Novel Use of a Diabetes Drug in Depression

The search for better treatment options in major depression is important because current antidepressant drugs fail to produce remission in a majority of patients.  Current research efforts are exploring novel antidepressant mechanisms. Some of the compounds being studied include pharmacologic agents with the following mechanisms:

• Neurotrophic and neuroplasticity agents
• Glutamine neurotransmitter agents
• Extracellular receptor coupled kinase agents
• Inhibitors of glycogen synthetase kinase-3
• Modulators of insulin signaling pathways

Insulin targeted drugs hold promise for several reasons.  Obesity and cardiometabolic disorders occur commonly in those treated in clinical populations with depression.  Elevated abdominal fat levels are associated with greater likelihood of developing depression.  Additionally, insulin resistance and metabolic syndrome appear to increase depression risk.  


Kemp and colleagues at Case Western Reserve University in Cleveland, Ohio have recently published a study of the diabetes drug pioglitazone in major depression.  Subject inclusion criteria for this study included:

• Outpatients aged 18 to 70
• Current diagnosis of major depression
• Abdominal obesity (waist circumference 36 inches or more in women or 40 inches or more in men) OR
• Metabolic syndrome (three of the following--elevated blood pressure, insulin resistance, elevated triglyceride levels with low HDL cholesterol, abdominal obesity)
• No current use of a glucose-lowering agent
• No recent drug alcohol alcohol dependence

Subjects could be taking standard antidepressant drugs but were required to have a significant level of depression at the time of study drug initiation.

The study drug was pioglitazone (U.S. trade name Actos) started at 15 mg per day and increased to 45 mg during the study as tolerated.  The study was an open-label study with all subjects receiving study drug with both subject and investigator unblinded to the study drug.

Twenty study subjects completed the trial and the reduction in depression symptom scores were pretty impressive.  The Inventory of Depressive Symptoms (IDS) declined from a mean of 40.3 at baseline to 19.2 at 12 weeks.  Sixty five percent of the group met criteria for response (50% reduction in IDS score) and 22% of the subjects met criteria for remission.  Response and remission rates were similar to rates found in outpatients with depression treated with standard antidepressant drugs. 

So how might a drug targeting insulin produce improvement in depression.  Insulin is known to regulate dopamine neurotransmitter release in animals.  Additionally the authors note pioglitazone has been shown to reduce CNS markers of inflammation including inflammatory cytokines.  Inflammatory cytokines have been noted to be correlated with symptoms of depression.  

This study will need to be replicated in a randomized double-blind controlled trial.  Nevertheless, the authors suggest that treatment of metabolic defects in those with depression holds promise for improving both the symptoms of depression as well as improving metabolic status (i.e. insulin sensitivity, blood glucose and blood lipid parameters).

Photo of sunrise at Juno Beach, Florida from author's collection.


Kemp DE, Ismail-Beigi F, Ganocy SJ, Conroy C, Gao K, Obral S, Fein E, Findling RL, & Calabrese JR (2011). Use of insulin sensitizers for the treatment of major depressive disorder: A pilot study of pioglitazone for major depression accompanied by abdominal obesity. Journal of affective disorders PMID: 21782251