Progress in Neuro-Psychopharmacology and Biological Psychiatry
Review article
Pharmacologic alternatives to antidepressants in posttraumatic stress disorder: A systematic review
Introduction
Posttraumatic stress disorder (PTSD) is a pathological response to a traumatic event that is characterized by the presence of three clusters of symptoms: reexperiencing (cluster B), avoidance/numbing (cluster C), and hyperarousal (cluster D). The symptoms must last for a minimum of one month and disrupt functioning. If the symptoms persist for more than three months, then PTSD is considered to be chronic (American Psychiatric Association, 1994).
The treatment of PTSD has several specific goals: to reduce the severity of symptoms, to prevent and/or treat comorbid disorders, to decrease functional impairment, to modify pathogenic fear schemas, to prevent relapse, to build resilience and to improve quality of life (Ursano et al., 2004). The most common definitions of treatment response in PTSD patients are a decrease of 30% or more (Hamner et al., 2004) in the Clinician Administered PTSD Scale (CAPS) score (Blake et al., 1990) or a score of 1 (“very much”) or 2 (“much improved”) (Stein et al., 2006) in the Clinical Global Impressions scale-Improvement item (CGI-I) (Guy, 1976).
The selective serotonin reuptake inhibitors (SSRIs), especially paroxetine and sertraline, are considered the first-line pharmacotherapeutic treatment for PTSD (Schoenfeld et al., 2004, Ursano et al., 2004, Asnis et al., 2004). However, even when treated with this class of drugs, response rates rarely exceed 60% and less than 20–30% of the patients achieve full remission (Stein et al., 2002, Zohar et al., 2002). A 6-month long double-blind, placebo-controlled study conducted by Davidson et al. (2006) found that 78% of PTSD patients treated with the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine ER presented a positive clinical response (a decrease of ≥ 30% in the CAPS scores) but, nevertheless, only 40.4% of the completers achieved remission (CAPS score ≤ 20). Furthermore, treatment with venlafaxine ER failed to significantly ameliorate hyperarousal symptoms. Even considering the SSRIs, the most studied class of drugs, only two studies were able to demonstrate the superiority of paroxetine over placebo on all the three clusters of PTSD (Ballenger, 2004, Tucker et al., 2001). These findings may reflect an intrinsic limitation of SSRIs or SNRIs in ameliorating the heterogeneous symptoms of PTSD (Davidson et al., 2006). In spite of that, there are relatively few studies concerned with orienting clinicians about the benefits of combining or switching medications to manage patients with PTSD who did not respond adequately to first-line treatments (Kinrys et al., 2006).
The aim of this study was to address this limitation by systematically reviewing the therapeutic options left for the treatment of PTSD when patients do not respond satisfactorily to or tolerate SSRIs and SNRIs. This review will focus on the following categories of pharmacological agents: antipsychotics, anticonvulsants, adrenergic-inhibiting agents, opioid antagonists, benzodiazepines and other medications.
Section snippets
Methods
A systematic review covering all original articles, letters and brief reports published in any language until October 2008 was conducted through searches in the ISI/Web of Science, PubMed and PILOTS databases. The search terms included the pharmacological class of each agent (e.g. anticonvulsant⁎, or alpha-antagonist⁎) or its generic name (e.g. topiramate) plus “PTSD” or “stress disorder” in the title, in the abstract or as a keyword. The reference lists of retrieved articles were further
Results
One thousand, five hundred and eighty-three articles, letters and notes were identified: 404 on antipsychotics, 285 on anticonvulsants, 390 on adrenergic-inhibiting agents, 69 on opioid antagonists, 234 on benzodiazepines, and on 201 other agents. After applying the exclusion criteria, sixty-three articles were selected and categorized according to the methodology, design, level of scientific evidence and clinical relevance (US Department of Health an Human Services, 1993), as follows:
- A
Multiple
Discussion
Antidepressants are considered the primary class of medications for the treatment of PTSD. Given that several RCTs have repeatedly demonstrated their efficacy (Brady et al., 2000, Connor et al., 1999, Davidson et al., 2001, Marshall et al., 2001a, Neylan et al., 2001, Tucker et al., 2001, van der Kolk et al., 1994), it is now well established that SSRIs are the first-line pharmacotherapy for PTSD (Ursano et al., 2004). Further options include the dual action selective serotonin and
Conclusions
The well-known difficulties in managing PTSD are aggravated when the patient does not respond to or do not tolerate treatment with antidepressants. Our review of the literature suggested that, in these cases, there are a few alternatives to be considered. Risperidone is the medication with the strongest empirical support for a role as an alternative treatment of PTSD, particularly as an augmentation strategy, despite not having its efficacy demonstrated on avoidance and emotional numbing
Conflict of interest
Drs. Berger, Mendlowicz, Marques-Portella, Figueira, Fontenelle and Marmar have no conflicts of interest. Dr. Kinrys has received research grants and support from AstraZeneca, Bristol-Myers Squibb, CNS Response, Cephalon, Elan, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Pfizer, Sanofi-Aventis, Sepracor, Takeda, and UCB Pharma.
Acknowledgments
This research was supported in part by the CNPq (Nacional Research Council)—Federal Government of Brazil and Grant R01-MH056350-06 from the National Institute of Mental Health. The authors thank the anonymous reviewers for the invaluable comments and suggestions.
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Department of Psychiatry and Mental Health, Universidade Federal Fluminense (MSM-UFF), Rua Tiradentes, 171 bloco 2 apartamento 903, Niterói, RJ 24210-510, Brazil.
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Institute of Psychiatry, Universidade Federal do Rio de Janeiro (IPUB/UFRJ), Av. Princesa Isabel, 150 sala 1003, Copacabana, Rio de Janeiro, RJ 22011-010, Brazil.
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Cambridge Health Alliance/Harvard Medical School, Department of Psychiatry, 1493 Cambridge St, Cambridge, MA 02139, USA.
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Institute of Psychiatry, Universidade Federal do Rio de Janeiro (IPUB/UFRJ), Rua Lopes Trovão, 88, Apartamento 1501, Bloco A, Icaraí, Niterói, RJ 24220-071, Brazil.
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Department of Psychiatry, University of California, 4150 Clement St (116 P), San Francisco, CA 94121, USA.
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Institute of Psychiatry, Universidade Federal do Rio de Janeiro (IPUB/UFRJ), Rua Bolívar, 54, sala 1001, Copacabana, Rio de Janeiro, RJ 22061-020. Brazil.