Advertisement

A Meta-Analysis of D-Cycloserine and the Facilitation of Fear Extinction and Exposure Therapy

      Background

      Translational research suggests that D-cycloserine (DCS), a partial N-methyl-D-aspartate (NMDA) receptor agonist, might facilitate fear extinction and exposure therapy by either enhancing NMDA receptor function during extinction or by reducing NMDA receptor function during fear memory consolidation. This article provides a quantitative review of DCS-augmented fear extinction and exposure therapy literature.

      Methods

      English-language journal articles that examined DCS augmented with fear extinction or exposure therapy were identified through public databases from June 1998 through September 2007, through references of originally identified articles and contact with DCS investigators. Data were extracted for study author, title, and year; trial design; type of subject (animal vs. human; clinical vs. nonclinical); sample size, DCS dose, and timing in relation to extinction/exposure procedures; dependent variable; group means and SDs at post-extinction/exposure; and follow-up outcome.

      Results

      D-cycloserine enhances fear extinction/exposure therapy in both animals and anxiety-disordered humans. Gains generally were maintained at follow-up, although some lessening of efficacy was noted. D-cycloserine was more effective when administered a limited number of times and when given immediately before or after extinction training/exposure therapy.

      Conclusions

      This meta-analysis suggests that DCS is a useful target for translational research on augmenting exposure-based treatment via compounds that impact neuroplasticity. D-cycloserine 's major contribution to exposure-based therapy might be to increase its speed or efficiency, because the effects of DCS seem to decrease over repeated sessions. This information might guide translational researchers in discovering more selective and/or effective agents that effectively enhance (or reduce) NMDA receptor function.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Baker J.D.
        • Azorlosa J.L.
        The NMDA antagonist MK-801 blocks the extinction of Pavlovian fear conditioning.
        Behav Neurosci. 1996; 110: 618-620
        • Royer S.
        • Pare D.
        Bidirectional synaptic plasticity in intercalated amygdala neurons and the extinction of conditioned fear responses.
        Neuroscience. 2002; 115: 455-462
        • Cox J.
        • Westbrook R.F.
        The NMDA receptor antagonist MK-801 blocks acquisition and extinction of conditioned hypoalgesic responses in the rat.
        Q J Exp Psychol B. 1994; 47: 187-210
        • Fanselow M.S.
        • LeDoux J.E.
        Why we think plasticity underlying Pavlovian fear conditioning occurs in the basolateral amygdala.
        Neuron. 1999; 23: 229-232
        • Goosens K.A.
        • Maren S.
        Long-term potentiation as a substrate for memory: Evidence from studies of amygdaloid plasticity and Pavlovian fear conditioning.
        Hippocampus. 2002; 12: 592-599
        • Rogan M.T.
        • Staubli U.V.
        • LeDoux J.E.
        Fear conditioning induces associative long-term potentiation in the amygdala.
        Nature. 1997; 390: 604-607
        • Davis M.
        Role of NMDA receptors and MAP kinase in the amygdala in extinction of fear: Clinical implications for exposure therapy.
        Eur J Neurosci. 2002; 16: 395-398
        • D'Souza D.C.
        • Charney D.S.
        • Krystal J.H.
        Glycine site agonists of the NMDA receptor: A review.
        CNS Drug Reviews. 1995; 1: 227-260
        • Gomperts S.N.
        • Rao A.
        • Craig A.M.
        • Malenka R.C.
        • Nicoll R.A.
        Postsynaptically silent synapses in single neuron cultures.
        Neuron. 1998; 21: 1443-1451
        • Emmett M.R.
        • Mick S.J.
        • Cler J.A.
        • Rao T.S.
        • Iyengar S.
        • Wood P.L.
        Actions of D-cycloserine at the N-methyl-D-aspartate-associated glycine receptor site in vivo.
        Neuropharmacology. 1991; 30: 1167-1171
        • Hood W.F.
        • Compton R.P.
        • Monahan J.B.
        D-cycloserine: A ligand for the N-methyl-D-aspartate coupled glycine receptor has partial agonist characteristics.
        Neurosci Lett. 1989; 98: 91-95
        • Watson G.B.
        • Bolanowski M.A.
        • Baganoff M.P.
        • Deppeler C.L.
        • Lanthorn T.H.
        D-cycloserine acts as a partial agonist at the glycine modulatory site of the NMDA receptor expressed in Xenopus oocytes.
        Brain Res. 1990; 510: 158-160
        • Krystal J.H.
        Neuroplasticity as a target for the pharmacotherapy of psychiatric disorders: New opportunities for synergy with psychotherapy.
        Biol Psychiatry. 2007; 62: 833-834
        • Walker D.L.
        • Ressler K.J.
        • Lu K.T.
        • Davis M.
        Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats.
        J Neurosci. 2002; 22: 2343-2351
        • Ledgerwood L.
        • Richardson R.
        • Cranney J.
        Effects of D-cycloserine on extinction of conditioned freezing.
        Behav Neurosci. 2003; 117: 341-349
        • Ressler K.J.
        • Rothbaum B.O.
        • Tannenbaum L.
        • Anderson P.
        • Graap K.
        • Zimand E.
        • et al.
        Cognitive enhancers as adjuncts to psychotherapy: Use of D-cycloserine in phobic individuals to facilitate extinction of fear.
        Arch Gen Psychiatry. 2004; 61: 1136-1144
        • Hofmann S.G.
        • Meuret A.E.
        • Smits J.A.
        • Simon N.M.
        • Pollack M.H.
        • Eisenmenger K.
        • et al.
        Augmentation of exposure therapy with D-cycloserine for social anxiety disorder.
        Arch Gen Psychiatry. 2006; 63: 298-304
      1. Tolin DF, Pearlson GD, Krystal JH, Davis M, Meunier SA, Brady RS, et al. (2007): A controlled trial of d-cycloserine with brief CBT for panic disorder. Presented at the Annual Meeting of the World Congress of Behavioral and Cognitive Therapies, July 2007, Barcelona, Spain.

      2. Wilhelm S, Buhlmann U, Tolin DF, Meunier SA, Pearlson GD, Reese HE, et al. (2008): D-cycloserine augmentation of behavior therapy for obsessive-compulsive disorder. Am J Psychiatry Epub ahead of print: February 1.

        • Kushner M.G.
        • Kim S.W.
        • Donahue C.
        • Thuras P.
        • Adson D.
        • Kotlyar M.
        • et al.
        D-cycloserine augmented exposure therapy for obsessive-compulsive disorder.
        Biol Psychiatry. 2007; 62: 835-838
        • Davis M.
        • Myers K.M.
        • Ressler K.J.
        • Rothbaum B.O.
        Facilitation of extinction of conditioned fear by d-cycloserine.
        Curr Dir Psychol Sci. 2005; 14: 214-219
        • Davis M.
        Neural systems involved in fear and anxiety measured with fear-potentiated startle.
        Am Psychol. 2006; 61: 741-756
        • Birk L.
        Pharmacotherapy for performance anxiety disorders: Occasionally useful but typically contraindicated.
        J Clin Psychol. 2004; 60: 867-879
        • Davis M.
        • Ressler K.
        • Rothbaum B.O.
        • Richardson R.
        Effects of D-cycloserine on extinction: Translation from preclinical to clinical work.
        Biol Psychiatry. 2006; 60: 369-375
        • Davis M.
        • Walker D.L.
        • Myers K.M.
        Role of the amygdala in fear extinction measured with potentiated startle.
        Ann N Y Acad Sci. 2003; 985: 218-232
        • Garakani A.
        • Mathew S.J.
        • Charney D.S.
        Neurobiology of anxiety disorders and implications for treatment.
        Mt Sinai J Med. 2006; 73: 941-949
        • Gillespie C.F.
        • Ressler K.J.
        Emotional learning and glutamate: Translational perspectives.
        CNS Spectrums. 2005; 10: 831-839
        • Hofmann S.G.
        Enhancing exposure-based therapy from a translational research perspective.
        Behav Res Ther. 2007; 45: 1987-2001
        • Hofmann S.G.
        • Pollack M.H.
        • Otto M.W.
        Augmentation treatment of psychotherapy for anxiety disorders with D-cycloserine.
        CNS Drug Reviews. 2006; 12: 208-217
        • Otto M.W.
        • Basden S.
        • Leyro T.M.
        • McHugh K.M.
        • Hofmann S.G.
        Clinical perspectives on the combination of d-cycloserine and CBT for the treatment of anxiety disorders.
        CNS Spectrums. 2007; 12 (59–61): 51-56
        • Richardson R.
        • Ledgerwood L.
        • Cranney J.
        Facilitation of fear extinction by D-cycloserine: Theoretical and clinical implications.
        Learn Mem. 2004; 11: 510-516
        • Glass G.V.
        • McGaw B.
        • Smith M.L.
        Meta-Analysis in Social Research.
        Sage Publications, London1981
        • Bailey J.E.
        • Papadopoulos A.
        • Lingford-Hughes A.
        • Nutt D.J.
        D-Cycloserine and performance under different states of anxiety in healthy volunteers.
        Psychopharmacology (Berl). 2007; 193: 579-585
        • Britton J.C.
        • Gold A.L.
        • Feczko E.J.
        • Rauch S.L.
        • Williams D.
        • Wright C.I.
        D-cycloserine inhibits amygdala responses during repeated presentations of faces.
        CNS Spectrums. 2007; 12: 600-605
        • Gabriele A.
        • Packard M.G.
        D-Cycloserine enhances memory consolidation of hippocampus-dependent latent extinction.
        Learn Mem. 2007; 14: 468-471
        • Port R.L.
        • Seybold K.S.
        Manipulation of NMDA-receptor activity alters extinction of an instrumental response in rats.
        Physiol Behav. 1998; 64: 391-393
        • van den Bergh F.S.
        • Bloemarts E.
        • Groenink L.
        • Olivier B.
        • Oosting R.S.
        Delay aversion: Effects of 7-OH-DPAT, 5-HT1A/1B-receptor stimulation and D-cycloserine.
        Pharmacol Biochem Behav. 2006; 85: 736-743
        • Van Vleet T.M.
        • Heldt S.A.
        • Pyter B.
        • Corwin J.V.
        • Reep R.L.
        Effects of light deprivation on recovery from neglect and extinction induced by unilateral lesions of the medial agranular cortex and dorsocentral striatum.
        Behav Brain Res. 2003; 138: 165-178
        • VanVleet T.M.
        • Heldt S.A.
        • Guerrettaz K.R.
        • Corwin J.V.
        • Reep R.L.
        Unilateral destruction of the dorsocentral striatum in rats produces neglect but not extinction to bilateral simultaneous stimulation.
        Behav Brain Res. 2002; 136: 375-387
        • Bertotto M.E.
        • Bustos S.G.
        • Molina V.A.
        • Martijena I.D.
        Influence of ethanol withdrawal on fear memory: Effect of D-cycloserine.
        Neuroscience. 2006; 142: 979-990
        • Botreau F.
        • Paolone G.
        • Stewart J.
        D-Cycloserine facilitates extinction of a cocaine-induced conditioned place preference.
        Behav Brain Res. 2006; 172: 173-178
        • Kelley J.B.
        • Anderson K.L.
        • Itzhak Y.
        Long-term memory of cocaine-associated context: Disruption and reinstatement.
        Neuroreport. 2007; 18: 777-780
        • Akirav I.
        NMDA Partial agonist reverses blocking of extinction of aversive memory by GABA(A) agonist in the amygdala.
        Neuropsychopharmacology. 2007; 32: 542-550
        • Yang Y.L.
        • Chao P.K.
        • Ro L.S.
        • Wo Y.Y.
        • Lu K.T.
        Glutamate NMDA receptors within the amygdala participate in the modulatory effect of glucocorticoids on extinction of conditioned fear in rats.
        Neuropsychopharmacology. 2007; 32: 1042-1051
        • Ledgerwood L.
        • Richardson R.
        • Cranney J.
        D-cycloserine and the facilitation of extinction of conditioned fear: Consequences for reinstatement.
        Behav Neurosci. 2004; 118: 505-513
        • Guastella A.J.
        • Lovibond P.F.
        • Dadds M.R.
        • Mitchell P.
        • Richardson R.
        A randomized controlled trial of the effect of D-cycloserine on extinction and fear conditioning in humans.
        Behav Res Ther. 2007; 45: 663-672
        • Mao S.C.
        • Hsiao Y.H.
        • Gean P.W.
        Extinction training in conjunction with a partial agonist of the glycine site on the NMDA receptor erases memory trace.
        J Neurosci. 2006; 26: 8892-8899
        • Tomilenko R.A.
        • Dubrovina N.I.
        Effects of activation and blockade of NMDA receptors on the extinction of a conditioned passive avoidance response in mice with different levels of anxiety.
        Neurosci Behav Physiol. 2007; 37: 509-515
        • Yang Y.L.
        • Lu K.T.
        Facilitation of conditioned fear extinction by d-cycloserine is mediated by mitogen-activated protein kinase and phosphatidylinositol 3-kinase cascades and requires de novo protein synthesis in basolateral nucleus of amygdala.
        Neuroscience. 2005; 134: 247-260
        • Guastella A.J.
        • Richardson R.
        • Lovibond P.F.
        • Rapee R.M.
        • Gaston J.E.
        • Mitchell P.
        • Dadds M.R.
        A randomised controlled trial of d-cycloserine enhancement of exposure therapy for social phobia.
        Biol Psychiatry. 2007; 63: 544-549
        • Heimberg R.G.
        • Horner K.J.
        • Juster H.R.
        • Safren S.A.
        • Brown E.J.
        • Schneier F.R.
        • Liebowitz M.R.
        Psychometric properties of the Liebowitz Social Anxiety Scale.
        Psychol Med. 1999; 29: 199-212
        • Cohen J.
        Statistical Power Analysis for the Behavioral Sciences.
        2nd ed. Lawrence Erlbaum Associates, Hillsdale, New Jersey1988
        • Rosenthal R.
        Meta-Analytic Procedures for Social Research.
        Sage Publications, London1991
        • Storch E.A.
        • Merlo L.J.
        • Bengtson M.
        • Murphy T.K.
        • Lewis M.H.
        • Yang M.C.
        • et al.
        D-cycloserine does not enhance exposure-response prevention therapy in obsessive-compulsive disorder.
        Int Clin Psychopharmacol. 2007; 22: 230-237
        • Guastella A.J.
        • Dadds M.R.
        • Lovibond P.F.
        • Mitchell P.
        • Richardson R.
        A randomized controlled trial of the effect of d-cycloserine on exposure therapy for spider fear.
        J Psychiatr Res. 2007; 41: 466-471
        • U.S. Food and Drug Administration
        Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers.
        U.S. Food and Drug Administration, Rockville, Maryland2005
        • Parnas A.S.
        • Weber M.
        • Richardson R.
        Effects of multiple exposures to D-cycloserine on extinction of conditioned fear in rats.
        Neurobiol Learn Mem. 2005; 83: 224-231
        • Margraf J.
        • Barlow D.H.
        • Clark D.M.
        • Telch M.J.
        Psychological treatment of panic: Work in progress on outcome, active ingredients, and follow-up.
        Behav Res Ther. 1993; 31: 1-8
        • Clark D.M.
        • Salkovskis P.M.
        • Hackmann A.
        • Middleton H.
        • Anastasiades P.
        • Gelder M.
        A comparison of cognitive therapy, applied relaxation and imipramine in the treatment of panic disorder.
        Br J Psychiatry. 1994; 164: 759-769
        • Brown T.A.
        • Barlow D.H.
        Long-term outcome in cognitive-behavioral treatment of panic disorder: Clinical predictors and alternative strategies for assessment.
        J Consult Clin Psychol. 1995; 63: 754-765
        • Davidson J.R.
        • Foa E.B.
        • Huppert J.D.
        • Keefe F.J.
        • Franklin M.E.
        • Compton J.S.
        • et al.
        Fluoxetine, comprehensive cognitive behavioral therapy, and placebo in generalized social phobia.
        Arch Gen Psychiatry. 2004; 61: 1005-1013
        • Foa E.B.
        • Liebowitz M.R.
        • Kozak M.J.
        • Davies S.
        • Campeas R.
        • Franklin M.E.
        • et al.
        Randomized, placebo-controlled trial of exposure and ritual prevention, clomipramine, and their combination in the treatment of obsessive-compulsive disorder.
        Am J Psychiatry. 2005; 162: 151-161
        • Barlow D.H.
        • Gorman J.M.
        • Shear M.K.
        • Woods S.W.
        Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: A randomized controlled trial.
        JAMA. 2000; 283: 2529-2536
        • Marks I.M.
        • Swinson R.P.
        • Basoglu M.
        • Kuch K.
        • Noshirvani H.
        • O'Sullivan G.
        • et al.
        Alprazolam and exposure alone and combined in panic disorder with agoraphobia.
        Br J Psychiatry. 1993; 162: 776-787
        • Ledgerwood L.
        • Richardson R.
        • Cranney J.
        D-cycloserine and the facilitation of extinction of conditioned fear: Consequences for reinstatement.
        Behav Neurosci. 2004; 118: 505-513
        • Ledgerwood L.
        • Richardson R.
        • Cranney J.
        D-cycloserine facilitates extinction of learned fear: Effects on reacquisition and generalized extinction.
        Biol Psychiatry. 2005; 57: 841-847
        • Santini E.
        • Muller R.U.
        • Quirk G.J.
        Consolidation of extinction learning involves transfer from NMDA-independent to NMDA-dependent memory.
        J Neurosci. 2001; 21: 9009-9017
        • Weber M.
        • Hart J.
        • Richardson R.
        Effects of D-cycloserine on extinction of learned fear to an olfactory cue.
        Neurobiol Learn Mem. 2007; 87: 476-482
        • Randolph C.
        • Roberts J.W.
        • Tierney M.C.
        • Bravi D.
        • Mouradian M.M.
        • Chase T.N.
        D-cycloserine treatment of Alzheimer disease.
        Alzheimer Dis Assoc Disord. 1994; 8: 198-205
        • Tuominen H.J.
        • Tiihonen J.
        • Wahlbeck K.
        Glutamatergic drugs for schizophrenia: A systematic review and meta-analysis.
        Schizophr Res. 2005; 72: 225-234
        • Goff D.C.
        • Tsai G.
        • Levitt J.
        • et al.
        A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia.
        Arch Gen Psychiatry. 1999; 56: 21-27
        • Goff D.C.
        • Coyle J.T.
        The emerging role of glutamate in the pathophysiology and treatment of schizophrenia.
        Am J Psychiatry. 2001; 158: 1367-1377
        • Tsai G.E.
        • Falk W.E.
        • Gunther J.
        • Coyle J.T.
        Improved cognition in Alzheimer's disease with short-term D-cycloserine treatment.
        Am J Psychiatry. 1999; 156: 467-469
        • Goff D.C.
        • Herz L.
        • Posever T.
        • et al.
        A six-month, placebo-controlled trial of D-cycloserine co-administered with conventional antipsychotics in schizophrenia patients.
        Psychopharmacology (Berl). 2005; 179: 144-150
        • Duncan E.J.
        • Szilagyi S.
        • Schwartz M.P.
        • Bugarski-Kirola D.
        • Kunzova A.
        • Negi S.
        • et al.
        Effects of D-cycloserine on negative symptoms in schizophrenia.
        Schizophr Res. 2004; 71: 239-248
        • Fakouhi T.D.
        • Jhee S.S.
        • Sramek J.J.
        • Benes C.
        • Schwartz P.
        • Hantsburger G.
        • et al.
        Evaluation of cycloserine in the treatment of Alzheimer's disease.
        J Geriatr Psychiatry Neurol. 1995; 8: 226-230
      3. Laake K, Oeksengaard AR (2002): D-cycloserine for Alzheimer's disease. Cochrane Database Syst Rev (2):CD003153.

        • Boje K.M.
        • Wong G.
        • Skolnick P.
        Desensitization of the NMDA receptor complex by glycinergic ligands in cerebellar granule cell cultures.
        Brain Res. 1993; 603: 207-214
        • Werner-Seidler A.
        • Richardson R.
        Effects of D-cycloserine on extinction: Consequences of prior exposure to imipramine.
        Biol Psychiatry. 2007; 62: 1195-1197
        • Foa E.B.
        • Hembree E.A.
        • Cahill S.P.
        • Rauch S.A.
        • Riggs D.S.
        • Feeny N.C.
        • Yadin E.
        Randomized trial of prolonged exposure for posttraumatic stress disorder with and without cognitive restructuring: Outcome at academic and community clinics.
        J Consult Clin Psychol. 2005; 73: 953-964
        • Lee J.L.
        • Milton A.L.
        • Everitt B.J.
        Reconsolidation and extinction of conditioned fear: Inhibition and potentiation.
        J Neurosci. 2006; 26: 10051-10056
        • Woods A.M.
        • Bouton M.E.
        D-cycloserine facilitates extinction but does not eliminate renewal of the conditioned emotional response.
        Behav Neurosci. 2006; 120: 1159-1162
        • Wolpe J.
        The Practice of Behavior Therapy.
        4th ed. Pergamon Press, New York1990
        • Mattick R.P.
        • Clarke J.C.
        Development and validation of measures of social phobia scrutiny fear and social interaction anxiety.
        Behav Res Ther. 1998; 36: 455-470
        • Shear M.K.
        • Brown T.A.
        • Barlow D.H.
        • Money R.
        • Sholomskas D.E.
        • Woods S.W.
        • et al.
        Multicenter collaborative panic disorder severity scale.
        Am J Psychiatry. 1997; 154: 1571-1575
        • Goodman W.K.
        • Price L.H.
        • Rasmussen S.A.
        • Mazure C.
        • Fleischmann R.L.
        • Hill C.L.
        • et al.
        The Yale-Brown Obsessive Compulsive Scale.
        Arch Gen Psychiatry. 1989; 46: 1006-1011