Liraglutide FDA-Approved for Obesity
The 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
A 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
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
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.
People with High Inflammation Respond Best to EPA Omega-3 Fatty Acids in Depression
Omega-3 fatty acids are found in some green vegetables, vegetable oils, and fatty fish. There is some evidence that omega-3 fatty acid supplements can reduce depression, but researchers are trying to clarify which omega-3s are most helpful, and for whom. A new study in Molecular Psychiatry suggests that depressed people with higher inflammation may respond best to EPA omega-3 fatty acids compared to DHA omega-3 fatty acids or placebo. Researchers led by M.H. Rapaport divided people with major depressive disorder into “high” and “low” inflammation groups based on their levels of the inflammatory markers IL-1ra, IL-6, high-sensitivity C-reactive protein, leptin, and adiponectin. Participants were randomized to receive eight weeks of treatment with EPA omega-3 supplements (1060mg/day), DHA omega-3 supplements (900mg/day), or placebo.
While overall treatment differences among the three groups as a whole were negligible, the high inflammation group improved more on EPA than on placebo or DHA, and more on placebo than on DHA. The authors suggest that EPA supplementation may help relieve symptoms of depression in people whose depression is associated with high inflammation levels, a link common among obese people with depression.
Editor’s Note: These data add to a study by Rudolph Uher et al. in which people with high levels of C-reactive protein responded better to the tricyclic antidepressant nortriptylene, while those with low levels of the inflammatory marker responded better to the selective serotonin reuptake inhibitor antidepressant escitalopram.
Obesity Worsens Bipolar Disorder, Decreases Gray and White Matter in Brain
According to researcher David J. Bond at the 2014 meeting of the International Society for Bipolar Disorders, “Up to 75% of people with bipolar disorder (BD) are overweight or obese, and these patients suffer more severe psychiatric symptoms than normal-weight patients, including more frequent depressions, more suicide attempts, lower response rates to pharmacotherapy, and greater inter-episode cognitive impairment.” Obesity is a chronic inflammatory condition that damages body organs, and it appears as though the brain may be one of these. Adipose (fatty) tissue is an endocrine organ that produces substances that cause inflammation in blood vessels and that damage the heart.
Obesity is associated with decreased total brain volume, and in children, decreased gray matter volume. Obesity increases the risk of cognitive impairment, and decreases memory, attention, and executive functioning. Obesity increases the risk of Alzheimer’s disease, as well as multiple sclerosis, Parkinson’s, and depression.
In bipolar disorder, obesity decreases response to mood stabilizers and atypical antipsychotics. Bond found that in patients with a first episode of mania, body mass index (BMI) was inversely related to white matter volume and temporal lobe gray matter volume. Higher BMIs also led to neurochemical changes including increased hippocampal glutamate and reduced N-acetylaspartate. Bond also noted findings by Roger S. McIntyre that weight loss surgery in patients with bipolar disorder led to more positive treatment outcomes.
Editor’s Note: These findings speak to the importance of exercise and good diet, using medications with the least likelihood of weight gain, and treating obesity once it has developed. We have previously noted the weight loss effects of topiramate and zonisamide, and new data support the substantial weight loss with the combination of bupropion (150-300mg) and naltrexone (50mg).
Bupropion Plus Naltrexone Reduces Brain Response to Food Cues
The combination of antidepressant bupropion (Wellbutrin) and naltrexone (Revia), a drug that helps alcoholics resist the craving for alcohol, can help patients keep their weight down. Last year we summarized an article by Smith et al. in the journal Diabetes, Obesity, and Metabolism that showed that obese patients with diabetes treated with the combination of bupropion and naltrexone had excellent weight loss and reduction in body fat compared to those treated with either drug alone or with placebo.
A more recent study by G. J. Wang et al. published in the International Journal of Obesity in 2013 shows that the combination of 360mg of bupropion sustained release and 32mg of naltrexone sustained release works by reducing patients’ response to food cues. Forty women were shown a video of their favorite food being prepared, which stimulated parts of the brain associated with visual stimuli and other functions. Those who received the combination of naltrexone and bupropion had lessened hypothalamic response to the videos compared to those who received placebo, and also showed activity in parts of the brain associated with inhibitory control (the anterior cingulate), internal awareness (the superior frontal cortex, the insula, and the superior parietal cortex), and memory (the hippocampus).
Editor’s Note: It looks like the drug combination prompts the brain to say, “Wow, that looks good, but maybe I shouldn’t take in any more calories today.”
Obesity and Bipolar Disorder
David Bond presented research at the 2013 meeting of the International Society of Bipolar Disorder about the connections between obesity and the course of bipolar disorder. Bipolar disorder has some of the highest rates of obesity among all psychiatric illnesses. Obese patients with bipolar disorder have more episodes of depression, more suicide attempts, worse response to psychiatric medications, and more cognitive impairment between episodes of illness.
Bond also found that higher body mass index (BMI) was associated with reduced white and gray matter volume in the brain, greater cognitive impairment, increased risk of Alzheimer’s disease, and increased glutamate concentration in the hippocampus (which is potentially neurotoxic) and decreased NAA (a marker of neuronal integrity). Those with 7% weight gain or higher in the first year of treatment show a greater loss of volume in the frontal and temporal lobes.
Editor’s Note: These data again speak to the importance of maintaining good lifestyle habits such as proper diet and exercise to attempt to slow or prevent the development of obesity. Also avoiding medications for bipolar disorder with the greatest liability for weight gain and using some that can help with weight loss would be good topics for discussion with a treating physician.
Adolescent Obesity Connected to Brain Impairment
As childhood obesity has increased over the past several decades, the metabolic syndrome has also become more prevalent among children and adolescents. The metabolic syndrome consists of five measures related to obesity: elevations in fasting glucose levels or insulin resistance, a high proportion of LDL (“bad” cholesterol) to HDL (“good” cholesterol), elevated triglycerides, hypertension, and abdominal obesity or high waist circumference. A patient with three of these abnormalities would be diagnosed with the metabolic syndrome.
In adults, the metabolic syndrome has been associated with neurocognitive impairments. Researchers decided to look at adolescents with the metabolic syndrome to determine whether these brain effects are a result of long-term metabolic impairment or whether they can take place after short-term periods of poor metabolism as well. In a study published by Yau et al. in the journal Pediatrics last year, 49 adolescents with the metabolic syndrome were compared to 62 adolescents without the syndrome who had been matched for similar age, socioeconomic status, school grade, gender, and ethnicity.
The adolescents with the metabolic syndrome had lower scores on tests of math, spelling, attention, and mental flexibility, as well as a trend for lower overall intelligence. In brain measures such as hippocampal volume, amount of brain cerebrospinal fluid, and microstructural integrity in white matter tracts, the seriousness of the metabolic syndrome correlated with the level of abnormality on these measures.
Editor’s Note: It seems as though even short-term problems with metabolism can lead to brain impairments like lower cognitive performance and decreased integrity of brain structures. These effects are even seen before vascular disease and type 2 diabetes are manifest.
It is doubly important, in terms of both cardiovascular and neurobiological risks, to look out for one’s medical and psychiatric health. Reducing the abnormal components of the metabolic syndrome should produce benefits for both the cardiovascular system and the central nervous system.
Almost 40% of patients with bipolar illness in the US have the metabolic syndrome, so considerable effort will be required to improve this public health crisis.
Good Weight Loss With Bupropion Plus Naltrexone
A 2013 article by Smith et al. in the journal Diabetes, Obesity, and Metabolism reports that obese patients treated with the combination of bupropion (Wellbutrin) and naltrexone (Revia) had excellent weight loss and reduction in body fat compared to those treated with either drug alone or with placebo. The combination resulted in about a 14% reduction in body fat, while placebo, bupropion alone, and naltrexone alone each brought about only a 3-4% reduction.
Editor’s Note: Researcher Roger McIntyre is an expert on the metabolic syndrome in patients with bipolar illness and has been using this combination with success in patients with mood disorders. He finds the combination of bupropion and naltrexone more helpful than the anticonvulsants topiramate (Topomax) or zonisamide (Zonegran) or the anti-diabetes drug metformin.
Since obesity and the metabolic syndrome occur in approximately 40 to 50% of bipolar patients and significantly increases cardiovascular risks such as heart attack and stroke, and since bupropion is widely used in the treatment of bipolar depression, this combination appears worthy of consideration for those with obesity. Its use should be accompanied by a good diet and an exercise regimen. Decreasing cardiovascular risk is a very important component of the treatment of bipolar disorder, and the combination of bupropion and naltrexone could have substantial benefits.
