Gfp et al: this is the discussion and conclusion of the recent ORG24448 trial at 500mg. Note in the discussion the distinction b/w side effects and lack of side effects and obvious and printed inference that lower dosages should be tested. Here it is:
Discussion: This is the first study to show effects of the ampakine farampator on memory and information processing. The results revealed that 500 mg farampator caused a clear-cut improvement in the short-term memory of healthy elderly volunteers, but appeared to impair episodic memory. In addition, it was found that the plasma levels of participants that reported SEs was higher than the levels found for the participants that did not experience any SEs. Post hoc analyses revealed that in contrast to placebo, farampator had selectively improved the memory performance in the group without SEs and not in the group with SEs.
Modulation of Cognitive Processes
Memory
Short-term memory was clearly enhanced after farampator: in the SDRT the drug always led to a superior performance, irrespective of the presence or absence of SEs, although the participants without SEs performed significantly better than the group with SEs.
Initially, the analyses of the episodic memory data generated negative effects of farampator both in the delayed recall conditions and in the recognition of verbal material. Supplementary analyses, however, revealed that the impairments predominantly occurred in the delayed free recall of the verbal material in the subjects that had reported drug-induced SEs; the effect was not found in the word recognition condition.
Analysis of the motor learning data initially yielded comparable results in that no effects were found when farampator was compared to placebo. Post hoc analyses demonstrated, however, that the presence of SEs had negatively affected maze learning in the farampator condition. The group without SEs showed a gradual increase in the number of loops they produced in the course of the test, indicating normal learning, whereas the group that had reported SEs did not show such progress in their performance.
The positive effects of farampator on memory are in line with the results for CX516 in human volunteers reported in the literature (Lynch, 2004). More important, although perhaps not surprising, was our finding that performance improvements tended to be dependent on the absence or presence of (subjective) side effects. Earlier studies had demonstrated that distractions (eg feeling unwell) could negatively affect performance because they tend to decrease concentration or divide attention (Carver, 1994; Lezak, 1995; Meyer et al, 2000; Schmidt and Lee, 1999). The adverse drug reactions that were reported in a study using high doses (900–1200 mg) of CX516 included mild headache, salivation and/or swallowing reactions and spontaneous leg movements (Lynch et al, 1996). Hence, barring headache, the adverse reactions our participants reported after farampator appear new, although it needs to be noted that to date reports on adverse reactions to ampakines are scarce. Our experimental setting, that is the long test days, the number of tests, the double-blind treatment and strange hospital environment, was likely to induce some tiredness and anxiety and perhaps even somnolence, headache, or nausea. To exclude the study environment as a cause for the SEs, the effects of the SEs reported for placebo were analyzed carefully. Apart from a few minor nonsignificant effects, they proved not to have affected performance. Although we did not explicitly check for the nature of placebo-related SEs, nor the intensity, time of onset and duration on performance, it is likely that they persisted less long and were less intense to have caused any effect on performance.
The overall lack of a positive effect of farampator on the episodic memory measures used in this study was unexpected. It was especially surprising for the VMT as in other studies using the ampakine CX516, it had been a nonsense syllable test that had generated the strongest effects (Lynch et al, 1996, 1997). It should be noted, however, that only those participants that had experienced SEs had shown a decrement in their performance. Moreover, this group proved to have higher plasma levels, which may imply that the beneficial effects on memory of ampakines are nonlinear, or that they are counteracted by the appearance of SE's at higher plasma levels. This may mean that improvements in performance are only induced by an optimal plasma level of farampator and that the dose of farampator may have been too high for some of the elderly subjects in this study.
Another tentative explanation for the negative results is that our memory tests may have been too difficult for this age-group. We opted for 18-item word lists and a set of 16 pictographs to prevent ceiling effects and to create a state of pseudo-dementia. However, lists comprising a maximum of ten items are more common in neuropsychological research in elderly subjects (Bouma et al, 1998; Lezak, 1995). It should be noted, though, that all the participants did show the expected learning curves in both the placebo and the drug conditions of the memory tasks.
Information processing
The effects of farampator on information processing are somewhat more subtle than its effects on memory. No significant effects were found in the first drug-placebo comparisons, although in the CTMT there was a trend indicating a decrease in the number of switching errors. This effect will be discussed in more detail in the section on ampakines for the treatment of schizophrenia.
The post hoc analyses also did not generate significant effects for the SDST, although it did reveal a trend: the participants without SEs were faster in matching the correct numbers to the symbols in the farampator condition than those with SEs.
For the tangle task, measuring more visuospatial processes, our extra analyses failed to detect a difference between the participants with or without SEs. Also in the CTMT, which requires matching as well as set-shifting skills, no significant effects were found although in the group without SEs the number of correctly connected letters and numbers proved to have increased noticeably in the farampator condition.
As ours are the first data reflecting the effects of an ampakine on information processing, it is not possible to compare the present results with other data from literature. To date, attention has mainly been focused on memory tests to examine cognitive effects of ampakines. One study did assess psychomotor performance with a finger tapping test and a digit cancellation test (Ingvar et al, 1997) but could not report any effects. The tests applied in the present study contained more prominent cognitive components than motor-speed components.
Ampakines and Schizophrenia
The positive results on short-term memory and the favorable trends in the trail making test (CTMT) are of interest in view of the development of farampator for schizophrenia. Memory is one of the cognitive domains that are found to be frequently impaired in schizophrenia (Nuechterlein et al, 2004). Although the CTMT version we used is considered as a test for processing speed (Nuechterlein et al, 2004), it also measures another process due to the necessity to shift continuously between numbers and letters. It is well known that set-shifting is also often disturbed in schizophrenia (Donohoe and Robertson, 2003; Pantelis et al, 1999) and it has even been identified as a predictor of relapse in first-episode schizophrenia (Chen et al, 2005).
Interestingly, in animal research it has been established that AMPA and NMDA receptors are essential in facilitating working memory and set-shifting. Schmitt et al (2005) demonstrated that gene-targeted mice lacking the AMPA receptor subunit GluR-A have deficits in hippocampal long-term potentiation (LTP) and spatial working memory deficits. In their study Stefani et al (2003) showed that blockage of AMPA receptors in the medial prefrontal cortex impaired set shifting in a maze-based task where rats were required to switch between brightness and texture discrimination strategies.
Suggestions for Future Research
The present study compared farampator with placebo at a single-dose level. It would be interesting to see whether future research will replicate these findings at other doses, with special emphasis on the lower doses, as the present findings indicate that impairments are more likely to occur at the higher plasma levels of farampator, which also induce side effects. It would also be worthwhile to study the effects of ampakines in other age-groups than the healthy elderly subjects of the current study. It is known that aging causes neurobiological changes, including metabolic and neurochemical changes, as well as changes in functional circuitry (Li and Dinse, 2002). Possibly, the interaction of SEs with drug-condition is partly caused for a large part by the slower metabolic processes in older age.
As farampator was developed to ameliorate the cognitive deficits seen in schizophrenia, the experimental results of the present study using healthy volunteers need to be compared with the findings from randomized controlled studies with patients.
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CONCLUSION
Farampator has a significant, positive effect on short-term memory functioning in healthy, elderly volunteers, regardless of plasma level or SEs. In addition, a modest reduction of errors was found in a set-switching task. In the participants that did experience side effects, episodic memory was impaired, but in subjects that did not experience side effects memory processes tended to be enhanced, though this did not reach the significance level.
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Notes
Conflict of interest
Funding for the study was provided by NV Organon.
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