Sodium Oxybate-Induced Psychosis and Suicide Attempt in an 18-Year-Old Girl

Case Report

An 18-year-old girl with no prior psychiatric diagnoses was admitted to the hospital for the treatment of self-inflicted cardiopulmonary injury with a knife. There was no family history of mental illness, she denied any history of illicit drug or alcohol abuse, and she had been a high-achieving student who ran cross-country on her high school team. Her outpatient neurologist had diagnosed her with narcolepsy after a multiple sleep latency test demonstrated a mean sleep latency of 4.2 minutes and sleep-onset REM periods in 3 out of 5 nap opportunities. An outpatient brain MRI and electroencephalogram (EEG) were unremarkable. She was briefly tried on modafinil, which was discontinued because the patient experienced increased irritability. She was then started on sodium oxybate 1.5 g p.o. twice nightly for 1 day, then 3 g p.o. twice nightly for 10 days, and finally increased to 4.5 g p.o. twice nightly. She was not taking any other medications. Three days after the last dose increase, the patient's family and school staff noticed a significant change in her behavior, describing her as “sluggish” and incoherent at times. The patient reported to family members, “I feel like I'm going crazy,” and began making vague suicidal comments. She exhibited paranoid thoughts, reporting that she believed that helicopters were circling her home, and experienced auditory hallucinations and symptoms of derealization. On the same day, in a state of acute agitation, she unexpectedly stabbed herself multiple times in the chest with a kitchen knife, resulting in significant cardiopulmonary injury and cardiac arrest. Her subsequent hospital course, lasting 4 months, was complicated by acute renal failure, digit necrosis secondary to pressor support, and multiple subsegmental cerebral infarcts. A serum or urine GHB level was never measured during the hospitalization. The patient underwent several surgeries and, after she stabilized, was transferred to another hospital for 2 months of inpatient rehabilitation. Sodium oxybate was never restarted, and throughout the duration of the hospitalization she had no recurrence of agitation, mood changes, or psychosis, and could not clearly remember or explain her thoughts leading up to her suicide attempt. On follow-up communication 6 months after her discharge, she had graduated from high school and had no recurrence of suicidal thoughts or psychotic symptoms.

Discussion

Reported adverse psychiatric effects of sodium oxybate are rare. In preclinical trials evaluating safety and efficacy of sodium oxybate in adults, 3.2% of patients experienced depression (an incidence not greater than placebo), and two suicides were reported (Xyrem^® [sodium oxybate] oral solution 2008). However, there have been several recent reports of adverse psychiatric side effects with the medication. Acute depression and suicidal ideation were reported in a 53-year-old patient on sodium oxybate, which appeared to be dose-related, and which resolved upon dose reduction (Ortega-Ablás et al. 2010). Similarly, emotional irritability and vague suicidal ideation were noted in a 25-year-old patient after sodium oxybate was added to modafinil, and resolved when the sodium oxybate was discontinued (Rossetti et al. 2010).

Fewer data exist on psychiatric effects in children and adolescents. Derealization and pessimism were noted in an 18-year-old male when sodium oxybate was added to modafinil (Rossetti et al. 2010). One study, a retrospective chart review, reported on the efficacy and tolerability of sodium oxybate in eight patients ages 9–16 (Murali and Kotagal 2006). Although the authors concluded that sodium oxybate was effective in treating childhood narcolepsy-cataplexy, the youngest patient had to discontinue the medication after developing nightmares and suicidal ideation, and another (aged 14) discontinued after developing symptoms of dissociation. The authors noted that the patient who became suicidal had a history of anxiety disorder and “oppositional disorder,” suggesting that a psychiatric history may predispose one to developing suicidal ideation on the medication. The fact that two of the eight subjects in this small study had to discontinue sodium oxybate because of psychiatric adverse effects, and the dramatic, sudden development of psychotic agitation and resultant suicide attempt in our case, together raise the question of whether younger populations may be more susceptible to the adverse psychiatric effects of this medication.

As a drug of abuse, GHB has a history in America dating back to the 1980s, when it was first promoted as a dietary supplement to body builders, then became a popular “club drug,” and most recently gained notoriety as the “date rape drug” used in sexual assaults (Fuller and Hornfeldt 2003; Gahlinger 2004). Consequently, there is more extensive literature on adverse psychiatric effects with the nonmedical use of GHB. Zvosec and Smith studied 66 patients presenting to an emergency department with GHB intoxication, and found that 40 of them presented with agitation, including 14 who were described as having “bizarre” or self-injurious behaviors (Zvosec and Smith 2005). Pretty and Hall reported a case of a 28-year-old woman who self-extracted 18 of her teeth while under the influence of GHB (Pretty and Hall 2004). Withdrawal from GHB has been known to cause a psychotic, delirious state (Dyer et al. 2001; Rosenberg et al. 2003; Tarabar and Nelson 2004) and suicidal ideation (Costanza et al. 1998). Collectively, these reports highlight the potential adverse psychiatric sequelae of GHB use and misuse.

The pharmacological mechanisms underlying adverse neuropsychiatric side effects of sodium oxybate are unknown. Gamma hydroxybutyrate is a naturally occurring neurotransmitter that serves as a precursor and degradation product of GABA (Mamelak 2009). It is an agonist at both the GHB and GABA-B receptors. GHB's pharmacologic mechanism is complex, involving multiple neurotransmitter systems, and GHB receptors have been identified in several structures including the hippocampus, thalamus, and cortex (Mamelak 2009). It is noteworthy that individuals with the hereditary condition gamma-hydroxybutyric aciduria, who have a deficiency in succinic semialdehyde dehydrogenase resulting in high levels of endogenous brain GHB levels, also demonstrate high rates of psychiatric symptoms including aggression, anxiety, and behavioral disturbances (Zvosec and Smith 2005). Psychotic symptoms caused by GHB may be mediated by its effects on dopamine; it is hypothesized that, through its actions at the GABA-B receptor, GHB inhibits the release of dopamine, and likely causes upregulation of dopamine receptors (Tarabar and Nelson 2004). More research on the underlying biological mechanism of psychosis and suicidal ideation in individuals on sodium oxybate is needed.

Conclusion

As most cases of narcolepsy have their onset in childhood or adolescence, it follows that the off-label use of sodium oxybate will continue to increase in this population (Aran et al. 2010; Sullivan 2010). Clinicians should carefully monitor for agitation and acute changes in mental status in patients on sodium oxybate, and be alert to possible suicidal ideation leading to suicide attempts, even in the absence of typical depressive symptoms. Our case serves to remind prescribers of the risks of sodium oxybate in children and adolescents, and the need to exercise special caution when using this medication in this population.