Working within an accepted model and definition of depression, the development of DBS of the SCC for TRD was based on the hypothesis that Brodmann Area 25 (BA25) served as a key node in a distributed network of brain regions involved in mood regulation [80
]. Activity in BA25 was noted to increase with sad mood, and a decrease in BA25 activity was a consistent finding associated with successful antidepressant response to a number of somatic treatments [80
]. According to this hypothesis, the many symptoms of depression were due to abnormalities in several discrete, but interconnected neural systems, and BA25 was a critical region that had direct connections to most of these circuits.
Proof-of-principle testing helped confirm the hypothesis that directly modulating BA25 activity and white matter tracts connecting this brain region to other nodes in a presumed depression network would have antidepressant effects in TRD patients [63
]. However, only
60% of patients responded. With DBS for patients with severe, treatment-resistant movement disorders [eg. Parkinson’s disease (PD)], nearly all patients show clinically significant improvement (of motor symptoms) with chronic stimulation [82
The critical question then becomes: if BA25 is a critical node in a depression network, whose activity and connectivity with other brain regions is specifically dysfunctional in TRD, why were response and remission rates not higher? One simple answer is, as above: depression is a complex disorder with multiple neurobiological etiologies – thus, only patients with “BA25-dependent” TRD may respond to this treatment. We reject this possibility for several reasons: (1) Several decades of neurobiological research have failed to identify clinically meaningful biological subtypes of “depression” as currently defined. (2) The vast majority of TRD patients have recurrent illness [i.e., they previously remitted with adequate (standard) treatment]. Thus, at an earlier stage of illness, TRD patients show response to the same biological interventions as non-TRD patients. TRD then cannot be simply defined as a “non-monoaminergic” depression. Further, this highlights the recurrence and potential malignant transformation of the disorder over time – and the limits of current treatments to address this. (3) Nearly all TRD patients enrolled in the SCC DBS study showed at least some (>30%) improvement, and these effects persisted over time [63
], suggesting that modulation of a BA25-associated network leads to sustained positive effects on mood regulation in nearly all patients. Thus, we conclude: that BA25 and connected brain regions are involved in the regulation of negative mood, and that modulation of this network via focal stimulation is likely to impact mood regulation in a potentially beneficial way in most patients. However, while this beneficial mood effect is necessary for the full syndrome of depressive symptoms to resolve, it may not in itself be sufficient to achieve complete remission in all patients.
With this supposition in mind, we propose another answer: the syndrome of depression, as currently defined, is too broad to serve as a useful construct for treatment development, especially for more focal treatments. By analogy, PD is recognized as a complex neurological syndrome (with motor, sleep, cognitive, mood and autonomic abnormalities), and it is widely recognized that certain treatments may improve a subset of symptoms but not affect, or even worsen, others. For example, subthalamic DBS can improve the core motor symptoms of PD [82
], but may not significantly affect postural instability, mood or cognition [85
] – and negative effects on mood and cognition have been reported [87
]. A similar approach to depression would identify specific symptoms or subsets of symptoms (e.g. depressed mood/anhedonia vs. sleep vs. anxiety) as targets for treatment; the efficacy of a particular treatment could then be gauged by its effect on these symptoms, rather than using improvement in the entire syndrome as the primary efficacy measure. A version of this approach has been recently suggested (using a dimensional construct for the depressive syndrome) as a way to develop novel antidepressant treatment strategies [89
]. Such approaches should not diminish the goal of achieving full symptomatic and functional recovery. But, they may be more useful in developing specific treatment targets for clinical and basic research studies.
However, it is our opinion that a re-definition of depression should go further. We recognize that the observed symptoms of “depression” clearly track together in presentation and improvement with treatment, including domains of mood (e.g., sadness, irritability, anxiety), cognition (eg. guilt, low self-esteem, poor concentration/attention, decreased/increased psychomotor speed, hopelessness, suicidal ideation), and somatic state (eg. sleep/appetite/libido disturbances, somatic anxiety, motoric retardation/agitation). But, we conclude that this depressive state, as currently defined, is not abnormal per se, but reflects an etiologically non-specific response to stress/distress (e.g., physical or emotional stress, infection, inflammation, etc.) that includes a stereotypical set of emotional, cognitive-behavioral and somatic responses. This is supported by the currently accepted clinical criteria, where the diagnosis of a MDE can only be made if the presentation is not clearly due to a state caused by withdrawal from an addictive substance, effects of a medical illness, effects of a medication or normal bereavement highlighting the non-specific nature of the phenomenology.
We instead propose that the primary abnormality of depression is not the depressive state itself, but rather the inability to appropriately regulate that state (): depressed patients become “depressed” without a trigger, become more severely “depressed” following a trigger (e.g, death of a loved one) than is considered normal, and/or remain “depressed” for longer than would be expected. By analogy, with cardiac arrhythmias (e.g., Wolff-Parkinson-White syndrome, sick sinus syndrome, etc.), the actual arrhythmia (e.g., tachycardia) is the symptomatic presentation that may need acute treatment, but treatment of the underlying disease requires addressing the tendency of the system to enter an aberrant rhythm it cannot exit. Similarly, we conceptualize the depressive state as an aberrant neural rhythm, but the depressive disorder as the brain’s tendency to go into and stay in that rhythm inappropriately.
Figure 2 Proposed model of depression: “stuck in a rut”. In response to a stressor, there is a mood reaction, i.e., a shift from the normal, euthymic state to a “down” state that includes the symptoms associated with the syndrome (more ...)
Such a view has important implications for treatment development. With cardiac arrhythmias, a number of diverse interventions with different mechanisms of action (e.g., most medications, cardioversion, time [i.e., spontaneous recovery]) may return the system to the physiological state, but others (eg. ablation, pacing, certain medications) may be needed to help maintain the “normal” state over time. Likewise, diverse “antidepressant” treatments (e.g., various medications, psychotherapy, ECT, or TMS) can shift a patient out of the depressive state but may not necessarily prevent re-entry into that state. This is especially true of treatments with purported acute “antidepressant” effects (such as sleep deprivation [90
], ketamine [38
], and scopolamine [41
]), where a positive mood/behavioral change is seen within minutes to hours, but effects are short-lived (with return of depressive symptoms within hours or days). Other treatments, with mechanisms of action distinct from those of more acute treatments, may be needed to prevent the abnormal recurrence of the depressive state. For example, certain psychotherapies may provide positive steps in this direction [9
]. It has been suggested that such treatments may work by strengthening the cognitive cortical-subcortical systems responsible for regulating mood [94
In light of our proposed re-definition of depression, we suggest a number of directions that may prove useful to take with future research on MDD (Box 2
). One important focus of such research should be on identifying interventions that not only alter the underlying state, but actually prevent the brain from entering or remaining in that state at inappropriate times. Although highly preliminary, emerging data for DBS suggest that such a treatment intervention may be possible. With SCC DBS, there are immediate changes in mood with initial acute stimulation that may or may not persist, with resolution of the full syndrome of the depressive episode requiring weeks to months [63
]. But critically, once patients are well, they appear to stay well over time: although the published follow-up data are currently limited to one year of treatment, it is notable that >70% of patients responding to SCC DBS at 6 months were still responders at 12 months [63
]. Though not described in detail, similar results may be seen with ventral capsule/ventral striatal DBS for TRD [64
]. Further, if stimulation ceases (e.g., the device is turned off or the battery depletes), patients will almost invariably return to the depressive state [63
Box 2. Future directions
- Further investigate the neurobiological bases for normal and abnormal mood regulation (rather than the depressed state per se)
- Further investigate the neurobiology of treatment resistance and depressive relapse
- Explore strategies to redefine the key endpoints for clinical trials, recognizing that specific treatments may only target a subset of depressive symptoms
- Develop animal models with face validity for key elements of MDD, such as relapse, tachyphylaxis and treatment resistance.
It is hoped that less invasive strategies to help prevent depressed patients from becoming “stuck in a rut” can be developed, which do not require brain surgery. However, it is our opinion that such strategies are likely to be very different than the treatments currently under development that focus primarily on shifting patients out of the depressive state. An important focus for future clinical and basic research in light of our proposed re-definition of depression would be the regulation of mood states, rather than the states themselves. Several imaging studies have implicated abnormal emotional processing (not just abnormal mood state) in the pathophysiology of depression [94
]. Furthermore, as discussed above, recent data suggest that cognitive-behaviorally based and chronobiological therapies (which can be effective in TRD patients [77
] and may decrease recurrence risk [9
]), may function via specific neurobiological routes related to mood regulation [96
]. With respect to the development of future animal models, an emphasis on symptom breakthrough/recurrence is needed, since there are currently no accepted animal models of TRD or highly recurrent depression. Such models are needed to better identify and develop novel treatment targets.