Links Between Mixed Depression, Insulin Resistance, Inflammation, and Cognitive Deficits

August 1, 2019 · Posted in Potential Treatments · Comment 

depressed man with woman

At the 2019 meeting of the International Society for Bipolar Disorders, researcher Roger McIntyre discussed links between obesity, diabetes, and cardiovascular problems; increased inflammation; and decreased functioning of the neural networks involved in cognition. 

He and his colleagues analyzed 121 studies that included empirical research and meta-analyses. McIntyre and colleagues found that patients with higher levels of inflammatory markers have more insulin resistance and cognitive dysfunction. A meta-analysis revealed that the inflammatory markers IL-6, TNF alpha, and CRP were significantly elevated in people with bipolar disorder compared to normal controls, while IL-1B was not.

People with depression who had a few manic traits (mixed depression) were particularly likely to have insulin resistance and elevated levels of pro-inflammatory markers.

People with mixed depression have increases in inflammation and increased incidence of cardiovascular disorder. People experiencing a first episode of mixed depression who are overweight show increased signs of brain aging.

In studies McIntyre and colleagues analyzed, diabetes or pre-diabetes occurred in 50% of depressed patients, and these patients had the greatest amount of cognitive dysfunction.

Treatment

McIntyre noted that taking the antipsychotic drug lurasidone for bipolar depression worked best in both adults and children who had elevated levels of CRP at baseline. The fast-acting antidepressant ketamine also works well in those who show baseline inflammation .

The anti-diabetes drug liraglutide (Victoza, Saxenda) improves mixed depression symptoms and cognition in obesity, diabetes, and mixed depression. Liraglutide belongs to a class of drugs called glucagon-like peptide-1 (GLP-1) receptor agonists or incretin mimetics. They work by increasing insulin release from the pancreas and decreasing excessive glucagon release.

McIntyre now routinely uses liraglutide for cognitive deficits in patients with obesity or diabetes, including patients with mixed depression. It is injected under the skin at 0.6 mg daily, then the dosage is increased to 1.2 mg and then 1.8 mg. Victoza reduces major cardiovascular events in those with type 2 diabetes. The higher-dose Saxenda (3mg) can be used for weight control.

Another anti-diabetes drug, pioglitazine, has also been reported to be helpful in bipolar depression.

McIntyre found that the antibody infliximab, which can be used as an intravenous treatment for chronic inflammation and works by blocking the effects of TNF-alpha, did not improve depression, but did improve cognition.

McIntyre also supports the use of acetyl-L-carnitine, a potential adjunctive treatment that can reverse the insulin resistance that often occurs with obesity and thus could theoretically improve cognition.

McIntyre described preliminary literature suggesting the effectiveness of drugs such as statins, calcium channel blockers, and biguanides such as the diabetes treatment metformin in reducing inflammation.

Bariatric surgery to reduce the size of the stomach was another option discussed by McIntyre. He said the intervention is safe for patients with bipolar disorder and can help them recover cognitive function.

McIntyre noted that offspring of a mother with obesity have decreased response to sensory cues, reward preference, cognitive control, and motor control. Obesity and the inflammation that goes along with it apparently affect offspring via epigenetic mechanisms, meaning obesity may change the structure of inherited DNA (without changing its sequence).

Obesity Associated with Inflammation and Brain Abnormalities

July 1, 2019 · Posted in Risk Factors · Comment 

obese family

At the 2019 meeting of the International Society for Bipolar Disorders, researcher David J. Bond reviewed the data on the multiple adverse effects of obesity in patients with bipolar disorder. These include increased cardiovascular risk, poorer response to treatment, brain abnormalities, and decreased cognitive function, which is correlated with the degree of overweight.

Editor’s Note: These data emphasize the importance of starting a nutritious diet early in life and sustaining it through adulthood, avoiding the drugs most associated with weight gain such as clozapine and olanzapine, and facilitating weight loss with drugs. There are several treatments that can aid in weight loss. One is the diabetes treatment metformin, starting at a high dose of 500mg twice daily, and increasing to 1000mg twice daily if tolerated. The anticonvulsants topiramate or zonisamide also promote weight loss. The most effective option is a combination of the antidepressant bupropion sustained release (at a dose of 150–300mg) plus the anti–substance abuse drug naltrexone (50mg). This combination was associated with a loss of 10% of body weight over 12 weeks in women with diabetes.

Adipokines May Be the Link Between Mood Disorders and Obesity

January 10, 2018 · Posted in Comorbidities, Resources · Comment 

weightResearchers David J. Bond and Lakshmi Yatham think they may have identified why bipolar disorder and obesity occur so often together. In North America, more than 60% of people with bipolar disorder are overweight or obese, and obesity rates are 60% higher in people with bipolar disorder than in people without bipolar disorder.

Bond and Yatham hypothesized that adipokines might be responsible for both bipolar disorder and obesity. Adipokines are cell signaling proteins that regulate both mood and appetite. Abnormal levels of adipokines in blood could cause both mood episodes and weight gain.

The researchers measured blood levels of five adipokines (leptin, adiponectin, resistin, adipsin, and lipocalin-2) in 53 young people with bipolar disorder. They found three interesting links between adipokines, mood, weight, and medications, which they reported in the Journal of Clinical Psychiatry in 2017.

The first finding was that low levels of leptin and adiponectin (adipokines with antidepressant properties) predicted a greater risk of depressive relapse over a 12-month period. The second finding was that high levels of leptin and adipsin predicted greater weight gain over a 12-month period. The third finding was that treatment with second-generation antipsychotics, which often leads to weight gain and other metabolic side effects, was associated with higher levels of resistin, an adipokine linked to type 2 diabetes.

The findings about leptin were particularly interesting, because leptin’s appetite-regulating effects change with a person’s weight. In the study, low leptin predicted depression, while high leptin predicted weight gain. In people of normal weight, low leptin predicts weight gain, while in overweight or obese people, high leptin predicts weight gain. Bond and Yatham suggest that leptin’s mood-regulating effects may be more consistent, with low leptin increasing depression risk regardless of weight.

These findings may help researchers find ways of treating mood episodes that do not encourage weight gain.

Child Abuse Linked to Adolescent Obesity

December 7, 2016 · Posted in Risk Factors · Comment 

child abuse linked to adolescent obesityNew research clarifies how trauma in early life can lead to obesity in adolescence. In a study of 160 young people between the ages of 9 and 15, researcher Janitza Montalvo-Ortiz and colleagues identified seven sites in the genome where DNA methylation predicted body mass index (BMI) in adolescence. The researchers also collected information on family traumas that occurred during the participants’ childhoods and found that DNA methylation and family trauma such as child abuse interacted to predict BMI.

Epigenetics describes the ways life experiences can change how easily DNA is turned on or off. While the genes coded by DNA sequences one inherits from one’s parents never change, the structure of DNA can change. DNA methylation is one type of epigenetic change that refers to the addition of methyl groups to promoter regions of DNA in response to life events.

In this research, which was presented at the 2016 meeting of the Society of Biological Psychiatry, Montalvo-Ortiz and colleagues found that the site of DNA methylation with the strongest link to BMI in adolescence was a gene called MAP2K3. This gene had previously been linked to obesity, but this is the first time DNA methylation at this site has been linked to both obesity and childhood trauma. Other relevant gene sites where DNA methylation occurred include ANKRD2, CPXM2, NUBPL, and RFK.

Weight Gain is a Common Issue with Antidepressants, But Buproprion is an Exception

October 3, 2016 · Posted in Current Treatments · Comment 

weight gain on antidepressants

A 2016 study by researcher David Arterburn and colleagues in the Journal of Clinical Medicine suggests that taking an antidepressant for two years is associated with an increase in body weight. Luckily, bupropion (trade name Wellbutrin) is an exception that may be a good choice for obese or overweight patients.

The researchers analyzed links between which antidepressants patients in a large health system in Washington State were prescribed and their body weight two years later.

The researchers used fluoxetine (Prozac) as a reference. Most antidepressants did not differ significantly from fluoxetine in terms of the weight gain experienced by people taking the drug.

There were a few exceptions. Compared to non-smoking fluoxetine users, who gained an average of 4.6 pounds in two years, non-smoking bupropion users actually lost weight—an average of 2.4 pounds. (Smokers taking bupropion still gained an average of 6.9 pounds.)

Sertraline (Zoloft) was another exception. Sertraline users gained more than users of other antidepressants—an average of 10.5 pounds over two years.

Bad Habits May Reduce Brain Volumes, May Cause Dementia

September 26, 2016 · Posted in Risk Factors · Comment 

bad habits can reduce brain volumes

Smoking, alcohol use, obesity, and diabetes aren’t just harmful to the body. They may actually lead to dementia.

Behavioral risk factors for cardiovascular disease like those listed above have been linked to reduced volume in the brain as a whole and several brain regions,  including the hippocampus, precuneous, and posterior cingulate cortex. A 2015 study by researcher Kevin King and colleagues found that these reduced brain volumes are early indicators of cognitive decline.

King and colleagues analyzed data on 1,629 participants in the long-term Dallas Heart Study. Their cardiovascular risk factors were assessed when they began the study, and their brain volume and cognitive function were measured seven years later.

Alcohol use and diabetes were associated with lower total brain volumes, while smoking and obesity were linked to low volumes in the posterior cingulate cortex.

Low hippocampal volume was linked to past alcohol use and smoking, while lower precuneous volume was linked to alcohol use, obesity, and blood glucose levels.King and colleagues suggested that subtle differences in brain volumes  in midlife are the first sign of developing dementia in participants who were still younger than 50 years of age.

Liraglutide FDA-Approved for Obesity

September 12, 2016 · Posted in Current Treatments · Comment 

new drug for obesityThe drug liraglutide (trade name Saxenda) has been approved by the Food and Drug Administration (FDA) as a treatment for obesity. It had previously been approved for the treatment of type 2 diabetes.

Liraglutide is taken as a daily injection and is meant to be used alongside a calorie-reduced diet and increased physical activity. Liraglutide works by mimicking a peptide (GLP-1) that regulates appetite and calorie intake.
Recommended dosage is 3 mg/day, but should begin at 0.6 mg/day for the first week and gradually increase by 0.6mg each week to reduce the likelihood of gastrointestinal side effects.

In three clinical trials, participants who were overweight or obese, some of whom had weight-related conditions such as high blood pressure, type 2 diabetes, or high cholesterol, either received training about following a reduced-calorie diet and increasing physical activity or had already lost up to 5% of their body weight by engaging in these practices.

Among those participants who did not have diabetes or a weight-related condition, 62% lost up to 5% of their body weight after a year of taking liraglutide, compared to 34% of those who were given a placebo injection.

Of the participants who had type 2 diabetes, 49% lost up to 5% of their body weight after a year of liraglutide, compared to 16% of those who received placebo.

Of those who had a weight-related condition other than diabetes, 42% lost up to 5% of their body weight compared to 21.7% who took placebo.

Depression and Obesity Linked in Study of Mexican Americans

February 29, 2016 · Posted in Risk Factors · Comment 

depression and obesityA 2015 study by Rene L. Olvera and colleagues in the Journal of Clinical Psychiatry indicated that among 1,768 Mexican-Americans living along the border from 2004–2010, 30% were currently depressed, 14% had severe depression, and 52% were obese. Women were more likely to be depressed, and more likely to have severe depression. Other factors making depression more likely included low education, obesity, low levels of “good” cholesterol, and larger waist circumference. Low education and extreme obesity were also linked to severe depression.

In a commentary on the article in the same issue, researcher Susan L. McElroy wrote that “the medical field needs to firmly accept that obesity is a risk factor for depression and, conversely, that depression is a risk factor of obesity.” She suggested that people with obesity, those who carry excess weight around their middles, and those who have related metabolic symptoms such as poor cholesterol should all be evaluated for depression. Likewise, those with depression should have their weight and body measures monitored. People with both obesity and depression should be evaluated for disordered eating.

Obesity Linked to Illness Severity

December 28, 2015 · Posted in Risk Factors · Comment 

obesity linked to illness severity

In a talk at the 2015 meeting of the International Society for Bipolar Disorder, researcher David Bond reported that 75% of patients in a study of first episode mania had unhealthy body mass indices (BMIs). Forty percent were overweight while thirty-five percent were obese. Higher weight was associated with greater illness severity. Bond said that in other studies obesity has been associated with less time well and a greater risk of relapse into depression.

Obese patients also had lower brain volume, worse memory, and a greater risk of developing early onset dementia compared to other patients. Those who were overweight or obese had a 35% higher risk of developing Alzheimer’s disease.

In a different talk at the same meeting, researcher Roger McIntyre reported that among patients with bipolar disorder, those who were obese have greater cognitive problems and more evidence of inflammation than those who were not obese. He has seen indirect antidepressant effects and other health benefits following weight loss from bariatric surgery.

New Injectable Treatment for Obesity

July 27, 2015 · Posted in Current Treatments · Comment 

injection for obesity

Liraglutide, an injectable drug used to treat Type 2 diabetes, has been approved by the Federal Drug Administration for the treatment of obesity. The drug is newly formulated in recommended doses of 3mg/day under the brand name Saxenda. Liraglutide is suggested for adults with a body mass of 30 or above, or 27 and above with other weight-related conditions such as hypertension, diabetes, or high cholesterol.

In clinical trials, out of 3,731 participants without weight-related comorbid conditions, 62% of those who received liraglutide lost at least 5% of their body weight, compared to 34% of those who received placebo. Of the 635 participants with Type 2 diabetes, 49% of those who received liraglutide lost at least 5% of their body weight, compared to 16% of those who received placebo. In the 422 participants with other weight-related comorbidities, 42% of those taking liraglutide lost 5% or more of their body weight compared to 21.7% of those on placebo.

There were also some improvements in risk factors for cardiovascular disease in people taking liraglutide.

Liraglutide affects appetite regulation, leading to reduced calorie intake that produces weight loss. The treatment is delivered in a pre-filled multidose pen that can be injected in the abdomen, thigh, or arm. Dosing begins at 0.6 mg/day to minimize unwanted gastrointestinal effects.

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