Ambien Mental Health and Mood Impact: What the Evidence Actually Shows

What the label says about mood

The Ambien label has a section headed Use in Patients with Depression. It states that in primarily depressed patients treated with sedative-hypnotics, worsening of depression and suicidal thoughts and actions, including completed suicides, have been reported; that suicidal tendencies may be present and protective measures may be required; and that because intentional overdosage is more common in this group, the lowest number of tablets that is feasible should be prescribed at any one time [1]. The Ambien CR label carries the same language [2].

The warning is framed around patients who are primarily depressed. It sits next to a second label statement: because sleep disturbance may be the presenting manifestation of a psychiatric or physical disorder, insomnia that does not remit after 7 to 10 days of treatment may indicate a primary psychiatric and/or medical illness that should be evaluated [1].

What the trials actually recorded

The clearest drug-specific numbers are adverse-event tables. These count reported events during trials, not events proven to be caused by the drug.

In a 3-week placebo-controlled trial of Ambien CR 12.5 mg in adults, with 102 patients on drug and 110 on placebo, the psychiatric and nervous-system events reported more often on zolpidem than on placebo included [2]:

• Hallucinations: 4% versus 0%
• Disorientation: 3% versus 2%
• Anxiety: 2% versus 0%
• Depression: 2% versus 0%
• Psychomotor retardation: 2% versus 0%
• Depersonalization: 1% versus 0%
• Disinhibition: 1% versus 0%
• Euphoric mood: 1% versus 0%
• Mood swings: 1% versus 0%
• Memory disorders (memory impairment, amnesia, anterograde amnesia): 3% versus 0%
• Somnolence: 15% versus 2%
• Dizziness: 12% versus 5%

In the longer immediate-release trials, which ran 28 to 35 nights with 152 patients on zolpidem and 161 on placebo, the rates were: depression 2% versus 1%, amnesia 1% versus none, abnormal dreams 1% versus none, drugged feeling 3% versus none, drowsiness 8% versus 5%, dizziness 5% versus 1% [1].

The 6-month Ambien CR study, 669 patients on 12.5 mg and 349 on placebo, is where the anxiety signal is largest. Anxiety was reported by 6.3% of patients on Ambien CR versus 2.6% on placebo, and more patients stopped treatment for anxiety, restlessness or agitation (1.5%, 10 of 669, versus 0.3%, 1 of 349) and for depression (1.5%, 10 of 669, versus 0.3%, 1 of 349). Overall, 8.5% of patients on zolpidem and 4.6% on placebo stopped for an adverse reaction [2].

Anxiety, withdrawal and rebound

Zolpidem is a Schedule IV controlled substance, and the label says use may lead to physical and psychological dependence, with risk rising with dose and duration and with a history of alcohol or drug abuse [1]. Abrupt discontinuation has produced withdrawal symptoms ranging from mild dysphoria and insomnia to cramps, vomiting, sweating, tremors, convulsions and delirium [1].

Rebound insomnia on stopping is not inevitable in trials. In a 24-week study of zolpidem extended-release 12.5 mg taken 3 to 7 nights per week (669 on drug, 349 on placebo), no rebound effect was observed during the first 3 nights of discontinuation [4]. In a 12-week trial of immediate-release zolpidem 10 mg taken 3 to 5 nights per week in 199 patients, there was no evidence of subjective rebound insomnia and no increase in the amount of medication used [5]. Both studies allowed nights off; neither establishes what happens after stopping nightly use.

Complex sleep behaviors

The boxed warning on Ambien, Ambien CR and generic zolpidem is titled Complex Sleep Behaviors. Sleep-walking, sleep-driving and other activities while not fully awake may occur after the first or any later use, can cause serious injuries including death, and patients usually do not remember them [1]. The label says these events can occur with zolpidem alone at recommended doses, with or without alcohol or other central nervous system depressants, and that zolpidem is contraindicated in anyone who has had such an episode [1].

FDA added the boxed warning and contraindication in April 2019, after reviewing reports submitted from December 1992 through February 2018. That review identified 66 cases (4 from the medical literature) involving eszopiclone, zaleplon or zolpidem: 20 deaths and 46 serious injuries, with 22 cases reporting an earlier episode of the same behavior on a Z-drug [6]. Among the fatal cases were apparent completed suicides; among the nonfatal serious injuries were self-injuries and suicide attempts [6]. FDA said these behaviors appear to be more common with eszopiclone, zaleplon and zolpidem than with other prescription sleep medicines [7].

Memory and next-day mental state

The trial tables report memory disorders and amnesia as adverse reactions. Separately, the labels warn that alertness and coordination may remain impaired the next morning: the risk rises with a higher dose, with less than 7 to 8 hours of sleep remaining, and with alcohol, opioids, benzodiazepines, tricyclic antidepressants or other drugs that raise zolpidem levels [1][2]. The Ambien CR label adds that impairment can occur in the absence of subjective symptoms and may not be reliably detected by an ordinary clinical exam [2].

FDA lowered the recommended doses in January 2013 because blood levels in some patients may be high enough the next morning to impair driving, and it says patients can be impaired even if they feel fully awake [8]. The labels now give an initial dose of 5 mg for women and 5 or 10 mg for men for immediate-release zolpidem, and 6.25 mg for women and 6.25 or 12.5 mg for men for Ambien CR; the Ambien label says the doses differ because zolpidem clearance is lower in women [1][2].

Antidepressants and other sedatives

The interaction data that touch mood are mostly pharmacokinetic. Sertraline raised zolpidem peak concentrations by 43% over 17 days in healthy women; fluoxetine raised the zolpidem half-life by 17% without an additive effect on psychomotor performance; imipramine and chlorpromazine produced additive decreases in alertness without a meaningful pharmacokinetic interaction, apart from a 20% fall in imipramine peak levels [1]. Alcohol and other central nervous system depressants add to sedation and impairment, and opioids add respiratory depression risk [1].

In a study of patients already taking SSRIs, four of seven discontinuations during zolpidem treatment (n=95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction [1]. One patient on placebo (of 97) was discontinued after an attempted suicide [1].

Older adults

For older adults the label recommends 5 mg immediate-release or 6.25 mg Ambien CR, and after a 20 mg dose elderly volunteers had 50% higher peak concentrations, 64% higher total exposure and a 32% longer half-life than young adults [1]. The 2023 AGS Beers Criteria make a strong recommendation to avoid zolpidem in adults 65 and older because of delirium, falls, fractures and crashes with minimal sleep benefit [3]. In the 3-week elderly Ambien CR trial (99 on 6.25 mg, 106 on placebo), anxiety was reported by 3% versus 2%, apathy by 1% versus 0%, depressed mood by 1% versus 0% and psychomotor retardation by 2% versus 0% [2].

What the label says to do about these effects

The label directs that Ambien be discontinued immediately if a patient experiences a complex sleep behavior, and it is contraindicated in patients who have had one [1]. It says any new behavioral sign or symptom of concern requires careful and immediate evaluation, and that in patients with depression the fewest tablets feasible should be prescribed [1]. Withdrawal symptoms may occur with rapid dose reduction or discontinuation [1]. Treatment should be as short as possible, and insomnia that persists beyond 7 to 10 days calls for reevaluation [1]. For chronic insomnia, the American College of Physicians recommends cognitive behavioral therapy for insomnia as the initial treatment, with medication added through shared decision-making when CBT-I alone does not work [9].

The limits of these data

The percentages above are adverse-event reports of events that were more frequent on zolpidem than on placebo, and the FDA case review is built on spontaneous reports, which cannot establish how often these events occur.