Future Prospects: Ampakines

An additional group of medications that may be helpful in children, and perhaps adults with FXS, are the ampakines. These medications are modulators of dl-alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors of glutamate stimulation. They can increase the amplitude and prolong the duration of AMPA responses in slices of hippocampus (Staubli et al. 1994). Ampakines enhance fast excitatory synaptic responses in the hippocampus and rapidly cross the blood-brain barrier. Because they augment glutamatergic synaptic responses, they can facilitate the induction of long-term potentiation and perhaps enhance memory and cognitive function in those with developmental disabilities.

Studies in rats have shown that ampakine compounds improve olfactory learning, facilitate acquisition of a conditioned fear response, improve short-term memory, reverse age-associated memory impairment in middle-aged rats, reduce spontaneous unmotivated exploratory activity in familiar environments, increase speed at which rats collect rewards in a spatial maze, and improve methamphetamine-induced hyperactivity and stereotypic behavior (Granger et al. 1993, 1996; Hampson et al. 1998; Staubli et al. 1994; Larson et al. 1996). Many of the ampakine studies in rats and humans have utilized a benzamide compound CX516 (1-quinoxalin-6-ylcarbonyl piperidine). Although this compound has a shorter half-life and lowered potency compared to newer ampakines, it has shown relative safety in human trials. In young adult men, CX516, in doses in the 600- to 1,200-mg range, helped delayed recall of nonsense words but not immediate recall, compared to controls (Lynch et al. 1996). There were no significant changes in mood or arousal as determined by self-report questionnaires after the use of CX516. A study by Ingvar et al. (1997) found improvement in visual associations, recognition of odors, and visuospatial information in a maze task in young adult males given 300 mg of CX516 per day. Improvement in a finger-tapping task and in a digit cancellation task was not seen, nor were changes in mood reported by the subjects who took CX516 (Ingvar et al. 1997). Improvements in delayed recall have been reported in elderly human subjects (65-76 years old) given CX516 (Lynch et al. 1997). With doses up to 900 mg of CX516 per day, a twofold improvement was seen 75 minutes posttreatment, but this seemed to diminish by 135 minutes after the dose.

Update on Ampakine Studies
- July 2006 –

Elizabeth Berry Kravis, MD, PhD
RUSH University Medical Center

The Ampakine trial with AMPA receptor activator CX516 has now been completed. This trial was funded by the FRAXA Research Foundation and in part by the UC Davis M.I.N.D. Institute for subjects enrolled by Dr. Randi Hagerman at the UC Davis site. The research was initiated because of findings of reduced AMPA receptors and AMPA-mediated LTP (long term potentiation; a form of memory) in cerebral cortex of the fragile knockout mouse. The trial consisted of a Phase II 4-week randomized double-blind placebo-controlled clinical trial which was conducted to evaluate the safety and efficacy of the Ampakine CX516 as a potential treatment to correct the deficient AMPA activity as a means of treating the underlying brain disorder in fragile X syndrome (FXS). After baseline screening, 49 subjects with FXS underwent a one-week placebo lead-in, then were treated with study drug or placebo for 4 weeks. There were minimal side effects in the subjects with FXS who were treated with CX516, no significant changes in safety parameters, and no serious adverse events. There was a 12.5% frequency of allergic rash in the CX516 group and one subject developed a substantial rash. There was also no significant improvement in memory, the primary outcome measure, or in secondary measures of language, attention/executive function, behavior, and overall functioning in CX516-treated subjects compared to placebo. This study did demonstrate that many outcome measures were reproducible in this test-retest setting for the FXS population, yet some were too difficult or variable. Outcome measures (tests that measure improvement due to medication effect) that were shown to be reproducible will now be able to be used for future clinical trials of new medications in FXS. The study also showed that adult subjects with FXS were able to complete an intensive clinical trial with an excellent completion rate for all the tests required by the trial. Problems with potency of CX516 in other studies have suggested dosing may have been inadequate for therapeutic effect. In fact, when only subjects treated with an antipsychotic upon entering the CX516 study were analyzed, there appeared to be improvement in global cognitive and behavioral functioning in the CX516-treated group relative to the placebo group. Given the known ability of antipsychotics to potentiate the effect of CX516 in animal models, this would suggest that the CX516 was likely insufficiently potent. Thus it remains unclear whether modulation of AMA-mediated neurotransmission is a viable therapeutic strategy for the treatment of FXS, but given the lack of major safety problems with CX516, and suggestion of effectiveness when combined with antipsychotics, it would be reasonable to propose further trials with more potent Ampakine molecules in the future.

This article is not intended to give medical advice for individual cases.  Any change in medical treatment should be done in consultation with appropriate medical personnel. This article is written for medical professionals.  Some of the terms will be unfamiliar to those who are not trained in medical fields. *This article is from the chapter on treatment in the 3rd edition of Fragile X Syndrome: Diagnosis, Treatment, and Research edited by Randi Jenssen Hagerman, M.D. and Paul Hagerman, M.D., Ph.D., to be published May 2002.  It is included with permission from The Johns Hopkins University Press. References to other chapters refer to chapters in the book which are not included as part of this website. The complete 3rd edition of Fragile X Syndrome: Diagnosis, Treatment, and Research can be ordered from the National Fragile X Foundation by calling 1-800-688-8765 or from The Johns Hopkins University Press at 1-800-537-5487.

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