The results of this study suggest that DBS of the VC/VS can provide benefit in highly treatment-refractory patients with depression. Efficacy was demonstrated in both categorical measures of response and remission and by a significant, sustained improvement in mean depression measures. Although follow-up durations varied, at last observation, five patients met accepted MADRS criterion for remission and eight met accepted MADRS criterion for clinical response. Mean MADRS scores were reduced by 52.6% at 3 months, 47.0% at 6 months, 45.7% at 1 year, and 56.4% at last follow-up with similar results for the HDRS. Improvements were also noted in measures of global functioning. These symptomatic and functional improvements were seen despite the highly refractory illness that these patients experienced.
Despite the invasive nature of DBS treatment, patients tolerated both the surgical procedure and stimulation well. Acute changes in mood and anxiety were frequently seen during programming sessions. Undesirable changes were rapidly reversed through stimulation parameter changes. Interestingly, the quality or intensity of these acute observations did not necessarily predict how patients would do with chronic stimulation. No adverse effects on cognitive functioning were noted on the basis of an extensive battery of neuropsychological measures. Importantly, none of the adverse events resulted in removal of the DBS system or withdrawal from the study. All patients were continuing on DBS therapy at last reported follow-up.
Stimulation parameter titration was a time-consuming process. Similar to the experience with DBS in movement disorders (32
), electrode configurations and stimulation parameters resulting in optimal response varied among patients. Testing a variety of different settings was therefore necessary to optimize response for individual patients. Variation in stimulation settings is expected and might arise from a variety of factors. These include slight differences in targeting on the basis of individual anatomy, variations in sensitivity to stimulation, and anatomical variation of fiber pathways. Consistent with results observed with DBS in OCD (28
), higher amplitudes were used in nonresponders in an attempt to attain therapeutic benefit.
Stimulation amplitudes were higher than those used in the treatment of movement disorders. This is not surprising, given the different structure and tissue impedance profile of the mixed VC/VS target compared with gray matter nuclear targets typical of movement disorder DBS therapies. It should also be noted that the larger contacts of the VC/VS lead have twice the surface area of standard leads, resulting in charge densities comparable to those used in other DBS applications. These factors all contribute to the need for more frequent battery replacements in these patients. The use of rechargeable devices, common in other neurostimulation therapies, will enhance acceptability.
Close monitoring of patients is a significant consideration with DBS therapies. Implanted stimulators can be turned off accidentally (e.g., theft detectors) or batteries can become depleted before replacement surgery. Depressive symptoms returned quickly in some patients when this occurred, resulting in a situation that required intervention. Even though symptoms did not typically worsen beyond preoperative levels, patients that had improved felt quite distressed by depressive symptom return. This risk during DBS treatment can be mitigated by the use of available devices that allow patients to monitor neurostimulator status.
A single bipolar patient, who experienced only one previous manic episode, was included in the study. This patient’s clinical course was the most variable. Although the patient had periods of depressive symptom improvement lasting weeks—not previously achieved after aggressive treatment including bilateral ECT and VNS—these were followed by hypomanic episodes. Hypomania reversed rapidly when stimulation was stopped. Another patient (MGH3) was noted to have had manic-like symptoms over 10 years before study enrollment. These symptoms occurred with the initiation of antidepressant treatment and quickly resolved. Subsequent antidepressant treatment failed to elicit this same response. This patient achieved stable remission with DBS. Although caution is indicated in interpreting these observations, nevertheless, the potential for DBS-induced affective instability in Bipolar I patients merits particular attention. Other patient variables such as personality or anxiety disorders might also influence patient response. The small number of subjects in this study precludes definitive evaluation of this. However, no significant differences were noted in patients with or without comorbid personality disorders.
This study had several limitations in addition to patient variables. These include a variable duration of patient follow-up and an open-label design. Although there was a wide range of follow-up periods, all patients had a minimum of 6 months of active stimulation and over two-thirds had 1 year of follow-up. Documenting long-term outcomes of DBS is especially important in this patient population. There could have been an effect of medication changes within the first 6 months in four subjects. Not surprisingly, these changes occurred in subjects with less overall improvement, although this was not statistically significant. An argument could be made to report only those patients without medication changes for a defined time period. This would eliminate these influences as possible confounding factors. However, this would only serve to improve the results, whereas our intention is to provide all data in order to inform future study design.
Due to the open-label nature of this study, the possible influence of rater bias and placebo response cannot be ruled out. The rate of response to placebo cannot be determined, but is expected to be low for several reasons. Patients enrolled had already undergone numerous interventions for their illness, including ECT. Individual treatment history far exceeded the stringent entry criteria. It is plausible that this level of refractoriness would reduce placebo response compared with less-refractory patients. The actual placebo response rate in such patients is unknown, in part because they are overwhelmingly excluded from treatment trials. In addition, some patients with minimal acute stimulation benefit eventually reached responder status, whereas others with positive acute changes ultimately were nonresponders, inconsistent with a placebo effect.
Data on placebo response are available from a study of VNS in a group of MDD patients with highly refractory illness (33
). Only 10% of patients responded to sham stimulation over a 10-week period. On average, these subjects had far fewer medication trials than our patients and were not required to have undergone ECT. It seems reasonable to expect that our patient cohort would have a placebo response rate at or below what was observed in that study.
Additional observations during the study, including the sustained response in many patients for periods of 1 year and greater, also support our conclusion of benefit from active stimulation. When patients were blind to the presence, absence, or type of stimulation during initial titration, individual responses were quite consistent to repeated testing of the same parameter settings over several days. Second, during chronic DBS, patients noted symptom worsening when stimulation was interrupted by either accidental shut-off or battery expiration, even though they were unaware of device status. These observations suggest that active DBS was responsible for the sustained symptomatic and functional improvements seen.
Another study of DBS for depression reported results from six patients stimulated in the subgenual cingulate region (21
). Although it is difficult to draw direct comparisons, results from that 6-month pilot study and those reported here seem qualitatively similar. Experience with DBS for movement disorders has shown that it is possible to treat a variety of related disorders through stimulation of different nodes of the cortico-striatal-thalamic-cortical circuit controlling motor function (32
). It is also possible that multiple DBS targets might similarly exist within the networks influencing mood and affective state. Neuroimaging studies of patients treated with VC/VS stimulation for OCD have demonstrated modulation of neural structures within this network, including orbital frontal cortex, basal ganglia, and subgenual cingulate (34
). These results are consistent with neuroanatomical studies in nonhuman primates, which suggest that fiber pathways connecting medial and orbital frontal cortex to thalamus coalesce within this region (11
). In addition, the VS in this area has complex architecture and includes structures such as the bed nucleus of the stria terminalis and the nucleus accumbens, regions believed to be involved with stress-related and reward-motivation components of depression (37
Finally, Schlaepfer et al.
) have reported improvement in depressive symptoms and anhedonia with DBS of the nucleus accumbens. The stereotactic target in their study is close in location to ours. However, the more dorsal contacts are much less proximate due to differences in surgical trajectory and model of DBS lead used. Long-term benefit in these patients is not yet known, and it remains unclear whether acute benefit results in continued response.
Overall, the results of this multicenter investigation of DBS of the VC/VS region provide encouraging preliminary evidence of a sustained therapeutic effect in an otherwise highly treatment-resistant population. These results are consistent with the findings of prior studies of DBS in treatment-resistant OCD and depression and provide additional support for the therapeutic potential of DBS in individuals suffering from these chronic, severe psychiatric disorders unresponsive to conventional treatments.