Infliximab Helps the Subgroup of Bipolar Depressed Patients Who Faced Adversity in Childhood

October 11, 2019 · Posted in Potential Treatments · Comment 

child with bruised face

At the 2019 meeting of the International Society for Bipolar Disorders, researcher Mike Cosgrove and colleagues described a study of the immune-suppressing drug infliximab in adults with bipolar disorder. The researchers found persistent significant improvements on infliximab only in those with bipolar disorder who also had a history of childhood adversity. Childhood adversity is consistently associated with elevated levels of inflammatory cytokines, and baseline inflammation may be a prerequisite for a positive effect from infliximab, which works by blocking the inflammatory cytokine TNF alpha.

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).

Treating Bipolar Depression in an Adolescent

July 9, 2019 · Posted in Potential Treatments · Comment 

At the 2019 meeting of the International Society for Bipolar Disorders, researcher Ben Goldstein discussed a case of a 15-year-old with bipolar depression and his recommended treatments for the adolescent. Goldstein endorsed the use of an atypical antipsychotic such as lurasidone, and perhaps also quetiapine. Goldstein noted 2015 findings from researcher Robert Findling that lamotrigine was significantly more effective than placebo in adolescents 13–18 years old, but was not effective in those aged 10–12.

(In adults, researcher John Geddes and colleagues found that in patients with an inadequate antidepressant response to quetiapine, the addition of lamotrigine was more effective than adding a placebo, both acutely and in long-term follow-up. The only caveat was that lamotrigine was less effective in those who were also being treated with folate.)

Editor’s Note: Some other treatments could augment the effects of the regimen proposed by Goldstein, including lithium and the antioxidant N-acetylcysteine, which, it should be noted, takes more than eight weeks to become effective. Vitamin D3 could also be considered, as it is often low in children with psychiatric disorders. One treatment that went unmentioned at the meeting was repeated transcranial magnetic stimulation, or rTMS, which is effective and well-tolerated in adolescents with depression.

For patients with more rapidly cycling bipolar disorder and only partial response to medications, the combination of the ‘three Ls’ (lurasidone, lamotrigine, and lithium) could have considerable appeal, given that each drug is from a different class of medications, has a different mechanism of action, targets a different mood phase, and is relatively well-tolerated both alone and in combination with other drugs.

Newly Identified Effects of N-Acetylcysteine

July 5, 2019 · Posted in Potential Treatments · Comment 

NACIn a talk at the 2019 meeting of the International Society for Bipolar Disorders, researcher Michael Berk, who was responsible for some of the initial findings on the effects of the antioxidant N-acetylcysteine (NAC), summarized some of the newer findings about the treatment.

NAC has been found to be effective in bipolar depression and in the treatment of both positive and negative symptoms of schizophrenia. It also helps in the avoidance of cocaine, alcohol, tobacco, and marijuana. It can reduce habitual behaviors such as gambling, obsessive compulsive disorder (OCD), and trichotillomania (compulsive hair-pulling) and irritability and motor stereotypy (repeated movements) in autism.

A 2016 study by researcher Sudie E. Back and colleagues in the Journal of Clinical Psychiatry found that NAC improved symptoms of post-traumatic stress disorder (PTSD) in veterans who also had depression and substance use disorders at a dosage of 2.4 grams/day.

According to Berk, NAC also reduces the incidence of lithium-related renal failure and reduces mitochrondrial toxicity. One study reported that it improved working memory in patients with schizophrenia.

In his talk, Berk also noted that statins offer an interesting new avenue for treatment. Several studies have suggested statins can improve mood or reduce the likelihood of a depressive recurrence. Angiotension-active drugs (inhibitors) have also been reported to decrease the incidence of depression and to improve cognition.

Study in Mice Suggests that Compound in Turmeric May Reduce Anxiety and Promote Resilience to Stress

June 12, 2019 · Posted in Potential Treatments · Comment 

turmericChronic stress is a risk factor for the development of mood and anxiety disorders. Researchers have begun to focus on how to promote resilience to stress. Curcumin is a micronutrient found in turmeric that has anti-inflammatory and antidepressant effects and may promote such resilience.

Researchers studying human depression often design studies to see how mice with chronic social defeat stress respond to various interventions. Mice who are repeatedly menaced by a larger mouse begin to show symptoms that resemble human depression, such as social avoidance, lack of interest in saccharin compared to plain water (a stand-in for loss of enjoyment or anhedonia in humans), and anxiety.

In a 2018 article in the journal Neuropsychopharmacology, researcher Antonio V. Aubry and colleagues described the effects of curcumin on mice undergoing chronic social defeat stress. Mice who were given a diet that consisted of 1.5% curcumin showed a 4.5-fold increase in resilience to social defeat stress, measured by their performance during a test of social interaction. Among the 129 mice in the study, 64% showed the increase in resilience, the remaining 36% did not respond to the curcumin diet and had the normal ‘depressed’ response. The mice who responded well to curcumin released less of the stress hormone corticosterone, and they also had lower levels of the inflammatory marker IL-6.

All of the mice on the curcumin diet showed reduced anxiety during tests that forced them to travel through open spaces (when they prefer to stay in more enclosed spaces or move along the edges of an enclosure).

Vitamin Methyl B12 Improved Autism Symptoms in Randomized, Placebo-Controlled Study

May 23, 2019 · Posted in Potential Treatments · Comment 

group of kids

In a 2016 article in the Journal of the American Academy of Child and Adolescent Psychiatry, Robert L. Hendren and colleagues described an 8-week study in which the vitamin methyl B12 improved symptoms of autism spectrum disorders in children.

Fifty-seven children were randomized to receive either 75??g/kg of methyl B12 injected under the skin every three days or saline injections as a placebo instead. Methyl B12 improved the children’s autism symptoms compared to placebo. The improvements correlated with increases in levels of the amino acid methionine in the blood and improvements in cellular methylation capacity. Children with autism spectrum disorders have reduced ability to methylate (i.e. add methyl groups to) DNA. The methylation process helps convert the toxic amino acid homocysteine into beneficial methionine. The children who received methyl B12 showed a reduction in homocysteine and a better ratio of methionine to homocysteine.

Homocysteine is bad for the heart, for cognition, and for fetal development, while methionine can help improve depression and is important to many cellular reactions. Converting homocysteine to methionine requires vitamin B12 and folate, another B vitamin found in foods such as green vegetables and beans.

Taking folate supplements can help make antidepressants more effective by aiding the methylation process. However, some people have a common variation in the MTHFR gene that makes it difficult for the body to make use of folate. These people would need to take the nutritional supplement L-methylfolate instead of regular folate to help in the conversion of homocysteine to s-adenosylmethionine (SAMe, which acts as an antidepressant).

Vitamin D Has More Benefits Than Previously Thought

May 17, 2019 · Posted in Potential Treatments · Comment 

supplementsVitamin D has long been known as an important vitamin for bone health, preventing conditions such as osteoporosis and rickets. More recently, research suggests that vitamin D may also protect against conditions such as cancer, heart failure, diabetes, respiratory tract infections, and autoimmune disease.

Many Americans have low vitamin D or a vitamin D deficiency. The human body produces vitamin D in large amounts when the skin is exposed to ultraviolet B rays in sunlight. Vitamin D can also be absorbed from vitamin D–fortified foods such as dairy products, some orange juice, and cereals. Some foods such as fatty fish, beef liver, and egg yolks naturally contain some vitamin D, but it is difficult to get enough vitamin D just from consuming these foods.

Low mood or seasonal affective disorder (SAD), in which people feel depressed during winter periods of limited exposure to sunshine, have been linked to low vitamin D.

Other symptoms of low vitamin D vary but can include pain in the joints, bones, or muscles; fatigue; and breathing problems.

Editor’s Note: A few small studies have suggested that 1,500 IU per day of vitamin D supplements can help depressed mood, even in those with normal vitamin D levels. Several studies have indicated that children or adolescents with psychiatric disorders are especially likely to be vitamin D–deficient. Another study found that higher amounts of vitamin D (4,000 IU) could improve cognition in healthy volunteers more than lower doses could. Vitamin D also improved cognition in people with multiple sclerosis and in those with the autoimmune disease Hashimoto’s thyroiditis.

Meta-Analysis Finds Omega-3 Fatty Acids Do Not Reduce Cardiovascular Disease Risk

May 1, 2019 · Posted in Potential Treatments · Comment 

heartIn a 2018 meta-analysis published in the journal JAMA Cardiology, researcher Theingi Aung and colleagues found that across 10 studies including a total of 77,197 participants, omega-3 fatty acid supplementation did not reduce risk of coronary heart disease in people at high risk. This newer finding conflicts with a 2017 advisory from the American Heart Association that suggested omega-3 fatty acid supplementation might prevent cardiovascular disease.

When it comes to mood disorders, it has been similarly difficult to pin down whether omega-3 fatty acids are helpful. Data on omega-3 fatty acid supplements for the prevention of depression have been ambiguous, with small numbers of studies and variations in study design that make it difficult to draw strong conclusions about whether these supplements can improve or prevent depression.

A 2016 systematic review by Paola Bozzatello and colleagues in the Journal of Clinical Psychiatry found only seven studies of omega-3 fatty acid supplementation in bipolar disorder. The studies had small sample sizes and widely varying dosage parameters, so the evidence that can be drawn from them is not strong, but the review did find a modest benefit on bipolar depression (but not mania) when omega-3 fatty acids were added to a treatment regimen, compared to treatment as usual.

The same review found that studies of omega-3 fatty acid supplementation in unipolar depression also varied widely, and thus it was difficult to draw inferences from them. Some meta-analyses found no benefit to omega-3 fatty acid supplementation, while others suggested that omega-3s could improve depression. The review found that the type of omega-3 fatty acids used might matter. Supplementation with EPA seemed to improve depression more than supplementation with DHA. The review also cited a 2014 comprehensive meta-analysis by Giuseppe Grosso and colleagues in the journal PLoS One that analyzed the findings from 19 studies in people with depression or depressive symptoms. Grosso and colleagues found that people with more severe depression seemed to benefit more from omega-3s.

Preventing Illness in the Offspring of a Parent with Bipolar Disorder

April 18, 2019 · Posted in Potential Treatments · Comment 

family with boy

A 2018 article by researcher Robert Freedman and colleagues in the American Journal of Psychiatry reported that prenatal nutritional supplements can reduce mental illness in at-risk offspring. The article made a good case for supplementation with folate, phosphatidylcholine, and vitamins A and D.

Here we describe some additional ways to minimize risk of mental illness in children who are at risk for bipolar disorder or other mental illnesses.

Some efforts at prevention can begin even before a child is conceived. Avoiding smoking or drinking alcohol and maintaining a nutritious diet to prevent inflammation and excessive weight gain before conception could reduce adverse epigenetic effects on the offspring. Epigenetics refers to environmental influences on gene transcription. The impact of life experiences such as a mother or father’s substance use is not registered in their child’s DNA sequence, but can influence the structure of the child’s DNA or its packaging.
Maternal good health and wellbeing during pregnancy has also been shown to improve neonatal health and functioning.

Once a child is born, they can be encouraged in healthy habits, including a nutritious diet, good sleeping habits, regular vigorous exercise, and mindfulness/meditation training (which pediatric psychiatrist James Hudziak has suggested should be universal).

For a child who is beginning to develop mood or behavioral symptoms, more intensive intervention may be prudent. Research supports the effectiveness of family interventions such as family-focused therapy (FFT) for youth with depression, cyclothymia, or bipolar disorder not otherwise specified (BP-NOS) and a family history of bipolar disorder. Researcher David J. Miklowitz described the effects of this intervention in a 2013 article in the Journal of the American Academy of Child and Adolescent Psychiatry.

Depression in children 3 to 6 years of age is as common as depression in older children (with rates around 1–2%), and robust improvements have been observed when families engage in parent child interaction therapy (PCIT) with a focus on emotional development. In PCIT, parents are coached while interacting with their children and encouraged to establish warm interactions while setting appropriate limits. In a study by Joan L. Luby and colleagues published in the American Journal of Psychiatry in 2018, using PCIT modified to include an emotional development component improved depression and associated symptoms in children aged 3 to 11, and it also improved mothers’ mood and behavior. Read more

Prenatal Prevention of Psychiatric Illness with Nutritional Supplements

April 15, 2019 · Posted in Potential Treatments · Comment 

pregnant woman with a pillIn a 2018 article in the American Journal of Psychiatry, researcher Robert Freedman and colleagues shared the results of a systematic review of data on nutritional supplements during pregnancy for the primary prevention of psychiatric illness in the child. Freedman and colleagues concluded that the evidence is robust that prenatal folic acid supplementation plus multivitamins not only can prevent birth defects such as cleft palate, spina bifida, and microcephaly, but also social withdrawal, decreased attention, and aggression at age 18 months. They wrote, “Supplements of up to 4 mg [of folic acid] before 12 weeks gestation have been found to be safe and effective.”

The effects of omega-3 fatty acid supplementation depended on when the supplements were taken. Taking omega-3 fatty acid supplements early in pregnancy was linked to an increase in schizophrenia and more symptoms of attention deficit hyperactivity disorder (ADHD) in the offspring. However, supplementation after 20 weeks of pregnancy decreased preterm delivery, low birth weight, and asthma.

As of 2017, choline supplementation during pregnancy is recommended by the American Medical Association. Their recommendation is based on research in which the choline precursor phosphatidylcholine (5,000-6,300 mg/day) was given to mothers beginning in the 18th week of pregnancy and continued in the newborn for two weeks to three months after birth in the form of 100mg of liquid phosphatidylcholine. This supplementation regimen normalized the P50 auditory evoked potential, a measure of inhibitory sensory gating that is abnormal in patients with schizophrenia and bipolar disorder and infants whose parents had psychosis, depression, or smoked (all risk factors for a later diagnosis of schizophrenia).

Healthy individuals show a reduced response to an auditory cue when it is repeated 50 milliseconds after the initial cue. In people with schizophrenia, response to the repeated cue is not suppressed. Not only did the P50 auditory evoked potential normalize with phosphatidylcholine supplementation, but at 3.5 years of age, those who received phosphatidylcholine supplements in utero and as newborns had fewer problems with attention and social interactions. The findings were even more robust in those with the CHRNA7 genotype (a genetic variation in the alpha 7 nicotinic receptor), which is a risk factor for schizophrenia.

Supplementation with vitamins A and D during gestation also decreased the risk for schizophrenia and autism spectrum disorders in offspring. Recommendations include Vitamin D at doses of 600 to 4,000 IU for pregnant mothers and 400 to 1,000 IU for infants. Because of potential toxicity, vitamin A should be limited to 8,000 units from diet and supplements combined. (Supplements typically contain 2,500 units.)

While there are some methodological limitations to the findings, Freedman and colleagues conclude, “As part of comprehensive maternal and fetal care, prenatal nutrient interventions should be further considered as uniquely effective first steps in decreasing risk for future psychiatric and other illnesses in newborn children.”

Editor’s Note: Given the high risk of psychiatric illness (74%) in the offspring of a parent with bipolar disorder and the finding of abnormal P50 auditory evoked potential in patients with bipolar disorder, the recommended nutritional supplements should be given special consideration during gestation of a child who has a parent with bipolar disorder. According to the 2018 article by Freedman and colleagues, this would include folate, phosphatidylcholine, vitamin A and vitamin D.

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