Pharmacotherapy For PTSD: A Status Report
By Matthew J. Friedman, M.D., Ph.D.
NCP Clinical Quarterly 7(4): Fall 1997
Most earlier randomized trials were published between 1987-1991 after which there was a hiatus in research on drug therapy for PTSD. These early investigations focused primarily on tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Despite some very promising leads from these early trials, results were inconsistent and too modest to stimulate further research until selective serotonin reuptake inhibitors (SSRIs) became available in recent years.
Antiadrenergic Agents: Propranolol, Clonidine And Guanfacine
Although it is well established that adrenergic dysregulation is associated with chronic PTSD (see 1, 2 for details and references), there has been little research and no randomized clinical trials with either the beta adrenergic antagonist, propranolol, or with the alpha-2 agonist, clonidine despite the fact that positive findings with both drugs were reported as early as 1984 (3). It should be noted that positive reports of open trials with both drugs continue to be published. In addition, preliminary success has been achieved with the adrenergic alpha-2 agonist, guanfacine which has a longer half-life (18-22 hours) than clonidine.
Selective Serotonin Reuptake Inhibitors
SSRIs have revolutionized pharmacotherapy and are beginning to emerge as the first choice of clinicians treating PTSD patients. In the only published randomized clinical trial of an SSRI, fluoxetine produced a marked reduction in overall PTSD symptoms, especially with respect to numbing and arousal symptoms (4).
In addition, a number of open trials and case reports have appeared concerning fluoxetine, sertraline, and fluvoxamine (see 5 for references). In general, investigators have been impressed by the capacity of SSRIs to reduce the numbing symptoms of PTSD since other drugs tested thus far, do not seem to have this property.
Trazadone And Nefazadone
Trazadone and nefazadone are serotonergic antidepressants with both SSRI and 5-HT2 blockade properties. They also exert alpha-adrenergic blockade and strong sedative effects. Trazadone has received renewed attention, recently, because of its capacity to reverse the insomnia caused by SSRI agents such as fluoxetine and sertraline. A recent open trial (6) indicated that trazadone may be an effective drug in its own right. Nefazadone is closely related to trazadone with respect to mechanism of action but appears to have greater potency. Multi-site trials with nefazadone are currently in progress.
Monoamine Oxidase Inhibitors (MAOIs)
Phenelzine produced excellent reduction of PTSD symptoms during an eight week randomized clinical trial, in two open trials, and in several case reports. It was less effective than placebo in a four week crossover study and one recent negative open trial with phenelzin (see 8 for references).
Southwick et al. (9) reviewed all published findings (randomized trials, open trials and case reports) concerning MAOI (phenelzine) treatment for PTSD. They found that MAOIs produced moderate to good global improvement in 82% of all patients, primarily due to reduction in reexperiencing symptoms such as intrusive recollections, traumatic nightmares and PTSD flashbacks. Insomnia also improved. No improvement was found, however, in PTSD avoidant/numbing, PTSD hyperarousal, depressive or anxiety/panic symptoms.
In summary, most published reports show that MAOIs effectively reduce PTSD symptoms. In practice, however, most clinicians appear reluctant to prescribe these agents because of concerns about the risk of administrating these drugs to patients who may ingest alcohol or certain illicit drugs or who may not adhere to necessary dietary restrictions.
Tricyclic Antidepressants (TCAs)
There have been three randomized clinical trials with tricyclic antidepressants involving 124 patients as well as numerous case reports and open trials (see 10 for references). Results have been mixed and generally modest in magnitude. In their analysis of fifteen randomized trials, open trials and case reports involving TCA treatment for PTSD, Southwick and associates (9) found that 45% of patients showed moderate to good global improvement following treatment whereas MAOIs produced global improvement in 82% of patients who received them. As with MAOIs, most improvement was due to reductions in re-experiencing rather than avoidant/numbing or arousal symptoms. It also appeared that a minimum of 8 weeks of treatment with either TCAs or MAOIs was necessary to achieve positive clinical results. Because of their relative lack of potency, their side effects and their failure to reduce avoidant/numbing symptoms that TCAs have been replaced by SSRIs as first-line drugs in PTSD treatment.
Benzodiazepines
Because of their proven anxiolytic potency, benzodiazapines have been prescribed widely for PTSD patients in some clinical settings, there are only four publications on benzodiazepine treatment for PTSD. In a randomized clinical trial (11), and two open label studies, alprazolam and clonazepan were no better than placebo in reducing core PTSD symptoms although modest reductions in generalized anxiety were observed.
Anticonvulsants
It has been proposed that following exposure to traumatic events, limbic nuclei become kindled or sensitized so that, henceforth, they exhibit excessive responsivity to less intense trauma-related stimuli (12). Arguing from this theoretical perspective, there have been several open trials of anticonvulsant/antikindling agents. In five studies carbamazepine produced reductions in reexperiencing and arousal symptoms, while in three studies, valproate produced reductions in avoidant/numbing and arousal (but not reexperiencing) symptoms (see 13 for references).
Narcotic Antagonists
There is growing evidence that the endogenous opioid system is dysregulated in PTSD patients. Spurred by the hypothesis that emotional numbing in PTSD might result from excessive endogenous opioid activity, an open trial of the narcotic antagonist, nalmefene, was conducted (14) in which some Vietnam veterans with PTSD exhibited reduced numbing whereas the others showed either no improvement or a worsening of anxiety, panic and hyperarousal symptoms.
Antipsychotics
Before the empirical and conceptual advances achieved during the past 15 years, PTSD patients were often considered to have psychotic disorder by treating physicians. Indeed the intense agitation, hypervigilance (that sometimes appeared to be paranoid delusions), impulsivity, and dissociative states seemed to call for neuroleptic treatment. It now appears that most of these symptoms will respond to anti-adrenergic or antidepressant drugs and that antipsychotic medications should only be prescribed for the rare PTSD patient who exhibits frank paranoid behavior, overwhelming anger, aggressivity, psychotic symptoms, fragmented ego boundaries, self-destructive behavior and frequent flashback experiences marked by auditory or visual hallucinations of traumatic episodes (15).
Conclusions
Most drugs tested in PTSD were developed as antidepressants and later shown to have efficacy against panic and other anxiety disorders. Given high comorbidity rates between PTSD and such disorders and given the symptomatic overlap between PTSD, major depression, panic disorder and generalized anxiety disorder (16), it seems reasonable to have tested such drugs in PTSD. On the other hand, PTSD appears to be distinctive in a number of ways. First, it seems to be more complex than affective or other anxiety disorders; and second, its underlying pathophysiology appears to be qualitatively different. For example, abnormalities in the hypothalamic-pituitary-adrenocortical axis (HPA) system, are markedly different than those present in major depressive disorder despite similarities in clinical phenomenology. In short, the time has come to develop and test drugs that have been developed specifically for PTSD rather than to recycle pharmacological agents that have been developed to treat affective or other anxiety disorders.
From this perspective, promising future directions might be to test drugs that antagonize the actions of Corticotropin Releasing Factor (CRF), the substance that appears to play such a central role in the stress response (17). Another promising direction for future research might be to design drugs that can reverse the dissociative and amnestic symptoms associated with PTSD (18).
Finally, there is certainly a need for further research on adrenergic alpha-2 agonists such as clonidine and guanfacine, on SSRIs and other serotonergic agents, and on anticonvulsants with anti-kindling/sensitization properties. It appears that we have barely begun to explore a variety of exciting pharmacotherapeutic approaches for PTSD. We can all look forward to important research findings in the coming years.
References
1. Friedman, M.J., Charney, D.S., & Deutch, A.Y. (Eds). (1995). Neurobiological and clinical consequences of stress: From normal adaptation to PTSD. Philadelphia: Lippincott-Raven Press.
2. Yehuda, R. & McFarlane, A.C. (Eds.). (1997). Psychobiology of posttraumatic stress disorder. Annals of the New York Academy of Sciences, 821. New York: New York Academy of Sciences.
3. Kolb, L.C., Burris, B.C., & Griffiths, S. (1984). Propranolol and clonidine in the treatment of the chronic post-traumatic stress disorders of war. In B.A. van der Kolk (Ed.), Post-traumatic stress disorder: Psychological and biological sequelae (pp.97-107). Washington DC: American Psychiatric Press.
4. van der Kolk, B.A., Dryfuss, D., Michaels, M. et al. (1994). Fluoxetine in post-traumatic stress disorder. Journal of Clinical Psychiatry, 55, 517-522.
5. Friedman, M.J. (1996). Biological alterations in PTSD: Implications for pharmacotherapy. In E. Giller & L.Weisaeth (Eds.), Bailliere's clinical psychiatry: International practice and research: Post-traumatic stress disorder, Volume 2(2), 245-262. London: Bailliere Tindall.
6. Hertzberg, M.A., Feldman, M.E., Beckham, J.C. et al. (1996). Trial of trazadone for posttraumatic stress using a multiple baseline group design. Journal of Clinical Psychopharmacology, 16, 294-298.
8. DeMartino, R., Mollica, R.F., & Wilk, V. (1995). Monoamine oxidase inhibitors in posttraumatic stress disorder. Journal of Nervous and Mental Disease, 183, 510-515.
9. Southwick, S. M., Yehuda, R., Giller, E.L. et al. (1994). Use of tricyclics and monoamine oxidase inhibitors in the treatment of PTSD: A quantitative review. In M.M. Murburg (Ed.), Catecholamine function in post-traumatic stress disorder: Emerging concepts (pp. 293-305). Washington, DC: American Psychiatric Press.
10. Ver Ellen P.& D.P. van Kammen. (1990). The biological findings in post-traumatic stress disorder: a review. Journal of Applied Social Psychology, 20(21,pt1), 1789-1821.
11. Braun, P., Greenberg, D., Dasberg, H. et al. (1990). Core symptoms of posttraumatic stress disorder unimproved by alprazolam treatment. Journal of Clinical Psychiatry, 51, 236-238.
12. Post, R.M., Weiss, S.R.B., & Smith, M.A. (1995). Sensitizationand kindling: Implications for the evolving neural substrate of PTSD. In M.J. Friedman et al. (Eds.), Neurobiological and clinical consequences of stress: From normal adaptation to PTSD (pp. 203-224). Philadelphia: Lippincott-Raven Press.
13. Friedman, M.J. & S.M. Southwick. (1995). Towards pharmacotherapy for PTSD. In M.J. Friedman et al. (Eds.), Neurobiological and clinical consequences of stress: From normal adaptation to PTSD (pp. 465-481). Philadelphia: Lippincott-Raven Press.
14. Glover, H. (1993). A preliminary trial of nalmefane for the treatment of emotional numbing in combat veterans with post-traumatic stress disorder. Israel Journal of Psychiatry Related Sciences, 30, 255-263.
15. Friedman, M.J. (1991). Biological approaches to the diagnosis and treatment of post-traumatic stress disorder. Journal of Traumatic Stress, 4, 67-91.
16. Friedman, M.J. & R. Yehuda. (1995). PTSD and co-morbidity: Psychobiological approaches to differential diagnosis. In M.J. Friedman et al. (Eds.), Neurobiological and clinical consequences of stress: From normal adaptation to PTSD (pp. 429-446). Philadelphia: Lippincott-Raven Press.
17. Stout, S.C., Kilts, C.D., & Nemeroff, C.B. (1995). Neuropeptides and stress: Preclinical findings and implications for pathophysiology. In M.J. Friedman et al. (Eds.), Neurobiological and clinical consequences of stress: From normal adaptation to PTSD (pp. 103-123). Philadelphia: Lippincott-Raven Press.
18. Krystal, J.H., Bennett, A., Bremner, J.D. et al. (1995). Toward a cognitive neuroscience of dissociation and altered memory functions in post-traumatic stress disorder. In M.J. Friedman et al. (Eds.), Neurobiological and clinical consequences of stress: From normal adaptation to PTSD (pp. 239-270). Philadelphia: Lippincott-Raven Press.
Matthew J. Friedman is a pharmacologist turned psychiatrist who has been actively concerned about PTSD since 1974. His current positions are Executive Director of the National Center for PTSD and Professor of Psychiatry and Pharmacology at Dartmouth Medical School. Throughout his professional career, he has tried to combine strong concerns about psychiatric care with a scientific commitment to understand the etiology, diagnosis, and treatment of clinical phenomena. As a result, his publications, and presentations span a variety of topics (in addition to PTSD) such as biological psychiatry, psychopharmacology, and clinical outcome research. Dr. Friedman was one of the first to publicize research on the biological alterations associated with PTSD and to clarify the implication of such research for rational pharmacotherapy for this disorder. Lastly, Dr. Friedman was President of the International Society of Traumatic Stress Studies, 1995-96.
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