment-resistant depression who can spend many more years trying to hit upon something that works. Given the sudden mood changes reported upon stimulation in the operating room in this and other studies, it’s unclear why some patients took longer to improve. Future research will have to elucidate how DBS at the subcallosal cingulate site works, and whether it increases the effectiveness of traditional antidepressants, or works alongside them via an independent mechanism. The findings also suggest that depressive and manic symptoms may be dissociable, in that stimulation at a certain node of the brain’s circuitry can turn a mood positive without tipping into mania.—Michele Solis.
Holtzheimer PE, Kelley ME, Gross RE, Filkowski MM, Garlow SJ, Barrocas A, Wint D, Craighead MC, Kozarsky J, Chismar R, Moreines JL, Mewes K, Posse PR, Gutman DA, Mayberg HS. Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Unipolar and Bipolar Depression. Arch Gen Psychiatry. 2012 Jan 2. Abstract