Escitalopram in the prevention of posttraumatic stress disorder: a pilot randomized controlled trial

This was a prospective, randomized, double-blind placebo controlled trial of escitalopram in the prevention of PTSD symptoms in traumatized adults with full or partial ASD.

31 participants who met the following criteria were included in the study: (i) experience of a traumatic event, such as a vehicle collision or other accident, physical or sexual assault within the previous 4 weeks; (ii) between 18 and 65 years of age; (iii) sufficient knowledge of English in order to read, understand and sign the Informed Consent form as well as study procedures and assessment instruments; (iv) presence of either full DSM-IV criteria or intrusion and hyper-arousal criteria for ASD. Two participants (one from each treatment group) were excluded prior to the first post-baseline assessment and analysis as they were not contactable. The sample thus comprised of 12 participants on escitalopram and 17 on placebo (Figure 1).

Exclusion criteria comprised (i) refusal of any medication therapy; (ii) serious physical injury at inclusion (an Abbreviated Injury Scale (AIS) score of 3 or more); (iii) concomitant medications not allowed in the study (monoamine oxidase inhibitors [MAOIs], reversible inhibitors of monoamine oxidase A [RIMAs], mood stabilisers, antipsychotics or psychoactive herbal remedies within the 3 weeks prior to screening, anxiolytics or serotonergic agonists within the 2 weeks prior to screening, treatment with any anticonvulsant drug); lifetime DSM-IV-TR criteria for mania or bipolar disorder, schizophrenia, any personality disorder, mental retardation or pervasive developmental disorder, or cognitive disorder; significant suicide risk and/or a score of ≥5 on item 10 of the Montgomery Asberg Depression Rating Scale (MADRS) scale; history of severe suicide attempt; electroconvulsive therapy within the last year; currently serving in the South African security forces.; history of drug allergy or hypersensitivity to escitalopram or citalopram; illness severe enough to prevent participation in the study (including liver or renal insufficiency; cardiovascular, pulmonary, gastrointestinal, endocrine (including uncontrolled thyroid), neurological (including epilepsy), infectious, neoplastic, or metabolic disturbances; pregnant or breast-feeding; refusal of adequate contraceptive use (if female).

Approval for the study was obtained from the University of Cape Town, Faculty of Health Sciences Human Research Ethics Committee (HREC ref: 221/2006), as well as from hospitals and clinics where recruitment took place. The study was conducted in accordance with the Declaration of Helsinki, and informed consent was obtained from all participants.

Eligible participants were recruited from University of Cape Town (UCT) affiliated hospitals (Groote Schuur, G F Jooste, Gugulethu Day Hospital, Vanguard Community Health Clinic) and were randomly allocated to one of the two treatment groups (active or placebo) according to a computer-generated randomization list. Randomization numbers were assigned consecutively. Escitalopram (10 mg) and placebo were supplied as capsules of identical appearance. Medication was supplied in wallet cards that were dispensed at each visit. Wallet cards were identified by visit (i.e., visit 2, visit 3, etc.) with the escitalopram and placebo packed by the study pharmacist in sequentially numbered identical blister packs. Participants and investigators were blinded to treatment allocation and there were no instances of un-blinding.

Enrolled participants were dispensed wallet cards at each visit after visit 2 (baseline/ week 0) and instructed to take one capsule of 10 mg escitalopram, or placebo, which was titrated up to 20 mg per day at week 4, orally. A decrease in dose, back to one capsule of 10 mg, or placebo, was permitted for intolerable side effects. Participants were instructed to return the blister pack and all unused medication at their next visit. Investigators noted whether or not the pack was returned and if any medication remained in the participant’s file. Participants were also asked whether they had been compliant since the previous visit. Noncompliance resulted in that participant being withdrawn from the study.

Assessments were conducted every 2 weeks until visit 8 (week 12) and thereafter every 4 weeks. At each assessment, rating scales were administered and concomitant medication use and adverse events noted.

-The essential features of ASD, and whether full or partial, were recorded according to DSM-IV criteria.

-Demographics details: sex, age, number of years of education, and, socioeconomic status.

-Trauma characteristics: type of event, event characteristics (evaluated by the PTSD Diagnostic Scale (PDS) [21].

-Physical condition: evaluated using the Abbreviated Injury Scale (AIS) [22].

-The following psychiatric rating scales were also used:

Primary measure:

Clinician Administered PTSD Scale (CAPS):

The CAPS [23] consists of 17 items that cover the core symptoms of PTSD according to the DSM-IV criteria. Eight additional items are included to measure the frequency and intensity of features frequently associated with PTSD. In addition, the CAPS includes five global rating scales that reflect the impact of symptoms on social and occupational functioning, general severity, any recent changes in severity, and the assessor’s evaluation of the validity of the participant’s report.

For each of the 17 items, the interviewer rates each of the frequency and the intensity of the symptoms on a 5 point scale rated from 0–4. A total score (ranges between 0–272) is calculated by summing the frequency and intensity scores for each item. A score of ≥50 indicates PTSD. The CAPS can also be scored according to the DSM diagnostic criteria for PTSD, rendering a dichotomous rating of the presence or absence of PTSD.

Secondary measures:

Clinical Global Impression Scales (CGI):

The CGI scales [24] consist of two separate scales: Clinical Global Impression – Severity (CGI-S) and Clinical Global Impression – Improvement (CGI-I). Both scales are rated from 1–7. The investigator uses his/her total clinical experience with this patient population to judge symptom severity at the time of rating (CGI-S). At follow-up overall improvement is rated (CGI-I).

Mini International Neuropsychiatric Interview (MINI 5.0.0):

The MINI [25] is a brief, structured diagnostic interview for clinical and research settings. It has a total of 120 questions that cover 17 current and past DSM-IV Axis I disorders.

Montgomery-Asberg Depression Rating Scale (MADRS):

The MADRS [26] is a depression rating scale consisting of 10 items that represent the core symptoms of depressive illness. The rating is based on a clinical interview with the participant, moving from broadly phrased questions about symptoms to more detailed ones, which allows a precise rating of severity, covering the last 7 days. The clinician who conducts the rating must decide whether the rating lies on the defined scale steps (0, 2, 4, 6) or between them (1, 3, 5), on a scale ranging from 0–60.

Visual Analogue Scale for Depression (VAS-D):

The VAS-D [27] is a self-rating scale, designed to assess depression severity, from a subjective point of view. The responder is required to indicate how depressed s/he is, on a scale ranging from 0–10.

Visual Analogue Scale for Anxiety (VAS-A):

The VAS-A [27] is a self-rating scale, designed to assess anxiety, from a subjective point of view. The responder is required to indicate how anxious s/he feels, on a scale ranging from 0–10.

Sheehan Disability Scale (SDS):

The SDS [28] is a 3-item self-rating scale of functional impairment. The items address the impact of symptoms of PTSD on three areas of functioning, namely, work, social, and family within the last 7 days.

Data were captured for all visits where PTSD was assessed with the CAPS (weeks 0, 4, 12, 24, 32, 40, 48 and 56/ visits 2, 4, 8, 11, 13, 15, 17, 19). Demographic and baseline data were compared using chi-square/Fisher’s exact tests or analysis of variance (ANOVA). Assessment of PTSD prevention was based on the CAPS total score. The mean change from baseline (visit 2/week 0) to the week 24 endpoint on the CAPS was used as the primary outcome measure. Using an intent-to-treat sample, defined as all participants with at least one post-baseline CAPS assessment, efficacy for escitalopram vs. placebo was tested using a mixed model repeated measures analysis of variance (RMANOVA). The mixed model approach allows for patients with incomplete data to be included and utilizes the data that is available for all patients. Generalised Estimating Equation (GEE) models were used for categorical outcomes. Rates of PTSD were determined by the cut off of 50 points on the CAPS. Maintenance efficacy was determined by the change in CAPS scores between weeks 24 and 56. Improvement on secondary outcome measures were also evaluated. CGI-responders were defined as those with CGI-I scores of 2 (much improved) or 1 (very much improved) at week 24. All tests were two-tailed with p-values <0.05 considered significant. Frequencies of the most common adverse events are tabled and reported if present in more than one subject in either of the study groups.