Review article
Pharmacologic alternatives to antidepressants in posttraumatic stress disorder: A systematic review

https://doi.org/10.1016/j.pnpbp.2008.12.004 Get rights and content

Abstract

The selective serotonin reuptake inhibitors (SSRIs) are considered the first-line pharmacological treatment for PTSD. 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. The aim of this study was to address this limitation by systematically reviewing the options left for the treatment of PTSD when patients do not respond satisfactorily to or tolerate SSRIs. 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 or its generic name plus “PTSD” or “stress disorder” in the title, in the abstract or as a keyword. Sixty-three articles were selected, covering the following categories: antipsychotics, anticonvulsants, adrenergic-inhibiting agents, opioid antagonists, benzodiazepines and other agents. None of the identified agents reached the level A of scientific evidence, 5 reached level B, 7 level C and 13 level D. The non-antidepressant agent with the strongest scientific evidence supporting its use in PTSD is risperidone, which can be envisaged as an effective add-on therapy when patients did not fully benefit from previous treatment with SSRIs. Prazosin, an adrenergic-inhibiting agent, is a promising alternative for cases of PTSD where nightmares and insomnia are prominent symptoms. So far, there is no consistent empirical support for using benzodiazepines in the prevention or in the treatment of PTSD, although these drugs could alleviate some associated non-specific symptoms, such as insomnia or anxiety. Further controlled clinical trials and meta-analysis are needed to guide clinicians in their search of effective pharmacological alternatives to antidepressants in PTSD.

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.

References (129)

  • KaminskaM. et al.

    Dehydroepiandrosterone sulfate (DHEAS) counteracts decremental effects of corticosterone on dentate gyrus LTP. implications for depression

    Brain Res Bull

    (2000)
  • LipperS. et al.

    Preliminary study of carbamazepine in post-traumatic stress disorder

    Psychosomatics

    (1986)
  • LooffD. et al.

    Carbamazepine for Ptsd

    J Am Acad Child Adolesc Psych

    (1995)
  • RaskindM.A. et al.

    A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with posttraumatic stress disorder

    Biol Psychiatry

    (2007)
  • AhearnE.P. et al.

    Quetiapine as an adjunctive treatment for post-traumatic stress disorder: an 8-week open-label study

    Int Clin Psychopharmacol

    (2006)
  • American Psychiatric Association

    Diagnostic and statistical manual of mental disorders

    (1994)
  • AsnisG.M. et al.

    SSRIs versus non-SSRIs in post-traumatic stress disorder—an update with recommendations

    Drugs

    (2004)
  • BallengerJ.C.

    Remission rates in patients with anxiety disorders treated with paroxetine

    J Clin Psychiatry

    (2004)
  • BerlantJ.

    Prospective open-label study of add-on and monotherapy topiramate in civilians with chronic nonhallucinatory posttraumatic stress disorder

    BMC Psychiatry

    (2004)
  • BerlantJ. et al.

    Open-label topiramate as primary or adjunctive therapy in chronic civilian posttraumatic stress disorder: a preliminary report

    J Clin Psychiatry

    (2002)
  • BlakeD.D. et al.

    A clinical rating scale for assessing current and lifetime PTSD: the CAPS 1

    Behav Ther

    (1990)
  • BradyK. et al.

    Efficacy and safety of sertraline treatment of posttraumatic stress disorder—a randomized controlled trial

    JAMA

    (2000)
  • BraunP. et al.

    Core symptoms of posttraumatic stress disorder unimproved by alprazolam treatment

    J Clin Psychiatry

    (1990)
  • BremnerJ.D. et al.

    Treatment of posttraumatic stress disorder with phenytoin: an open-label pilot study

    J Clin Psychiatry

    (2004)
  • BriereJ.

    Trauma symptoms checklist for children

    (1996)
  • ButterfieldM.I. et al.

    Olanzapine in the treatment of post-traumatic stress disorder: a pilot study

    Int Clin Psychopharmacol

    (2001)
  • CarvalhoA.F. et al.

    Augmentation strategies for treatment-resistant depression: a literature review

    J Clin Pharm Ther

    (2007)
  • ClarkR.D. et al.

    Cyproheptadine treatment of nightmares associated with posttraumatic stress disorder

    J Clin Psychopharmacol

    (1999)
  • ClarkR.D. et al.

    Divalproex in posttraumatic stress disorder: an open-label clinical trial

    J Trauma Stress

    (1999)
  • ConnorK.M. et al.

    Further psychometric assessment of the TOP-8: a brief interview-based measure of PTSD

    Depress Anxiety

    (1999)
  • ConnorK.M. et al.

    SPRINT: a brief global assessment of post-traumatic stress disorder

    Int Clin Psychopharmacol

    (2001)
  • ConnorK.M. et al.

    Fluoxetine in post-traumatic stress disorder. Randomised, double-blind study

    Br J Psychiatry

    (1999)
  • ConnorK.M. et al.

    Tiagabine for posttraumatic stress disorder: effects of open-label and double-blind discontinuation treatment

    Psychopharmacology

    (2006)
  • CraftM. et al.

    Lithium in the treatment of aggression in mentally handicapped patients. A double-blind trial

    Br J Psychiatry

    (1987)
  • DalyC.M. et al.

    Clinical case series: the use of prazosin for combat-related recurrent nightmares among Operation Iraqi Freedom combat veterans

    Mil Med

    (2005)
  • DavidD. et al.

    Adjunctive risperidone treatment in combat veterans with chronic PTSD

    J Clin Psychopharmacol

    (2004)
  • DavidD. et al.

    Adjunctive risperidone treatment and sleep symptoms in combat veterans with chronic PTSD

    Depress Anxiety

    (2006)
  • DavidsonJ.R.T. et al.

    Assessment of a new self-rating scale for post-traumatic stress disorder

    Psychol Med

    (1997)
  • DavidsonJ.R.T. et al.

    Fluvoxamine in civilians with PTSD

    J Clin Psychopharmacol

    (1998)
  • DavidsonJ. et al.

    Efficacy of sertraline in preventing relapse of posttraumatic stress disorder: results of a 28-week double-blind, placebo-controlled study

    Am J Psychiatry

    (2001)
  • DavidsonJ. et al.

    Treatment of posttraumatic stress disorder with venlafaxine extended release: a 6-month randomized controlled trial

    Arch Gen Psychiatry

    (2006)
  • DavidsonJ.R.T. et al.

    The efficacy and tolerability of tiagabine in adult patients with post-traumatic stress disorder

    J Clin Psychopharmacol

    (2007)
  • DavisL.L. et al.

    Divalproex for the treatment of posttraumatic stress disorder: a retrospective chart review

    Int J Psychiatr Clin Pract

    (2005)
  • DavisL.L. et al.

    Divalproex in the treatment of posttraumatic stress disorder: a randomized, double-blind, placebo-controlled trial in a veteran population

    J Clin Psychopharmacol

    (2008)
  • DeebieJ.A.C.E. et al.

    Noradrenergic signaling in the amygdala contributes to the reconsolidation of fear memory. treatment implications for PTSD

    Ann N Y Acad Sci

    (2006)
  • DerogatisL.R.

    The SCL-9OR: scoring, administration and procedures manual: II

    (1977)
  • EidelmanI. et al.

    Risperidone in the treatment of acute stress disorder in physically traumatized in-patients

    Depress Anxiety

    (2000)
  • FamularoR. et al.

    Propranolol treatment for childhood posttraumatic stress disorder, acute type. A pilot study

    Am J Dis Child

    (1988)
  • FeslerF.A.

    Valproate in combat-related posttraumatic-stress-disorder

    J Clin Psychiatry

    (1991)
  • FilteauM.J. et al.

    Quetiapine reduces flashbacks in chronic posttraumatic stress disorder

    Can J Psychiatry

    (2003)
  • Cited by (254)

    View all citing articles on Scopus
    1

    Department of Psychiatry and Mental Health, Universidade Federal Fluminense (MSM-UFF), Rua Tiradentes, 171 bloco 2 apartamento 903, Niterói, RJ 24210-510, Brazil.

    2

    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.

    3

    Cambridge Health Alliance/Harvard Medical School, Department of Psychiatry, 1493 Cambridge St, Cambridge, MA 02139, USA.

    4

    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.

    5

    Department of Psychiatry, University of California, 4150 Clement St (116 P), San Francisco, CA 94121, USA.

    6

    Institute of Psychiatry, Universidade Federal do Rio de Janeiro (IPUB/UFRJ), Rua Bolívar, 54, sala 1001, Copacabana, Rio de Janeiro, RJ 22061-020. Brazil.

    View full text