Zolpidem-induced Brief Psychotic Reactions: A Case Series

Zolpidem, classified as an imidazopyridine hypnotic, recognized for its prompt onset and brief duration of effect, has been employed as an alternative to benzodiazepines for the short-term treatment of insomnia due to its advantageous side effect profile, reduced risk of overdose, and supposedly reduced likelihood of misuse. Zolpidem has also been linked to atypical side effects. These include psychotic reactions in non-psychotic people. A correlation between the use of zolpidem and the prevalence of visual hallucinations as a psychotic symptom has been observed. The hallucinations typically occur as singular events. However, instances of additional psychotic reactions resulting from using zolpidem, including delusional thinking, peculiar and unconventional behavior, and restlessness have been documented.^1–3 Prior research has revealed a connection between zolpidem-induced psychotic reactions and various patient characteristics, including age, gender, drug dosage, and concurrent utilization of psychotropic medications.^4–6 This case series links zolpidem to three additional psychotic reactions: first, auditory and visual hallucinations, second, delusional ideation, and lastly, restlessness and abnormal behavior. The observed symptoms substantially decreased following the discontinuation of zolpidem. Furthermore, we initiate a discussion concerning these incidents within the context of previous research, emphasizing any common trends or divergent findings.

Case 1

A male, aged 52, had clinical manifestations consistent with depression, including anhedonia, fatigue, impaired concentration, pessimistic ideation about the future, and diminished self-confidence, persisting for one month. His sleep patterns or appetite had no noticeable change and there was no history of attempted suicide or familial history of psychiatric illness. The only substance he used was tobacco. The physical examination was within the normal range. He was diagnosed with a depressive episode and prescribed a daily dose of sertraline 50 mg. The patient demonstrated improvement in 10 days. However, he encountered challenges in attaining a state of restful sleep. The recommended course of treatment involves taking sertraline tablets along with 5 mg of zolpidem before going to sleep. After 48 hours, the patient returned to the medical facility with his son, who conveyed concerns regarding the recently prescribed sedative. After about 30 minutes of taking zolpidem the night before, he displayed unusual and idiosyncratic behavior. He showed a strong resistance to sleep initiation and no signs of sleepiness. He showed a noticeable increase in talkativeness and agitation, and he claimed to have seen tree-dwelling beings inside the room. He would adopt a posture that suggested levitation, mimic the sounds of birds, and laugh wildly. He occasionally lacked logical consistency in his verbal communication. He removed his clothing, and his family had to prevent such behavior. The event lasted approximately 1 hour. Subsequently, the relatives contacted a local doctor. However, by the time the doctor arrived, the patient had already returned to his baseline. The healthcare professional reassured the patient’s family and recommended that they postpone administering the patient’s psychotropic medication until additional consultation is obtained. The patient slept without any external assistance within approximately 30 minutes. The next morning, he awoke with a sense of renewed energy and a clear loss of memory regarding what had happened the previous evening. On the following day, the family refrained from administering zolpidem to him out of concern for a potential reoccurrence of the previous episode. Once again, he encountered challenges in sleep initiation. The son requested the attending psychiatrist to discontinue zolpidem, as the patient found it to be a “maddening medication”. The son requested an alternative sleep aid that does not elicit similar undesirable effects.

In the present instance, psychotic symptoms included visual hallucinations, reduced inhibitions, and incongruous episodes of laughter. The symptoms occurred within 30 minutes of administering a 5 mg dose of zolpidem, persisted for approximately 60 minutes, and resolved spontaneously without any therapeutic intervention after the cessation of zolpidem administration. It is plausible that age may have contributed to the psychotic symptoms in this instance. Notably, sertraline, a selective serotonin reuptake inhibitor (SSRI) with high protein-binding capacity, may have caused the displacement of zolpidem from its carrier protein, leading to an elevation in its free concentration. Additionally, it is worth considering the potential occurrence of paradoxical disinhibition with zolpidem, given its mechanism of action on the GABA-A receptor and the potential for age-related alterations in drug metabolism, receptor sensitivity, and central nervous system functionality. Consuming zolpidem can result in paradoxical disinhibition through pathological intoxication behavior, which is similar to the effects of alcohol.

Case 2

A female postgraduate medical student, aged 27, expressed concerns to a fellow psychiatry resident regarding her difficulty sleeping while in bed until 2 or 3 a.m. and experiencing frequent awakenings throughout the night. She was very upset about this because she knew she wouldn’t feel refreshed the next morning because of the upcoming exams. She requested a sleep aid to facilitate prompt sleep onset without negatively affecting cognitive function or causing residual sedation the subsequent day. She had moderately severe anxiety symptoms. She had no documented psychiatric disorder, significant medical ailment, or substance misuse. However, her maternal grandmother had a documented history of bipolar affective disorder.

She was prescribed a 6.25 mg dose of extended-release zolpidem upon going to sleep for seven consecutive days. However, she sought treatment at the emergency department of the psychiatry department later that evening. The unusual behavior she exhibited led her fellow residents in the dormitory to accompany her. After taking zolpidem, she did not experience drowsiness as expected. Instead, she became more agitated and began seeking the attention of others in the hostel by forcefully hitting the doors. She revealed increased anxiety during an examination and claimed to have seen a man standing beneath her bed. When the young women helped her find her room, they discovered that the room was empty. Notwithstanding the assurances provided, she remained unsatisfied. She emphasized numerous times that the male person followed her and kept looking in her direction. She started to quickly descend the stairs when she claimed to have heard a male person persistently pursuing her, regardless of the direction she was going. She displayed distress and restlessness while conversing with auditory hallucinations. In the psychiatric emergency department, she received a slow intravenous injection of lorazepam 2 mg. The physical examination revealed a slender and pallid physique, while EEG and MRI Brain had inconclusive results. Hemoglobin level was 9.2 g/dL, while all other observations fell within the established normal range. After administering lorazepam, she experienced a restful sleep and underwent overnight monitoring. Upon awakening the following morning, she had partial amnesia to occurrences that transpired after zolpidem ingestion. Zolpidem was discontinued due to the emergence of psychotic symptoms. Following the initial presentation, there was no subsequent recurrence of these symptoms.

The onset of symptoms in Case 2 was noted within 1 hour of administration of zolpidem, and the symptoms lasted approximately 2 hours until the patient was sedated using intravenous lorazepam. Following the cessation of zolpidem usage, the symptoms resolved. A spectrum of psychotic symptoms was present, including visual and auditory hallucinations and increased agitation. Multiple potential explanations exist for this phenomenon, including the administration of dosages above 5 mg, the female gender, a slender physique, anemia, and a genetic predisposition originating from a positive family psychiatric history.

Case 3

A 29-year-old male business executive, displaying asthenic characteristics, presented alone at the psychiatry outpatient department. He had insomnia for 15 days, following the termination of a romantic relationship. Apart from occasional reflections on the factors leading to the end of the relationship, he did not have any further symptoms or meet the diagnostic criteria for a major depressive episode or an anxiety disorder. He was instructed to take a 5 mg dose of zolpidem before his regular bedtime for a week. After three days, he was brought to the hospital by his family in an unstable condition. He had visual hallucinations (seeing human shadows on the walls). Additionally, he experienced a sensation of the room’s opposing walls converging toward him and a perception that the ceiling fan was on the brink of collapsing onto him. He had severe fear and attributed his distress to his romantic partner, whom he accused of orchestrating an assault against him. Moreover, he alluded to the existence of enigmatic figures adorning the walls of his living space. The reassurances by his family members concerning the lack of any individuals present in the room proved ineffective. He began to spit at the family acquaintances. He was taken to the doctor late at night, who gave him 10 mg of diazepam intravenously to cause sedation. He had a headache and was complaining in the early morning hours. He had only a hazy recollection of what had happened the previous evening. He remained skeptical, though, about the likelihood that the person for whom he had feelings would be cleared of all charges. He was brought to the psychiatry outpatient department, where he described a persistent inability to sleep despite 5 mg of zolpidem on the first day. As a result, he increased the dosage to 10 mg; however, his sleep duration remained limited to only 3 hours. On the following day, in anticipation of experiencing inadequate sleep quality, he took 5 mg of zolpidem after taking 10 mg first. The subject reported experiencing peculiar phenomena as a consequence of the escalated dosage. There were no reported precursors of psychosis or substance abuse except tobacco consumption. The family members presented strong evidence that refuted the existence of the said condition, in contrast to the manifestation of any additional symptoms connected with neurological or ophthalmologic disorders and the thorough assessment of the individual’s overall health and bodily functions. Following the suspicion that zolpidem was the causal factor, it was discontinued. Reassurance was given to the family members, and clonazepam tablets were prescribed as an alternative to zolpidem. After one week, he observed a significant improvement in his sleep patterns and a lack of any recurrence of distressing events after the change in medication.

In the present instance, psychotic symptoms appeared approximately 30 minutes after administering zolpidem. These were characterized by visual hallucinations, persecutory delusion, agitation, and disorganized behavior. They lasted approximately 5 hours and were relieved following the intravenous administration of a benzodiazepine. The potential risk factors include an asthenic physique and taking an excessive amount of zolpidem, specifically 15 mg, one and half times the recommended dosage.

Discussion

In accordance with the findings of Ansseau et al., it was observed that two patients experienced visual hallucinations and amnesia in close temporal proximity to the administration of zolpidem. ⁷ A patient had macropsia, without any concurrent amnesia, as reported by Iruela et al. ⁸ There has been an observed increase in the incidence of neuropsychiatric reactions, specifically hallucinations and sensory distortions, among those prescribed zolpidem. This indicates that one should be cautious about zolpidem, even when administered at therapeutic dosages, due to its potential to induce temporary cognitive and behavioral impairments similar to those induced by benzodiazepines. ⁹

None of the three cases exhibited any signs of ophthalmological or neurological disorders or had alcohol or substance abuse. Two subjects did not have any psychiatric disorders, and no concurrent medical conditions could explain the observed symptoms. The absence of drowsiness, coupled with visual distortions, illusions, and hallucinations, effectively negates the likelihood of hypnagogic hallucination. The etiology of the psychotic symptoms remained unidentified in physical examination. Except for the slight pallor observed in Case 2, laboratory and imaging findings yielded no definitive evidence. In each of the three cases, psychotic symptoms appeared within a period ranging from 30 minutes to 2 hours following the administration of zolpidem. The symptoms had a duration ranging from 1 to 5 hours. They were found to resolve spontaneously or with injectable benzodiazepine, with partial or complete amnesia for the episode. The discontinuation of zolpidem led to the cessation of the symptoms. Iruela et al. observed that even a lower dosage of zolpidem, specifically 5 or 2.5 mg, can induce milder hallucinations. ⁸ The precise psychotropic effects of zolpidem are yet to be definitively determined. The occurrence of visual hallucinations with zolpidem is infrequent.^10,11 Regarding the potential risk factors for the occurrence of psychotic symptoms associated with zolpidem, one of our cases took doses surpassing 10 mg. Furthermore, the patient who manifested symptoms after ingesting a mere 5 mg was an older adult who had been also prescribed an SSRI. Females have been observed to get a significantly higher concentration of zolpidem in their plasma, approximately 40% more than males. After administering a comparable dose of zolpidem, the average blood concentration was approximately 45% higher in females aged 20–40 years compared to males in the same age group.^12,13 This disparity in serum concentration is more pronounced among older females. The drug’s blood concentration exhibited a statistically significant increase of 63% in females aged 60 and above compared to males in the same age group.^14,15 We observed clinical manifestations of psychosis that resemble those previously reported by Huang et al. and Salvà et al., where the patients reported pronounced visual symptoms.^10,12 Based on the available literature, the most common psychotic symptoms are visual and auditory hallucinations, delusion of persecution, restlessness, incoherent speech, and disorganized and uninhibited behavior. When prescribing zolpidem, it is crucial to consider the patient’s body weight. Macropsia has been documented in underweight females due to using zolpidem. ⁸ Notably, approximately 92% of zolpidem binds to proteins, primarily two proteins: albumin (66%) and 1-acid glycoprotein (56%). ⁸ Hypoalbuminemia, resulting from anorexia nervosa and malnutrition, has been frequently observed to cause an elevation in the levels of unbound drugs. This effect may have accounted for or contributed to the observed symptoms. It is worth mentioning that two of our three cases had an asthenic constitution.

Several adverse events have been documented in patients concurrently prescribed SSRIs and zolpidem. In a study, 58.8% of patients who reported hallucinations were concurrently using antidepressant medications. ¹⁶ The primary facilitator of the metabolic breakdown of zolpidem is the CYP3A4 isoenzyme, with CYP2C9 and CYP1A2 playing a subordinate role. Previous studies have reported that administering SSRIs or other pharmaceutical agents that inhibit CYP3A4 can increase the serum concentration of zolpidem. Previous studies have provided evidence of psychotic symptoms in individuals who are concurrently prescribed zolpidem along with fluoxetine, fluvoxamine, or paroxetine. ¹¹ The inhibitory effects of sertraline on the activity of CYP2D6 have been observed. Previous studies have suggested that zolpidem and sertraline have a strong affinity for binding to proteins and compete for binding sites. This competition can increase levels of zolpidem, leading to adverse reactions.

Conclusion

From a clinical perspective, it can be argued that zolpidem is effective and has some advantages in managing insomnia. Although rare, zolpidem can induce psychotic symptoms. It is advisable to administer zolpidem at the minimal effective dose, for the shortest feasible period, and try to avoid doses above 5 mg. Females and older adults may require lower dosages. It is crucial for medical practitioners, including physicians and psychiatrists, to exercise a high degree of caution when prescribing zolpidem in conjunction with psychotropic medications, especially those that are highly protein-bound, such as SSRIs, or in patients who exhibit asthenic symptoms. To determine whether smoking, anemia, and genetic predisposition to psychiatric disorders increase the susceptibility to zolpidem-induced psychotic reactions, additional studies are necessary. Primary care physicians must maintain a state of constant vigilance to identify potential psychotic reactions that may arise during the administration of zolpidem. Psychotic reactions can be managed with injectable benzodiazepines and reassuring the patient and their family.