Long-Term Effects of Nucleus Accumbens Deep Brain Stimulation in Treatment-ResistantDepression: Evidence for Sustained Efficacy
Bettina H Bewernick
Sarah Kayser
Volker Sturm
Thomas E Schlaepfer
Department of Psychiatry, University Hospital,Sigmund-Freud-Strasse 25, Bonn53105, Germany, Tel: +49 228 287 14715, Fax: +49 228 28715025, E-mail:schlaepf@jhmi.edu
Received 2011 Dec 21; Revised 2012 Feb 20; Accepted 2012 Mar 2; Issue date 2012 Aug.
Abstract
Deep brain stimulation (DBS) to the nucleus accumbens (NAcc-DBS) was associated withantidepressant, anxiolytic, and procognitive effects in a small sample of patientssuffering from treatment-resistant depression (TRD), followed over 1 year. Results oflong-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. Elevenpatients were stimulated with DBS bilateral to the NAcc. Main outcome measures wereclinical effect (Hamilton Depression Rating Scale, Montgomery-Asperg Rating Scale ofDepression, and Hamilton Anxiety Scale) QoL (SF-36), cognition and safety at baseline, 12months (n=11), 24 months (n=10), and last follow-up(maximum 4 years,n=5). Analyses were performed in an intent-to-treatmethod with last observation carried forward, thus 11 patients contributed to each pointin time. In all, 5 of 11 patients (45%) were classified as responders after 12months and remained sustained responders without worsening of symptoms until lastfollow-up after 4 years. Both ratings of depression and anxiety were significantly reducedin the sample as a whole from first month of NAcc-DBS on. All patients improved in QoLmeasures. One non-responder committed suicide. No severe adverse events related toparameter change were reported. First-time, preliminary long-term data on NAcc-DBS havedemonstrated a stable antidepressant and anxiolytic effect and an amelioration of QoL inthis small sample of patients suffering from TRD. None of the responders of first yearrelapsed during the observational period (up to 4 years).
Keywords: DBS, nucleus accumbens, treatment-resistant major depression, anxiety, quality of life, relapse
INTRODUCTION
A large number of depressive patients cannot be helped with evidence-based treatmentsteps (eg, pharmacotherapy, psychotherapy, and electroconvulsive therapy). Up to40% of patients responding to antidepressant therapy suffer from clinicallyrelevant residual symptoms despite optimized treatment (Fava andDavidson, 1996). These patients suffer from debilitating, life-threateningsymptoms, face a reduced quality of life (QoL), and are a burden for society (Murray and Lopez, 1996;Pincus and Pettit,2001). For these patients, suffering from so-called treatment-resistantdepression (TRD), deep brain stimulation (DBS) is currently under research as a possibletreatment option.
DBS aims to modulate dysfunctional neuronal networks involved in depression (Krishnan and Nestler, 2010). Three major brain regions have beenselected in a hypothesis-driven way for major depression: nucleus accumbens (NAcc)(Bewernicket al, 2010;Schlaepfer and Lieb, 2005), subgenual cingulate cortex (Cg25)(Lozanoet al, 2008;Mayberget al, 2005) and the anterior limb of the capsula interna(ALIC) (Maloneet al, 2009). Although the precisemechanism of action is not known yet, significant antidepressant effects have been shownin a 1-year follow-up period in 50–60% of the about 45 treated patients(Bewernicket al, 2010;Lozanoet al, 2008;Maloneet al,2009). A normalization of brain metabolism in the target region and in brainareas belonging to neuronal network modulated by DBS has been demonstrated (Bewernicket al, 2010;Lozanoetal, 2008). Neuropsychological assessment showed a normalization ofpreviously sub-average performance in several cognitive domains in a 1-year follow-up(Grubertet al, 2011;McNeelyet al, 2008).
Despite encouraging antidepressant effects of all targets, long-term outcome beyond 1year has only been described recently in 14 patients stimulated at Cg25 with45% response after 2 years, 60% response after 3 years, and 55%response at last follow-up visit (up to 6 years) (Kennedyetal, 2011) and in a sample of 17 patients targeting the ALIC (Malone, 2010). Response rates were 53% after 12 months and71% at last follow-up (ranging from 14 to 67 months) (Malone,2010). The response criterion was a minimum of 50% reduction inHamilton Depression Rating Scale (HDRS) or Montgomery-Asperg Rating Scale of Depression(MADRS) in all studies.
In this study, long-term effects of DBS to the NAcc are described in a group of 11patients suffering from TRD. Clinical effects, QoL, cognition, and safety over a 2-yearfollow-up period, in five patients up to 4 years, are reported.
Contrary to the high relapse rates after treatment-as-usual (TAU) (eg, pharmacotherapy,psychotherapy) (Rushet al, 2006), but in linewith stable antidepressant, anti-anhedonic, and anxiolytic effects of NAcc-DBS duringfirst year, we hypothesized, that clinical effects as well as an increase in QoL would bestable during long-term follow-up (from 12 to 48 months).
PATIENTS AND METHODS
Patients
The study has been approved by the institutional review boards of the Universities ofBonn and Cologne. Eleven patients between 32 and 65 years of age received NAcc-DBS (seeTable 1 for demographic data) Selection criteria were aminimum score on the 28-item HDRS (HDRS28) of 21, a score in Global Assessment ofFunction below 45. Further inclusion criteria were at least four episodes of majordepressive disorder (MDD) or chronic episode over 2 years; >5 years after firstepisode of MDD; failure to respond to adequate trials of primary antidepressants from atleast three different classes, adequate trials of augmentation/combination of aprimary antidepressant using at least two different augmenting/combination agents;an adequate trial of ECT (>6 bilateral treatments); an adequate trial of individualpsychotherapy (>20 sessions); and no psychiatric co-morbidity and drug free or onstable drug regimen at least 6 weeks before study entry. Exclusion criteria were currentor past nonaffective psychotic disorder; any current clinically significant neurologicaldisorder or medical illness affecting brain function, or severe personality disorder.Patients met diagnostic criteria for MDD, unipolar type, and were in a current episode.All patients to be included in the study suffered from severely TRD (Sackeim, 2001).
Table 1. Demographic and Clinical Characteristics.
| Variable | Mean | SD | Responders | Non-responders | ||
|---|---|---|---|---|---|---|
| Mean | SD | Mean | SD | |||
| Age at implant (years) | 48.36 | 11.08 | 45.6 | 12.9 | 50.6 | 9.8 |
| Sex (% female) | 33 | 60 | 16.6 | |||
| Duration of education (years) | 14.30 | 2.36 | 14.25 | 2.5 | 14.3 | 2.5 |
| Retirement because of depression (% retired) | 90.00 | 80 | 100 | |||
| Length of current episode (years) | 9.26 | 7.64 | 5.98 | 3.5 | 12 | 9.3 |
| Number of previous episodes (lifetime)a | 1.29 | 1.75 | 0.9 | 0.6 | 0.5 | |
| Age at onset (years) | 32.55 | 12.41 | 34.8 | 14.4 | 30.6 | 11.4 |
| Time since diagnosis of affective disorder (years) | 17.45 | 9.91 | 12.6 | 4.7 | 21.5 | 11.6 |
| Lengths of previous hospitalizations (months) | 20.18 | 11.24 | 18.4 | 10.2 | 21.6 | 12.7 |
| Number of antidepressive pharmaceuticals at implant | 4.36 | 1.21 | 3.8 | 1 | 4.8 | 1.1 |
| Number of past medical treatment courses | 22.18 | 7.73 | 19 | 5.5 | 24.8 | 8.7 |
| Number of medications included in formula | 13.82 | 5.34 | 12 | 4 | 15.3 | 6.1 |
| Mean total of ATHF scoreb | 40.27 | 15.24 | 38.6 | 14.3 | 41.6 | 17.1 |
| Mean ATHF score and SD | 3.18 | 0.40 | 3.4 | 0.5 | 3 | 0 |
| Average number of treatment trials with ATHF ⩾3 | 7.91 | 3.36 | 7.6 | 3.3 | 8.1 | 3.6 |
| Past ECT/MST | 21.09 | 8.48 | 22.2 | 8.7 | 20.1 | 8.9 |
| Psychotherapy (h) | 263.64 | 263.88 | 185.2 | 143.8 | 329 | 333.8 |
| Suicide attempts (% of patients preoperative) | 27 | 20 | 33.3 | |||
Fifty percent of patients did not have separate episodes.
Modified antidepressant treatment history form (ATHF). A score of ‘3'is the threshold for considering a trial adequate and the patient resistant to thetreatment.
Mean and SD, if applicable, are reported.
Surgery/Target
Bilateral DBS electrodes were implanted as described previously (Schlaepferet al, 2008) using a Leksell-stereotactic frame.Standard Medtronic model 3387 leads were used. This lead has four contacts over a lengthof 10.5 mm, each spaced 1.5 mm apart: (1) the shell and (2) the coreregions of the NAcc, and (3) the ventral and (4) the medial internal capsule. The lowestcontact was targeted at 7.5, 1.5, and 4 mm from the upper front edge of theanterior commissure, corresponding to MNI coordinates ±7.5, 5.5, and 9.0. Targetsand trajectories were defined using stereotactic 3 Tesla MR imaging. Electrodepositioning was verified after surgery as described inHuffetal (2010). Electrode type and location differed from the ALIC targetonly dorsally (Maloneet al, 2009), because theelectrodes used in this study had a smaller spacing of 10.5 mm and the electrodesused in the ALIC study had a wider space covering a larger brain area (Maloneet al, 2009). Thus, the two most ventral ALICcontacts cover approximately the same brain area as the four contacts used in thisstudy.
Assessment and Study Protocol
Psychiatric assessments were performed on a weekly basis during the first and secondmonth after stimulation onset and up to half a year on a 2-weekly basis. From month 7 upto 2 years, patients were tracked on a monthly basis, then up to 4 years on a 3-monthlybasis.
Primary outcome measure was antidepressant response (50% reduction of depressivesymptom severity as assessed by the 28-item HDRS28 (Endicottet al, 1981;Hamilton,1967;Rosenthal and Klerman, 1966) orremission (HDRS-score of <10)). Patients were classified as responders andnon-responders with regard to their response to NAcc-DBS 12 months post-surgery.Secondary outcome measures included MADRS (Montgomery andÅsberg, 1979) and Hamilton Anxiety Scale (HAMA) (Hamilton, 1976).
The Hautzinger list of positive activities is a list of 280 pleasant activities(Hautzinger, 2000;Lewinsohn andGraf, 1973). This score is used as a tool to assess progress in cognitivebehavioral therapy. Lacking meaningful standardized measures of anhedonia, we used thislist to assess changes in anhedonia and level of activity. Social functioning wasmeasured with the Short-Form Health Survey Questionnaire (SF-36) (Ware and Sherbourne, 1992). The SF-36 assesses QoL in eight subscales thatcan be summarized into a score in ‘physical health dimension' and‘mental health dimension'. Additionally, information about safety of thetreatment method (see Table 4 for adverse events) was recorded.
Neuropsychological assessment with standardized tests was administered to the patientsbefore implantation and once a year during follow-up. Thirteen cognitive tests wereanalyzed comparing baseline and last follow-up covering learning and memory (verbal andvisual-spatial as well as working memory), attention, language, visual perception, andexecutive functions. Standard neuropsychological tests are clustered according to theCompendium of Neuropsychological Tests and described in detail elsewhere (Spreen, 1991). SeeGrubertet al(2011) for a detailed description of neuropsychological tests applied. Someverbal test could not be performed on all patients for language reasons (see Table 3 fornumber of patients included in the analysis).
Stimulation Parameters and Additional Treatments
Stimulation was applied with permanent pulse-train square wave stimulation startingwith the parameters amplitude 2 V, pulse width 90 μs, frequency130 Hz, and the electrode setting electrodes 1 and 2 negative against case. Afteran intra-operative trial, stimulation was switched off for 1 week to allow consolidationof the tissue surrounding the electrode tips (eg, changes in resistance) and to controlfor microlesional effects (Cersosimoet al, 2009;Granzieraet al, 2008). One weekpost-operatively, this DBS setting was resumed and the voltage was successivelyincreased from 2 to 4 V.
Stimulation parameters were kept constant approximately for 4 weeks in order toretrieve sufficient observations of first acute and sub-acute effects (eg, improvementin clinical impression as assessed by HDRS). Next, only when side effects occurred orwhen the antidepressant response was not satisfying, DBS parameters were varied in orderto optimize the individual response. The sequence and priority of changes was:amplitude, pulse width, selection of poles, (all possible monopolar and bipolarcombinations), and frequency in the range 1.5–10.0 V,100–150 Hz, and 60–210 μs. Stimulation was always bilateraland symmetric. The individual optimum DBS setting was kept constant in each patient atleast one month before and during the final follow-up.
Additional pharmacological treatment was kept constant at least 6 weeks before andafter surgery. During follow-up, especially in non-responders, changes inpharmacological regime were allowed. Patients undergoing psychotherapy entering thestudy were allowed to continue the treatment.
Statistical Analysis
To evaluate clinical response, all rating scales were analyzed with ANOVA for repeatedmeasures and the factor time.Post-hoc paired comparisons were calculated foreach time point compared with baseline. Level of significance was set at 5% forall analyses. Data from early terminators (n=1, 12 months) or patientsin follow-up under 24 months (n=1, 13 months) were analyzed in the lastobservation carried forward manner. Missing values were interpolated. Last follow-up wasup to 4 years (five patients completed year 4). All analyses were performed asintent-to-treat analysis in order to avoid overestimation of clinical effect.Significance of change in cognitive performance between baseline and last observation(up to 36 months) was analyzed via pairedt-tests for each neuropsychologicaltest as recommended byOkunet al (2007) inorder to evaluate whether surgery and stimulation lead to deterioration frombaseline.
RESULTS
Demographic and Clinical Characteristics
All patients were diagnosed as severely treatment resistant with a mean length ofcurrent major depressive episode of 9.2 years (SD 7.6), and had 7.9 medical treatmentcourses in average with an antidepressant treatment resistance score (ATHF score) above3 defining an adequate treatment dose and length, including augmentation and combinationtherapy. At time of implantation, the mean number of antidepressant medications was 4.3.All patients had received ECT and psychotherapy without response (seeTable 1 for demographic information). Responders and non-responders werecompared concerning severity of depression at baseline (HDRS_28, MADRS) and clinicalcharacteristics. No difference could be detected regarding baseline depressivity((responders/non-responders HDRS_28 score: 34.5 (SD 5.2)/30.2 (SD 53);responders/non-responders MADRS score: 33.6 (SD 1.6)/31.2 (SD 4.6)) ordemographic differences. Only the number of women in each group differed: three womenwere classified as responders (vs two men) and one woman was classified asnon-responder (vs five men).
Clinical Outcomes
All measures are reported at baseline (mean baseline score over up to five visits inthe last 3 months before surgery),n=11, and at several time points upto 4 years after stimulation onset (n=11).
Primary outcome (HDRS28)
Patients were classified as responders (50% reduction in HDRS) andnon-responders (<50% reduction in HDRS) with regard to their response toNAcc-DBS 12 months post-surgery (Table 2,Figure 1a). Five patients (45.5%) reached the responsecriterion at this point; six patients (54.5%) were classified asnon-responders. During the second year, response status remained stable in allpatients. None of the non-responders reached response status for >2 consecutivemonths. One patient was in stable remission (HDRS28⩽10).
Table 2. Psychopathological Measures at Multiple Time Points During DBS Treatment.
| Baseline | 1 Month | 3 Months | 6 Months | 9 Months | 12 Months | 15 Months | 18 Months | 21 Months | 24 Months | Last observation | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | |
| p-Value main effect | p-Value | p-Value | p-Value | p-Value | p-Value | p-Value | p-Value | p-Value | p-Value | p-Value | |
| HDRS_28 | |||||||||||
| Group | 32.2 (5.5) | 23.2 (5.6) | 23.4 (5.1) | 20.9 (4.6) | 23.3 (5.5) | 20.2 (7.5) | 21.3 (7.1) | 21 (8.9) | 21.5 (8.1) | 19.5 (9) | 22.1(13.4) |
| F=4.1 | p<0.001 | p<0.005 | p<0.001 | p=0.001 | p<0.005 | p<0.005 | p<0.005 | p<0.005 | p<0.01 | p<0.01 | p<0.05 |
| df=10 | |||||||||||
| MADRS | |||||||||||
| Group | 32.3 (3.7) | 24.2 (4.8) | 23.4 (4.7) | 20.9 (5.6) | 22.8 (6.8) | 20.2 (7.3) | 21.2 (7.8) | 21.1 (8.5) | 21.7 (9.3) | 19.1 (8.5) | 21.6 (10.7) |
| F=5.1 | p<0.001 | p<0.001 | p<0.001 | p<0.001 | p<0.005 | p=0.001 | p<0.005 | p<0.005 | p<0.05 | p<0.005 | p<0.05 |
| df=10 | |||||||||||
| HAMA | |||||||||||
| Group | 23.3 (5.7) | 17.9 (7.3) | 17.6 (5.9) | 15.4 (3.9) | 17.4 (3) | 14.3 (5.8) | 15.7 (9) | 16 (10.4) | 13.7 (6.4) | 13.9 (4.9) | 14.7 (8.8) |
| F=2.7 | p<0.005 | p<0.01 | p<0.05 | p<0.005 | p<0.005 | p<0.005 | p<0.05 | p<0.05 | p<0.005 | p=0.001 | p<0.05 |
| df=10 | |||||||||||
| Activities | |||||||||||
| Group | 28.5 (16) | 43.9 (24.8) | 39 (21.8) | 41.6 (24.4) | 43.2 (20.5) | 45.7 (20.7) | 45.5 (25.4) | 46.4 (25.3) | 48 (29.6) | 51.9 (35.5) | 57.9 (37.7) |
| F=2.4 | p<0.05 | p<0.05 | p<0.05 | p=0.100 | p<0.05 | p<0.05 | p=0.052 | p<0.05 | p=0.075 | p=0.083 | p<0.05 |
| df=10 | |||||||||||
| SF 36 | |||||||||||
| Mental health | |||||||||||
| Group | 19.4 (4.9) | 23.3 (6.3) | 19.5 (3.4) | 20.5 (6.5) | 19.9 (3.8) | 24.3 (11.4) | 29.9 (11.2) | ||||
| F=4.9 | p<0.001 | p<0.05 | p=0.953 | p=0.551 | p=0.749 | p=0.172 | p<0.05 | ||||
| df=6 | |||||||||||
| Physical health | |||||||||||
| Group | 34.0 (4.5) | 35.4 (7.9) | 38.0 (5.9) | 35.7 (4.6) | 34.8 (3.9) | 37.6 (8.5) | 34.1 (13.3) | ||||
| F=0.7 | p=0.651 | p=0.42 | p=0.40 | p=0.267 | p=0.565 | p=0.182 | p=0.980 | ||||
| df=6 | |||||||||||
Abbreviations: Activities, number of positive activities after Hautzinger; HAMA,Hamilton Anxiety Scale; HDRS_28, Hamilton-28-Items Depression Rating Scale; MADRS,Montgomery-Asberg Depression Rating Scale; SF-36, Health Survey Questionnaire.
Mean, SD, ANOVAs for repeated measures with the factor time andpost-hoccontrasts for each time point in comparison with baseline.
Figure 1.
Clinical outcomes over time. Hamilton depression rating over time (top left);Montgomery-Asperg rating over time (top right); positive activities over time (bottomleft); Hamilton anxiety rating over time (bottom right). In red responders(>50% reduction from baseline), in blue non-responders (<50%reduction from baseline), in green group mean scores. For the activities, panel redrefers to patients who responded >50% in the HDRS score. At each time point,11 patients contributed, as data were analyzed in an intent-to-treat method with lastobservation carried forward.
The mean total HDRS28 score was significantly improved under stimulationat all-time points. Improvements were seen after first month of stimulation in thesample as a whole (HDRS28-score: 32.2 (SD 5.5) at baseline, 23.2 (SD 5.6)after 1 month) and remained stable throughout the follow-up period(HDRS28-score: 20.2 (SD 7.5) after 1 year, 19.5 (SD 9) after 2 years, 22.1(SD 13.4) last follow-up). Responders and non-responders descriptively differed inHDRS score after first month of stimulation and differences were more pronouncedduring follow-up period. In the second year, group differences were even morepronounced. Stability of anti-depressive effect in each patient is demonstrated inFigure 2. Responders at 12 months remained responders at24 months and last follow-up, non-responders kept their status respectively.
Figure 2.
Stability of clinical effect. Individual response over time. Red lines are responders(>50% reduction from baseline),n=5, in blue non-responders(<50% reduction from baseline),n=6, at time points 12 and 24months. Diamonds represent corresponding group mean values.
Secondary outcome variables (MADRS, HAMA, positive activities, QoL,cognition)
MADRS was used to capture changes in additional depressive symptoms (eg, cognitivefunctioning, level of activity, interest, and negative thinking). Group effects weresimilar to those measured with the HDRS28 (MADRS group mean at baseline:32.3 (SD 3.7); group mean after 1 year: 20.2 (SD 7.3) after 2 years: 19.1 (SD 8.5)last follow-up: 21.6 (SD 10.7)) (Table 2,Figure 1b).
Improvement in depression was accompanied by a reduction in anxiety as measured bythe HAMA (Table 2,Figure 1c).Compared with baseline, the sample as a whole showed a significant reduction inanxiety symptoms (HAMA at baseline: 23.3 (SD 5.7), after 1 year: 14.3 (SD 5.8), after2 years 13.9 (SD 4.9), last follow-up: 14.7 (SD 8.8)). From first month ofstimulation, the group mean was below 19, which is the cut-off for anxiety disordersin pharmacological studies (Hamilton, 1976). Similar toresults in depression scales, responders had a more pronounced reduction in anxietycompared with non-responders.
The level of hedonic activities (as measured by the Hautzinger's list ofpositive activities) rose significantly in the sample as a whole from first month ofsimulation. Descriptively, the number of activities further increased in the group ofresponders during the follow-up period (Table 2,Figure 1d) and not in the group of non-responders. Physicalhealth dimension (as one dimension of the QoL scale SF-36) changed from 34.0 (SD 4.5)at baseline to 34.1 (SD 11.2) at last follow-up for the group as a whole, thuspatient's physical health remained stable. On a descriptive level, responders hada better physical health at baseline and this difference was more pronounced at lastfollow-up. ‘Mental health' (the second QoL dimension of the SF-36)improved significantly from 19.4 (SD 4.5) at baseline to 29.99 (SD 11.2) at lastfollow-up for the sample as a whole. Thus, the group as a whole moved about 1 SD from‘much below average' (–3 SD) to ‘below average'(–2 SD). Descriptively, responders improved more than non-responders.
In addition to observed long-term changes, acute effects occurred frequently afterparameter change. Patients had acute improvements of depression, anxiety, andanhedonia lasting up to 2 weeks. These acute effects were not predictive for long-termoutcome. Only weak symptoms of hypomania (elevated mood, less hours of sleep) wereobserved in two patients after parameter change, which disappeared within 24 hand did not meet diagnostic criteria for hypomania.
Comprehensive neuropsychological assessment revealed no detrimental effects oncognitive function after 12 months in a paper byGrubertetal (2011) on 10 patients of our current sample. In the contrary,cognitive performance significantly improved in tests of attention, learning andmemory, executive functions, and visual perception during first year of follow-up. Inaddition, there was a general trend toward cognitive improvement from below average toaverage performance (Grubertet al, 2011).These effects were independent of the antidepressant effects of NAcc-DBS or changes inNAcc-DBS parameters (see for details). Analysis of the assessment at last observation(24 to 36 months) confirmed no changes in cognition from baseline except for nonverbalfluency, which was significantly improved at last follow-up (seeTable 3 for an overview on tests and statistical analysis).
Table 3. Neuropsychological Assessment of Cognitive Changes at Baseline and at LastObservation.
| Cognitive domain/test | Mean | N | SD | Paired samplest-test | T-value | df | p-Value | |
|---|---|---|---|---|---|---|---|---|
| Mean change | SD change | |||||||
| Verbal learning and memory | ||||||||
| VLMT total learning | ||||||||
| Baseline | 40.3 | 10 | 12.28 | −1.20 | 15.67 | −0.24 | 9.00 | 0.81 |
| Last observation | 41.50 | 10 | 14.88 | |||||
| VLMT delayed recall | ||||||||
| Baseline | 7.40 | 10 | 2.76 | −0.40 | 4.17 | −0.30 | 9.00 | 0.77 |
| Last observation | 7.80 | 10 | 3.43 | |||||
| VLMT recognition | ||||||||
| Baseline | 12.10 | 10 | 2.13 | −0.50 | 1.96 | −0.81 | 9.00 | 0.44 |
| Last observation | 12.60 | 10 | 2.17 | |||||
| General cognitive functions | ||||||||
| MMSE | ||||||||
| Baseline | 28.73 | 11 | 1.68 | 0.09 | 2.02 | 0.15 | 10.00 | 0.88 |
| Last observation | 28.64 | 11 | 1.43 | |||||
| Language | ||||||||
| HAWIE lexis test | ||||||||
| Baseline | 18.78 | 9 | 4.32 | −0.11 | 3.10 | −0.11 | 8.00 | 0.92 |
| Last observation | 18.89 | 9 | 3.55 | |||||
| HAWIE finding similarities | ||||||||
| Baseline | 22.67 | 9 | 5.00 | −1.22 | 3.19 | −1.15 | 8.00 | 0.28 |
| Last observation | 23.89 | 9 | 4.04 | |||||
| Working memory | ||||||||
| Wechsler digit span | ||||||||
| Baseline | 13.09 | 11 | 2.95 | −0.18 | 2.79 | −0.22 | 10.00 | 0.83 |
| Last observation | 13.27 | 11 | 4.76 | |||||
| Wechsler visual memory span | ||||||||
| Baseline | 13.45 | 11 | 3.50 | 1.18 | 3.25 | 1.21 | 10.00 | 0.26 |
| Last observation | 12.27 | 11 | 5.62 | |||||
| Executive function | ||||||||
| TMT A (s) | ||||||||
| Baseline | 52.73 | 11 | 29.12 | −3.91 | 14.23 | −0.91 | 10.00 | 0.38 |
| Last observation | 56.64 | 11 | 32.87 | |||||
| TMT B (s) | ||||||||
| Baseline | 134.64 | 11 | 87.49 | −30.82 | 49.90 | −2.05 | 10.00 | 0.07 |
| Last observation | 165.45 | 11 | 113.31 | |||||
| STROOP interference (s) | ||||||||
| Baseline | 302.57 | 7 | 70.23 | −7.43 | 29.07 | −0.68 | 6.00 | 0.52 |
| Last observation | 310.00 | 7 | 76.16 | |||||
| Five-point test | ||||||||
| Baseline | 20.20 | 10 | 10.84 | −5.80 | 5.45 | −3.36 | 9.00 | 0.01 |
| Last observation | 26.00 | 10 | 10.75 | |||||
| Visual spatial learning and memory | ||||||||
| RVDLT total learning | ||||||||
| Baseline | 27.20 | 10 | 9.05 | −5.50 | 10.50 | −1.66 | 9.00 | 0.13 |
| Last observation | 32.70 | 10 | 14.62 | |||||
| RVDLT delayed recall | ||||||||
| Baseline | 6.10 | 10 | 2.92 | −0.50 | 2.22 | −0.71 | 9.00 | 0.50 |
| Last observation | 6.60 | 10 | 3.34 | |||||
| RVDLT recognition | ||||||||
| Baseline | 24.89 | 9 | 2.03 | 1.00 | 2.92 | 1.03 | 8.00 | 0.33 |
| Last observation | 23.89 | 9 | 4.01 | |||||
| Visual perception | ||||||||
| VOT | ||||||||
| Baseline | 18.00 | 8 | 4.99 | −1.75 | 2.62 | −1.89 | 7.00 | 0.10 |
| Last observation | 19.75 | 8 | 5.00 | |||||
| Attention | ||||||||
| D2 total minus errors | ||||||||
| Baseline | 280.44 | 9 | 124.47 | −5.44 | 51.57 | −0.32 | 8.00 | 0.76 |
| Last observation | 285.89 | 9 | 97.84 | |||||
Abbreviations: HAWIE, Hamburg Wechsler Intelligence Test for adults; MMSE,Mini-Mental Status Examination; RVDLT, Rey Visual Design Learning Test; TMT, TrailMaking Test; VLMT, Verbal Learning and Memory Test; VOT, Hooper Visual OrganizationTest.
Mean, number of patients in analysis, SD, two-tailed pairedt-tests withscores at baseline and at last observation (24 to 36 months) within each test asdependent variable. Percentile rank (PR) at baseline and last follow-up comparingour data with published normative data.
Stimulation Parameters
Stimulation parameters varied between patients. Most patients were stimulated between 5and 8 V, at 90 μs, 130 Hz, monopolar. Individual best settingswere analyzed and parameters only changed (mostly raise in amplitude or change ofcontacts) when side effects occurred or when the antidepressant response was notsatisfying. In three patients, wider pulse widths or higher frequencies led to anincrease in tension and restlessness. Small differences could be found on averagebetween responders and non-responders: non-responders experienced parameter changes morefrequently and later during follow-up (responders had only minor parameter adjustmentafter 13 months, whereas non-responders had parameter changes on average at 17 months).Responders were stimulated little less than non-responders (responders:6.8 V/90 PW/130 rate, non-responders: 7.1 V/100 PW/135.5rate on average). After approximately 6 months, most patients had all four contactsactivated negative against the case.
Adverse Events and Dropouts
Adverse events were either related to the surgical procedure (eg, swollen eye,dysphagia, pain), directly to parameter change (eg, erythema, subjective transientincrease in anxiety or tension, sweating, within minutes to few hours) (seeTable 4) or unrelated to the DBS treatment (eg, gastritis, legfracture, herniated disc). Most importantly, all side effects related to the DBStreatment were transient or could be stopped immediately by means of parameter change,so that patients did not suffer any permanent adverse effects.
Table 4. Adverse Events.
| Adverse events | Related to surgical procedure | Related to parameter change | Unrelated to DBS |
|---|---|---|---|
| Seizure | 1 | ||
| lead dislodgment | 1 | ||
| Dysphagia | 3 | ||
| Pain | 4 | ||
| Swollen eye | 6 | ||
| Psychotic symptoms | 1 | ||
| Muscle cramps | 1 | ||
| Vision/eye movement disorder | 1 | ||
| Headache | 1 | ||
| Paresthesia | 2 | ||
| Transient mood elevation | 2 | ||
| Agitation | 3 | ||
| Disequilibrium | 3 | ||
| Erythema | 4 | ||
| Transient increase in anxiety (subjective) | 4 | ||
| Increased sweating | 4 | ||
| Suicide attempt | 1 | ||
| Suicide | 1 | ||
| Dyskinesia | 1 | ||
| Syncope | 1 | ||
| Herniated disc | 1 | ||
| Aneurysm in groin | 1 | ||
| Reduced pulmonary function | 1 | ||
| Cataract surgery | 1 | ||
| Breast cancer | 1 | ||
| Leg fracture | 2 | ||
| Aconuresis | 2 | ||
| Gastritis | 5 |
Number of patients experiencing adverse events related to the surgical procedure,to parameter changer or judged to be unrelated to DBS.
One patient attempted suicide and one patient committed suicide during 12 monthsfollow-up. These patients were non-responders to DBS.
One patient had the device explanted after 2 years because of breast cancer andassociated infection after chemotherapy. Two patients have been followed under 24months; five patients have been tracked for 4 years. In order to prevent overestimationof clinical effect, all patients (n=11) contributed in anintent-to-treat analysis to all points in time.
DISCUSSION
This study demonstrated sustained antidepressant effects over 2 years of NAcc-DBS in 11patients suffering from severe TRD. Some patients were followed up to 4 years (lastobservation).
Effect of NAcc-DBS on TRD
Response rates
About 45% of patients responded significantly (reduction in HDRS⩾50% in all studies) during the first 6 months of NAcc-DBS and reached theresponse threshold after 12 months of stimulation at the latest (for a detaileddescription of response during first year of follow-up seeBewernicket al (2010)). This response rate was similar tostudies on other stimulation targets after 24 months, namely Cg25 (Kennedyet al, 2011;Lozanoet al, 2008) and ventral striatum (Malone,2010;Maloneet al, 2009)(Cg25: response rate 45% after 24 months, 55% at lastfollow-up; ventral striatum: response rate 53.3%) and 12 months (ventralstriatum: response rate 53 after 12 months, 71% at last follow-up, ranging from14 to 67 months).
Comparing time courses of response in DBS studies with courses in TAU studies usingpharmacotherapy, psychotherapy, or ECT, DBS-induced changes seem to require more timethan effects induced by conventional treatment methods; first antidepressant effectscould be observed after first months, however, the establishment of stableamelioration required up to 6 months, which might be at least partly explained by theneed to adapt stimulation parameters for treatment optimization.
Typical 24 months response rates in TAU studies for TRD (mostly pharmacotherapy) arearound 19% (Dunneret al, 2006).Response rates of DBS in the present small sample as well as in other studies onCg25 (Kennedyet al, 2011) andALIC seem to be substantially higher, keeping in mind that the selected patients wereper inclusion criteria non-responders to conventional treatments.
Stability of antidepressant effect
After about 8–12 months of treatment, patient's response status neverchanged, thus response remained stable during second year and up to 4 years.Responders had a sustained reduction in depressive and anxiety. Clinically equallyimportant, the significant anti-anhedonic effect measured as number of positiveactivities remained also stable in responders during follow-up. This stabilization inpsychopathological measures was also reflected in social functioning. QoL (mentalhealth) changed from ‘far below average' to ‘slightly belowaverage', whereas the patient's physical health score did not change. Ithas to be kept in mind that the main burden on the patient is depression itselfcausing reduced QoL. Nonetheless, patients started to work part-time, took care oftheir personal matters, resumed new hobbies, one patient developed the desire to havea child, and so on. In this small group of patients, these anecdotal changes were moreconvincing than any QoL measure could possibly point out.
It has to be kept in mind that no conventional treatment method (pharmacotherapy,psychotherapy, and ECT) lead to significant amelioration of any of these patientsbefore and the majority of patients had not been in remission since first diagnosis.This long-term antidepressant effect is especially remarkable as in conventionalantidepressant treatment approaches relapse is the rule. Relapse rates are up to90% for third episode patients (Rushet al,2006). The more treatment steps a patient requires, the higher will be therelapse rate (Rushet al, 2006). In thepresent sample, all patients had by definition numerous treatment steps and several ordecades lasting episodes. After conventional treatments, most patients relapse withinthe first 6 months (Kellneret al, 2006;Rushet al, 2006). Studies on treatment asusual, assessing long-term effect beyond 1 year are rare in depression research. Inthis study, none of the responders suffered an aggravation in depression in 2 to 4years.
Thus, DBS seems to be a promising therapy option for TRD so far, offering persistentantidepressant effects over many years.
Non-responders
More parameter settings were tried in the group of non-responders compared with theresponders. Unfortunately, only short time or minimal long-term (from 5 to 45%response) antidepressant effects could be achieved in these patients. Increasingexperience with NAcc-DBS allow more effective parameter search procedures and largerpatient samples will make it possible to evaluate predictors of response. Although,antidepressant effects were small in the group of non-responders, only one patienteven considered removing the DBS system but chose to remain stimulated. It isdebatable, if non-responders to one target might be implanted to another targetcurrently under research (eg, Cg25, medial forebrain bundle, and habenula).Non-responders did not differ from responders in depression score at baseline or indemographic characteristics, but more men were classified as non-responders comparedwith women.
Cognition
It has been demonstrated at two target sites that DBS does not have negative effectson cognition (Grubertet al, 2011;McNeelyet al, 2008). To the contrary, wedemonstrated cognitive improvements in 10 patients treated with NAcc-DBS, which werenot explained by the improvement in depression severity and could be shown independentof response status (Grubertet al, 2011).Analysis of last observation (24 to 36 months) compared with baseline performance havedemonstrated no negative and in the domain of nonverbal fluency even an ameliorationof function. Larger samples will further investigate possible procognitive effects inseveral cognitive domains.
Side effects and adverse events
Side effects occurred rarely directly after parameter change (minutes to few hours)and could be counteracted by small adjustments of stimulation settings. Adverse eventswere related to the surgery or not related to DBS as assessed by the investigator. Onepatient committed suicide and one patient attempted suicide during first year. It hasto be taken into account that severe depression is associated with a 4–5 timeselevated risk for suicide compared with moderate or mild depression (Hardy, 2009). Given the high risk of suicide (approximately15% in TRD) (Isometsaet al, 1994;Wulsinet al, 1999) and compared with thesuicide rate found in DBS to Cg25 (10%) (Kennedyet al, 2011), in our sample, the one tragic suicide of apatient (suicide rate in our sample 9%) still remains below statisticalexpectation. Therefore, and because the suicide was judged not to be related to thesimulation (Bewernicket al, 2010), DBS astreatment option for TRD should not be abandoned because of risk of suicide, but closepatient tracking is necessary as well as close collaboration with additional healthcare providers (local psychiatrist, psychotherapy, and professional socialsupport).
Given robust antidepressant effects and minimal side effects, patients were verycompliant to DBS-related duties (battery recharge, regular visits).
Parameters
It was important to carefully determine individual best parameters. This requiredfrequent visits during first months. Acute effects at the beginning of treatment werenot predictable for long-term outcome. Stable clinical effects after parameter changeoccurred within 2 to 4 weeks, thus it is generally not indicated to change parametersmore frequently. Depending on stimulation parameters, patients daily recharge thebattery for up to 2 h (n=5 patients) or need to have a batteryreplacement about once every 15 months (n=6).
Limitations
All DBS studies so for are reporting on a relatively small number of patients, thusresponse ratios between 40 and 60% (Kennedyet al,2011;Lozanoet al, 2008;Maloneet al, 2009;Maybergetal, 2005) are limited in interpretation. Especially in long-termstudies, dropouts, and patients who have not yet completed the whole observation periodrequire special care in statistical analysis. Obviously, larger sample sizes are neededto convincingly ascertain clinical efficacy.
At study initiation, first patients entered a blinded sham stimulation phase. Owing tosymptom aggravation and delayed recurrence as well as weaker antidepressant effect, thedesign was changed leaving out the sham condition. These problems have been reportedalso byHoltzheimeret al (2012) during asingle-blind discontinuation phase in therapy-resistant depression and byDenyset al (2010) in patients suffering fromobsessive-compulsive disorder. This is a strong limitation in respect to placeboeffects. Although this study was not sham controlled, none of our patients was able toguess immediately whether the stimulator is on or off. Incidental interruption ofstimulation (for reason of battery depletion or programming error), always led to anaggravation of symptoms after several days to weeks (for a discussion of placebo-effectsin TRD, seeBewernicket al, 2010). In furtherstudies it has to be planned thoroughly how a sham condition can be included in thedesign, possibly as a lead-in sham condition. A discontinuation criterion (eg, suicidalideation, increase in depression score to 70% of baseline score) has to bedetermined prior.
Stimulation amplitudes were higher than in DBS for the treatment of neurologicaldiseases. This applies to all targets under research so far (Cg25, ALIC, andNAcc). This requires regular battery recharge (2 h per day) or battery exchange(every 8–15 months) and means an additional burden for the patient. As all targetsare interconnected in the neuronal network for mood regulation (Krishnan and Nestler, 2010;Nestler and Carlezon,2006), it is questionable, if the optimal target has been found. Actually,the medial forebrain bundle is under debate as a new target possibly reducing electriccurrent (Coenenet al, 2011).
Conclusion/outlook
DBS to the NAcc has demonstrated sustained antidepressant effects over up to 4 years ina small sample. Anxiolytic effects and amelioration of social functioning were observedat this stimulation site. A favorable side-effect profile contributed to very goodcompliance and adherence. Nonetheless, surgical risk and the possible aggravation ofdepression or other psychiatric side-effects (especially suicidality) require a veryexperienced team of experts; neurosurgeons specialized in stereotactic surgery,psychiatrist experts in the treatment of depression, psychologist to assess severity ofdepression and cognitive effects. In addition, a central registry for DBS shouldguarantee that positive and negative results as well as information from smallfeasibility and single case studies are brought to notice to the scientific community(Synofziket al, 2011). Taken into accountsmall sample size in all DBS studies in depression, larger studies have to be initiatedbefore DBS can be seen as treatment option in less severe TRD.
Acknowledgments
We thank patients and their relatives for participating in this study.
This investigator-initiated study was supported in part (DBS device, battery exchange andlimited support for study nurse) by a grant of Medtronic to Drs Schlaepfer and Dr Sturm aremembers of a project group, ‘Deep Brain Stimulation in Psychiatry: Guidance forResponsible Research and Application,' funded by the Volkswagen Foundation (Hanover,Germany). The remaining authors declare no conflict of interest. The sponsor had noinfluence on design and conduct of the study; collection, management, analysis, andinterpretation of the data; and preparation, review, or approval of the manuscript. Thecorresponding author had full access to all of the data in the study and takesresponsibility for the integrity of the data and the accuracy of the data analysis.
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