Post-traumatic stress disorder (PTSD) is a prevalent, and often disabling consequence of trauma exposure in children and adolescents (Breslau et al., 1991; Berman et al., 1996).
Empirical data, gleaned primarily from adult populations, reinforces the specific neurobiological basis of PTSD, its diagnostic validity, and responsiveness to both pharmacotherapeutic and psychotherapeutic strategies (van der Kolk, 1997). More recently, the role of serotonin in underlying the pathophysiology of PTSD, has been highlighted by a wealth of preclinical and clinical data (Connor and Davidson, 1998). Results of animal and clinical studies (paroxetine binding, pharmacologic challenge tests, and neuroimaging techniques) suggest that serotonergic agents, specifically, selective serotonin reuptake inhibitors (SSRIs) might be beneficial in ameliorating PTSD symptoms (Connor and Davidson, 1998). The safety and efficacy of SSRIs in treating both core and secondary PTSD symptoms has been borne out by several open and randomized-controlled trials in adults (Brady et al., 1995; Fichtner et al., 1997; Davidson et al., 1998; Marshall et al., 1998; Meek and Kablinger, 1998).
The few pharmacological studies in children with PTSD have reported benefits from clonidine patches (n = 7 children) (Harmon and Riggs, 1996), propranolol (n = 11 children) (Famularo et al., 1988), carbamazepine (n = 28 children) (Looff et al., 1995), and guanfacine (n = 1 child) (Horrigan, 1996). None of these studies utilized a control group. In addition, anecdotal evidence exists for using antidepressants (tricyclics and SSRIs) in children with PTSD characterized by prominent depressive or panic symptoms (Brent et al., 1995).
Despite the lack of open and controlled trials in children and adolescents, SSRIs have been recommended as first-line agents in clinical practice (Cohen et al., 1998). However, some authors recommend that their use in child and adolescent PTSD be reserved for comorbid or disabling symptoms (Marmar et al., 1994). Considering their favourable side-effect profile and broad therapeutic index, SSRIs offer specific advantages over tricyclic antidepressants in paediatric populations (Leonard et al., 1997).
To date, the most convincing evidence for the efficacy of SSRIs in paediatric samples is for the treatment of depression and obsessive-compulsive disorder (DeVane and Sallee, 1996). For other childhood anxiety disorders, additional research remains necessary (Allen et al., 1995).
In this preliminary study, we undertook to treat a sample of adolescents presenting with PTSD with the most selective of SSRIs, citalopram. Citalopram is a bicyclic phthalane derivative, with no effect on the uptake of noradrenaline, dopamine, or GABA. Moreover, neither citalopram, nor its metabolites have significant antidopaminergic, antiadrenergic, antiserotonergic, antihistaminergic, or anticholinergic properties (Milne and Goa, 1991). Our objective was to investigate: (1) the overall efficacy of citalopram in treating PTSD symptoms in adolescents and (2) its tolerability in this age group.
Adolescents aged 12-18 years meeting DSM-IV criteria for PTSD, as determined by the CAPS-CA (Clinician Administered Posttraumatic Stress Disorder Scale-Child and Adolescent version) (Nader et al., 1996) were entered into a treatment protocol approved by the ethics committee of the University of Stellenbosch Medical School, Cape Town, South Africa. Adolescents were recruited from the Bathuthuzele Clinic, an outpatient unit for adolescents exposed to traumatic experiences. Written informed consent for study inclusion was obtained from a parent or legal guardian. A criterion for entry into the study was a Clinical Global Impression (CGI) severity score of ≥ 4 (at least moderate severity PTSD).
The presence of comorbid mood and anxiety disorders was not an exclusion criterion, provided these disorders did not precede the PTSD diagnosis. Comorbidity was screened for with the K-SADS (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version) (Kaufman et al., 1997). K-SADS interviews were conducted by a clinical psychologist.
Adolescents who had been treated with SSRIs at therapeutic antidepressant doses for at least 4 weeks prior to study entry were excluded, as were adolescents meeting DSM-IV criteria for psychotic, bipolar, or mental disorders due to a general medical condition. Adolescents with a substance abuse/dependency diagnosis in the preceding 6 months, or an unstable medical condition, were also excluded. Prior to study entry, adolescents were kept medication-free for at least 2 weeks. Concomitant psychotropic medications and formal psychotherapies (excluding supportive psychotherapy) were contraindicated for the duration of the trial (Table 1).
The primary outcome variable was a mean change from baseline in PTSD symptoms, as assessed by the CAPS-CA. All CAPS-CA interviews were performed by the treating psychiatrist. The CAPS-CA was used both as a reference standard to establish PTSD caseness and treatment outcome. Modelled after the adult CAPS (Blake et al., 1990), the CAPS-CA provides scalar and categorical assessment of PTSD and PTSD-related psychopathology, such as hostility and school problems (Nader et al. (1996). The CAPS-CA measures 17 PTSD symptoms based on DSM-IV criteria. Symptoms are grouped into categories of: (1) re-experiencing symptoms (items 1-5, maximum score 40); (2) avoidance/numbing symptoms (items 6-12, maximum score 56); and (3) hyperarousal symptoms (items 13-17, maximum score 40). The CAPS-CA is considered useful in children aged 8 years through to adolescence. Besides establishing a current and/or lifetime diagnosis of PTSD; the scale measures overall severity of PTSD symptoms, frequency and severity of each symptom, and impact of symptoms on developmental, social, and scholastic functioning.
Secondary outcome measures of depression, and PTSD symptom severity and improvement, were assessed using the Zung Depression Self-Rating Scale, and Clinical Global Impression-Severity and Improvement Scales (CGI-S and CGI-I) (Guy, 1976). CGI-Improvement scores at endpoint distinguished responders from non-responders. A final CGI-I score of 1 or 2 (much or very much improved) defined 'response', while a final CGI-I score of ≥ 3 (minimally improved or worse) defined 'non-response'. Adolescents were assessed at 2 weekly intervals over 12 weeks of open treatment with citalopram. Citalopram was initiated at 20 mg, and this dose was fixed throughout the 12-week period. At every visit, the CAPS-CA (clinician-rated), Zung Depression Scale (patient-rated), and CGI (clinician-rated), were administered. Adverse events were documented at visits.
Description of sample
Eight adolescents entered the study, and seven completed 12 weeks of treatment. One subject was withdrawn at 2 weeks due to adverse events (nose bleeds). The mean age of subjects was 14.8 years (SD = 2.7), with a mean level of schooling of 8.75 years (SD = 2.4). There were seven girls and one boy, their racial composition being: mixed race (n = 4), Black (n = 2), White (n = 1) and Asian (n = 1). The majority presented with chronic PTSD, with mean duration of PTSD symptoms 16.5 months (SD = 16.4, range 2-48 months, median 14 months). Only two of the eight adolescents met criteria for 'acute PTSD' (duration of symptoms < 3 months). Four adolescents had a 'delayed onset' (symptoms ≥ 6 months after the traumatic event).
Traumatic events reported included: rape (n = 3), childhood sexual abuse (n = 3), physical abuse (n = 2), physical injury from a gunshot (n = 1), witnessing sudden death of a friend (n = 1), and witnessing domestic violence (n = 1) (Table 2). Six had directly experienced trauma, while two had been witnesses to trauma. Five of the eight adolescents had been victims of multiple traumas leading to the development of PTSD. Six of the eight met criteria for current major depressive episodes (which were mild in severity), while none met criteria for a past (lifetime) diagnosis. One adolescent had comorbid panic disorder (current) and separation anxiety disorder (past).
All seven subjects were responders to citalopram on the CGI-Improvement Scale at endpoint (week 12), with three completers much improved (CGI-I = 2), and four very much improved (CGI-I = 1).
Paired t-tests (n = 7 completers) demonstrated significant differences between baseline and endpoint CAPS scores for all three symptom clusters (Table 3). There was a mean reduction of 50 points (38%) in total CAPS scores between baseline and endpoint (Table 4 and Fig. 1). There was also a significant difference between baseline and endpoint CGI severity scores (t = 6.97, P = 0.0004). There was no significant difference between baseline and endpoint Zung depression scores.
Citalopram (20 mg) was well tolerated, and reported adverse effects were mild and self-remitting. Common adverse effects experienced were increased sweating (n = 3), nausea (n = 2), headache (n = 2), and tiredness (n = 2). One adolescent experienced akathisia (of moderate severity), which resolved without any intervention, 3 weeks into the trial.
The only adolescent who did not complete the trial was withdrawn at 2 weeks (at the request of his parents) after three episodes of nose bleeding (epistaxis) on day 10. He had one further episode 2 weeks after citalopram discontinuation. All four nose bleeds were mild, and did not require medical intervention. Physical examination at the time revealed no abnormalities. In retrospect, the nose bleeds did not appear to be related to the study drug.
Our findings suggest that citalopram may be an effective agent in adolescents with PTSD, as demonstrated by a 38% mean symptom reduction score between baseline and endpoint, as well as significant reduction in all three PTSD symptom cluster scores (intrusive, avoidance, hyperarousal) over 12 weeks. Both the magnitude of symptom reduction and the time-to-improvement, are in line with open trials of SSRIs in adults (van der Kolk et al., 1994; Hertzberg et al., 1998). Despite the low placebo response in a number of controlled trials of adult PTSD (5-10%); placebo response rate has tended to be higher in non-veteran samples. The small sample size of this trial, and absent placebo arm, are limiting factors. The findings of this study will need to be confirmed in larger-sample, controlled trials.
Six adolescents satisfied criteria for comorbid depression (MDD) at study entry. While five of the six no longer met criteria for MDD at study end; depressive symptoms as measured by the self-report Zung Scale (paired t-tests of means) did not improve. The latter finding may reflect a type II error in the context of a small sample size and low base-line scores. Comorbidity between PTSD and depression has been well documented in the literature (Goenjian et al., 1995; Hubbard et al., 1995), and it has been hypothesized that PTSD might precede and predispose to the onset of depression (Goenjian et al., 1995).
Citalopram was well tolerated overall. This is consistent with studies of citalopram in child and adolescent obsessive-compulsive disorder (Thomsen and Mikkelsen, 1995; Thomsen, 1997).
In conclusion, to our knowledge, this preliminary open trial of citalopram in eight adolescents is the first published trial of SSRI use in adolescent PTSD. The findings of this study appear to indicate that the beneficial effects of citalopram on PTSD symptoms might not necessarily be a function of its antidepressant effects.
Given the approved safety and tolerability of the SSRIs, and given the morbidity associated with PTSD, these findings hold promise for the treatment of this disorder in an adolescent population. Systematic, double-blind, placebo-controlled studies of SSRIs are required to establish their safety and efficacy in child and adolescent PTSD.
This work is supported by the MRC Unit on Anxiety and Stress Disorders and by a fellowship from the Lundbeck Psychiatric Institute.
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