Sertraline vs. Placebo for Symptoms Following Traumatic Brain Injury

The objectives of this protocol are the following:

1. To investigate the efficacy of sertraline, a selective serotonin reuptake inhibitor
(SSRI), in treating neurobehavioral sequelae of irritability, depression, frustration,
anxiety and other post-concussive symptoms following traumatic brain injury (TBI).

2. To explore possible relationships between anosmia (deficits in smell) and irritability/
aggression.

This study will test the hypotheses:

Sertraline is effective in treating Post TBI neurobehavioral symptoms of irritability,
depression, frustration, anxiety, and other elements of the postconcussive syndrome.

Patients who receive sertraline will have significantly less post-concussive symptoms at 12
weeks than patients who received placebo. Post-concussive symptoms will be measured by the
Gouvier Post-Concussive Syndrome Scale (PCSC) and the Affective Cluster score of the
Cicerone Post Concussive Scale.

Patients with anosmia will have greater irritability and aggressive symptoms than those
without anosmia.

. Subjects: One hundred people will take part in this study: approximately 50 subjects will
take sertraline and 50 will take placebo. These patients will be selected from referrals to
the Defense and Veterans Head Injury Program at WRAMC. Patients will be active duty or other
military beneficiaries, between 18 and 65 years of age. Males and non-pregnant females may
participate.

b. Inclusion and Exclusion Criteria:

1. Inclusion:

1. Traumatic brain injury patients within 6 months of injury.

2. Traumatic brain injury with:

Minimum severity - TBI with post traumatic amnesia. Maximum severity - recovery to
a Rancho los Amigos (see Appendix II) level 7 or 8 by six months after injury.

3. The C Criterion of DSM IV diagnosis of Post Concussive Disorder (PCD- Research
Criteria), with symptoms persisting for a minimum of 4 weeks.

4. Military beneficiary.

2. Exclusion criteria:

1. Severe prior neurologic or psychiatric illness, such as stroke or psychosis.
(Previous nonpsychotic depression is not an exclusion criterion)

2. Contraindication to the use of sertraline.

3. Previous severe traumatic brain injury (defined as TBI with period of
unconsciousness greater than 1 week prior. This exclusion refers only to TBI's
prior to the current injury, which is within the past 6 months).

4. Pregnancy

5. Current active suicidal ideation

c. Study Design: This study will be a prospective, double-blind, randomized 1:1 control
trial study with two groups: active drug and placebo. Block randomization will be used
so neither the patient nor the study physician will be able to guess the study drug
assignment.

d. Methodology: Patients will receive a multidisciplinary evaluation consisting of
neurology exam, neuropsychology, psychiatry, speech and language, psychosocial,
rehabilitation medicine (FIM/FAM), EEG, MRI, phlebotomy, and family interview. Blood
samples will be kept at the DVHIP labeled with the patient's study number for possible
future use in studies to better understand recovery from head injury. No studies would
be performed on the blood samples until the patients have signed an additional informed
consent with additional details on the blood studies planned. After signing the
volunteer informed consent for the current sertraline protocol, evoked potentials and
the smell test ( see Appendix III) will be administered and patients will be randomized
into an active drug or placebo group. Patients will receive an increasing dose of
sertraline or placebo up to a dose of 200 mg of sertraline. See Table I, Appendix I,
for dosing schedule. All patients will receive a two part counseling session regarding
brain injury and recovery from brain injury. The first session will cover the types of
symptoms that may be experienced after brain injury, the expected course of recovery,
and recommendations for symptom management. The second will begin with a brief
assessment of material retained from the first counseling session, and continue with
specific recommendations that match general principles to the patient's specific life
situation. A brief pre-test and post-test (see Appendix IV) on general TBI information
will be given with the first counseling session; a pre-test will be administered prior
to the second session. These tests will permit better understanding of how much
information patients have regarding TBI and how much is retained after a first
counseling session.

The medication phase will last 12 weeks. Patients will receive standard TBI care during
this period. Current standard of care for patients with moderate-severe TBI following a
full evaluation with medical/surgical treatment of any acute medical/surgical
conditions is approximately 8 weeks of Convalescent Leave Home (CVL) followed by a
gradual return to duty. Mild TBI patients typically receive 1-4 weeks of CVL followed
by a gradual return to duty. Civilians would have similar schedules for resumption of
activities. From current referral patterns, we expect most patients to have moderate
traumatic brain injuries. The DVHIP experience suggests that patients are virtually
never referred to DVHIP severely depressed and already on therapeutic levels of
antidepressants. More commonly, patients are referred with mild-moderate symptoms of
sleep difficulties, headache, irritability and/or depression. Because no randomized,
controlled trials exist to suggest that current medical treatment is effective in these
patients, and because a substantial placebo effect is a known reality, the design of
this study (randomization to sertraline or placebo) is appropriate. Also, we have cared
for a few patients who, although clinically depressed, refused medications. We worked
with them in a supportive educational framework, and in some cases, their depressions
remitted. Thus, the best treatment for these patients is far from established. It is
likely that future research will help clarify which treatments are best for which
patients. For this study, patients who may have been started on a tricyclic
antidepressant (e.g., for headache) or an SSRI will be withdrawn from these medications
for 10 days prior to the start of the study medication. Patients will be informed of
concomitant medication options if the test article (sertraline or placebo) is not
sufficient for treating their symptoms, or if they feel they need medication prior to
the start of the test article. All patients will be contacted weekly during the
medication phase to assess general condition, current symptoms, and assessment of
compliance. Patients will be rated for improvement at weeks 3, 6, and 9 for possible
medication adjustment. The determination of medication adjustment will be made by study
personnel at Walter Reed only. If patients require a clinical medical appointment
during the 12 weeks, patients will be seen at WRAMC if possible. If not possible, study
personnel will be available to speak with the patient's clinician at a local medical
facility. Patients will return to WRAMC at 12 weeks for a follow-up evaluation of their
symptoms, or they will be contacted by phone if unable to return to WRAMC for their 12
week evaluation. After the 12 week evaluation, patients will be tapered off sertraline
or placebo over 2 weeks. Tapering and discontinuation of the study medication or
placebo will be done on a gradual basis over the 2 weeks (e.g., If the patient is on
150 mg, s/he could take 100 mg for 1 week, 50 mg for one week, then D/C). If, following
the 12 week evaluation, subjects have recurrent symptoms which are distressing to them,
or believe they need medication to keep their symptoms from recurring, pharmacologic
and nonpharmacologic treatments will be discussed with them. Patients will be offered
appropriate treatment, including sertraline, if medically indicated. The blind will not
yet be broken, that is, patients will not be able to learn if they were being treated
with placebo or sertraline. Subjects will then be contacted by phone or seen at 3, 6,
9, and 12 months following their 12 week follow-up evaluation for an assessment of
their symptoms and general level of functioning. If patients are in the area, these
follow-up evaluation may be done in person.

Concomitant medications:

Patients with difficulty sleeping will be instructed in sleep hygiene, interviewed for
possible deterrents to sleep induction, and encouraged to permit the test medication
time to begin if depression is felt to contribute to the sleep disturbance. If
difficulty initiating or maintaining sleep persist, Ambien 5-10 mg po qd (a
non-serotoninergic hypnotic) will be offered. Benadryl 25-50 mg may also be considered
for sleep induction. If clinically indicated, other medication may be prescribed.

Patients with headaches will be counseled about precipitants in an attempt to maximize
non-pharmacologic management of headache. If pain persists, enteric-coated ASA will be
prescribed. For patients non-responsive to ASA (headache or other pain syndromes),
non-steroidal antiinflammatory medications will be permitted. For vascular headaches,
Midrin or sumatriptin may be used. If clinically indicated, other medication may be
prescribed.

If a patient has severe depression not responding to test article/placebo, and the
treating physician deems antidepressant medication necessary, a non-SSRI medication,
nortriptyline, will be used as the first line medication. Nortriptyline has been shown
effective in post stroke depression (18), and may be monitored by plasma levels, thus
being a good medication to combine with either placebo or sertraline. If nortriptyline
is not effective (or if nortriptyline is not appropriate for that particular patient),
the treating physician will chose whatever antidepressant is clinically indicated.
Appropriate clinical care of the patient is the first priority.

Pregnant women may not participate in this study. Women of childbearing age will take a
urine or blood pregnancy test before starting this study to confirm they are not
pregnant. As part of the informed consent, women are advised to avoid pregnancy for at
least 6 weeks after receiving the drug treatment and will be advised about reliable
methods of birth control. Breast-feeding women will also be excluded.

Inclusion Criteria:

- Traumatic brain injury patients within 6 months of injury.

- Traumatic brain injury with:

- Minimum severity - TBI with post traumatic amnesia.

- Maximum severity - recovery to a Rancho los Amigos (see Appendix II) level 7 or
8 by six months after injury.

- The C Criterion of DSM IV diagnosis of Post Concussive Disorder (PCD- Research
Criteria), with symptoms persisting for a minimum of 4 weeks.

- Military beneficiary.

Exclusion Criteria:

- Severe prior neurologic or psychiatric illness, such as stroke or psychosis.
(Previous nonpsychotic depression is not an exclusion criterion)

- Contraindication to the use of sertraline.

- Previous severe traumatic brain injury (defined as TBI with period of unconsciousness
greater than 1 week prior. This exclusion refers only to TBI's prior to the current
injury, which is within the past 6 months).

- Pregnancy

- Current active suicidal ideation