Nicotine treatment of mild cognitive impairment: a 6-month double-blind pilot clinical trial

Abstract

Objective: To preliminarily assess the safety and efficacy of transdermal nicotine therapy on cognitive performance and clinical status in subjects with mild cognitive impairment (MCI).

Methods: Nonsmoking subjects with amnestic MCI were randomized to transdermal nicotine (15 mg per day or placebo) for 6 months. Primary outcome variables were attentional improvement assessed with Connors Continuous Performance Test (CPT), clinical improvement as measured by clinical global impression, and safety measures. Secondary measures included computerized cognitive testing and patient and observer ratings.

Results: Of 74 subjects enrolled, 39 were randomized to nicotine and 35 to placebo. 67 subjects completed (34 nicotine, 33 placebo). The primary cognitive outcome measure (CPT) showed a significant nicotine-induced improvement. There was no statistically significant effect on clinician-rated global improvement. The secondary outcome measures showed significant nicotine-associated improvements in attention, memory, and psychomotor speed, and improvements were seen in patient/informant ratings of cognitive impairment. Safety and tolerability for transdermal nicotine were excellent.

Conclusion: This study demonstrated that transdermal nicotine can be safely administered to nonsmoking subjects with MCI over 6 months with improvement in primary and secondary cognitive measures of attention, memory, and mental processing, but not in ratings of clinician-rated global impression. We conclude that this initial study provides evidence for nicotine-induced cognitive improvement in subjects with MCI; however, whether these effects are clinically important will require larger studies.

Classification of evidence: This study provides Class I evidence that 6 months of transdermal nicotine (15 mg/day) improves cognitive test performance, but not clinical global impression of change, in nonsmoking subjects with amnestic MCI.

Figures

Figure 1. Study design, subject allocation, and subject course

AD = Alzheimer disease; AE = adverse event.

Figure 2. Primary efficacy variables

(A) Continuous Performance Task: hit reaction time standard error change over interstimulus intervals, change from baseline (n = 67). Nicotine treatment significantly improved performance on this measure (F1,57 = 14.96, p = 0.0003) compared to placebo treatment. (B) Clinical Global Impression of Change (CGIC). CGIC all categories (n = 67): there was no statistical difference between treatments in the distribution of subjects rated improved or not improved (p = 0.13).

Figure 3. Secondary verbal memory cognitive performance variables

(A) Paragraph recall: immediate recall minus delay recall; change from baseline (n = 67). Note that negative score indicates improvement (less forgetting from immediate to delay trials). Nicotine treatment produced a significant (F1,60 = 4.42, p = 0.04) effect showing reduced loss of information between the immediate and delayed trials compared to the placebo-treated group. (B) Delayed word recall accuracy, Cognitive Drug Research Battery. Change from baseline (n = 67). There was a significant effect of nicotine treatment (F1,70 = 5.92, p = 0.018) with the nicotine-treated group showing a significant improvement over time in delayed word recall accuracy compared to the placebo group.