Abstract
Rationale
Preliminary results suggest a potential benefit of agents that enhance gamma-aminobutyric acid (GABA) neurotransmission in treating posttraumatic stress disorder (PTSD).
Objectives
It is the aim of this study to evaluate the effect of a selective GABA reuptake inhibitor (SGRI), tiagabine, in patients with PTSD.
Methods
Twenty-nine adult outpatients with PTSD were treated with open-label tiagabine for 12 weeks. Those who responded to treatment (i.e., demonstrated at least minimal clinical improvement) were randomly assigned to double-blind treatment with either tiagabine or matching placebo. Efficacy assessments included measures of PTSD, anxiety, depression, sleep quality, resilience, and disability. Safety evaluation included changes in vital signs and weight and treatment-emergent adverse events.
Results
In subjects completing open-label treatment (n=19), significant improvement was observed on all outcome measures (P<0.05) and the treatment was well tolerated. Eighteen subjects responded and were randomized into the double-blind phase. Following randomization, benefits of treatment were generally upheld, but there was no greater incidence of relapse in the placebo group. However, continued treatment with tiagabine was associated with a greater trend toward likelihood of remission than if one was switched to placebo (P<0.08).
Conclusions
These findings suggest a possible role for the SGRI tiagabine in the treatment of PTSD. As the role of GABAergic drugs in PTSD is poorly defined, larger, randomized, double-blind, placebo-controlled trials are needed.
Similar content being viewed by others
References
American Psychiatric Association (1994) Diagnostic and statistical manual for mental disorders, 4th edn. American Psychiatric, Washington, DC
Berigan T (2002) Treatment of posttraumatic stress disorder with tiagabine. Can J Psychiatry 47:788
Berlant J, Van Kammen DP (2002) Open-label topiramate as primary or adjunctive therapy in chronic civilian posttraumatic stress disorder: a preliminary report. J Clin Psychiatry 63:15–20
Brady K, Pearlstein T, Asnis GM, Baker D, Rothbaum B, Sikes CR, Farfel GM (2000) Efficacy and safety of sertraline treatment of posttraumatic stress disorder: a randomized controlled trial. JAMA 283:1837–1844
Braun P, Greenberg D, Dasberg H, Lerer B (1990) Core symptoms of posttraumatic stress disorder unimproved by alprazolam treatment. J Clin Psychiatry 51:236–238
Bremner JD, Innis RB, Southwick SM, Staib L, Zoghbi S, Charney DS (2000) Decreased benzodiazepine receptor binding in prefrontal cortex in combat-related posttraumatic stress disorder. Am J Psychiatry 157:1120–1126
Buysse DJ, Reynolds CF III, Monk TH, Berman SR, Kupfer DJ (1989) The Pittsburgh sleep quality index: a new instrument for psychiatric practice and research. Psychiatry Res 28:193–213
Chiu CS, Brickley S, Jensen K, Southwell A, McKinney S, Cull-Candy S, Mody I, Lester HA (2005) GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum. J Neurosci 25:3234–3245
Clark RD, Canive JM, Calais LA, Qualls CR, Tuason VB (1999) Divalproex in posttraumatic stress disorder: an open-label clinical trial. J Trauma Stress 12:395–401
Connor KM, Davidson JR (2001) SPRINT: a brief global assessment of post-traumatic stress disorder. Int Clin Psychopharmacol 16:279–284
Connor KM, Davidson JRT (2003) Development of a new resilience scale: the Connor-Davidson resilience scale (CD-RISC). Depress Anxiety 18:76–82
Connor KM, Sutherland SM, Tupler LA, Malik ML, Davidson JR (1999) Fluoxetine in post-traumatic stress disorder. Randomised, double-blind study. Br J Psychiatry 175:17–22
Couve A, Moss SJ, Pangalos MN (2000) GABAB receptors: a new paradigm in G protein coupling. Mol Cell Neurosci 16:296–312
Davidson JR (2004) Remission in post-traumatic stress disorder (PTSD): effects of sertraline as assessed by the Davidson trauma scale, clinical global impressions and the clinician-administered PTSD scale. Int Clin Psychopharmacol 19:85–87
Davidson JR, Malik MA, Travers J (1997a) Structured interview for PTSD (SIP): psychometric validation for DSM-IV criteria. Depress Anxiety 5:127–129
Davidson JR, Book SW, Colket JT, Tupler LA, Roth S, David D, Hertzberg M, Mellman T, Beckham JC, Smith RD, Davison RM, Katz R, Feldman ME (1997b) Assessment of a new self-rating scale for post-traumatic stress disorder. Psychol Med 27:153–160
Davidson J, Pearlstein T, Londborg P, Brady KT, Rothbaum B, Bell J, Maddock R, Hegel MT, Farfel G (2001a) Efficacy of sertraline in preventing relapse of posttraumatic stress disorder: results of a 28-week double-blind, placebo-controlled study. Am J Psychiatry 158:1974–1981
Davidson JR, Rothbaum BO, van der Kolk BA, Sikes CR, Farfel GM (2001b) Multicenter, double-blind comparison of sertraline and placebo in the treatment of posttraumatic stress disorder. Arch Gen Psychiatry 58:485–492
Davidson JR, Landerman LR, Farfel GM, Clary CM (2002) Characterizing the effects of sertraline in post-traumatic stress disorder. Psychol Med 32:661–670
Davidson JR, Connor KM, Hertzberg MA, Weisler RH, Wilson WH, Payne VM (2005) Maintenance therapy with fluoxetine in posttraumatic stress disorder: a placebo-controlled discontinuation study. J Clin Psychopharmacol 25:166–169
Farrant M, Nusser Z (2005) Variaitions on an inhibitory theme: phasic and tonic activation of GABAA receptors. Nat Rev Neurosci 6:215–229
Fesler FA (1991) Valproate in combat-related posttraumatic stress disorder. J Clin Psychiatry 5:361–364
Fink-Jensen A, Suzdak PD, Swedberg MD, Judge ME, Hansen L, Nielsen PG (1992) The gamma-aminobutyric acid (GABA) uptake inhibitor, tiagabine, increases extracellular brain levels of GABA in awake rats. Eur J Pharmacol 220:197–201
Fujita M, Southwick SM, Denucci CC, Zoghbi SS, Dillon MS, Baldwin RM, Bozhurt A, Kugaya A, Paul N, Verhoeff LG, Seibyl JP, Innis RB (1994) Central type benzodiazepine receptors in Gulf War veterans with posttraumatic stress disorder. Biol Psychiatry 56:95–100
Gelpin E, Bonne O, Peri T, Brandes D, Shalev AY (1996) Treatment of recent trauma survivors with benzodiazepines: a prospective study. J Clin Psychiatry 57:390–394
Guy W (1976) ECDEU assessment manual for psychopharmacology. (ADM) 76–388, US Department of Health, Education, and Welfare. National Institute of Mental Health, Rockville, MD, pp 218–222
Hanchar HJ, Wallner M, Olsen RW (2004) Alcohol effects on gamma-aminobutyric acid type A receptors: are extrasynaptic receptors the answer? Life Sci 76:1–8
Hevers W, Lüddens H (1998) The diversity of GABAA receptors. Pharmcological and elctrophysiological properties of GABAA channel subtypes. Mol Neurobiol 18:35–86
Lipper S, Davidson JR, Grady TA, Edinger JD, Hammett EB, Mahorney SL, Cavenar JO Jr (1986) Preliminary study of carbemazepine in post-traumatic stress disorder. Psychosomatics 27:849–854
Londborg PD, Hegel MT, Goldstein S et al (2001) Sertraline treatment of posttraumatic stress disorder: results of 24 weeks of open-label continuation treatment. J Clin Psychiatry 62:325–331
Marshall RD, Beebe KL, Oldham M, Zaninelli R (2001) Efficacy and safety of paroxetine treatment for chronic PTSD: a fixed-dose, placebo-controlled study. Am J Psychiatry 158:1982–1988
Martenyi F, Brown EB, Zhang H, Prakash A, Koke SC (2002a) Fluoxetine versus placebo in posttraumatic stress disorder. J Clin Psychiatry 63:199–206
Martenyi F, Brown EB, Zhang H, Koke SC, Prakash A (2002b) Fluoxetine v. placebo in prevention of relapse in post-traumatic stress disorder. Br J Psychiatry 181:315–320
Mellman TA, Byers PM, Augenstein JS (1998) Pilot evaluation of hypnotic medication during acute traumatic stress response. J Trauma Stress 11:563–569
Meltzer-Brody S, Connor KM, Churchill E, Davidson JR (2000) Symptom-specific effects of fluoxetine in post-traumatic stress disorder. Int Clin Psychopharmacol 15:227–231
Mody I (2001) Distinguishing between GABAA receptors responsible for tonic and phasic conductances. Neurochem Res 26:907–913
Petty R, Davis LL, Nugent AL, Kramer GL, Teten A, Schmitt A, Stone RC (2002) Valproate therapy for chronic, combat-induced posttraumatic stress disorder. J Clin Psychopharmacol 22:100–101
Randall PK, Bremner JD, Krystal JH, Nagy LM, Heninger GR, Nicolaou AL, Charney DS (1995) Effects of the benzodiazepine antagonist flumazenil in PTSD. Biol Psychiatry 38:319–324
Sheehan D (1983) The anxiety disease. Bantam Books, New York
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The mini-international neuropsychiatric interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59[Suppl 20]:22–33 (quiz 34–570)
Sundtrom I, Ashbrook D, Backstrom T (1997) Reduced benzodiazepine sensitivity in patients with premenstrual syndrome: a pilot study. Psychoneuroendocrinology 22:25–38
Taylor FB (2003) Tiagabine for posttraumatic stress disorder: a case series of 7 women. J Clin Psychiatry 64:1421–1425
Tucker P, Zaninelli R, Yehuda R, Ruggiero L, Dillingham K, Pitts CD (2001) Paroxetine in the treatment of chronic posttraumatic stress disorder: results of a placebo-controlled, flexible-dosage trial. J Clin Psychiatry 62:860–868
Wallner M, Hanchar HJ, Olsen RW (2004) Ethanol enhances alpha 4 beta 3 delta and alpha 6 beta 3 delta fgamma-aminobutyric acid type A receptors at low concentrations known to affect humans. Proc Natl Acad Sci USA 100:15218–15223
Wei W, Faria LC, Mody I (2004) Low ethanol concentrations selectively augment the tonic inhibition mediated by delta subunit-containing GABAA receptors in hippocampal neurons. J Neurosci 24:8379–8382
Wolf ME, Alavi A, Mosnaim AD (1988) Posttraumatic stress disorder in Vietnam veterans: clinical and EEG findings; possible therapeutic effects of carbamazepine. Biol Psychiatry 23:642–644
Zigmond AS, Snaith RP (1983) The hospital anxiety and depression scale. Acta Psychiatr Scand 67:361–370
Acknowledgement
This study was supported by a grant from Cephalon, Inc. to Dr. Davidson. This trial was conducted in compliance with the current laws of the United States.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Connor, K.M., Davidson, J.R.T., Weisler, R.H. et al. Tiagabine for posttraumatic stress disorder: effects of open-label and double-blind discontinuation treatment. Psychopharmacology 184, 21–25 (2006). https://doi.org/10.1007/s00213-005-0265-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-005-0265-3