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

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 co-habiting
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 (eg 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.

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.