Antimnemonic Therapy for Hypermemory Syndromes

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In a rare attempt at clinically inhibiting memory, Pitman et al.(Bio). Psychiatry 51:189-192, 2002) administered propranolol with the aim of preventing the onset of PTSD. This study was designed on the basis of preclinical research showing that post-training propranolol administration blocked the consolidation of emotion-related memory in rats (Cahill et al., 2000). Within 6 hours of experiencing an acute psychologically traumatic event, patients at risk for PTSD began a 10-day course of propranolol, 40 mg, or placebo four times daily. When assessed 3 months after the trauma, ratings of PTSD symptoms were slightly, but significantly, lower in propranolol-treated patients. Propranolol was not administered in association with memory reactivation as in the present invention, which provides a novel treatment for already established PTSD. The results of Pitman et al. , supra, may have been more favorable if propranolol was administered in conjunction with cue-, psychotherapy-, or homework-induced memory reactivation as in the embodiments described below.

Behavioral disorders such as drug and alcohol addiction have been treated with very limited success using the "cue elicited craving paradigm." The existing version of the cue-elicited craving paradigm involves presenting addicts with drug-related cues designed to elicit craving. This paradigm has aimed to habituate the craving response by repeatedly presenting these cues. This particular paradigm has at least three obvious disadvantages: 1) No olfactory cues: Clinical experience with drug addicts and alcoholics suggests that olfactory cues are particularly potent triggers of craving ; 2) Small scope of cues: The cues typically presented in laboratory or clinical settings probably represent only a small subset of the many drug-related cues encountered by addicts in their everyday lives. 3) No antimnemonic drug treatment: Finally, and most importantly, current cue-elicited craving paradigms rarely have been combined with drug treatments designed to accelerate the habituation process and antimnemonic drugs have not been employed.

Repetitive transcranial magnetic stimulation (rTMS) was recently developed as a noninvasive method of altering the excitability of neuronal circuitry in the brain. Preliminary studies of patients with focal dystonia, epilepsy, PTSD, depression, or schizophrenia have revealed modest symptom reductions after rTMS treatment . rTMS might decrease excitability in neuronal pathways mediating the presently hypothesized entrenched memory consolidation underlying hypermemory disorders. However, it is not clear if these memory-related neuronal pathways can be selectively affected by rTMS administered from the scalp. Nader et al. proposed that a selective reversal of memory-related mechanisms mediated the anisomycin-induced inhibition of reconsolidation in the fear conditioning paradigm. A number of behavioral disorders (e.g., anxiety disorders, borderline personality disorder, and drug or alcohol addiction) have been treated with varying degrees of success by repeatedly exposing patients to situations that elicit symptoms of these disorders (Barlow DH, Ed., Clinical Handbook of Psychological Disorders: A Step-by-Step Treatment Manual, 3rd Ed. New York: Guilford Press, 2001). This exposure treatment aims to induce extinction of the tendency for patients to respond to these situations with increased symptoms. Animal models of anxiety disorders have been used to screen for drugs that promote the extinction of conditioned fear. For example, D-cycloserine, a drug that promotes NMDA receptor activity, was recently found to facilitate the extinction of conditioned fear (Davis M. Biol. Psychiatry 51:1S, 2002; Walker DL. J. Neurosci. 22:2343-2351, 2002). Based on this preclinical research, clinical trials have begun using D- cycloserine with the aim of promoting extinction during exposure therapy for anxiety disorders (Davis, supra). However, an obstacle for this treatment approach is that symptoms of anxiety disorders can show resistance to extinction (Poulton R, et al. Behav. Res. Ther. 39:29-43, 2001; Poulton R and Menzies RG. Res. Then 40:197-208, 2002). Furthermore, extinction is a learning process that masks, but does not erase, memories potentially involved in generating symptoms of behavioral disorders.

Like other forms of learning, extinction is blocked by NMDA receptor antagonists, which is a class of antimnemonic drugs used in the present invention. Thus, a course of antimnemonic therapy described herein may tend to block extinction while producing the more important effect of erasing symptom-generating memories. The net effect would be reduced symptoms with no need for extinction because an effective erasure of symptom-related memories would leave nothing to be extinguished.