A popular anti-insomnia medication, zolpidem (Ambien, sanofi-aventis US), increases the ability to remember images, but only those that have negative or highly arousing content, new research shows.

Investigators at the University of California, Riverside, improved memory by pharmacologically manipulating sleep in 28 healthy volunteers.

Although the participants did not have sleep problems, study coauthor Sara Mednick, PhD, said that the findings have potential ramifications for patients prescribed zolpidem for relief of insomnia due to anxiety disorders, including posttraumatic stress disorder (PTSD).

"Physicians should watch out for this countertherapeutic effect in patients with anxiety disorders and PTSD," Dr. Mednick told Medscape Medical News. "These are people who already have heightened memory for negative and high-arousal memories."

She cautioned, however, that it is premature to warn patients taking this drug of the potential for increased recollection of sad, frightening, or stimulating memories, saying further research is needed.

The findings were published online June 14 in the Journal of Cognitive Neuroscience.

Manipulating Memory

The study also identified sleep "spindles" as the mechanism that enables the brain to consolidate emotional memory. Sleep spindles are brief bursts of brain activity that occur primarily during non–rapid eye movement (REM) sleep.

Previously, Dr. Mednick and colleagues found that sleep spindles play a critical role in consolidating information from short-term to long-term memory. Other researchers have focused on REM sleep as key to emotional memory, but Dr. Mednick's group found in the current study that sleep spindles, not REM sleep, affect emotional memory.

These findings give hope that memory can be manipulated in positive ways, said William Kohler, MD, a spokesman for the American Academy of Sleep Medicine in Darien, Illinois, and the medical director of Florida Sleep Institute in Spring Hill, Florida.

Dr. Kohler, who was not involved in the study, told Medscape Medical News, "The more we know about the processes in memory, the better our ability to intervene clinically in patients with emotional problems and memory problems such as dementia — patients who have a high prevalence of insomnia."

The study included 15 men and 13 women, aged 18 to 39 years, all of whom were normal sleepers. The researchers used 2 hypnotic medications, zolpidem and sodium oxybate (Xyrem, Jazz Pharmaceuticals, Inc.), to pharmacologically manipulate sleep spindle density, which they defined as the number of spindles in stage 2 divided by the minutes of stage 2.

The authors note that previous research has shown that zolpidem increased spindle activity, whereas sodium oxybate decreased it.

On 3 separate occasions in this crossover design, the participants received, in an order that was "counterbalanced across participants," 10 mg of zolpidem orally, 2.5 g of sodium oxybate, or a placebo, with at least 5 days between study days to allow for drug washout.

On the study days and 2 days before, participants reportedly did not consume alcohol, caffeine, or stimulants.

Participants performed a memory test before and after a 90-minute morning nap in a polysomnography-monitored sleep laboratory, where they had spent the preceding night.

To encode memories before the nap, participants viewed on a computer monitor 100 target images, 20 from each of 5 stimulus groups known to evoke positive, negative, or neutral responses.

The groups were as follows: (1) positive, low arousal, which Dr. Mednick said included an image of a kitten; (2) positive, high arousal, such as a picture of a roller coaster; (3) negative, low arousal, for instance, an image of people gathered around a grave site; (4) negative, high arousal, such as a picture of a snake about to attack; and (5) neutral images, such as a tree.

Participants received the study drug immediately before the nap. Several hours after their nap, they performed a memory retrieval test, which involved viewing the same 100 target images, which were randomly rearranged and mixed with 100 new, irrelevant images.

A computer prompt asked them to respond by indicating how certain they were that the image was old or new, to determine memory accuracy ("memory discriminability").

Ceiling Effect

Electroencephalography tracked sleep spindles in stage 2 sleep, with the electrodes at C3 and C4 positions.

Sleep spindles, Dr. Mednick said, appeared to be vital for enhancing emotional memory. The participants' sleep spindle density was significantly higher when they received zolpidem before sleep and significantly lower with sodium oxybate compared with placebo. Reported results (mean ± standard deviation) were 3.23 ± 1.38 for zolpidem, 1.93 ± 1.24 for sodium oxybate, and 2.67 ± 1.58 for placebo (F[degrees of freedom 2, 54] = 13.18; P < .001, 1-way analysis of variance).

In contrast, memory accuracy was significantly better in zolpidem-enriched sleep (P = .005) vs placebo, but not significantly better with sodium oxybate, the researchers reported.

They found, however, that increasing sleep spindle density was associated with increased memory accuracy for highly arousing and negative stimuli only when the participants received sodium oxybate.

The authors suggested that the lack of a significant positive correlation between spindle density and memory accuracy with zolpidem might be because that drug does not produce a great enough range of spindles, creating a "ceiling effect."

High Specificity

The significant difference in memory accuracy with zolpidem existed for both negative and high-arousal stimuli but not for positive or low-arousal stimuli.

"I was surprised by the specificity of the results, that the emotional memory improvement was specifically for negative and high-arousal memories," Dr. Mednick said in a statement.

Dr. Kohler said he also found the effect that zolpidem had on memory surprising.

"This article, even though a relatively small number of patients were involved, does give some correlation between zolpidem and increased spindle density, which was found to increase memory discrimination. It's very interesting, but whether it's replicable in other studies, we don't know yet. We need to do a lot more investigating."

Because benzodiazepines produce similar effects on sleep as zolpidem, Dr. Mednick said that future research should investigate whether benzodiazepinelike drugs increase retention of negative and arousing memories, especially in patients with PTSD.

The US Department of Veterans Affairs (VA) in 2010 recommended against treatment of PTSD with benzodiazepines, but the VA's National Center for PTSD reported that 30% of veterans with PTSD are still prescribed benzodiazepines in the VA system (PTSD Res Q, 2013;23:1).

This study was funded by an award from the National Institutes of Health. Dr. Mednick and Dr. Kohler have reported no relevant financial relationships.

J Cogn Neurosci. Early access publication June 14, 2013. Abstract