From benzodiazepines to off-label sedatives: Shifting sleep-promoting drug use in schizophrenia spectrum disorders across Nordic registries and a clinical cohort

Background

Sleep disturbances are highly prevalent in schizophrenia spectrum disorders (SSD) and are often treated pharmacologically. In the general population, tighter regulation of benzodiazepines and Z-drugs has led to increased off-label use of sedative alternatives. It is not known whether similar trends are seen in patients with SSD, where drug interactions and side effects pose particular risks.

Aims

We aimed to characterize the use of sleep-promoting drugs in SSD using both nationwide, registry-based data from the Nordic countries and detailed, prospective data from a clinical cohort.

Methods

Using nationwide prescription registries, we identified all individuals with hospital-based diagnoses of an SSD in Denmark, Finland, Iceland, Norway and Sweden. For the period 2005-23 we calculated annual proportions redeeming ≥1 prescription for licensed hypnotics or common off-label alternatives, such as low-dose quetiapine, low-dose mirtazapine or histamine-receptor antagonists.

To complement registry data with real-world usage patterns, we collected prospective data in an ongoing Danish clinical cohort of patients with first-episode schizophrenia or schizotypal disorder. Each individual was followed for 12 weeks with weekly interviews on their use of sleep-promoting drugs or self-medication, such as alcohol or cannabis to aid sleep. For each drug, we calculated the proportion of participants reporting ≥1 day of use in the 12 weeks.

Results

From 2005 to 2023, the proportion of patients with SSD redeeming any sleep-promoting prescription declined across all Nordic countries, though with marked national variation (e.g. from 88% to 77% in Denmark and from 51% to 49% in Sweden). Use of GABA-positive allosteric modulators (GABA-PAMs; benzodiazepines and z-drugs) decreased substantially (e.g., from 69% to 30% in Denmark), while low-dose quetiapine use increased markedly (e.g. from 7%→25% in Denmark).

In the clinical cohort of 102 individuals, overall exposure was higher than captured by registries alone: 71% used any type of sleep-promoting drug or self-medication at some point during only 12 weeks. 19% used a GABA-PAM, 30% used low-dose quetiapine with a mean-dose of 60 mg, while 21% used alcohol for sleep-promoting purposes. Usage patterns suggested limited treatment efficacy; 35% used more than one drug in the same week and 41% changed drug at least once during the 12 weeks. As the clinical cohort is ongoing, updated proportions will be presented at the congress.

Conclusions

Both nationwide registers and week-by-week clinical data demonstrate a high prevalence of sleep-promoting drug use in SSD. Over two decades prescribing patterns in the Nordic countries have shifted away from benzodiazepines and Z-drugs toward off-label sedative drugs. While reflecting reduced reliance on addictive hypnotics, this trend raises concerns about safety and metabolic burden. The high rate of drug switching and self-medication in real-world practice suggests that many patients do not achieve adequate symptom relief. Head-to-head trials of commonly used drugs are needed to optimize insomnia treatment in this vulnerable population.

References

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