Combined prolonged exposure plus paroxetine was superior to prolonged exposure plus placebo in reducing the symptoms of PTSD related to the World Trade Center attacks over 10 weeks of treatment. This finding offers the strongest evidence to date that combining trauma-focused CBT with medication may be a more efficacious initial treatment strategy than CBT alone for PTSD. Both primary outcome measures (CAPS and remission rate) and secondary measures (response rate and quality of life) demonstrated significant advantages for combined treatment. Based on remission rates for each group at week 10, the number needed to treat is three (i.e. three patients would need to be treated with combined treatment to yield one additional remission during initial CBT treatment). Given the evidence supporting trauma-focused CBT as a treatment of choice for PTSD, the findings here advance the field by demonstrating that a combined treatment approach can further improve acute response. More study will be needed, however, to determine if these benefits persist.
The advantage of combined medication and CBT in the initial treatment of PTSD may reflect additive mechanisms. Prolonged exposure is believed to act through learning, including basic processes of extinction of conditioned responses and re-appraisal of cognitive schemas linked to the trauma (33
). Paroxetine decreases presynaptic reuptake of serotonin, which may lead to stabilization of CNS circuits mediating hyperarousal and activation of memories by conditioned aversive stimuli.
A specific contribution of prolonged exposure to response in the combined therapy group is suggested by the prolonged exposure + placebo group's clinically meaningful within-group effect size on the CAPS (Cohen's d
=1.12). This is within the range reported for exposure therapy for PTSD in prior trials, although larger effects have been reported at some expert sites (34
). Without a group controlling for nonspecific effects of prolonged exposure, this study cannot determine the contribution of techniques specific to prolonged exposure to response in either group.
Outcomes for the prolonged exposure plus placebo group in this study could have been influenced by factors related to study design and implementation. This study limited prolonged exposure to the 10-week course established in prior trials, but a longer course continuing through weeks 10–22 might have produced greater improvement. Both treatments in this study appear to have been adequately implemented and tolerated, based on assessment of therapy tapes, paroxetine doses, and attrition rates of 36.8% for combined treatment and 27.8% for prolonged exposure plus placebo, which are comparable to the 30.3% and 20.5% rates reported across all PTSD randomized trials of SSRI and exposure therapy, respectively (35
). Features of study treatments that may have contributed to attrition include the confrontation of traumatic memories in prolonged exposure therapy and adverse effects of medication. This is the first report of efficacy for the controlled release form of paroxetine for PTSD, which yields slower release of paroxetine and thus slightly more stable plasma levels than the immediate release form that has established efficacy for PTSD (22
Features of the sample may also have affected outcome. Characteristics of persons with PTSD, such as avoidance behavior and loss of trust may tend to increase attrition. Although most subjects reported inadequate response to some prior treatment, which might suggest treatment-resistance, few had received an adequate trial of an evidence-based treatment. Features specific to the WTC attacks also might have affected outcomes. The violence was both intentional and catastrophic, which tends to increase severity of PTSD (37
). Ongoing stressors related to high rates of personal loss, additional terrorist threats following 9/11, and the downward spiral of consequences of chronic illness (job loss, family conflict, divorce) could have reduced treatment-responsiveness. Good prognostic factors, however, include relatively high educational status, and the fact that the index trauma was a single event in adulthood, which generally has better treatment outcome than severe childhood trauma or the multiple traumatic exposures typical of combat- or abuse-related PTSD. Thus, on balance, we do not believe this sample can be characterized as treatment-resistant or uniquely distinct from other traumatized populations in respect to treatment responsiveness. Generalizability of these findings, however, will need to be tested in other PTSD samples.
The sample was also distinguished by openness to trying both medication and CBT treatments, as was required by the study design. Persons with PTSD have been shown to have strong treatment preferences, especially favoring non-medication treatments (40
). Participants may have been less compliant with their less-favored treatment than participants entering studies of a single treatment modality. Future studies of combined treatment should assess treatment preferences and their impact on outcome.
Over the 12 weeks after PE was discontinued and patients were maintained on double-blind paroxetine or placebo, no group differences were observed. Interpretation is subject to important limitations: The diminished sample size in this phase limited power to detect smaller effects, and patients who entered this phase were not a random selection, which may have further obscured treatment differences. Future studies with larger samples will need to address the important question of whether the initial advantage of combined treatment persists over time.
The primary limitation of this study is its relatively small sample. The full sample of 37 patients, however, represents the largest randomized clinical trial to date in persons with World Trade Center-related PTSD. The findings here of superiority for combined treatment diverge somewhat from those of the one PTSD study that failed to find an advantage for paroxetine over placebo augmentation for non-remitters to 8 weeks of prolonged exposure treatment (16
). Design differences in that study included a smaller randomized sample (N=23), randomization of only those patients who remained symptomatic after a course of prolonged exposure, and continued provision of PE during placebo-controlled augmentation, which could have obscured any drug-specific effects. Nevertheless, the paroxetine group in that study had more than double the remission rate of the placebo group (33% vs. 14%), though the effect was not statistically significant in the small sample. A methodological advantage shared by these studies is the incorporation of pill placebo as a control. None of the PTSD studies that have reported superiority of CBT augmentation of SSRIs over SSRI treatment alone incorporated any form of “placebo” therapy to control for nonspecific effects of CBT, such as therapist attention.
The study findings support clinical consideration of combined paroxetine and prolonged exposure treatment at the outset for patients with PTSD, due to superior efficacy for the initial treatment of PTSD symptoms. These advantages must be weighed against potential disadvantages of the greater cost of combined treatments, the risk of adverse effects of medication, and the risk that eventual discontinuation of medication might be associated with risk of relapse, as has been shown after discontinuation of SSRI monotherapy (41
). Future studies should assess moderators of response to combined treatments and monotherapy, with the goal of developing clinically useful predictors of treatment selection. The finding of medication effects also underscores the importance of assessing the impact of concurrent medication use in any studies assessing psychosocial treatments of PTSD.
On September 11, 2001 Mr. J, a 35-year-old, married man with two daughters, was working for a financial company at the World Trade Center. After the planes hit, he was evacuated from his building and eventually made his way to safety. He had no prior psychiatric history, and Mr. J remembers thinking immediately after the event that he would be fine if he just resumed working and went back to his usual optimistic coping style. As time went by, however, he noticed that he had intrusive memories of 9/11, was emotionally disconnected from his family, had trouble getting to work in downtown Manhattan, and was increasingly avoidant of trains and airports. By the time he presented for treatment, he had lost his job and his marriage, had become distant from his kids and reported feeling “panicky, anxious, and for the first time in my life, hopeless.”
Mr. J enrolled in the study, feeling it was his last chance, and he threw himself into the prolonged exposure treatment with a deliberate seriousness. During imaginal exposure exercises he described his 9/11 experience with great affect: “I watched over and over as people jumped off the tower. I can still clearly see them; hear their bodies hitting the ground.” After evacuating from his building, he remained by the towers as others ran away, waiting for his close friend Peter to emerge. Suddenly the tower collapsed and Mr. J was overtaken by a choking cloud of white debris: “I put my newspaper around my face and dove under a car for cover. I was thinking, `You're going to die,' and then I thought, `Oh no, I can't die like this, I have a 3-month-old who needs me,' and then I lost consciousness.” The next thing he remembered was a cop, pulling him out by his feet, and yelling, “This one's still alive.” Others around him were dead, and he recalled seeing hundreds of women's shoes that must have been abandoned in the streets as they fled. When he finally got home that night, he cleaned up and went to Peter's house. “It was full of people crying and praying. Peter's wife was crying and asked me if Peter made it out. I lied and told her he was probably in a hospital, but after what I saw, I knew he was dead.” During the first imaginal exposure session Mr. J was intensely distressed (Subjective Units of Distress Score=100), but his distress decreased with each retelling. Between sessions he conscientiously completed his behavioral exposure exercises to confront his multiple avoidances. Afterwards, he explained, “I'm a straightforward sort of person and I liked this therapy because it was straightforward. You explained everything, and told me exactly what to do. I did it and I got a lot better.” Mr. J also took study medication daily (he had been randomized to active paroxetine), which he tolerated without significant side effects. After ten weeks of combined treatment Mr. J was significantly improved, with minimal anxiety or avoidance symptoms: “I'm back to my old self. I can connect to my kids, planes don't scare me anymore, and I was even able to visit the memorial stone for Peter for the first time. I'm feeling optimistic again, and I think I can work in Manhattan without freaking out.”