Research report
A double-blind, placebo-controlled study of the effects of lithium on cognition in healthy subjects: mild and selective effects on learning

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Abstract

Background: Several studies have shown cognitive impairment in short-term memory, long-term memory and psychomotor speed in bipolar patients taking lithium. The aim of the study was to look at the effect of lithium in normal subjects (N=30) taking lithium for 3 weeks. A comprehensive battery was used to assess attention and memory. Methods: Subjects were randomized to double-blind treatment with either lithium (N=15) or placebo (N=15) for a 3-week period. Thirteen participants in the lithium group and 15 in the placebo group completed the study. The lithium and placebo were administered twice daily in doses varying from 1050 to 1950 mg (mean=1569 mg). The initial daily dose was calculated according to the Pepin formula to achieve a blood serum lithium level of about 0.8 mmol/l. Cognitive performance (attention, memory) was assessed in each subjects during three periods, i.e. at baseline, after 3 weeks of lithium or placebo, and 2 weeks after discontinuation of study medication. Results: In short-term memory tasks, the performance of subjects in the lithium group was worst 3 weeks after lithium treatment compared to 2 weeks after discontinuation. In long-term memory, a significantly higher number of words was recalled by the placebo group but not the lithium group. Conclusions. Lithium may have an effect on learning when long-term explicit memory test are administered repeatedly. It means that the practice effect when a subject performs the same task several times is less in the lithium-treated group than in the placebo group. This practice effect is related to the learning of a task.

Introduction

Cognitive impairment is a common complaint among patients taking lithium for treatment of bipolar disorder. This is a significant clinical problem as it often leads to non-compliance with lithium treatment. Although several studies assessed the effects of lithium on cognition (for a recent review, see Dufresne and Stip, 1998), the results have been inconsistent (Bajor, 1977; Ghadirian et al., 1983; Judd, 1979a; Makeeva et al., 1974; Marusarz et al., 1981; Rapp and Thomas, 1979; Runions et al., 1978; Saxena and Mallikarjuna, 1988; Squire et al., 1980). This may be because of many methodological biases and theoretical divergence in the field of cognition. For instance, some studies have been conducted with mood disorder patients and the psychopathology can be a potential confound (Table 1).

One study eliminated mood disorder as a source of variance by assessing the cognitive effects of lithium on normal students during a week (Weingartner et al., 1985). Subjects received lithium with a controlled plasma level and were assessed on free recall and recognition of words. There was no difference in the results except in regard of intrusion errors with the lithium group. Another study with normal subjects showed a global slowing on information processing during 2 weeks (Judd, 1979a, Judd, 1979b).

Lithium is often given for patients for weeks to years but there is no study that assessed the long term effects of lithium. Furthermore, most studies conducted to date were open and hence subject to potential bias. The present study was undertaken to assess the effects of lithium in normal subjects taking lithium during a 3-week period using a double blind placebo controlled design. Their cognitive performance was assessed before (T0), after a 3-week period of treatment with either placebo or lithium (T1), and 2 weeks after discontinuation of study medication (T2). Our hypothesis was that lithium but not the placebo impairs performance on some of the cognitive tasks.

Section snippets

Subjects

Participants were recruited through advertisements in local papers. Individuals were eligible to take part in the study provided they met the following criteria: (1) 18–50 years of age; (2) fluent in French; (3) no heart, thyroid or kidney condition; (4) no psychiatric illness; and (5) no general anesthesia in the past 6 months. The subjects were screened in detail. Full personal and family histories were obtained, and any diagnostic criteria used were taken from the DSM IV. The subjects also

Results

For the alertness, selective attention and sustained attention tasks, the performance of participants corresponded to the median reaction time required to detect the target on the screen. For the divided attention task, the performance of the participants corresponded to the success rate in maintaining the cursor within the box. Regarding the digit span test and the word-pair explicit and implicit recall test, the performance of the participants corresponded to the number of words or digits

Discussion

We were prompted to undertake this study following numerous unsolicited complaints reported by patients treated with lithium, regarding lack of concentration, attention and memory. Our purpose was to determine whether these impairments could be measured objectively under the same conditions of lithium intake as those for stable patients under treatment.

For better understanding these neuropsychological findings, it is necessary to ensure that each task in itself allows to measure a performance

Conclusion

The results of this study suggest that lithium does not impair per se the explicit memory and attention of healthy controls but lithium may have an effect on the learning when the short-term memory test and long-term memory test are administered repeatedly. Although both groups improved their performances on the selective attention test over time as expected but the time when the improvement occurred differed, as there was a latency of this improvement in the group receiving lithium.

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