Dose-related illusions and hallucinations with zaleplon

Dose-related illusions and hallucinations with zaleplon

To the Editor:

Ms. A, a 20-year-old Caucasian woman who had a history of DSM-IV diagnoses of major depressive disorder and borderline personality disorder, reported insomnia characterized by difficulty falling asleep, but no difficulty maintaining sleep for a six-month period. She had no history of psychosis or any significant medical history. She smoked one-half pack of cigarettes per day and, otherwise, had no other substance abuse history.

To improve her sleep, Ms. A was prescribed zaleplon 10mg capsules and advised to take one at bedtime as needed. Ms. A was also taking fluoxetine 60mg every morning, ziprasidone 40mg per day, and the oral contraceptive Alesse® (0.10mg levonorgestrel/0.02mg ethinyl estradiol). At a follow-up psychiatric appointment four weeks later, the patient reported that she took zaleplon 10mg on four nights and her initial insomnia persisted. The patient was advised to increase the zaleplon to 20mg at bedtime as needed. On her next follow-up appointment, Ms. A reported taking 20mg of zaleplon approximately six times during the month. She reported that on three separate occasions subsequent to taking zaleplon, she had some unusual perceptual experiences. These experiences include seeing tree branches moving closer to her, seeing movement of water and fire in a painting on a wall, and seeing people moving and talking to her on another picture. She denied having consumed any alcohol or recreational drugs during this period of time. After all of these episodes, Ms. A reported that she was able to fall asleep and to awake the next morning with no additional negative effects.

Zaleplon is a pyrazolopyrimidine hypnotic indicated for the short-term treatment of insomnia. It preferentially binds to the benzodiazepine type 1 (also referred to as ω₁) receptor subtype in the GABA_A receptor complex. Zaleplon has a rapid time to peak plasma concentration and a short half-life, both approximately one hour in healthy individuals (1–3). In the United States, the manufacturer recommends a dosage range of 5–20mg, with 10mg being the recommended dose for most non-elderly adults (4). Perceptual disturbances with zaleplon are reported to be uncommon (1–3). The manufacturer reports that the incidence of hallucinations with zaleplon is less than 1% in those taking 10mg and 1% in those taking 20mg (4). When four of 12 normal volunteers were administered zaleplon 20mg they reported visual illusions (5). In one previous case report of zaleplon-induced illusions and hallucinations, a 25-year-old woman taking Ortho Tri-Cyclen experienced visual illusions and hallucinations after taking one dose of zaleplon 10mg (6). Another case report exists of a 14-year-old adolescent who took an intentional nonlethal overdose of zaleplon and experienced a transient episode of somnambulism and confusion without medical sequelae(7). However, the relationship of this case to FDA approved dosages in adults is unclear.

In examining the pharmacokinetics of zaleplon, the manufacturer reports there to be no significant gender difference in zaleplon's pharmacokinetics (4). The metabolism of zaleplon creates no active metabolites and occurs primarily via aldehyde oxidase with Cytochrome P450 (CYP) 3A4 being a minor metabolic pathway (4). Ethinyl estradiol is known to be a weak inhibitor of CYP 3A4, while levonorgestrel is less likely than ethinyl estradiol to be involved in drug-drug interactions (8). Fluoxetine, ziprasidone, and smoking tobacco are not known to inhibit or induce aldehyde oxidase or CYP3A4 (9,10). Zaleplon is approximately 60% bound to plasma protein and not expected to be sensitive to protein binding changes (4). However, it is interesting that in the one other case report of illusions and hallucinations with zaleplon, the woman was also taking ethinyl estradiol (6). The possibility exists that in these cases, the metabolism of zaleplon was slowed by concurrent administration of oral contraceptives and this may have contributed to the unusual experiences described here. Ultimately, the mechanism by which zaleplon might induce perceptual disturbances in rare instances is unknown.

To our knowledge, this is the first case report of a dose-dependent relationship of these side effects in a single individual. Although zaleplon is thought to be a very safe sleeping medication, this case suggests that caution be exercised when titrating zaleplon.

Notes

*Drs. Stone and Zorick report no financial or other relationship relevant to the subject of this report. Dr. Tsuang has participated as a speaker and advisory boards for Abbott, Eli Lilly, and Janssen.

4. King Pharmaceuticals, Wyeth Pharmaceuticals. Sonata® prescribing information, July 2003.