A Pilot Study of Deep Brain Stimulation of the Amygdala for Treatment-Refractory Combat Post-Traumatic Stress Disorder

NCT01658748 | Withdrawn DMC

• 3 other identifiers: N1112-I1/01RX001112-01PCC-2012
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Post Traumatic Stress Disorder

Keywords

Pilot Study; Longitudinal Study; Amygdaloid Body; Insula of Reil; Cortex, prefrontal; Stimulation, Deep Brain; Chronic Post Traumatic Stress Disorder; Combat Stress Disorder; Social Adjustments; Positron-Emission Tomography, Computed Tomography

Outcome Measures

Primary Outcomes (1)

• 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 (142)

• The Clinician-Administered PTSD scale (CAPS) change from week 0

  1 month

• The Clinician-Administered PTSD scale (CAPS) change from week 0

  2months

• The Clinician-Administered PTSD scale (CAPS) change from week 0

  3 months

• The Clinician-Administered PTSD scale (CAPS) change from week 0

  4 months

• The Clinician-Administered PTSD scale (CAPS) change from week 0

  5 months

Other Outcomes (38)

• Life Function in PTSD Scale (LFIPS) change from week 0

  1 month

• Life Function in PTSD Scale (LFIPS) change from week 0

  2 months

• Life Function in PTSD Scale (LFIPS) change from week 0

  3 months

Study Arms (2)

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

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.

Also known as: Implanted Hardware (Medtronic, Minneapolis, MN), DBS electrodes 3387, Stimloc device to hold the electrode in place, Activa PC dual channel pulse generator

Week 0 Medtronic 3387 electrodes/Activa PC amygdala DBS

Week 12 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. This group has stimulators turned on at week 12.

Also known as: Implanted Hardware (Medtronic, Minneapolis, MN), DBS electrodes 3387, Stimloc device to hold the electrode in place, Activa PC dual channel pulse generator

Week 0 Medtronic 3387 electrodes/Activa PC amygdala DBS; Week 12 Medtronic 3387 electrodes/Activa PC amygdala DBS

Eligibility Criteria

• Age: 25 Years - 65 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• US Department of Veterans Affairs: lead
• VA Greater Los Angeles Healthcare System: collaborator

Study Sites (1)

VA Greater Los Angeles Healthcare System

Los Angeles, California, 90073, United States

Location

Related Publications (2)

• 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.

  PMID: 22826810 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.

  PMID: 20537659 BACKGROUND

MeSH Terms

Conditions

Stress Disorders, Post-Traumatic; Combat Disorders; Social Adjustment

Condition Hierarchy (Ancestors)

Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Mental Disorders; Social Behavior; Behavior

Study Officials

• 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

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 28, 2012
• First Posted: August 7, 2012
• Study Start: January 1, 2013
• Primary Completion: December 1, 2015
• Study Completion: December 1, 2015
• Last Updated: May 29, 2013

Record last verified: 2013-05

Locations

US (1)