Dr. Post’s Recommendations For Treating Youth with Bipolar Symptoms

April 14, 2020 · Posted in Current Treatments, Potential Treatments · Comment 

Teens

Our Editor-in-Chief, Dr. Robert M. Post, shares his personal recommendations for the treatment of children and adolescents with symptoms of bipolar disorder. Remember: Patients and family members must consult a physician about all information conveyed in the BNN. With the exception of lithium, none of the medications or supplements discussed above have been approved by the US Food and Drug Administration for use in children under 10. The findings reported here are in many cases preliminary and cannot be taken as recommendations based on the short summaries provided here. All treatment decisions must be made in conjunction with a patient’s treating physician, who is solely responsible for initiating any treatment discussed in the BNN or elsewhere.

In symptomatic and functionally impaired children, medication is almost always necessary. Many treating psychiatrists would start with an atypical antipsychotic, since there is clear evidence of the efficacy of such treatments. The side effects profile should be considered, as there is a considerable difference in the degree of weight gain associated with different atypical antipsychotics. The largest weight gains occur with olanzapine and clozapine, intermediate gains occur with aripiprazole and quetiapine, and the least gains occur with ziprasidone and lurasidone (and the latter has the advantage of being approved by the US Food and Drug Administration for the treatment of bipolar depression in children who are 10–17 years old). The addition of the diabetes drug metformin to decrease weight gain in people taking atypical antipsychotics is increasingly common.

The addition of an anticonvulsant medication (such as lamotrigine, carbamazepine/oxcarbazepine, or valproate) or the mood stabilizer lithium may be needed, as multiple studies indicate that combination treatment is typically needed in children (as in adults) to achieve a more complete response or remission.

Interestingly, oxcarbazepine was effective in younger but not older children with mania in a previous placebo-controlled study by Karen D. Wagner and colleagues published in the American Journal of Psychiatry in 2006.

Conversely, in a 2015 article in the journal JAACAP, researcher Robert Findling reported that in a placebo-controlled study of lamotrigine, 13–17-year-olds responded better than 10–12-year-olds.
Lithium treatment deserves consideration in children with classical presentations of bipolar disorder and those who have family members who have responded well to lithium treatment.

Lithium has the benefit of improving the white matter abnormalities seen in the brains of patients with early-onset bipolar disorder. Hafeman and colleagues reported in a 2019 article that children with bipolar disorder who were treated with lithium had better long-term results upon follow up than those treated with atypical antipsychotics or anticonvulsants.

There is much less scientific consensus about other adjunctive treatments for young people with additional bipolar symptoms and comorbidities, but this editor often uses several. Vitamin D3 is often low in children with psychiatric illness, and may improve mood and cognition.

The antioxidant N-acetylcysteine (NAC) helps depression, anxiety, and irritability, and is effective at treating habit-related behaviors such as trichotillomania (compulsive hair-pulling), obsessive-compulsive disorder (OCD), and drug use, including specifically reducing marijuana use in adolescents. A typical dose is 500–600 mg capsules, one capsule twice a day for one week, then two capsules in the morning and two in the evening thereafter.

Folate or folic acid may enhance antidepressant effects and those of lithium. In patients who have a particular low-functioning variant of a gene known as MTHFR, L-methylfolate is required instead of folate.

The widely-used supplement acetyl-L-carnitine (ALC) is poorly studied in children, but deserves consideration as a supplemental treatment for patients with histories of childhood adversity. In adults with depression, blood levels of ALC may be low, particularly in those with an early onset of bipolar symptoms and a history of childhood adversity (see a 2018 article by Carla Nasca in the journal PNAS). There is a modicum of evidence that ALC produces antidepressant effects in adults. ALC may also sensitize insulin receptors and normalize blood pressure.

There is increasing evidence of the role of inflammation in depression, mania, post-traumatic stress disorder (PTSD), and schizophrenia. Checking for abnormalities in inflammatory markers in the blood (especially Il-6 and CRP) may point the way to appropriate therapy with anti-inflammatory drugs such as minocycline (100 mg twice a day) or celecoxib (200 mg twice a day) in patients who do not respond fully to first-line medications.

Folate Supplements Reduce Autism Rates in Offspring of Women Taking Anti-Epileptic Drugs During Pregnancy

March 9, 2018 · Posted in Current Treatments · Comment 

supplementsA 2017 study form Norway suggests that the offspring of women taking anti-epileptic drugs during pregnancy are less likely to develop autism if the women also take folic acid supplements.

The study by Marte Bjørk and colleagues in the journal JAMA Neurology used data from 104,936 children aged 18 to 36 months. Those whose mothers took anti-epileptic drugs during pregnancy had elevated autism rates, but only if their mothers did not use folic acid supplements. The mothers’ folate levels in weeks 17 to 19 of their pregnancies were inversely related to the degree of autistic traits in their offspring.

Women without epilepsy and women whose epilepsy went untreated during pregnancy had children with similarly low rates of autism to those whose mothers supplemented their anti-epileptic medications with folic acid during pregnancy.

In Case Control Study, Two-Thirds of Patients With Severe Depression Had Underlying Metabolic Abnormalities

July 18, 2017 · Posted in Diagnosis, Risk Factors · Comment 

depressed manA recent study suggests that potentially treatable metabolic abnormalities in the central nervous system may underlie a large proportion of cases of severe, treatment-resistant depression. These abnormalities, such as folate deficiency in the cerebrospinal fluid, are not screened for regularly, as they require a spinal tap to diagnose.

Researchers led by Lisa A. Pan were inspired to assess metabolic function in people with treatment-resistant depression after a young patient with severe, persistent depression who had attempted suicide several times improved dramatically after being diagnosed with a tetrahydrobiopterin deficiency in his cerebrospinal fluid and treated for the deficiency. Tetrahydrobiopterin is critical to the production of monoamine neurotransmitters.

The researchers carried out a case-control study of 33 teen and young adult patients who had had treatment-resistant depression since childhood and 16 healthy control participants. Twenty-one of the 33 patients with severe depression had metabolic abnormalities in their cerebrospinal fluid. Twelve had cerebral folate deficiencies (but no folate deficiency in blood tests). Those who took folinic acid for at least six weeks (1–2 mg/kg/day) in addition to their regular medications showed sometimes dramatic improvement in their depression.

Other metabolic issues identified in the patients with severe depression included abnormal levels of acylcarnitine in five patients, low tetrahydrobiopterin intermediates in one, low guanidinoacetate in another, and unusual creatine/creatinine ratios in three patients. None of the healthy participants had any metabolic abnormality.

While the study, published in the American Journal of Psychiatry in 2017, was small, it suggests that the underlying causes of some severe depression cases are going undiagnosed and untreated. The authors suggest that assessment of metabolic function should be more common in cases of severe treatment-resistant depression.

Folate Fortification in Commercial Foods Led to Greater Cortical Thickness

January 20, 2017 · Posted in Potential Treatments · Comment 

enriched breadIn 1996, the US began to require that enriched cereal grain products be fortified with folate, a vitamin that is particularly important to fetal brain development. A new study of children born before and after this policy change suggests that the increased folate in commercial foods after 1996 led to increases in cortical thickness in the children born after the change.

At the 2016 meeting of the Society of Biological Psychiatry, Joshua L. Roffman and colleagues described their research into the effects of folate fortification. The researchers identified 3,309 children born between 1993 and 2001 who had had a magnetic resonance imaging (MRI) brain scan. Analysis of the scans showed that children born after folate fortification began had thicker cortices than those born before the change. The frontal and temporal regions of the brain were particularly affected.

A thin cortex is a risk factor for schizophrenia and other cognitive problems.

Editor’s Note: Folate supplementation has also been shown to enhance the effects of selective serotonin reuptake inhibitor (SSRI) antidepressants in adults with lingering symptoms of depression.
Up to a third of the population may have a deficit of MTHFR, an enzyme important for folate metabolism, and for these people, l-methylfolate is recommended rather than folate itself.

Metabolized Form of B Vitamin Improves Depression in People with MTHFR Deficiency

October 14, 2016 · Posted in Potential Treatments · Comment 

metabolized B vitamins may improve depression

MTHFR is an enzyme needed for the body to break down vitamin B9, also known as folate or folic acid. It also helps convert the toxic amino acid homocysteine into the antidepressant amino acid s-adenysl-methionine. However, a significant segment of the population (some estimate 40%) have a genetic mutation in the MTHFR gene that interferes with the body’s ability to break down B vitamins and is linked to higher levels of homocysteine. MTHFR mutations are also linked to depression.

A 2016 study by Arnold W. Mech and Andrew Farah in the Journal of Clinical Psychiatry found that treating people with major depression and a MTHFR deficiency using a combination of micronutrients and already-broken-down B vitamins improved their depression and reduced their homocysteine levels compared to placebo.

The study included 330 adult patients with major depression and one of two genetic variants in the MTHFR gene—C677T or A1298C. Of those who received the metabolized vitamins, 82.4% showed reduced homocysteine levels. Those who received placebo showed a small average increase in homocysteine. The vitamin group also saw a large drop in depression symptoms on average after 8 weeks, with 42% achieving full remission. There were no side effects.

These findings suggest that homocysteine levels play a role in depression and that metabolized B vitamins can be an effective treatment for depression, particularly in those with a MTHFR deficiency. A metabolized form of folate that is commercially available is called L-methylfolate.

Folate Supplementation May Delay Onset of Depression in Those at High Risk

September 25, 2014 · Posted in Potential Treatments · Comment 

supplements

Low levels of folate, also known as folic acid or vitamin B9, have been associated with depressive symptoms in the general population. A 2014 article by A.L. Sharpley et al. in the Journal of Affective Disorders explored whether folate has protective effects. Teens and young adults (ages 14–24) at high risk for mood disorders due to a family history of these illnesses were randomly assigned to receive either folate supplements (2.5 mg daily) or placebo for up to three months. While there were no significant differences in the percentage of young people in each group who went on to be diagnosed with a mood disorder, in the folate group there was a delayed onset of illness in those who went on to become unwell.

The Importance of Folate in Bipolar Disorder

May 7, 2014 · Posted in Potential Treatments, Risk Factors · Comment 

chard

Researchers are exploring the therapeutic potential of nutraceuticals, or nutritional treatments. Folate, also known as folic acid or vitamin B9, is one of the most important nutritional elements for mental health.

The folate found in foods such as dark leafy greens must be broken down further in order to be used in the body. Folate first breaks down into dihydrofolate (DHF), which is turned into tetrahydrofolate (THF). At the 2014 meeting of the International Society for Bipolar Disorders, researcher J.H. Baek described a pathway by which THF is turned into a form called 5,10 MTHF, which is turned into a form called 5 MTHF. 5 MTHF is important for the function of the enzyme tryptophan hydroxylase and for clearing homocysteine, an amino acid that is cardio- and neuro-toxic.

L-methylfolate, the active ingredient in the medication Deplin, is an already-broken-down form of folate that the brain can use more readily than the folate from food. L-methylfolate is converted directly to 5 MTHF, so it is effective in 15% to 35% of the normal population who have a deficiency in the enzyme MTHF reductase, which converts THF to 5 MTHF. One genetic variant (a C to T allele variation 677) that results in one type of deficiency in MTHF reductase has a 42% incidence among Asians, 34% among Caucasians, and 8% among Africans, and these individuals would benefit from l-methylfolate.

Folate and Medications for Bipolar Disorder

Certain medications lead to deficits in folate, so patients should consider taking a nutritional supplement.

The anticonvulsant drug lamotrigine inhibits the conversion of folate to DHF and DHF to THF, so folate supplementation is a good idea for those patients taking lamotrigine.

The mood stabilizer valproate inhibits the conversion of toxic homocysteine to methionine and then to s-adenosyl methionine (SAMe), which acts like an internally-produced antidepressant. Thus valproate increases homocysteine, and patients on valproate should be routinely treated with folate and vitamin B12 to help lower homocysteine levels in the blood.

Folate supplements are recommended for depressed patients who are having an inadequate response to antidepressants, since the nutrient helps antidepressants work better even when patients do not have a folate deficiency. Researcher Andrew Stoll recommends folate (1mg for women and 2mg for men). However, those patients who have one of the genetic conditions that leads to a deficiency in MTHF reductase should take l-methylfolate instead of regular folate. Researcher Mauricio Fava and colleagues showed that l-methylfolate at doses of 15mg (but not 7.5mg) was more effective than placebo in patients with unipolar depression.

Extra Folate in Those Taking L-Methylfolate Could Be Counterproductive

November 26, 2013 · Posted in Current Treatments · Comment 

folate

While the nutritional supplement folate (also known as folic acid or vitamin B9) can be useful for depression, there appears to be one instance when augmentation with regular folate could be counterproductive. In those with a transport defect associated with a MTHR (methyl tetrahydrofolate reductase) deficiency, folate can compete with l-methylfolate for uptake into the brain. Folate would thus limit the beneficial effects of l-methylfolate supplementation, which is required for this 15% of the population.

Folic Acid During Pregnancy May Lower Autism Risk

February 18, 2013 · Posted in Current Treatments, Peer-Reviewed Published Data · Comment 

folic acid during pregnancyA study of 85,000 children in Norway that was recently published in the Journal of the American Medical Association showed that women who took folic acid during pregnancy were 40% less likely to have a child who developed autism.

A summary of the research by National Public Radio explained:

Folic acid is the synthetic version of a B vitamin called folate. It’s found naturally in foods such as spinach, black-eyed peas and rice. Public health officials recommend that women who may become pregnant take at least 400 micrograms of folic acid every day to reduce the chance of having a child with spina bifida.

The folic acid’s effect reduced the most severe cases of autism but did not seem to have an effect on the incidence of more mild forms, such as Asperger syndrome. The benefits were seen in those women who had been taking folic acid for 4 weeks before conception and continued to take the supplement during the first 8 weeks of pregnancy.

L-Methylfolate Augments the Antidepressant Effects of SSRIs in Treatment-Resistant Major Depression

September 14, 2011 · Posted in Current Treatments, Potential Treatments · Comment 
broccoli

Folate occurs naturally in foods such as broccoli

The B vitamin folate has been shown to be a useful augmentation treatment for patients who are nonresponsive or only partially responsive to selective serotonin reuptake inhibitor (SSRI) antidepressants. Treatment with folate works even in those who are not folate-deficient at baseline.

When folate is broken down in the body by reductase enzymes, it turns into the active form L-methylfolate, and crosses the blood-brain barrier. Maurizio Fava and colleagues at Massachusetts General Hospital (MGH) performed two placebo-controlled, randomized studies of L-methylfolate for depression. There was significantly greater improvement when SSRIs were augmented with L-methylfolate than when they were augmented with placebo. The results were significant with the use of 15mg of L-methylfolate, but not with 7.5mg, suggesting dose-related effects. Read more