Pharmacologic treatment of acute and chronic stress following trauma: 2006

Pharmacologic Treatment of
Acute and Chronic Stress Following Trauma: 2006
Jonathan R. T. Davidson, M.D.
This article reviews pharmacologic treatment options for posttraumatic stress disorder (PTSD), focusing on goals of pharmacotherapy and the clinical trial evidence for drug treatments available forPTSD. The selective serotonin reuptake inhibitors (SSRIs) are recommended as first-line therapy forPTSD; the roles of these and other drug classes including anticonvulsants, mood enhancers, atypicalantipsychotic agents, benzodiazepines, α -adrenergic antagonists, and provement in PTSD symptom and outcome scores, achieving remission, and avoiding relapse are dis-cussed. Treatment of PTSD in association with other comorbid conditions is addressed, and the roleof pharmacotherapy in treating early PTSD and acute stress disorder is examined. Dosing strategiesfor the SSRIs sertraline and paroxetine are provided, and an algorithm for PTSD pharmacotherapy isdiscussed.
(J Clin Psychiatry 2006;67[suppl 2]:34–39) osttraumatic stress disorder (PTSD) can be a severe, cial functioning; to strengthen resilience, or the ability chronic, and disabling condition with major con- to cope and thrive in adversity; to relieve comorbid sequences for the individual and society in terms of mor- disorders commonly associated with PTSD, including bidity, mortality, impact on economic productivity, and depression and panic disorder; and to prevent relapse.
health-care/welfare costs. Effective treatment is critical, While there is no single gold standard by which outcomes and it is fortunate that well-controlled, double-blind trials in PTSD treatment are measured, scales such as the over the past decade have demonstrated superiority of se- Davidson Trauma Scale,1 the Clinician-Administered lective serotonin reuptake inhibitor (SSRI) drugs over pla- PTSD Scale (CAPS),2 the Short PTSD Rating Interview cebo. It is reasonable to believe that the use of these, and (SPRINT),3 and the 8-item Treatment Outcome Posttrau- related compounds, can become an effective tool in pro- matic Stress Disorder Scale (TOP-8)4 provide measures moting the long-term psychological and psychosocial by which the changes achieved by pharmacotherapy can health, and economic recovery, of those in the region af- fected by the tsunami on December 26, 2004.
The SSRIs are currently recommended as first-line The objectives of medical treatment for PTSD are to therapy for the treatment of PTSD,5 and the SSRIs sertra- reduce its core symptoms (i.e., reexperiencing via intru- line and paroxetine are licensed for treatment of PTSD in sive thoughts, nightmares, and flashbacks; avoidance of the United States and elsewhere. Following recognition of trauma-related situations and activities; emotional numb- PTSD as a distinct clinical entity in the 1980s, efficacy ing; and hyperarousal); to improve function, including so- data from well-controlled, double-blind trials of pharma-cotherapy were initially slow to accumulate, but have be-come available more recently. SSRIs are effective acrossall PTSD symptom clusters and improve quality of life From the Department of Psychiatry and Behavioral and functional impairment, though sleep disturbances and Science, Duke University Medical Center, Durham, N.C. nightmares may respond less well in some cases.6,7 Presented at the symposium “After the Tsunami: Mental Health Challenges to the Community for Todayand Tomorrow,” which was held February 2–3, 2005, in Bangkok, Thailand, and supported by an educational grantfrom Pfizer Inc. Fluoxetine. Three randomized, double-blind, placebo-
Corresponding author and reprints: Jonathan R. T. controlled trials8–10 have confirmed a significantly higher Davidson, M.D., Department of Psychiatry and Behavioral response in patients with PTSD receiving fluoxetine ver- Science, Duke University Medical Center, Durham, NC 27710(e-mail: [email protected]). sus placebo for up to 3 months. In a 5-week study8 com- COPYRIGHT 2006 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2006 PHYSICIANS POSTGRADUATE PRESS, INC.
paring fluoxetine at up to 60 mg per day (N = 33) versus resilience-enhancing effect, as well as overall benefit in placebo (N = 31), fluoxetine significantly reduced overall PTSD: a significantly greater improvement in CD-RISC PTSD symptomatology assessed using CAPS-2 (p = .01).
scores was seen at endpoint for venlafaxine XR versus pla- Changes were most marked in the arousal and numbing symptom subcategories. A 12-week trial9 comparing flu-oxetine up to 60 mg per day (N = 27) versus placebo (N = 27) demonstrated that fluoxetine was more effective on most measures using the Duke Global Rating for Post-Traumatic Stress Disorder and the Structured Interview Early onset of action of SSRI therapy in PTSD was con- PTSD measure at week 12, including global improvement firmed by a study featuring mixed-models analysis of 2 (p < .06), with the effects of therapy evident using the twelve-week, placebo-controlled trials of sertraline treat- Duke scale as early as week 2. In a larger-scale, 12-week ment.17 Sertraline was found to markedly improve anger study10 comparing fluoxetine at 20 to 80 mg per day (N = by week 1, an effect that was sustained throughout the re- 226) and placebo (N = 75), fluoxetine was associated mainder of the treatment period and that largely explained with a greater improvement from baseline in TOP-8 scale the ensuing improvement on intrusive symptoms. Other total score versus placebo at week 12 (p = .006).
symptoms improved later, such as emotional upset at re- Paroxetine. A 12-week study11 comparing paroxetine
minders, anhedonia, and detachment at week 6 and avoid- (20–50 mg per day; N = 151) and placebo (N = 156) ance of trauma-related activities by week 10. While it is showed significantly greater improvement in CAPS-2 clear that onset of SSRI action may be rapid, and the ma- total score from baseline beginning at week 4 (p < .05 jority of SSRI efficacy trials in PTSD have been of 3 vs. placebo), with significantly greater proportions of months’ duration or less, short-term therapy is insufficient paroxetine-treated patients achieving a response (p < .001 for full recovery, and optimal results may not be seen until vs. placebo) and remission (p = .008) by week 12 on the Clinical Global Impressions-Improvement scale. In a sec- There is evidence that continuation of SSRI therapy ond 12-week study12 comparing paroxetine 20 mg per brings about sustained improvement in PTSD: in an day (N = 183), 40 mg per day (N = 182), and placebo open-label continuation phase of a 12-week acute study,18 (N = 186), paroxetine-treated patients in both dose groups patients treated with sertraline showed continued improve- demonstrated significantly greater improvement on the ment up to 9 months. The mean CAPS-2 score was re- CAPS-2 (p < .001). A pooled analysis of these trials plus a duced from 45 (representing mild PTSD) at 3 months to 20 third 12-week, placebo-controlled study of paroxetine (equivalent to minimal or no PTSD symptoms and high- confirmed that treatment resulted in significantly better response and remission rates, improvement in sleep dis-turbance, and a reduction in symptom clusters in PTSD Sertraline. A 12-week study14 with sertraline at 50
The noradrenergic and specific serotonergic antidepres- to 200 mg per day (N = 94) versus placebo (N = 93) sant mirtazapine was effective in treating PTSD in an showed that sertraline produced a significantly greater 8-week, placebo-controlled, double-blind pilot study (N = improvement from baseline at endpoint in CAPS-2 total 29) in which response rates on the Short Posttraumatic score (p = .02). In a second 12-week study15 with sertra- Stress Disorder Rating Interview Global Improvement line (50–200 mg per day; N = 100) or placebo (N = 108), measure were 60% for mirtazapine versus 22% for pla- Davidson et al. reported significantly greater benefit for cebo (p < .05).19 Mirtazapine also helps to alleviate sleep this drug, relative to placebo, on most measures.
disturbance in PTSD patients; its main disadvantages areside effects of weight gain and somnolence.
The SNRI venlafaxine XR has demonstrated efficacy in Treatment with fluoxetine and sertraline and with Mood stabilizers and anticonvulsants can also be useful the serotonin/norepinephrine reuptake inhibitor (SNRI) for treating PTSD symptoms. There is, however, a limited venlafaxine extended release (XR) has been shown to database regarding their efficacy and safety; most pub- improve resilience in PTSD patients. Open-label treat- lished studies are open label, and as these agents produce ment with fluoxetine (N = 25) and sertraline (N = 54) troublesome or serious side effects or require closer mon- resulted in significant changes from baseline in Connor- itoring, they should be classed as second- or third-line Davidson Resilience Scale (CD-RISC) scores (p < .001 treatments. In a small double-blind trial of lamotrigine in and p < .0001, respectively).7 A long-term (24-week) 1999, Hertzberg et al.21 showed preliminary evidence, study16 comparing the effects of venlafaxine (N = 151) based on 1 out of several rating measures, that lamotrigine and placebo (N = 161) on all aspects of PTSD showed a may be effective. A single-center trial of topiramate and COPYRIGHT 2006 PHYSICIANS POSTGRADUA
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placebo presented by Tucker22 provided mixed but encour- Psychotherapy has been shown to benefit patients with aging results for the drug. Carbamazepine and divalproex only a partial response to SSRIs. In a psychotherapy aug- sodium both require regular blood tests, and topiramate mentation study, 60 patients received sertraline for 10 produces cognitive side effects. One positive, placebo- weeks.31 Those not achieving complete clinical remission controlled trial of nefazodone exists,23 as does a negative were randomly assigned to receive 10 sessions of pro- placebo-controlled study of bupropion.24 Interestingly, bu- longed exposure therapy over a further 5 weeks in addition propion appeared to aggravate dissociative symptoms.
to sertraline or to receive drug alone. Patients who initially Both of these trials by Davis and colleagues23,24 were con- showed only a partial response benefited greatly from the addition of prolonged exposure therapy to sertraline There is a growing literature on the use of atypical anti- psychotic agents as adjunctive therapy in PTSD. Olanza-pine was shown to be a successful adjunct treatment in a study population with combat-related PTSD who werenonresponsive to 12 weeks of SSRI therapy.25 Patients Although SSRIs are recommended as first-line therapy who received adjunctive olanzapine for a further 8 weeks for PTSD, approximately 20% to 40% of PTSD patients (N = 19) showed greater improvement in CAPS-2 scores fail to respond to treatment as well as one might hope. Re- (p < .05) and sleep disorder symptoms (assessed by the mission rates with SSRIs after 12 weeks are relatively low, Pittsburgh Sleep Questionnaire; p = .01) than those who at 30% or less,32 though better than might be expected given the severity and chronic nature of PTSD. Many pa- Similarly, Bartzokis et al.26 showed that the use of tients discontinue SSRIs because of side effects, including adjunctive risperidone in combat veterans with PTSD gastrointestinal symptoms, sleep impairment, agitation, achieved significantly better improvement than placebo in insomnia, sexual side effects, and weight gain. As many as a broad range of psychiatric symptoms as measured by the half of all U.S. patients stop taking antidepressants within CAPS-total scale and subscales (reexperiencing, avoid- 3 to 4 months of initiating therapy,33 for a variety of rea- ance, and arousal). In a 5-week, double-blind, placebo- sons including cultural and social factors, and this impacts controlled trial of 40 combat veterans, those receiving negatively on response and remission rates in PTSD.
adjunctive risperidone showed a significantly greater One strategy to move PTSD patients from partial re- improvement in psychotic symptoms, measured by the sponse to full response, and to achieve higher remission Positive and Negative Syndrome Scale, than those given rates, is long-term drug therapy.34,35 Treatment can also be placebo (p < .05), as well as a greater improvement in augmented with another drug or with psychotherapy, and CAPS reexperiencing subscale score at the study endpoint high side effect rates can be avoided by using a low start- (p < .05).27 The potential risk of side effects with the atypi- ing dose and titrating steadily upward. Physicians can en- cal antipsychotic agents, including weight gain, postural courage patients to persist with taking their medication by hypotension, extrapyramidal symptoms, hyperglycemia, providing them with information and education on PTSD and diabetes,28 does however need to be taken into account Several studies have demonstrated the efficacy of the α -adrenergic antagonist prazosin in PTSD. In a 20-week, placebo-controlled crossover, add-on study of Vietnam SSRI therapy appears to protect against PTSD relapse.
veterans, in which participants received a mean dose of When a 6-month, open-label study with fluoxetine 9.5 mg per day of prazosin (N = 10) or placebo (N = 10), was followed by 6 months of double-blind, randomized prazosin produced a greater improvement in nightmares, treatment with fluoxetine or placebo, 50% of patients re- sleep disturbance, and global change in PTSD severity and ceiving placebo suffered a major relapse versus 22% functional status than placebo, measured using CAPS and treated with fluoxetine (p < .05).36 In a relapse prevention Clinical Global Impression of Change scale (CGIC).29 To- study with sertraline, patients who completed a 12-week, tal score and symptom cluster scores for reexperiencing, double-blind, placebo-controlled study and a subsequent avoidance/numbing, and hyperarousal were also signifi- 24-week, open-label continuation phase were randomly cantly more improved with prazosin. In a small 6-week, assigned to 28 weeks of maintenance treatment with open-label trial involving non–combat-related PTSD, sertraline (N = 46) or placebo (N = 50).37 The rates of in which 5 individuals received prazosin at increasing relapse (including discontinuation due to clinical deterio- doses, all subjects experienced moderate-to-marked im- ration) were 48% with placebo versus only 16% with ser- provement on the CGIC, as well as an improvement in traline (p = .005). In a double-blind, placebo-controlled Clinical Impression of Change-Nightmares score and study of positive responders to 12 weeks of fluoxetine CAPS One Week Symptom Version PTSD nightmare and treatment, patients randomly assigned to receive a further 24 weeks of fluoxetine therapy (N = 69) were found to be COPYRIGHT 2006 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2006 PHYSICIANS POSTGRADUATE PRESS, INC.
less likely to relapse than those given placebo (N = 62; Table 1. Suggested Dose Titration for Sertraline and
Paroxetine in Posttraumatic Stress Disorder
It is currently recommended that treatment should be tried initially for at least 3 months,5,38 with effective phar- macotherapy continued for at least 1 year. Discontinuing medication after 6 months exposes patients to a higher risk of relapse. There are currently no published PTSD relapse prevention studies using agents other than SSRIs.
ued. If symptoms return, then it is advisable to continue Because PTSD is commonly associated with other psychiatric disorders,39 and because the SSRIs are recog- Two studies, one randomized44 and the other non- nized as effective broad-spectrum therapy for depression randomized,45 suggest that treatment with the β-blocker and anxiety disorders, it was expected that these drugs drug propranolol immediately after trauma might prevent would be effective in treating PTSD with some comorbid some symptoms of PTSD, such as hyperarousal in re- conditions. Acute, randomized, double-blind, placebo- sponse to traumatic memories, but may not prevent PTSD controlled studies indicate that both sertraline40 and parox- overall. Further larger-scale studies are required.
etine13 are effective in treating PTSD both with and with- Benzodiazepines are useful in controlling anxiety and out depression, anxiety, or both. An early open-label trial agitation and assisting sleep. They are not particularly ef- with sertraline (N = 9) suggested that it was effective in fective in ASD, however, and may impair learning in a treating PTSD in patients with alcohol dependence, with clinical situation and have withdrawal symptoms.5 They participants showing decreased alcohol consumption.41 A are therefore not recommended for ASD or early PTSD. In subsequent 12-week placebo-controlled trial with sertra- 6-week and 6-month studies in trauma patients, more than line in 94 patients failed to show an overall benefit for ser- twice as many patients receiving benzodiazepine still had traline, but suggested in a post hoc analysis the possibility PTSD compared with controls receiving no treatment or that there may be subgroups who respond better to sertra- placebo, suggesting a harmful effect (although it is impor- line; those with less severe alcohol dependence and later- tant to remember that assignment to treatment was not ran- onset PTSD had significantly fewer drinks per drinking domized in 1 trial, thus leaving open the possibility of im- portant confounding differences between the groups).46,47Hypnotic antidepressants may be more useful in treating Antipsychotic agents may be useful in the short term SSRIs should be initiated at a low dose, with slow titra- for acute agitation, but, in general, experience with these tion (up to the maximal daily dose if required) until a good drugs is limited to use as an adjunct to SSRIs in chronic response or remission is achieved, or until side effects pre- PTSD, mainly if patients exhibit psychotic-like symp- vent further dose increases. If side effects are troublesome toms, bipolar features, lack of impulse control, and ag- and the response is poor, other agents should be consid- gression, or if there has been lack of response to other ered. Suggested dose titration schedules for sertraline and Effective pharmacotherapy of PTSD may be compli- Very few studies have investigated pharmacologic pre- cated by a number of cultural and social factors. It cannot vention of acute stress disorder (ASD) or early PTSD (i.e., be assumed that treatments are universally accepted in all occurring within 1 month of trauma). One study43 in chil- cultures, and one needs to consider different beliefs, con- dren suggests that short-term antidepressant therapy may cerns, and taboos surrounding illness and treatment in dif- be helpful in ASD or early PTSD. In a prospective, ran- ferent settings, and the varying degree to which family domized, double-blind pilot study in children with severe members become involved, for example. Skepticism to- burns and ASD, treatment with the tricyclic antidepressant ward medication on the part of patients needs to be ad- imipramine at 1 mg/kg for just 1 week produced an 83% dressed by providing more education, increasing patient response rate, versus only 38% for control patients who contact, and offering assistance with problems. Failure to received chloral hydrate to assist sleep.43 It is unknown for do so may result in high rates of attrition or treatment non- how long successful treatment of ASD should be contin- COPYRIGHT 2006 PHYSICIANS POSTGRADUA
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A shortage of trained professionals and a lack of re- (Lamictal), mirtazapine (Remeron), olanzapine (Zyprexa), paroxetine sources can also pose challenges, particularly after a major (Paxil, Pexeva, and others), prazosin (Minipress and others), propran-olol (Inderal and others), risperidone (Risperdal), sertraline (Zoloft), disaster such as the 2004 Asian tsunami. Worldwide, much topiramate (Topamax), venlafaxine (Effexor).
of the burden of diagnosis and prescription of psycho-tropic medications falls on the family doctor, and it is Disclosure of off-label usage: The author has determined that, to thebest of his knowledge, bupropion, carbamazepine, divalproex sodium, therefore necessary to optimize the management of PTSD fluoxetine, imipramine, lamotrigine, mirtazapine, nefazodone, olanza- pine, prazosin, propranolol, risperidone, topiramate, and venlafaxine Ethnic differences in drug metabolism require attention are not approved by the U.S. Food and Drug Administration for thetreatment of posttraumatic stress disorder.
to dosing issues and side effects when treating trauma. Insome Asian populations, for example, higher plasma drug levels occur with tricyclic antidepressants, lithium, andhaloperidol, leading to a greater incidence of side effects.48 1. Davidson JRT, Book SW, Colket JT, et al. Assessment of a new There is currently a lack of studies assessing the effi- self-rating scale for post-traumatic stress disorder. Psychol Med cacy and safety of pharmacotherapy in children with PTSD. SSRIs are effective in other anxiety disorders such 2. Weathers FW, Keane TM, Davidson JR. Clinician-Administered PTSD Scale: a review of the first ten years of research. Depress Anxiety 2001; as obsessive-compulsive disorder, social phobia, and gen- eralized anxiety disorder in children, and although these 3. Connor KM, Davidson JR. SPRINT: a brief global assessment of post- findings may be reasonably extrapolated to PTSD for traumatic stress disorder. Int Clin Psychopharmacol 2001;16:279–284 4. Davidson JR, Colket JT. The eight-item treatment-outcome post- the purposes of routine clinical practice, PTSD-specific traumatic stress disorder scale: a brief measure to assess treatment out- trials are needed. It is also unclear for how long children come in post-traumatic stress disorder. Int Clin Psychopharmacol 1997; should receive medication. If the response is good after 9 5. Ballenger JC, Davidson JR, Lecrubier Y, et al. Consensus statement on months, discontinuation may be considered, although this posttraumatic stress disorder from the International Consensus Group on should depend on the stability of the individual’s life and Depression and Anxiety. J Clin Psychiatry 2000;61(suppl 5):60–66 6. Meltzer-Brody S, Connor KM, Churchill E, et al. Symptom-specific effects of fluoxetine in post-traumatic stress disorder. Int ClinPsychopharmacol 2000;15:227–231 7. Davidson JR, Payne VM, Connor KM, et al. Trauma, resilience and saliostasis: effects of treatment in post-traumatic stress disorder. Int ClinPsychopharmacol 2005;20:43–48 The International Psychopharmacology Algorithm 8. Van der Kolk BA, Dreyfuss D, Michaels M, et al. Fluoxetine in posttrau- Project (accessible at http://www.ipap.org) has completed matic stress disorder. J Clin Psychiatry 1994;55:517–522 the development of psychopharmacology algorithms for 9. Connor KM, Sutherland SM, Tupler LA, et al. Fluoxetine in post-traumatic stress disorder: randomised, double-blind study.
the management of PTSD. These algorithms, which are re- flections of consensus opinions from experts throughout 10. Martenyi F, Brown EB, Zhang H, et al. Fluoxetine versus placebo in the world, are intended to provide helpful guidance for all posttraumatic stress disorder. J Clin Psychiatry 2002;63:199–206 11. Tucker P, Zaninelli R, Yehuda R, et al. Paroxetine in the treatment of professionals engaged in the treatment of PTSD, particu- chronic posttraumatic stress disorder: results of a placebo-controlled, larly with respect to clinical decision making during the flexible-dosage trial. J Clin Psychiatry 2001;62:860–868 various stages of the management of PTSD.
12. Marshall RD, Beebe KL, Oldham M, et al. Efficacy and safety of paroxetine treatment for chronic PTSD: a fixed-dose, placebo-controlledstudy. Am J Psychiatry 2001;158:1982–1988 13. Stein DJ, Davidson J, Seedat S, et al. Paroxetine in the treatment of post- traumatic stress disorder: pooled analysis of placebo-controlled studies.
Expert Opin Pharmacother 2003;4:1829–1838 SSRIs and SNRIs are recommended as first-line ther- 14. Brady K, Pearlstein T, Asnis GM, et al. Efficacy and safety of sertraline apy for PTSD. They are effective across all symptom clus- treatment of posttraumatic stress disorder: a randomized controlled trial.
ters, demonstrate no firmly established gender differences 15. Davidson JR, Rothbaum BO, van der Kolk BA, et al. Multicenter, in efficacy, and appear to be useful in treating PTSD fol- double-blind comparison of sertraline and placebo in the treatment of lowing all types of trauma. They are also effective in treat- posttraumatic stress disorder. Arch Gen Psychiatry 2001;58:485–492 ing PTSD with comorbid disorders, such as depression 16. Davidson JRT, Baldwin DS, Stein DJ, et al. A 24 week, placebo- controlled study of venlafaxine XR in the treatment of posttraumatic and anxiety disorders. While further information is re- stress disorder [poster]. Presented at the 45th annual meeting of the New quired on the role of SSRIs and SNRIs in the treatment of Clinical Drug Evaluation Unit; June 6–9, 2005; Boca Raton, Fla survivors of mass trauma and disaster, many people be- 17. Davidson JR, Landerman LR, Farfel GM, et al. Characterizing the effects of sertraline in post-traumatic stress disorder. Psychol Med lieve that effective pharmacotherapy of PTSD in survivors of the 2004 Asian tsunami can contribute in important 18. Londborg PD, Hegel MT, Goldstein S, et al. Sertraline treatment of post- ways toward both the recovery process for individuals and traumatic stress disorder: results of 24 weeks of open-label continuationtreatment. J Clin Psychiatry 2001;62:325–331 public health and economic recovery in the region.
19. Davidson JR, Weisler RH, Butterfield MI, et al. Mirtazapine vs placebo in posttraumatic stress disorder: a pilot trial. Biol Psychiatry 2003;53: Drug names: bupropion (Wellbutrin and others), carbamazepine (Tegretol and others), divalproex sodium (Depakote), fluoxetine 20. Davidson JRT, Lipschitz A, Musgnung J. Treatment of PTSD with venla- (Prozac and others), imipramine (Tofranil and others), lamotrigine faxine XR, sertraline, or placebo: a double-blind comparison [abstract].
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