Brexpiprazole as an augmentation agent to antidepressants in treatment resistant major depressive disorder.

Introduction: Approximately 50% of adults with major depressive disorder (MDD) who receive a first-line antidepressant treatment, at an appropriate dose, do not achieve an adequate response. Brexpiprazole is a novel serotonin-dopamine activity modulator in the second generation/atypical antipsychotic class that was approved by the United States Food & Drug Administration in 2015 for use as an adjunctive agent in the treatment of MDD inadequately responsive to antidepressant treatment. In general, second generation/atypical antipsychotics are widely used in the treatment of treatment resistant depression with brexpiprazole providing preliminary evidence for broad-spectrum efficacy across multiple domains affected by MDD, providing a basis for further elucidating its mechanistic effects to inform novel drug discovery. Areas covered: The review herein presents the evidence base for the use of brexpiprazole as an augmentation agent to antidepressants in individuals with treatment resistant MDD, including its efficacy, safety, and tolerability profile. Expert opinion: Brexpiprazole has been demonstrated to be effective and safe to use as an augmentation agent to antidepressant treatment among individuals with treatment resistant MDD due to its considerably improved tolerability profile when compared to other second generation/atypical antipsychotics; however, it is important to exercise clinical judgment when selecting disparate augmentation agents on a case-by-case basis weighing individual risks versus benefits.

Treatment with a GLP-1R agonist over four weeks promotes weight loss-moderated changes in frontal-striatal brain structures in individuals with mood disorders.

Cognitive deficits are a core feature across psychiatric disorders. Emerging evidence indicates that metabolic pathways are highly relevant for the substrates and phenomenology of the cognitive domain. Herein, we aimed to determine the effects of liraglutide, a GLP-1R agonist, on brain structural/volumetric parameters in adults with a mood disorder. This is the secondary analysis of a 4-week, pilot, proof-of-concept, open-label study. Participants (N=19) exhibiting impairments in executive function with either major depressive disorder (MDD) or bipolar disorder (BD) were recruited. Liraglutide 1.8mg/day was added as an adjunct to existing pharmacotherapy. Structural magnetic resonance imaging (MRI) scanning was obtained at baseline and endpoint. Results showed that at endpoint there was significant weight loss (mean: 3.15%; p<0.001). Changes in frontal and striatal volumes were significantly correlated with changes in body mass index (BMI), indicating the weight loss was associated with volume increase in most regions (e.g. r=-0.561, p=0.042 in the left superior frontal area). After adjusting for intracranial volume, age, gender, and BMI, we observed significant changes from baseline to endpoint in multiple regions (e.g. RR: 1.011, p=0.049 in the left rostral middle frontal area). Changes in regional volumes were associated with improvement in executive function (e.g. r=0.698, p=0.003 for the right superior frontal area). Adjunctive liraglutide results in clinically significant weight loss, with corresponding improvement in cognitive function; changes in cognitive function were partially moderated by changes in brain morphometry, underscoring the interrelationship between weight and brain structure/function.

Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mood disorders: A pilot, open-label study.

BACKGROUND: There is a paucity of treatments that are capable of reliably and robustly improving cognitive function in adults with mood disorders. Glucagon-like peptide-1 is synthesized centrally and its receptors are abundantly expressed in neural circuits subserving cognitive function. We aimed to determine the effects of liraglutide, a GLP-1 receptor (GLP-1R) agonist, on objective measures of cognition in adults with a depressive or bipolar disorder. METHODS: In this 4-week, pilot, open-label, domain-based study (e.g. cognition), we recruited 19 individuals with major depressive disorder (MDD) or bipolar disorder (BD) and an impairment in executive function, defined as a below-average performance in the Trail Making Test-B (TMTB). Liraglutide 1.8mg/day was added as an adjunct to existing pharmacotherapy. RESULTS: Participants had significant increases from baseline to week 4 in the TMTB standard score (age and education corrected) (Cohen's d=0.64, p=0.009) and in a composite Z-score comprising multiple cognitive tests (i.e. Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, Stroop test) (Cohen's d=0.77, p<0.001). Neither changes in mood rating scales nor metabolic parameters were associated with changes in cognitive performance (all p>0.05); however baseline insulin resistance (IR) and body mass index (BMI) moderated the changes in the composite Z-score (p=0.021 and p=0.046, respectively), indicating larger responses in individuals with higher IR and BMI at baseline. There was a significant increase in lipase (p<0.001), but individual values were above the upper limit of normality. LIMITATIONS: Small sample size, open-label design, lack of a placebo group. CONCLUSIONS: Liraglutide was safe and well tolerated by a sample of non-diabetic individuals with mood disorders and had beneficial effects on objective measures of cognitive function. Larger studies with controlled trial designs are necessary to confirm and expand the results described herein.