The efficacy of adjunctive intranasal insulin for the treatment of neurocognitive dysfunction in bipolar disorder

Background: Neurocognition in bipolar disorder (BD) is often severely impaired which can impact daily functioning and overall quality of life. Currently, there are no recommended treatments for neurocognitive deficits in BD and some first line medications may aggravate cognitive difficulties. Extensive evidence has demonstrated the role of insulin in cognitive function in cognitively normal and impaired populations. Administration of insulin via the nasion passes the blood brain barrier and mitigates peripheral effects. Thus, insulin holds promise as a cognitive treatment for BD.

Aims and objectives: The objective of this study was to examine the efficacy of adjunctive intranasal insulin compared to placebo in improving neurocognitive and psychosocial functioning in people with BD and diminished neurocognition. It was hypothesised that the intranasal insulin arm would show significantly greater improvements in global cognition (MCCB, TMTB, D-KEFS Stroop) from baseline to 12-weeks, compared to the placebo arm.

Methods: A 12-week, 2-arm, placebo-controlled, single-centre randomised controlled trial (RCT) testing the effect of 40 international units (IU) of daily insulin (20IU, two times per day) versus placebo was conducted. Treatment as usual was continued. Adults with DSM-5 bipolar disorder (type I/II) were recruited. The sample was enriched on the basis of prespecified objective or subjective cognitive deficits. The primary outcome was global cognition on a cognitive battery comprising tests of speed of processing, visual memory, verbal memory, attention, working memory, reasoning & problem solving, social cognition and executive function. Secondary outcomes were quality of life, social and occupational functioning. Outcomes were assessed at baseline and 12 weeks (+/- 7 days). Mixed linear models were used to examine for change between groups.

Results: The primary outcome was significant; a significant interaction occurred between treatment allocation and time, b=-0.17, se=0.07, t(35) = −2.43, p = .02. Post-hoc pairwise comparisons showed that participants in the insulin treatment arm experienced a significant improvement from baseline to week 12, b=-0.82, se=0.19, t(18) = −4.36, p < .001, whereas no significant change was observed in the placebo arm. The improvement in the insulin group was associated with a large effect size (d = 1.14, 95% CI [0.14, 2.13]). Psychosocial functioning improvements were also noted in the insulin group based on the quality-of-life measure (d = 2.14), but not measures of social and occupational functioning. Minor/moderate transient adverse events were recorded, demonstrating acceptable safety.

Conclusion: Adjunctive intranasal insulin significantly improved global cognition in bipolar disorder. Enriching the sample for impaired cognition at study entry resulted in larger cognitive gains than previously reported in the literature, indicating that this intervention has significant promise for a subgroup of bipolar patients. Insulin is an approved therapy for insulin resistance in diabetes. We provide preliminary evidence to support the repurposing of intranasal insulin to target cognitive deficits in psychiatric disorders.

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