Abstract
Nitrous oxide (N2O) is a widely used and readily available drug of abuse [1], as well as being commonly used as a dissociative anaesthetic in medicine and dentistry. The negative effects of chronic nitrous oxide inhalation, such as cognitive and neurological deficit secondary to disrupted vitamin B12 metabolism, are well documented [2,3]. Psychiatric manifestations of acute inhalation have not received as much attention. We describe a case of nitrous oxide precipitated mania with psychosis and discuss implications for psychiatric practice.
A 31 year old teacher with a 10 year history of bipolar affective disorder (BPAD) presented with a fifth episode of mania with psychosis 10 days after the birth of her first child. She had been compliant with amisulpride that had replaced the mood stabilizer sodium valproate at conception. There was a family history of affective illness and a past history of substance abuse but she had been abstinent for several years. Pain relief prior to labour was discussed and N2O offered as an option. The patient had been aware of the abuse potential for N2O and discussed her reservations at length with her midwife who assured her of the safety of use. Four hours into the use of N2O the patient reported a heady rush, experiencing auditory hallucinations, a feeling of well-being and thought processes becoming abstract and philosophical. She and her partner were clearly able to temporally correlate the onset of the current relapse with the use of nitrous oxide. Her initial symptoms were predominantly those of increased energy and neurovegetative difficulties. She continued to experience auditory hallucinations from the time of N2O use to the time of admission. Her levels of agitation required a period of closed ward management and her symptoms responded to treatment with a combination of olanzapine and benzodiazepines. She was discharged on amisulpride alone and continues to maintain improvement at three month follow up.
While many of these symptoms can be attributed to nitrous oxide intoxication [4], auditory hallucinations are a rare symptom and are better explained by the presence of a psychotic state or delirium. It could also be argued that perinatal stress and sleep pattern disruption could precipitate a manic episode in susceptible individuals; however, the close temporal correlation between the onset of N2O use and the onset of symptoms would suggest otherwise. The persistence of the perceptual abnormalities over a period of weeks after the use of N2O in the absence of altered sensorium would rule out intoxication or delirium.
While the neuropathic effects of chronic N2O inhalation and consequent vitamin B12 deficiency have been established, the time course of this episode necessitates an alternative explanation. A recently proposed mechanism for N2O analgesia suggests that it stimulates the uptake of L-arginine at pre-synaptic nerve terminals where the nitric oxide synthase (NOS) enzyme converts it to nitric oxide (NO) [5]. Animal studies have demonstrated increased NOS activity throughout the brain after N2O exposure [5]. NO reacts with superoxide free radicals generating peroxynitrite (ONOO−), which in turn reacts with thiol groups in amino acids, interfering with normal protein function and making it highly neurotoxic. Researchers have measured NO activity in bipolar patients and found it to be elevated [6].
Anaesthetic use of nitrous oxide is widespread in both medicine and dentistry. In light of the current case it is our hypothesis that in the setting of affective illness N2O is capable of triggering a manic episode. With a plenitude of anaesthetic alternatives available it may be prudent to advocate the use of other agents that circumvent this risk in patients with a history of affective illness.