A Pilot Study of Deep Brain Stimulation of the Amygdala f... | NCT01658748

ID	Type	Description	Link
1/01RX001112-01	Other Grant/Funding Number	Department of Veterans Affairs
PCC-2012	Other Identifier	VA Greater Los Angeles Healthcare System

Name	Class
VA Greater Los Angeles Healthcare System	FED

Description Module

Detailed Description

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.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Week 0 Medtronic 3387 electrodes/Activa PC amygdala DBS	Active Comparator	Patients randomized to this arm will have stimulators turned on approximately 1 week after the 3-4 week post-surgery EEG telemetry session that determines safety parameters for stimulator settings. Subjects will be followed weekly for the next 12 weeks, with adjustments in stimulator settings according to prescribed protocol based on changes in rating scale scores (CAPS, CGI-I, ADIPS, LFIPS, HAMA, MADRS, YMRS).	Device: Week 0 Medtronic 3387 electrodes/Activa PC amygdala DBS Device: Week 12 Medtronic 3387 electrodes/Activa PC amygdala DBS
Week 12 Medtronic 3387 electrodes/Activa PC amygdala DBS	Sham Comparator	Patients randomized to this arm will undergo the same procedures and same visit frequency as those in the week 0 stimulation arm, except that the actual stimulation settings will be kept at 0 V, 0 Hz, and the patient, study psychiatrist who does the ratings, and study neurosurgeon who does neurological clinical assessments will be blind to whether the subject is receiving actual or sham stimulation. Only the study neurophysiologist will know whether the patient is in the active or sham stimulation arm during these 12 weeks. After week 12, subjects in this week will begin to receive active stimulation according to pre-specified protocol.	Device: Week 12 Medtronic 3387 electrodes/Activa PC amygdala DBS

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Week 0 Medtronic 3387 electrodes/Activa PC amygdala DBS	Device	Subjects undergo the placement of a Leksell (Elekta, Atlanta, GE) stereotactic frame. Electrode trajectory planned using stereotactic software (BrainLab, Germany). Traditional trans-frontal trajectory used to implant Medtronic #3387 DBS electrodes bilaterally in the BLn. A curvilinear incision will be made 3 cm lateral to midline and 1 cm in front of the coronal suture. A burr hole will be placed with a high-speed drill for placement of a Stimloc device to hold the electrode in place. The dura will be opened, coagulated back and the cortex exposed, coagulated, and pierced. The electrode will be introduced using a cannula. Each electrode contact will be stimulated up to 7 V to confirm the absence of immediate side effects; first left, then right. Electrode wires will be tunneled under skin to upper chest and connected to Medtronic Activa PC dual channel pulse generator. Both groups keep stimulators off until week 0, then this group has stimulators turned on.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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.	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).	12 months

Secondary Outcomes

Measure	Description	Time Frame
The Clinician-Administered PTSD scale (CAPS) change from week 0	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).

Other Outcomes

Measure	Description	Time Frame
Life Function in PTSD Scale (LFIPS) change from week 0	The LFIPS was developed specifically for this study as the current literature does not contain any standardized instruments that assess patient functioning from the perspective of a significant other. It consists of several operationalized measures in each of six domains: Family Life, Marriage, Leisure, Children, Social Interactions, and Work/Productivity. Each question is rated on a scale of 1-5 with 5=Excellent and 1=Terrible. Total scores range from 18-80 with a lower score indicative of poor life functioning.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

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 > 9.
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).

Exclusion Criteria:

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.

Name	Affiliation	Role
Ralph J Koek, MD	VA Greater Los Angeles	Principal Investigator
Jean-Philippe Langevin, MD	Southern Arizona VA Healthcare System AND VA Greater Los Angeles	Principal Investigator

PubMed Identifier	Type	Citation	Retractions
22826810	Background	Langevin JP. The amygdala as a target for behavior surgery. Surg Neurol Int. 2012;3(Suppl 1):S40-6. doi: 10.4103/2152-7806.91609. Epub 2012 Jan 14.
20537659	Background	Langevin JP, De Salles AA, Kosoyan HP, Krahl SE. Deep brain stimulation of the amygdala alleviates post-traumatic stress disorder symptoms in a rat model. J Psychiatr Res. 2010 Dec;44(16):1241-5. doi: 10.1016/j.jpsychires.2010.04.022. Epub 2010 May 26.

ID	Term
D013313	Stress Disorders, Post-Traumatic
D003130	Combat Disorders
D012917	Social Adjustment

ID	Term
D040921	Stress Disorders, Traumatic
D000068099	Trauma and Stressor Related Disorders
D001523	Mental Disorders
D012919	Social Behavior
D001519	Behavior