Treatment of Citalopram for Anxiety Disorders Following a Traumatic Brain Injury

Anxiety occurs commonly after traumatic brain injury and may influence cognitive,
behavioral, and somatic presentations that may interfere with patients' recovery and
adaptation to life after brain injury. TBI involves both diffuse brain injury as well as
frequent focal injuries to frontal and temporal structures, including hippocampus and
amygdala, areas that are also implicated in the neurobiology of anxiety. Although there are
anecdotal reports of the benefits of SRIs in the treatment of anxiety in association with
TBI, there are unfortunately no controlled trials to establish SRI efficacy in patients
whose anxiety is considered secondary to brain injury.

A randomized placebo controlled clinical trial design will be used to investigate the
effectiveness of citalopram in patients with anxiety disorder due to a general medical
condition, specifically traumatic brain injury (TBI). Beneficiaries who are between 3 and 24
months post injury and who meet criteria for DSM-IV diagnosis of anxiety disorder due to TBI
will be recruited from the 7 DVBIC VA and Military Medical Centers. Participants will be
randomized to receive an increasing dose of citalopram or placebo up to a dose of 40 mg of
citalopram or 4 pills of placebo over a 12-week treatment period. Patients will receive
comprehensive multidisciplinary evaluations at a DVBIC site, including neurology,
neuropsychology and psychiatry interviews and evaluations at baseline, 12 weeks and 12
months.

Participants will sign informed consent prior to the administration of research tests and
scales. An informational script is read to individuals seen within the protocol timeframe.
This script will provide a necessary standardization for the presentation of the protocol to
potential participants. It also specifies the research coordinator as the individual to
present the protocol, rather than a primary clinical care provider. After the script is
read, the individual will be given the informed consent to review.

Patients will not be eligible to participate/consent to participate in the study until they
reach a Rancho Los Amigos level of 7 or 8. If there is any question as to a patient's
capacity to consent, the neuropsychologist and/or psychiatrist involved in the study will
assess the subject's intellectual and mental faculties prior to consent. Any confusional
state prohibits a subjects from being rated as a 7 or 8. Additionally, in our experience,
most patients are not able to undergo a full evaluation in the Walter Reed DVBIC program
until they reach this level of recovery. Therefore, we anticipate that almost all patients
evaluated in our program will have the capacity to give informed consent.

After signing the volunteer informed consent, the tests and scales will be administered and
patients will be randomized to receive a 12-week course of citalopram or placebo. Female
participants of childbearing potential will be given a serum pregnancy test (up to 1
tablespoon) prior to being randomized to the study medication. If the result of this test is
positive, she will not be allowed to participate in this study. The study physician will
discuss alternative treatment options.

Patients will receive an increasing dose of citalopram or placebo up to a dose of 40 mg of
citalopram or 4 pills of placebo. See Table 2 for dosing schedule. A blood sample (up to 1
tablespoon) drawn after completion of the 12-week treatment period will be used to obtain
citalopram levels as a measure of medication compliance. A two-week taper will follow the
treatment period. Patients will receive comprehensive multidisciplinary evaluations at a
DVBIC site, including neuropsychological and psychiatric interviews and evaluations at
baseline, 12 weeks and 12 months.

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 (citalopram vs. placebo) is appropriate. Patients are commonly
referred to the DVBIC with mild-moderate mood and anxiety symptoms. We have cared for
several clinically anxious patients who refused medications. We worked with them in a
supportive educational framework, and in some cases, their anxiety remitted. Thus, the best
treatment for these patients is far from established. It is likely that this and other
future research will help clarify which treatments are best for which patients.

All patients will be contacted weekly (in person or by phone) during the medication phase to
assess general condition, current symptoms and compliance. Female participants will also be
asked if there is a possibility that she may be pregnant. If there is a chance, she will be
discontinued from the study medication and asked to return to the clinic for a serum
pregnancy test. If the result of this test is positive, she will be followed by the study
staff for the remainder of the study. If the result of this test is negative, she will be
re-started on the study medication at 1 pill or 10 mg of citalopram or placebo per day.

Patients will be rated for improvement at weeks 3, 6, and 9 for possible dosage adjustment.
The determination of medication adjustment will be made based upon scores on the Clinical
Global Improvement Scale given to the participant at these time points (see Table 2). Dosage
adjustment will be considered if the clinician rates the patient as a score of 3 or higher
on this scale (Minimally Improved to Very Much Worse). However, the CGI Efficacy Index for
drug effect will determine the direction of dosage adjustment. A side effect that is rated
as significantly interfering with patient functioning or outweighing therapeutic effect will
result in one or more of the following courses of action: (1) addition of concomitant
medication, (2) decrease in the study agent dose, (3) discontinuation of the study agent. In
other words, a patient who is scored as 3 or higher on the CGI Global Improvement Scale who
does not have significant side effects on the CGI Efficacy Index will have the study agent
dose increased. Any patient who experiences significant side effects at any time during the
treatment period will be considered for dose decrease, discontinuation or concomitant
medication use. A decision regarding the proper course of action will be dependent on the
severity of the side effect, overall therapeutic effect and patient input.

Patients will return to the study center at the end of the 12-week treatment period for the
follow-up evaluation. After the 12-week evaluations, patients will be tapered off citalopram
or placebo within 2 weeks. Tapering and discontinuation of the study medication or placebo
will be done on a gradual basis (e.g., If the patient is on 30 mg, s/he could take 20 mg for
1 week, 10 mg for one week, then D/C). If, following the 12-week participation in the
treatment protocol and the 1-2 week taper period, subjects have recurrent symptoms that are
distressing to them or believe they need medication to keep their symptoms from recurring
they will be evaluated clinically.

Once participants complete the 12- week treatment period, they will be tapered off the study
agent. After the taper has been completed, they may be treated with any therapy or
pharmacological intervention that their physician feels is clinically indicated. Although we
will be collecting data for one year after participants complete the treatment phase, our
primary outcome measures will be collected at the end of the 12th week of the treatment
period. We will record all concomitant medications used during the study and all medications
being used at the follow-ups for data analysis.

Following the 12-week treatment period and taper, patients may be offered appropriate
treatment, including citalopram, if medically indicated. All treatment drugs will be
recorded. The blind will not yet be broken, that is, patients will not be able to learn if
they were being treated with placebo or citalopram.

Inclusion Criteria:

- Traumatic brain injury patients between 3 and 24 months post injury.

- Clear evidence/documentation of brain injury:

i. documented/witnessed loss of consciousness, post traumatic amnesia ii. alteration
in mental status (dazed/confused), and/or physical evidence of iii. trauma (MRI/CT
hemorrhage/contusion)

- Traumatic brain injury with recovery to a Rancho los Amigos level 7 or 8 (alert and
oriented).

- Meet criteria for DSM IV diagnosis Anxiety Disorder Due to a General Medical
Condition.

- The symptoms of the anxiety disorder are not being controlled adequately with or
without treatment at the time of referral.

- Military or Veteran beneficiary

- Men and non-pregnant/non-breastfeeding females

- Aged 18-65

Exclusion Criteria:

- Severe prior neurologic or psychiatric illness (based on DSM-IV criteria), such as
stroke or psychosis. (Previous non-psychotic depression/anxiety is not an exclusion
criterion)

- Current/prior unstable medical condition that could affect current brain function
(ex. clear anoxic episode, cardiac arrest, current uncontrolled diabetes)

- Contraindication to the use of citalopram.

- Concomitant use of monoamine oxidase inhibitors (MAOIs), cimetidine, lithium,
theophylline, digoxin, sumatriptan, warfarin, carbamazepine, triazolam, ketoconazole,
CYP3A4 and 2C19 inhibitors, and metoprolol.

- Hypersensitivity to citalopram or any of the inactive ingredients in Celexa®

- Previous severe traumatic brain injury (defined as TBI with period of unconsciousness
greater than 1 week. This exclusion refers only to TBIs prior to the current injury.

- Pregnancy (blood test required for females)

- Breastfeeding

- Current active suicidal ideation

- Inability to discontinue other psychotropic medications, such as tricyclic
antidepressants or another SRI

- Current drug/alcohol abuse or dependence

- Previous unsuccessful trial of citalopram

- Participation in a concurrent drug or treatment trial