Bupropion Plus Naltrexone Reduces Brain Response to Food Cues

March 6, 2014 · Posted in Potential Treatments · Comment 

woman considering eating a cookie

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

August 15, 2013 · Posted in Risk Factors · Comment 

obese man before and after behavior changes

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

April 19, 2013 · Posted in Peer-Reviewed Published Data, Risk Factors · Comment 

teen doing homework

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

April 17, 2013 · Posted in Current Treatments · Comment 

man on scaleA 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.

Rats Exposed to Jet Fuel Pass Epigenetic Changes on to Third Generation

April 8, 2013 · Posted in Risk Factors · Comment 

rat

A recent study of rats showed that exposure to hydrocarbons (jet fuel JP-8) can bring about disease not just in the rats who were exposed, but also in subsequent generations. Epigenetics is the study of how environmental events or biochemical changes can affect the structure of DNA, e.g. by attaching extra methyl groups. (These kinds of “epimutations” are separate from the inherited genetic makeup we receive from our parents, but new evidence suggests that some can be passed on to future generations.)

When first generation female rats were exposed to jet fuel, third generation rats showed 33 different examples of DNA methylation as well as obesity.

Previous research has shown similar signs of transgenerational transmission of disease resulting from first generation exposure to chemicals such as bisphenol A, phthalates, dioxins, and pesticide mixtures.

The Impact of Obesity on Brain and Behavior

December 21, 2012 · Posted in Risk Factors · Comment 

Overweight Santa Claus

In an abstract presented at the 5th Biennial Conference of the International Society for Bipolar Disorders, K. Sim and colleagues discussed the impact of increased body mass index on the integrity of white matter in the brain during a first episode of mania. The researchers found significant abnormalities in white matter integrity in the temporal pole and occipital brain regions in overweight and obese patients compared to patients of normal weight. These data highlight the need to clarify the neural mechanisms that link obesity and poorer functional outcomes in bipolar disorder.

Other investigators have reported that bipolar patients with obesity have a less robust response to naturalistic treatment compared to those of normal weight. At least one study suggested that patients with overweight and obesity experience more cognitive difficulties.

Editor’s Note: The pathophysiological mechanisms involved in the relationship between weight and brain function are not yet clear, although one possibility is that in obese patients, some fat cells in the abdominal area become too big to survive and are scavenged by other cytokine-producing cells. These inflammatory cytokines are then able to cross the blood-brain barrier, enter the brain, and affect neuronal functioning. Whether a mechanism like this is at play in relation to these particular findings remains for further investigation.

Nonetheless, these data suggest the importance of good diet, exercise, and other means of maintaining a good body weight in order to attempt to avoid some of the adverse associations of obesity with deficits in cognition, white matter integrity, and treatment outcome.

Obesity and Bipolar Disorder: News from the American Academy of Child and Adolescent Psychiatry

April 23, 2012 · Posted in Current Treatments, Risk Factors · Comment 

Overweight boyAt the annual meeting of the American Academy of Child and Adolescent Psychiatry in Toronto in October 2011, a symposium on the impact of obesity on the course of childhood onset bipolar illness was held.

Typical Treatment of Bipolar Disorder in Youth

David Axelson described the typical outcome of bipolar illness and the medications used during naturalistic treatment. The data came from the large collaborative Course and Outcome of Bipolar Illness among Youth (COBY) study, in which he and his colleagues followed 255 patients with bipolar I disorder (BP I), 30 patients with bipolar II (BP II), and 153 patients with bipolar not otherwise specified (BP NOS) for a mean of 5 years. He discussed only BP I children at the symposium.

The study initially followed 270 BP I children for a mean of 582 weeks. They ranged in age from 7 to 17 years (average 14.4 years). Ninety-three percent of the children were treated with one or more antimanic (AM) agents. These included atypical antipsychotics (AA) in 77%, valproate or carbamazepine in 44%, and lithium in 47%. Antidepressants (ADs) were used in 46% of the children, stimulants in 43%, and benzodiazepines in 21%. Sixty percent had been on two classes of antimanic medications concurrently at some point.

A univariate analysis showed that older children received smaller amounts of antipsychotics and more anticonvulsants and lithium. Variables associated with better response, that is, a rating of either much or very much improved on the Clinical Global Impressions scale for bipolar disorder (CGI-BP), included older age and treatment with atypical antipsychotics. Those who had comorbid attention deficit hyperactivity disorder (ADHD) or psychosis at baseline did more poorly.  Mean symptom scores were better when the children received any anti-manic treatment including an atypical or lithium, but worse when they received valproate or carbamazepine.

These data are similar to those from other prospective treatment outcome studies in childhood-onset bipolar I illness. Taken together they all suggest that the illness is difficult to treat and stabilize even when multiple medicines are used in combination.

Obesity and Mood Disorders in Youth

Another speaker, Ben Goldstein, indicated that in the scientific literature, obesity has been associated with a higher number of depressive episodes and longer length of depression, more recurrences of depression, more anxiety disorders, increased numbers of hospitalization, more suicide attempts, and worse functional outcomes. In the same group of patients discussed by Axelson above, 42% were overweight or obese, compared to a 34% incidence in the general population of children in this age range.

Factors associated with overweight included substance abuse, a history of physical abuse, prior hospitalization, and being on 2 or more medications. Those who were overweight or obese spent more time ill in a manic or depressive episode. Read more

Inflammation and Mood Disorders

April 13, 2012 · Posted in Risk Factors · Comment 

There is increasing evidence of a link between inflammation, brain function, and treatment resistance in the mood disorders. Obesity is also linked to inflammatory processes and thus may contribute to the development of treatment resistance in both unipolar and bipolar mood disorders.

Causes of Inflammation

scaleObesity is one factor that can lead to increases in inflammation. When people gain weight, the size of fat cells can increase to the point that the cells are deprived of oxygen and disintegrate. Then macrophages and other cells come in to sweep up the remaining particles of the fat cells. These scavenger cells then become activated and produce more regulatory chemicals called cytokines. The cytokines produced in the periphery (in the body outside the brain) can then enter the brain and affect brain function in a process that may ultimately be linked to fatigue, depression, and other adverse mood and behavior states that contribute to treatment resistance. There is a two-way street: the brain can influence the body and what goes on in the body can influence the brain.

Other factors that can lead to increases in inflammation and eventually to treatment resistance in the unipolar and bipolar mood disorders include early life stress, medical illness, and anxiety and personality disorders.

Anti-Inflammatory Treatments

Given the close links between inflammation and depression (discussed in BNN Volume 15, Issue 1 from 2011), Andrew H. Miller of Emory University decided to test a specific anti-inflammatory agent called infliximab (a TNF monoclonal antibody that inhibits TNF alpha actions) as an antidepressant. One sign of inflammation is a C-reactive protein (CRP) level of 2mg/L or greater. The effect of infliximab on the population of treatment refractory depressed patients who participated in Miller’s study was not significant on the whole, but the drug did have significantly greater antidepressant effects than placebo in those patients with the highest levels of CRP. The investigators believe this demonstrates the principle that a drug that inhibits TNF alpha may be useful in patients with the greatest degree of inflammation.

Other approaches to anti-inflammatory mechanisms are also being pursued, including use of aspirin, COX-2 inhibitors, and the antibiotic minocycline. Minocycline has anti-inflammatory and neuroprotective effects and has been reported to have positive effects in cognition and negative symptoms of schizophrenia.

The Evolving Omega-3 Fatty Acid Story: The Icing on the Cake (And Why It Shouldn’t Be Eaten)

October 3, 2011 · Posted in Current Treatments · Comment 

sources of omega-3 fatty acidsOmega-3 fatty acids are important for brain development and function and are essential to the human diet since they cannot be synthesized by the body. Omega-3 fatty acids are derived from canola oil, walnuts, flax seed oil, leafy vegetables, and especially fish. The main omega-3 fatty acids include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). They have anti-inflammatory effects, unlike omega-6 fatty acids, which are pro-inflammatory. The omega-6 fatty acids come from soy, peanuts, corn oil, and meats, and are associated with increases in obesity, myocardial infarction, and stroke.

In a recent review of the literature, John Davis and Joe Hiblen found that diets that include high levels of omega-3 fatty acids are associated with decreased incidence of depression, suicide, and cardiovascular disease. The researchers performed a meta-analysis of all the prospective depression treatment studies of omega-3 fatty acids compared to placebo. They found that EPA had antidepressant effects in humans, with moderate effect size and a high degree of statistical significance. DHA, however, did not appear to have an antidepressant effect, and pure DHA was even associated with some worsening of depression.

Editor’s note: This meta-analysis helps clarify some of the ambiguities in the literature about the antidepressant efficacy of the omega-3 fatty acids, clarifying that EPA alone is an effective antidepressant. The one study that did not find antidepressant effects with EPA was carried out by the Bipolar Collaborative Network, in which I am an investigator. Our study, published in an article by Keck et al., showed that 6g of EPA was not significantly more effective than placebo in bipolar depression or in rapid cyclers. However, there is some indication that 6g may be too high a dose of EPA, and most of the recommendations now suggest using 1-2g of either EPA or an EPA/DHA combination. Read more

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