Sarah Kayser

Nucleus Accumbens Deep Brain Stimulation Decreases Ratings of Depression and Anxiety in Treatment-Resistant Depression

BACKGROUND While most patients with depression respond to combinations of pharmacotherapy, psychotherapy, and electroconvulsive therapy (ECT), there are patients requiring other treatments. Deep brain stimulation (DBS) allows modulation of brain regions that are dysfunctional in depression. Since anhedonia is a feature of depression and there is evidence of dysfunction of the reward system, DBS to the nucleus accumbens (NAcc) might be promising. METHODS Ten patients suffering from very resistant forms of depression (treatment-resistant depression [TRD]), not responding to pharmacotherapy, psychotherapy, or ECT, were implanted with bilateral DBS electrodes in the NAcc. The mean (+/-SD) length of the current episode was 10.8 (+/-7.5) years; the number of past treatment courses was 20.8 (+/-8.4); and the mean Hamilton Depression Rating Scale (HDRS) was 32.5 (+/-5.3). RESULTS Twelve months following initiation of DBS treatment, five patients reached 50% reduction of the HDRS (responders, HDRS = 15.4 [+/-2.8]). The number of hedonic activities increased significantly. Interestingly, ratings of anxiety (Hamilton Anxiety Scale) were reduced in the whole group but more pronounced in the responders. The [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography data revealed that NAcc-DBS decreased metabolism in the subgenual cingulate and in prefrontal regions including orbital prefrontal cortex. A volume of interest analysis comparing responders and nonresponders identified metabolic decreases in the amygdala. CONCLUSIONS We demonstrate antidepressant and antianhedonic effects of DBS to NAcc in patients suffering from TRD. In contrast to other DBS depression studies, there was also an antianxiety effect. These effects are correlated with localized metabolic changes.

Rapid Effects of Deep Brain Stimulation for Treatment-Resistant Major Depression

BACKGROUND Treatment-resistant major depressive disorder is a prevalent and debilitating condition. Deep brain stimulation to different targets has been proposed as a putative treatment. METHODS In this pilot study, we assessed safety and efficacy of deep brain stimulation to the supero-lateral branch of the medial forebrain bundle in seven patients with highly refractory depression. Primary outcome criterion was severity of treatment-resistant major depressive disorder as assessed with the Montgomery-Åsberg Depression Rating Scale. General psychopathologic parameters, social functioning, and tolerance were assessed with standardized scales, the Global Assessment of Functioning scale, quality of life (Short-Form Health Survey Questionnaire), and neuropsychological tests. RESULTS All patients showed strikingly similar intraoperative effects of increased appetitive motivation. Six patients attained the response criterion; response was rapid--mean Montgomery-Åsberg Depression Rating Scale of the whole sample was reduced by>50% at day 7 after onset of stimulation. At last observation (12-33 weeks), six patients were responders; among them, four were classified as remitters. Social functioning (Global Assessment of Functioning) improved in the sample as a whole from serious to mild impairment. Mean stimulation current was 2.86 mA; all side effects (strabismus at higher stimulation current, one small intracranial bleeding during surgery, infection at the implanted pulse generator site) could be resolved at short term. CONCLUSIONS These preliminary findings suggest that bilateral stimulation of the supero-lateral branch of the medial forebrain bundle may significantly reduce symptoms in treatment-resistant major depressive disorder. Onset of antidepressant efficacy was rapid (days), and a higher proportion of the population responded at lower stimulation intensities than observed in previous studies.

Long-Term Effects of Nucleus Accumbens Deep Brain Stimulation in Treatment-Resistant Depression: Evidence for Sustained Efficacy

Deep brain stimulation (DBS) to the nucleus accumbens (NAcc-DBS) was associated with antidepressant, anxiolytic, and procognitive effects in a small sample of patients suffering from treatment-resistant depression (TRD), followed over 1 year. Results of long-term follow-up of up to 4 years of NAcc-DBS are described in a group of 11 patients. Clinical effects, quality of life (QoL), cognition, and safety are reported. Eleven patients were stimulated with DBS bilateral to the NAcc. Main outcome measures were clinical effect (Hamilton Depression Rating Scale, Montgomery-Asperg Rating Scale of Depression, and Hamilton Anxiety Scale) QoL (SF-36), cognition and safety at baseline, 12 months (n=11), 24 months (n=10), and last follow-up (maximum 4 years, n=5). Analyses were performed in an intent-to-treat method with last observation carried forward, thus 11 patients contributed to each point in time. In all, 5 of 11 patients (45%) were classified as responders after 12 months and remained sustained responders without worsening of symptoms until last follow-up after 4 years. Both ratings of depression and anxiety were significantly reduced in the sample as a whole from first month of NAcc-DBS on. All patients improved in QoL measures. One non-responder committed suicide. No severe adverse events related to parameter change were reported. First-time, preliminary long-term data on NAcc-DBS have demonstrated a stable antidepressant and anxiolytic effect and an amelioration of QoL in this small sample of patients suffering from TRD. None of the responders of first year relapsed during the observational period (up to 4 years).

Antidepressant effects, of magnetic seizure therapy and electroconvulsive therapy, in treatment-resistant depression

Major depression is a common mental health problem and associated with significant morbidity and mortality, including impaired social and physical functioning and increased risk for suicide. Electroconvulsive therapy (ECT) is highly efficacious in treatment-resistant depressive disorders, but cognitive side effects are frequently associated with the treatment. Magnetic seizure therapy (MST) is a form of convulsive therapy, using magnetic fields in order to induce therapeutic seizures. First studies suggested that cognitive side effects of MST, including postictal recovery time, are more benign than those resulting from ECT treatment. In this open-label study we tested the hypothesis that MST is associated with clinically significant antidepressant effects in treatment-resistant depression (TRD) as an add-on therapy to a controlled pharmacotherapy. Twenty patients suffering from TRD were randomly assigned to receive either MST or ECT starting from July 2006 until November 2008. Primary outcome measure was antidepressant response assessed by Montgomery Åsberg Depression Scale. Secondary outcome measures included Hamilton Depression Rating Scale, Hamilton Anxiety Scale, Beck Depression Inventory and 90-Item Symptom Checklist. Antidepressant response (improvement of 50% in MADRS ratings) was statistically significant and of similar size in both treatment groups. Cognitive side effects were observed in neither group. Characteristics in MST- and ECT-induced seizures were comparable, especially regarding ictal activity and postictal suppression. Thus, MST may be a potential alternative to ECT if efficacy and safety are validated in larger clinical trials.

Deep Brain Stimulation of the Human Reward System for Major Depression—Rationale, Outcomes and Outlook

Deep brain stimulation (DBS) as a putative approach for treatment-resistant depression (TRD) has now been researched for about a decade. Several uncontrolled studies—all in relatively small patient populations and different target regions—have shown clinically relevant antidepressant effects in about half of the patients and very recently, DBS to a key structure of the reward system, the medial forebrain bundle, has yielded promising results within few days of stimulation and at much lower stimulation intensities. On the downside, DBS procedures in regions are associated with surgical risks (eg, hemorrhage) and psychiatric complications (suicidal attenuation, hypomania) as well as high costs. This overview summarizes research on the mechanisms of brain networks with respect to psychiatric diseases and—as a novelty—extrapolates to the role of the reward system in DBS for patients with treatment-resistant depression. It further evaluates relevant methodological aspects of today’s research in DBS for TRD. On the scientific side, the reward system has an important yet clearly under-recognized role in both neurobiology and treatment of depression. On the methodological side of DBS research in TRD, better animal models are clearly needed to explain clinical effects of DBS in TRD. Larger sample sizes, long-term follow-up and designs including blinded sham control are required to draw final conclusions on efficacy and side effects. Practical research issues cover study design, patient tracking, and the discussion of meaningful secondary outcome measures.

Neuropsychological safety of nucleus accumbens deep brain stimulation for major depression: effects of 12-month stimulation.

Abstract Objectives. Deep brain stimulation (DBS) to the nucleus accumbens (NAcc-DBS) has antidepressant effects in patients suffering from treatment-resistant depression (TRD). However, limited information exists regarding the impact of NAcc-DBS on cognitive functioning. The aim of this study was to examine whether NAcc-DBS in patients with TRD has any cognitive effects. Methods. A comprehensive neuropsychological battery was administered to 10 patients with TRD before onset of bilateral NAcc-DBS and after 1 year of DBS stimulation. Neuropsychological testing covered the domains of attention, learning and memory, executive functions, visual perception, and language. Performance was analyzed at baseline and after 1 year of continuous DBS. Results. No evidence was found for cognitive decline following NAcc-DBS comparing test results after 1 year of NAcc-DBS with baseline. However, significantly improved cognitive performance on tests of attention, learning and memory, executive functions and visual perception was found. In addition, there was a general trend towards cognitive enhancement from below average to average performance. These procognitive effects were independent of the antidepressant effects of NAcc-DBS or changes in NAcc-DBS parameters. Conclusions. These results not only support cognitive safety of NAcc-DBS but also stress its beneficial role in augmenting cognitive performance in patients with TRD.

Magnetic seizure therapy of treatment-resistant depression in a patient with bipolar disorder.

Electroconvulsive therapy (ECT) is a highly efficacious treatment for severe depression. However, a disadvantage of ECT is the risk of cognitive side effects. Magnetic seizure therapy (MST) is a novel treatment modality, by which therapeutic seizures are induced using rapidly alternating strong magnetic fields. In this case study, we report on successful MST treatment of an episode of otherwise treatment-resistant depression in a patient with bipolar I disorder. Compared with published ECT results, MST seizures in this case report were of shorter duration, lower ictal electroencephalogram amplitude, and less pronounced postictal suppression. Furthermore, the patient did not experience subjective side effects and particularly recovered time to full orientation more quickly with MST than what has been previously described for ECT. Taken together, these results suggest that MST, compared with ECT, might have antidepressant effects and may have fewer clinical side effects.

Magnetic seizure therapy in treatment-resistant depression: clinical, neuropsychological and metabolic effects

BACKGROUND Magnetic seizure therapy (MST), despite being in an early phase of clinical research, has been demonstrated to be associated with antidepressant efficacy. However, safety, tolerability and efficacy data in connection with functional brain activity from larger samples are lacking. The aim of this study was to determine clinical and cognitive effects of MST and the influence of MST on regional brain glucose metabolism. METHOD Twenty-six patients suffering from treatment-resistant depression (TRD) underwent MST. Ten patients underwent a randomized trial and 16 patients an open-label study design. The primary outcome criterion was the severity of depressive symptoms assessed with the Hamilton Depression Rating Scale (HAMD). Depressive symptoms, tolerability and cognitive safety, along with social functioning and quality of life parameters, were assessed using various rating scales. A clinical follow-up visit 6 months following the completion of a course of MST and [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scans of 12 patients were analysed. RESULTS A significant response to MST was demonstrated by 69% of the patient sample, with 46% meeting remission criteria. Anxiety ratings were significantly reduced in responders and their quality of life was improved. Half of the responders relapsed within 6 months. No cognitive side-effects were observed. FDG-PET scans showed a metabolic increase in the frontal cortex bilaterally and a decrease in the left striatum. CONCLUSIONS Robust antidepressant and anti-anxiety efficacy of MST was demonstrated, and found to be associated with localized metabolic changes in brain areas that are strongly implicated in depression. Thus, MST presents an effective, well-tolerated and safe treatment option for patients unable to respond to other forms of therapy for depression.

Modulating affect, cognition, and behavior - prospects of deep brain stimulation for treatment-resistant psychiatric disorders.

Most patients suffering from psychiatric disorders respond to combinations of psycho- and psychopharmacotherapy; however there are patients who profit little if anything even after many years of treatment. Since about a decade different modalities of targeted neuromodulation – among them most prominently – deep brain stimulation (DBS) – are being actively researched as putative approaches to very treatment-resistant forms of those disorders. Recently, promising pilot data have been reported both for major depression (MD) and obsessive–compulsive disorder (OCD). Given the fact that patients included in DBS studies had been treated unsuccessfully for many years with conventional treatment methods, renders these findings remarkable. Remarkable is the fact, that in case of the long-term studies underway for MD, patients show a stable response. This gives hope to a substantial percentage of therapy–resistant psychiatric patients requiring new therapy approaches. There are no fundamental ethic objections to its use in psychiatric disorders, but until substantial clinical data is available, mandatory standards are needed. DBS is a unique and very promising method for the treatment of therapy–resistant psychiatric patients. The method allows manipulating pathological neuronal networks in a very precise way.

Deep brain stimulation to the medial forebrain bundle for depression- long-term outcomes and a novel data analysis strategy

BACKGROUND Deep brain stimulation (DBS) of the supero-lateral branch of the medial forebrain bundle (slMFB) in treatment-resistant depression (TRD) is associated with acute antidepressant effects. OBJECTIVE Long-term clinical effects including changes in quality of life, side effects and cognition as well as long-term data covering four years are assessed. METHODS Eight TRD patients were treated with DBS bilateral to the slMFB. Primary outcome measure was a 50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) (response) and remission (MADRS <10) at 12 months compared to baseline. Secondary measures were anxiety, general functioning, quality of life, safety and cognition assessed for 4 years. Data is reported as conventional endpoint-analysis and as area under the curve (AUC) timeline analysis. RESULTS Six of eight patients (75%) were responders at 12 months, four patients reached remission. Long-term results revealed a stable effect up to four years. Antidepressant efficacy was also reflected in the global assessment of functioning. Main side effect was strabismus at higher stimulation currents. No change in cognition was identified. AUC analysis revealed a significant reduction in depression for 7/8 patients in most months. CONCLUSIONS Long-term results of slMFB-DBS suggest acute and sustained antidepressant effect; timeline analysis may be an alternative method reflecting patients overall gain throughout the study. Being able to induce a rapid and robust antidepressant effect even in a small, sample of TRD patients without significant psychiatric comorbidity, render the slMFB an attractive target for future studies.