Clinical trial NCT04530942: The Efficacy and Prediction of Deep Brain Stimulation for Treatment-resistant Depression
Official title: The Efficacy and Prediction of Deep Brain Stimulation for Treatment-resistant Depression
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Major Depressive Disorder
Deep Brain Stimulation
Keywords: Treatment Resistant Depression
Deep Brain Stimulation
Ventral Capsule/Ventral Striatum
Lead sponsor: Ruijin Hospital
Sponsor class: OTHER
First posted: 2020-08-28
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: The study starts with a longitudinal open-label phase followed by a randomized, double blind crossover phase. In the crossover phase, patients are randomized to active DBS for 2 weeks, followed by sham DBS for 2 weeks, or vice versa. The patients' post-surgery duration need to be more than 6 months when they entered the randomized cross-over phase.
Primary purpose: TREATMENT

Brief summary: Several open-label trials have shown the therapeutic promise of deep brain stimulation (DBS) targeted to striatal and surrounding capsular areas in treatment-resistant depression (TRD). However, the results of placebo-controlled trials have been mixed, with one showing a large difference between active and sham DBS and another finding no difference.

Main aim of this study is establishing whether active DBS results in more treatment responders than sham DBS. Secondary aims are establishing an adverse events profile, establishing effects on quality of life,neuropsychological and neuroimaging measures, and finding predictors of response.

Detailed description: Major Depressive Disorder (MDD) is a highly prevalent psychiatric disorder, with an estimated lifetime prevalence of 14.6% across high-income countries.Effective therapeutic options for MDD include psychotherapy, different classes of antidepressants, and electroconvulsive therapy (ECT). Nevertheless, up to 30% of patients do not respond to four consecutive antidepressant strategies and 52% of pharmacotherapy resistant patients do not respond to ECT.Such patients are designated an advanced stage of Treatment Resistant Depression (TRD), which is associated with more hospitalizations, more suicide attempts, and higher costs than non-TRD patients.

Deep Brain Stimulation (DBS) is a promising therapeutic option for TRD patients. DBS consists of implanting electrodes in specific brain areas and then optimizing stimulation parameters (e.g. voltage, frequency, pulse width) to modulate brain activity of the targeted area. Since 2005, several open label trials have reported promising effects of DBS in TRD, targeting different brain structures involved in the neurobiology of MDD: the Subcallosal Cingulate Gyrus (SCG),Medial Forebrain Bundle (MFB),Ventral Capsule/Ventral Striatum (VC/VS), and Nucleus Accumbens (NAc). Response rates, defined as a symptom decrease of at least 50%, range from 30% to 90% with most studies finding a response rate around 50%.

However, results of the first two randomized trials are mixed. The first randomized, controlled trial (RCT) of VC/VS DBS in TRD did not find differences in response rates following active (3 of 14 patients) or sham stimulation (2 of 15 patients) after four months of stimulation. In contrast, another group found a strong antidepressant effect in 16 patients with TRD following active ventral Anterior Limb of the Internal Capsule (vALIC) DBS compared to sham stimulation in a randomized crossover phase.

Therefore, this trial aims to establishing whether active DBS results in more treatment responders than sham DBS. Secondary aims are establishing an adverse events profile, establishing effects on quality of life,neuropsychological and neuroimaging measures, and finding predictors of response.

Eligibility criteria: Inclusion Criteria:

* Primary diagnosis: Major Depressive Disorder according to the ICD-10 criteria based on a psychiatric interview
* Age: 18-65 years old
* HAMD-17 total ≥17
* Chronic illness with current episode ≥ 24 months duration and/or Illness with at least a total of 4 lifetime episodes (including current episode≥ 12 months) and a minimum of 5 years since the onset of the first depressive episode
* Treatment refractory defined as failure of: at least 3 adequate treatments from at least two distinctly different classes (SSRI, SNRI, NaSSA, TCA +, lithium-addition) for a period of 6-8 weeks or more weeks. Adequate psychotherapy. At least 1 session of ECT, for which the series of ECT was terminated either due to adverse effects or insufficient response (including at least 6 sessions of bilateral ECT); unavailable, rejective or intolerable to ECT
* remain stable with the current anti-depressive medicine for the last month
* Able and willing to give written informed consent
* Able to fully understand the consequences of the procedure

Exclusion Criteria:

* Schizophrenia /history of psychosis unrelated to MDD
* Severe personality disorder (assessed by SCID-II)
* Abnormal brain MRI
* Neurological disease (e.g., Parkinson's disease)
* Previous sterosurgery
* Any medical contraindication to surgery

Primary outcomes:
measure: the comparison between the Hamilton Depression Scale(HAMD-17) scores after active and sham phase
timeFrame: Baseline (preoperative),one month, 3 months, 6 months, 6.25 months, 6.5 months, 9 months, 12 months, 18months
Secondary outcomes:
measure: changes in the Montgomery-Asberg Depression Rating Scale(MADRS)
timeFrame: Baseline (preoperative),one month, 3 months, 6 months, 6.25 months, 6.5 months, 9 months, 12 months, 18months
measure: changes in the Quick Inventory of Depression Scale(QIDS-SR16)
timeFrame: Baseline (preoperative),one month, 3 months, 6 months, 6.25 months, 6.5 months, 9 months, 12 months, 18months
measure: changes in the Depression and Somatic Symptoms Scale(DSSS)
timeFrame: Baseline (preoperative),one month, 3 months, 6 months, 6.25 months, 6.5 months, 9 months, 12 months, 18months
measure: changes in the Dimensional Anhedonia Rating Scale(DARS)
timeFrame: Baseline (preoperative),one month, 3 months, 6 months, 6.25 months, 6.5 months, 9 months, 12 months, 18months
measure: changes in Hamilton Anxiety Scales(HAMA)
timeFrame: Baseline (preoperative),one month, 3 months, 6 months, 6.25 months, 6.5 months, 9 months, 12 months, 18months
measure: changes in World Health Organization Quality of Life-BREF(WHO-BREF)
timeFrame: Baseline (preoperative),one month, 3 months, 6 months, 6.25 months, 6.5 months, 9 months, 12 months, 18months
measure: changes in the MOS item short from health survey (SF-36)
timeFrame: Baseline (preoperative),one month, 3 months, 6 months, 6.25 months, 6.5 months, 9 months, 12 months, 18months
measure: changes in Sheehan Disability Scale
timeFrame: Baseline (preoperative),one month, 3 months, 6 months, 6.25 months, 6.5 months, 9 months, 12 months, 18months
measure: changes in Neuropsychological measures(Scores of Thinc-it tasks)
timeFrame: Baseline (preoperative), 6.25 months, 6.5 months, 18months
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Functional neurosurgery of Shanghai Jiaotong University affiliated Ruijin Hospital
Study officials:
affiliation: Ruijin Hospital
name: Bomin Sun, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dougherty DD, Rezai AR, Carpenter LL, Howland RH, Bhati MT, O'Reardon JP, Eskandar EN, Baltuch GH, Machado AD, Kondziolka D, Cusin C, Evans KC, Price LH, Jacobs K, Pandya M, Denko T, Tyrka AR, Brelje T, Deckersbach T, Kubu C, Malone DA Jr. A Randomized Sham-Controlled Trial of Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Chronic Treatment-Resistant Depression. Biol Psychiatry. 2015 Aug 15;78(4):240-8. doi: 10.1016/j.biopsych.2014.11.023. Epub 2014 Dec 13.
citation: Bergfeld IO, Mantione M, Hoogendoorn ML, Ruhe HG, Notten P, van Laarhoven J, Visser I, Figee M, de Kwaasteniet BP, Horst F, Schene AH, van den Munckhof P, Beute G, Schuurman R, Denys D. Deep Brain Stimulation of the Ventral Anterior Limb of the Internal Capsule for Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2016 May 1;73(5):456-64. doi: 10.1001/jamapsychiatry.2016.0152.
citation: Dandekar MP, Fenoy AJ, Carvalho AF, Soares JC, Quevedo J. Deep brain stimulation for treatment-resistant depression: an integrative review of preclinical and clinical findings and translational implications. Mol Psychiatry. 2018 May;23(5):1094-1112. doi: 10.1038/mp.2018.2. Epub 2018 Feb 27.