Sedation is not sleep: treatment-resistant insomnia in a psychotic disorder responding to targeted GABAergic intervention

Introduction

Sleep disturbances are common in psychotic disorders and may represent an intrinsic component of the illness rather than merely a secondary symptom. Dysregulation of circadian rhythms and the neurobiology of the sleep–wake cycle contributes to persistent insomnia, which is associated with relapse, functional impairment, and increased suicide risk. Antipsychotic medications are often considered sedative, particularly due to their effects on dopamine D2, serotonin 5-HT2A, and histamine H1 receptors. However, sedation does not always correspond to physiologically organised sleep. This case aims to highlight the clinical importance of sleep initiation mechanisms in persistent insomnia despite sedative treatments in psychotic disorders. Case presentation: A 54-year-old male diagnosed with a non-organic psychotic disorder was hospitalised due to severe, persistent insomnia accompanied by suicidal ideation. The patient had an approximately five-year history of psychotic symptoms, with prominent paranoid thoughts, and a prior suicide attempt during a similar untreated period of insomnia. Before hospitalisation, he was receiving long-acting injectable paliperidone (150 mg/month), quetiapine (600 mg/day), and mirtazapine (15 mg/day). Despite this, he reported an almost complete inability to fall asleep, remaining awake for most of the night, with significant daytime fatigue and functional impairment. During hospitalisation, treatment was intensified: quetiapine was increased to 800 mg/day, mirtazapine to 30 mg/day, and olanzapine (20 mg/day) was added. Insomnia persisted and was mainly characterised by inability to initiate sleep, with minimal or absent sleep periods. Clinical evaluation revealed no akathisia, manic activation, or significant psychomotor agitation; neurological examination was normal. The severity of insomnia was considered disproportionate to the psychotic symptoms. Considering treatment-resistant insomnia, quetiapine and mirtazapine were discontinued, and the gamma-aminobutyric acid type A (GABA-A) receptor modulator zopiclone (7.5 mg/day) was initiated. This led to rapid and clinically significant improvement in sleep initiation. Discussion: This case highlights the important distinction between sedation and physiological sleep. In psychotic disorders, sleep disturbances are not merely accompanying symptoms but are associated with prolonged sleep onset latency, poorer clinical outcomes, and increased suicide risk. In this patient, the persistence of insomnia despite multiple antipsychotic and sedative agents suggests that the problem cannot be explained solely by insufficient sedation. Although the histaminergic effects of antipsychotics may induce subjective drowsiness, they may not effectively engage the neurobiological processes required for sleep initiation. The GABAergic system plays a central role in sleep initiation. In this context, the rapid response to zopiclone, a GABA-A receptor modulator, suggests that the insomnia may be related to a dysfunction in sleep initiation mechanisms rather than a deficiency in sedation. This finding is consistent with studies emphasizing the role of the GABAergic system in the treatment of insomnia. Furthermore, it is in line with neurophysiological findings indicating that sleep regulation in psychotic disorders is associated with thalamocortical networks and GABAergic transmission. Conclusion: In the presence of treatment-resistant insomnia in psychotic disorders, increasing the sedative burden may not always be effective. Approaches targeting sleep initiation mechanisms, along with rational deprescribing, may provide more effective and clinically meaningful outcomes. Keywords: Psychotic disorder; insomnia; GABA-A receptor modulators; antipsychotic polypharmacy

References

no references