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).

Vitamin D3 Improves Depression in Older Adults

December 3, 2018 · Posted in Potential Treatments · Comment 

vitamin D

Researcher Negin Masoudi Alavi and colleagues reported in the journal Clinical Nutrition in 2018 that compared to placebo, 50,000 IU of vitamin D3 taken weekly for eight weeks improved depression in depressed patients over the age of 60.

Although the literature about vitamin D3’s effects on depression are mixed, a 2014 meta-analysis by Simon Spedding in the journal Nutrients found that in studies of vitamin D-deficient depressed participants whose vitamin D levels were restored to normal levels by the end of the study, vitamin D significantly improved depression. (Spedding attributed earlier mixed results to studies that did not clearly correct a vitamin D deficiency.) A 2013 study by Nayereh Khoraminya and colleagues in the Australian and New Zealand Journal of Psychiatry suggested that a 1500 IU dose of vitamin D3 combined with the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine improved depression more than fluoxetine plus placebo in depressed patients who were not necessarily deficient in vitamin D. Another study by Jacqueline A. Pettersen in the journal Experimental Gerontology found that in healthy adults, 4,000 IU of vitamin D3 improved cognitive functioning (namely visual memory) more than 400 IU.

Editor’s Note: Given these promising studies, the safety of D3, and fact that psychiatric patients are often deficient in vitamin D3, taking vitamin D3 supplements to improve depression might be worth trying.

Using Light to Improve Sleep and Depression

November 13, 2018 · Posted in Current Treatments, Risk Factors · Comment 
blue-blocking glasses

Blue-blocking glasses

At the 2018 meeting of the North Carolina Psychiatric Association, researcher Chris Aiken described the phenomenon of sleep inertia, when people are awakened from deep sleep by an alarm, rather than waking at the end of a sleep cycle, and are groggy for 15 minutes. Depressed people may stay groggy for 4 hours. A dawn simulator may help. These lights turn on gradually over the course of 30 to 60 minutes, reaching 250 lux while the patient is still asleep. Dawn simulators have worked in eight out of ten controlled clinical trials to help people with seasonal affective disorder, adolescents, and normal adults wake up more easily. They range in cost from $25 to $90 and some brands include PER2LED or LightenUp. Aiken says dawn simulators can improve depression, sleep quality, and cognition.

Evening and nighttime light: Bright lights and blue light, like the light that comes from electronic screens, can shut down the body’s secretion of melatonin, making people awake and alert in the evening when they should be getting sleepy. Dim light or glasses that filter out blue light allow increases in melatonin secretion in the evening, while bright light suppresses it. Missing this early melatonin pulse creates “night owls” who have delayed sleep onset.

Because light still reaches our eyes through our eyelids as we sleep, even low-level light during the night impairs sleep, cognition, and learning, and increases the risk of depression by a hazard ratio of 1.8 (about double the risk). A 2017 study by Kenji Obayashi in the American Journal of Epidemiology found that bedroom light above 5 lux elevated rates of depression in older adults after two years of followup. Living room light averaged around 50 lux and increased depression further.

Lux chart

A slide from Aiken’s presentation shows comparative levels of light

The treatment is turning off TVs, electronic screens, and cellphones in the evening or wearing blue-blocking glasses, which can be found for less than $10. Blue-blocking glasses can increase calmness and reduce anxiety, and even are effective in treating mania. Then, during sleep, wear an eye mask or get light-blocking blinds or curtains for windows. For a complete blackout, use blackout curtains, aluminum foil over windows, electric tape over LED lights, or try sleeping in the basement.

Aiken suggests that to re-instate healthy sleep patterns, people should institute virtual darkness from 6pm to 8am, including wearing blue-blocking glasses when out of bed. Then they should institute total darkness or wear an eye mask when in bed. When symptoms improve, this routine can gradually be shifted to begin later in the evening, such as two hours before bedtime.

Blue light filters are also available for smartphones and tablets including Apple Nightshift mode, Kindle BlueShade, and Android Twilight and Blue Light Filter.

Glasses that filter out blue light include Uvex Ultraspec 2000, 50360X ($7 on Amazon) and Uvex Skyper 351933X ($7-10 on Amazon). The website lowbluelights.com sells blue-blocking glasses from $45 and a variety of other blue-free lighting products such as lightbulbs and flashlights.

Bright light therapy for unipolar and bipolar depression: 30 minutes of bright light (7,500 to 10,000 lux) in the morning can help treat depression in unipolar and bipolar disorder and seasonal affective disorder. The effects usually take 3 to 7 days to set in, but they only last while a patient continues using the bright light in the morning. Researcher Dorothy K. Sit and colleagues found that bright light therapy in the morning sometimes caused hypomanic reactions in people with bipolar disorder, and reported in a 2018 article in the American Journal of Psychiatry that midday light therapy (from noon to 2:30pm) was also effective without this unwanted effect. However, a 2018 article by Ne?e Yorguner Küpeli and colleagues in the journal Psychiatry Research suggested that a half hour of morning light for two weeks was sufficient to bring about improvement in 81% of patients with bipolar disorder and did not cause serious side effects.

Melatonin regimen for sleep onset delay: Melatonin can be used to treat severe night-owls with a very late onset of sleep (for example, going to bed at 2 or 3am and sleeping late into the morning). Melatonin can help with sleep onset to some extent when used at bedtime, but in those with an extreme phase shift, researcher Alfred J. Lewy recommends a regimen of low dose priming with 400–500 micrograms of melatonin at 4pm and then a full dose of 3 milligrams of melatonin at midnight. The 4pm priming dose helps pull back the delayed onset of the body’s secretion of melatonin toward a more normal schedule.

Grape Extract May Improve Cognition

January 31, 2018 · Posted in Potential Treatments · Comment 

Polyphenolic compounds in colored fruits and vegetables are thought to improve memory and cognition. Extracts from Vitis vinifera, the grape species that includes almost all well-known varieties of wine, have been found to have many beneficial effects: antioxidant, antibacterial, anti-inflammatory, anticancer, antidiabetic effects, in addition to protective effects on skin, the heart, the liver, and neurons.

For about a decade, researchers have known that polyphenolic compounds from grapes could improve cognitive impairment and reduce neuropathological lesions in the brain in animals with a model of Alzheimer’s disease. New research suggests that the same compounds that protect the plant against damage, fungus, or UV rays may also protect the human brain against damage.

Researchers led by Gioacchino Calapai tested a trademarked nutritional supplement called Cognigrape, which includes extracts from Vitis vinifera, in healthy adults between the ages of 55 and 75 in Italy. One group of 57 participants received 250mg of Cognigrape per day while the other group of 54 received placebo once a day for twelve weeks. Several weeks after the supplementation period, the group taking Cognigrape showed significant improvement in cognitive function compared to baseline and compared to the group taking placebo. The Cognigrape group also showed significant reductions in depression symptoms, improvements in somatic symptoms, and improvements in attention, language, immediate memory, and delayed memory. This is the first study to find an improvement in cognitive performance in humans after supplementation with a Vitis vinifera extract.

The study by Calapai and colleagues was published in the journal Frontiers in Pharmacology in 2017.

High-Dose Vitamin D May Improve Cognition More Than Low-Dose Vitamin D

August 16, 2017 · Posted in Potential Treatments · Comment 

Woman taking vitaminVitamin D deficiency has been associated with dementia and cognitive decline, but supplements may help. In a study of 82 healthy individuals with low vitamin D levels, high-dose vitamin D supplements (4000 IU/day) improved visual/nonverbal memory more than did low-dose vitamin D supplements (400 IU/day) over 18 weeks.

The 2017 study took place in Canada, where short winter days can make it more difficult to get sufficient levels of vitamin D from sunlight. The higher-dose supplements raised blood levels of vitamin D compared with the lower-dose supplements.

Those who received the higher doses performed better at tests of visual memory such as the Pattern Recognition Memory Task and the Paired Associates Learning Task, but their performance on tests of verbal memory was not significantly different from those in the lower-dose group. This suggests that higher vitamin D levels are particularly important to visual/nonverbal memory.

The study by Jacqueline A. Pettersen was published in the journal Experimental Gerontology.

Antipsychotic Drug Pimavanserin Seems to Reduce Psychosis in People with Alzheimer’s

August 1, 2017 · Posted in Potential Treatments · Comment 

elderly womanThe antipsychotic drug pimavanserin was approved by the US Food and Drug Administration last year as a treatment for hallucinations and delusions in Parkinson’s disease. Now it looks as though it may also help people with Alzheimer’s disease. Pimavanserin works differently than other antipsychotic medications—a selective serotonin inverse agonist, it acts at serotonin HT2A receptors to produce effects opposite to those that serotonin would produce at the same receptor.

In a trial of 181 patients with Alzheimer’s and psychotic symptoms, those who received 34 mg/day of pimavanserin had a significant improvement in psychotic symptoms in six weeks compared to those who received placebo.

Over 12 weeks of treatment, pimavanserin did not impair cognition, as atypical antipsychotics can do.

Pimavanserin was well tolerated. The most common side effects were falls, urinary tract infections, and agitation. Like other atypical antipsychotics, the drug carries a box warning from the FDA that there is an increased risk of death when the drug is used to treat older people with dementia-related psychosis.

The FDA has designated pimavanserin a breakthrough therapy and is giving it priority review. These designations can speed up the development and review of a drug and are granted when a drug looks like it will be substantially better or safer than existing treatments for a serious condition.

Treatment with Hormone EPO Improved Cognition in People with Unipolar and Bipolar Disorder

January 10, 2017 · Posted in Potential Treatments · Comment 

improved cognition

People with unipolar depression and bipolar disorder may experience cognitive difficulties, even when they’re not currently depressed. In a study published in the journal European Neuropsychopharmacology in 2016, researchers led by Caroline Vintergaard Ott determined that treatment with the hormone erythropoietin (EPO) may help.  EPO is produced in the kidney and increases the production of hemoglobin and red cells.

Seventy-nine participants with unipolar or bipolar disorder were randomized to receive infusions of either EPO or a saline solution once a week for eight weeks. By the end of the study, those who received EPO showed significant improvements in the speed of their complex cognitive processing compared to those who received saline. EPO is known to induce the production of red blood cells. The improvements in processing speed lasted for at least another six weeks after red blood cell production would have normalized.

Those participants who received EPO not only had improved scores on tests of processing speed, they also reported fewer cognitive complaints. The EPO treatment was most likely to be effective in participants who had more impaired cognition at the beginning of the study.
In previous research by the same research group presented by Kamilla W. Miskowiak at the 2014 meeting of the International Society of Bipolar Disorders, EPO also improved sustained attention and recognition of happy faces.

Inactivity in Young Adulthood May Worsen Cognition Later in Life

September 22, 2016 · Posted in Risk Factors · Comment 

inactivity can worsen cognition later in life

The couch potato lifestyle common in the US may have consequences later, in the form of deficits in memory, executive functioning (including planning and execution) and processing speed.

At the 2015 Alzheimer’s Association International Conference, researcher Kristine Yaffe and colleagues reported that low levels of physical activity and high rates of television viewing in young adulthood may reduce cognitive capabilities in midlife.

The Centers for Disease Control report that less than 50% of adults aged 18–64 get the recommended minimum of physical activity each week. The guidelines recommend at least 150 minutes of moderate intensity aerobic activity (such as walking briskly) and two or more days of muscle-strengthening activities that work all major muscle groups.

Yaffe says that physical activity can protect against cognitive decline or dementia later on.
Participants in the long-term study who reported burning fewer than 300 calories per 50-minute session three times per week during two-thirds of their followup visits had worse cognition at year 25 than those participants who were more active. Those who watched more than four hours of television per day also had reduced cognition in midlife.

Yaffe stresses that exercising regularly is not just important in keeping weight down and protecting the heart, but also in protecting the brain. Regular physical activity may even prevent illnesses such as Alzheimer’s disease.

Guanfacine Improves Cognition in Schizophrenia

April 19, 2016 · Posted in Potential Treatments · Comment 

cognitive function in schizophrenia

People with disorders on the schizophrenia spectrum often suffer cognition problems that affect skills such as the processing of information about people and social situations (social cognition) and the execution of plans (executive function). At the 2015 meeting of the Society for Biological Psychiatry, researcher Larry J. Siever reported that the drug guanfacine improved these types of thinking in people with disorders on the schizophrenic spectrum compared to placebo. Participants were enrolled in a 7.5-week training program to improve cognition.

Exercise Improves Cognition and Normalizes Brain Activity

February 12, 2016 · Posted in Potential Treatments · Comment 

exercise improves cognition

Exercise isn’t just good for the body—new research suggests it can improve cognition and normalize brain activity.

At the 2015 meeting of the American Academy of Child and Adolescent Psychiatry, researcher Benjamin I. Goldstein reported that 20 minutes of vigorous exercise on a bike improved cognition and decreased hyperactivity in the medial prefrontal cortex in adolescents with and without bipolar disorder.

At the same meeting, researcher Danella M. Hafeman reported that offspring of parents with bipolar disorder who exercised more had lower levels of anxiety.

A plenary address by James J. Hudziak also suggested that exercise, practicing music, and mindfulness training all lead to improvements in brain function and should be an integral part of treatment for children at high risk for bipolar disorder and could be beneficial for all children.

Editor’s Note: Recognizing and responding to mood symptoms is key to the prevention and treatment of bipolar disorder in children and adolescents at high risk for the illness. For these young people, exercise, a nutritious diet, good sleep habits, and family psychoeducation about bipolar disorder symptoms may be a good place to start. Joining our Child Network may also be helpful.

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