A Pilot Study to Examine Deep Brain Stimulation (DBS) in the Basolateral Nucleus (BLn) of the Amygdala for the Management of Symptoms in Veterans With Chronic and Treatment-Refractory Combat-related Post-Traumatic Stress Disorder (PTSD)
试验速览
- 阶段
- 不适用
- 状态
- 撤回
- 试验地点
- 2
- 主要终点
- The Clinician-Administered PTSD scale (CAPS) will be the primary outcome measure. A clinical response will be defined as a reduction of 30 % in CAPSSx from baseline to 12 months post-stimulation, without adverse events leading to stopping stimulation.
研究概览
简要总结
The purpose of this study is to determine whether deep brain stimulation of the basolateral nucleus (BLn) of the amygdala, on both sides of the brain, can safely reduce symptoms of post-traumatic stress disorder (PTSD) in combat veterans whose condition has not improved despite extensive treatment with currently available medication and psychotherapy interventions.
详细描述
For this pilot feasibility study, combat veterans whose PTSD has been associated with severe symptomatic suffering and functional impairment, despite treatment with all currently available pharmacological and psychotherapeutic treatments, will be recruited from clinics at a large, academically affiliated VA facility. An extensive screening over an extended baseline by the study psychiatrist and neurosurgeon will be conducted using standard interviews and clinical rating scales. Eligible subjects are required to have a cohabiting significant other willing to participate in safety and function monitoring throughout the study.
After successful completion of baseline eligibility requirements, comprehensive neuropsychological testing will be performed, as will structural MRI and FDG PET/CT of the amygdala, insula and medial Prefrontal cortex. PET/CT will be performed and analyzed by a nuclear medicine specialist collaborator familiar with this type of imaging research. Six consenting subjects meeting all eligibility criteria will then receive bilateral basolateral nucleus of the amygdala (BlnA) implantation of Medtronic Activa Primary Cell (PC) implantable deep brain stimulator systems (purchased through the VA Merit Review Grant) by functional neurosurgeons specialized in the procedure. This will be done during a 3-4 day inpatient stay on the VA Greater Los Angeles Neurosurgical Service. After a month of weekly safety monitoring with stimulators off, subjects will be will be hospitalized for 1 day on the Neurology Service's electroencephalography (EEG) telemetry unit, under the care and supervision of an epilepsy specialist neurologist who is a co-investigator in the study, for stimulator initiation. Stimulator settings will be adjusted by the study clinical neurophysiologist while patients are monitored by the study neurologist and psychiatrist. Only stimulator settings that do not cause epileptiform discharges, or potentially significant adverse psychiatric or medical (e.g., blood pressure, heart rate) changes will be used over the subsequent long-term follow-up.
After the EEG telemetry safety check, subjects will be randomized (3/3) to either have their stimulators turned on then (Week 0), or 3 months later (week 12). This staggered onset double-blind design has been used in other DBS trials in psychiatry. After week 0, for the next 2 years, subjects will be followed at regular intervals (weekly for 5 months, then monthly for 7 months, then quarterly for 12 months) by a psychiatrist, neurosurgeon, neurologist and neurophysiologist who will conduct an extensive battery of psychiatric and neurological testing (including periodic EEG recordings), as well as significant other interviews, while stimulator settings are adjusted based on standardized rating scale outcomes and adverse effects so as to optimize treatment outcome. The principal study hypothesis is that the symptomatic and functional benefits of chronic stimulation will outweigh the risks and adverse-effects, and that symptomatic improvement will be greater, without unacceptable adverse effects, in subjects with week 0, compared to week 12 stimulator initiation. Neuropsychological testing will be repeated after 6 months of stimulation to assess changes in cognitive function. Functional neuroimaging with PET/CT will be repeated after a year of stimulation to assess changes in the activity of brain regions known to function abnormally in PTSD.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 25 Years 至 65 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Male aged 25-65 years.
- •Able to give informed consent in accordance with institutional policies and participate in the 2-year follow-up, involving assessments and stimulator adjustments.
- •Patients must be stable on their current psychotropic medication for a period of 2 months before implantation and agree to not increase dosages or add any new medications for the first 6 months of the study, unless medically necessary.
- •Chart diagnosis of chronic and treatment-refractory PTSD as the principal psychiatric diagnosis and cause of distress and social/occupational impairment.
- •Confirmation of PTSD as the primary psychiatric diagnosis by the study psychiatrist via clinical interview and CAPS.
- •Confirmation of combat trauma exposure via military record review and a Combat Exposure Scale score >
- •Minimum 5 year total illness duration, with no 6 month period of clinical remission during the 5 years prior to entry in the study.
- •Clinical record documentation of non-response to at least 2 of the following antidepressants, alone or in combination, at maximally tolerated FDA recommended doses for ≥ 6 months: sertraline, paroxetine, fluoxetine, citalopram, escitalopram, amitriptyline, imipramine, nortriptyline, desipramine, clomipramine, phenelzine, tranylcypromine, venlafaxine, mirtazapine. Antidepressant trials must include at least one SSRI and one SNRI or TCA at maximally tolerated FDA recommended doses for a minimum of 3 months.
- •A minimum 3 month trial of prazosin at 10 mg per day or, if less, maximally tolerated FDA recommended doses, unless considered contraindicated based on co-morbid medical conditions or concomitant medications.
- •Trial of at least 3 months of one of the following: lithium, divalproex sodium, carbamazepine, lamotrigine, olanzapine, risperidone, bupropion either alone or in conjunction with one or more of the agents in #8 and # 9 above.
- •6 months of continuous individual psychotherapy, conducted at least twice monthly for minimum 45 minute sessions, and consisting of a) clinician-defined cognitive-behavioural psychotherapy directed toward reducing conditioned fear symptoms of PTSD; b) cognitive processing psychotherapy for PTSD; c) prolonged exposure therapy for PTSD (imaginal, in vivo, and/or virtual reality); or d) Eye movement desensitization and reprocessing therapy for PTSD including a trauma exposure component, with chart documentation of inadequate benefit despite concerted effort. Other forms of individual or group psychotherapy are permitted but not required for inclusion. (Patients who are unable to complete 6 months of psychotherapy may be included if the cause of treatment cessation was that the risks of further treatment, including intense psychological suffering, outweighed the potential benefits of continuing the treatment).
- •All evidence based psychotherapy for PTSD (cognitive behavioural, cognitive processing, prolonged exposure, eye movement desensitization) has been completed a minimum of 3 months prior to enrollment.
- •Minimum baseline CAPS17 of 85 at entry, with a) scores of at least 4 (combined frequency and severity) on at least one symptom from each cluster (intrusion, avoidance and hyperarousal); b) score of 5 or more on CAPS17 items 4 or 5 (intense psychological distress or physiological reactivity on exposure to a reminder of the traumatic event); and c) no questionable validity (QV) rating greater than 1 on any CAPS item.
- •Clinically significant impairment in occupational functioning due to PTSD, manifested by one or more of the following: a) Total federal (service connected ≥ 70%), or State (SSI) disability compensation for at least the past 2 years for PTSD; b) global assessment of functioning score ≤ 45; c) no period of full time gainful employment ≥ 3 months in the past 5 years.
- •Clinically significant impairment in social functioning due to PTSD, manifested by one or more of the following: a) little or no social activity outside the household other than as necessary for medical appointments, practical matters such as grocery shopping, or to interact with other veterans; b) reliable description by a spouse or significant other, living with the patient, of repeated avoidance/refusal to participate in customary social engagements with friends, family or for recreational activities due to PTSD; c) two or more verbal or physical interpersonal altercations within the past year requiring another person's intervention to prevent further escalation, or involving law enforcement
- •Cohabitation with a spouse or significant other adult person who a) can confirm the symptoms and impairment from PTSD and lack of significant symptomatic remission in the past 5 years; and b) is willing to participate with the study psychiatrist in answering questions for the life functioning in PTSD scale (LFIPS) at scheduled follow-up visits; and c) is willing to report unexpected adverse neurological or psychiatric events to study investigators and if advised by study investigators, assist the patient in accessing necessary services to address these.
- •Willingness to have unexpected neurological or psychiatric symptom shared with the study psychiatrists and other study clinicians.
- •Other medical conditions must be stable for at least 1 year, (conditions that require intermittent use of steroids or chemotherapy are excluded).
排除标准
- •Suicide attempt in the last 2 years and/or presence of a suicide plan (an answer of "Yes" to Question C4 in Section C-Suicidality of MINI International Neuropsychiatric Interview);
- •Psychosis or bipolar disorder; significant acute or ongoing risk for violence;
- •Patients primarily diagnosed with DSM-IV-TR Axis I disorder other than PTSD as determined by the MINI;
- •Within the 3 months prior to enrollment, subject has started a new psychotherapy program;
- •Alcohol or illicit substance use disorder within the last 6 months, unstable remission of substance abuse, or chart evidence that co-morbid substance use disorder could account for lack of treatment response;
- •Current significant neurological conditions, including epilepsy, stroke, movement disorder; history of serious head injury with loss of consciousness
- •Uncontrolled medical condition including cardiovascular problems and diabetes;
- •Uncontrolled chronic pain;
- •Baseline Montgomery Asberg Depression Rating Scale (MADRS) of ≥ 28;
- •Use of warfarin;
- •Significant abnormality on preoperative structural brain MRI;
- •ECT in the past 6 months;
- •Contraindications to MRIs or the need for recurrent body MRIs;
- •Immunosuppression;
- •High risk for surgery;
- •Current pursuit of new or increased disability compensation for PTSD;
- •Has cardiac pacemaker/defibrillator, implanted medication pump, intra-cardiac lines, any intracranial implants (aneurysm clip, shunt, cochlear implant, electrodes) or other implanted stimulator;
- •Patient has had past cranial neurosurgery;
- •Patient unable to discontinue therapeutic diathermy;
- •Use of other investigational drugs or psychotropic herbs within 30 days of baseline.
结局指标
主要结局
The Clinician-Administered PTSD scale (CAPS) will be the primary outcome measure. A clinical response will be defined as a reduction of 30 % in CAPSSx from baseline to 12 months post-stimulation, without adverse events leading to stopping stimulation.
时间窗: 12 months
This is a standardized structured, clinician administered interview that includes both questions confirming the diagnosis of PTSD (CAPSDx) as well as symptom severity over specified time periods (lifetime, past week or past month) based on the 17 symptoms of PTSD in DSM-III/II-R and IV across clusters of recurrence, avoidance/numbing and hyper-arousal symptoms (CAPS1-17 or CAPSSx).
次要结局
- The Clinician-Administered PTSD scale (CAPS) change from week 0(12 months)
- Hamilton Anxiety Rating Scale (HAM-A) change from week 0(24 months)
- Montgomery Asberg Depression Rating Scale (MADRS) change from week 0(24 months)
- Young Mania Rating Scale (YMRS) change from week 0(24 months)
- Columbia-Suicide Severity Rating Scale (C-SSRS) change from week 0(24 months)
- Clinical Global Impression and Improvement Scales (CGI-S and CGI-I) change from week 0(10 months)
- Veterans Quality of Life Assessment Scale (SF-36v) change from week 0(24 months)
- Davidson Trauma Scale (DTS) change from week 0(24 months)
- Global Assessment of Functioning Scale (GAF) change from week 0(24 months)
- Wechsler Adult Intelligence Scale III (WAIS-III)-Digit Span Subtest change from baseline(24 months)
- Controlled Oral Word Association Test (COWAT) change from baseline(24 months)
- Ruff Figural Fluency Test (RFFT) change from baseline(24 months)
- Hopkins Verbal Learning Test - Revised (HVLT-R) change from baseline(24 months)
- Brief Visual Memory Test - Revised (BVMT-R) change from baseline(24 months)
- Boston Naming Test (BNT) change from baseline(24 months)
- Hooper Visual Organization Test (VOT) change from baseline(24 months)
- Rey-Osterrieth Complex Figure (CFT) change from baseline(24 months)
- Clock Drawing Test change from baseline(24 months)
- Wisconsin Card Sorting Test (WCST) change from baseline(24 months)
- Stroop Color and Word Test (STROOP) change from baseline(24 months)
- Iowa Gambling Task (IGT) change from baseline(24 months)
- Mini Mental State Exam (MMSE) change from baseline(24 months)
- Change in PET CT 18-fluorodeoxyglucose metabolism from baseline(15 months)