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

Promoting Health: Interval vs Steady Running vs Strength Training

The optimum physical exercise regimen for promoting health is a key public health issue.  Aerobic exercise can be obtained via running either using a steady pace or an interval-based approach.  Interval approaches typically includes high intensity exercise over shorter bursts of time.  Additionally, strength training provides a variety of health benefits and it’s role compared to aerobic exercise is unclear.

A Danish study was designed and recently published to compare the health benefits of interval training, prolonged steady paced running and strength training.  The key elements of the three interventions were:

• Interval training: 5 minute warm-up followed by 5 two minute intervals at near-maximal running with heart rate above 95% maximum (3 times per week)—total exercise time over 12 weeks approximately 480 minutes
• Steady running: one hour of continuous running three times per at 80% of maximum heart rate—total exercise time over 12 weeks 1800 minutes
• Strength training: progressive heavy-resistance strength training primarily in lower extremities for one hour twice a week—total exercise time over twelve weeks 1500 minutes

Subjects participated in their respective programs for twelve weeks and had a variety of baseline performance, physiologic and lab measures collected.  The main findings showing differences between the groups were:

• Maximum oxygen uptake improvement better in interval group than other two groups
• HDL to total cholesterol improved in the steady running group, remained the same in the interval group and tended to worsen in the strength training group
• Blood glucose (fasting and two hours after glucose load) improved in both running groups but not the strength training group
• Body weight/body fat/muscle mass: Only the steady running group decreased body weight and fat percentage, strength group increased weight, increased lean body mass 

This study helps understand the relative contribution to health promotion for a variety of exercise programs.  Interval training provides the most bang for the buck in increasing oxygen uptake and in glucose metabolism.  Steady running seems superior to other techniques for weight loss and cholesterol reduction.  Strength training alone has limited health promotion benefits primarily in the development of lean body mass.

Since the health benefits of the three types of training studied in the experiment are complementary, it seems reasonable to consider a workout routine using all three types.  Although combining the three would lead to a significant time demand that many are unable to accommodate.  A good study is needed that answers the following question: “Given one hour to exercise, what is the optimum combination of steady running, interval training and strength training?”

Photo of fish from Oklahoma Aquarium (modified using psychedelic mode in iPad Photogene app) courtesy of Yates photography.

Nybo L, Sundstrup E, Jakobsen MD, Mohr M, Hornstrup T, Simonsen L, Bülow J, Randers MB, Nielsen JJ, Aagaard P, & Krustrup P (2010). High-Intensity Training Vs. Traditional Exercise Interventions for Promoting Health. Medicine and science in sports and exercise PMID: 20195181