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.

Eating Beef Jerky and Other Nitrate-Cured Meats Linked to Increased Mania Risk

April 10, 2019 · Posted in Risk Factors · Comment 

In a 2018 article in the journal Molecular Psychiatry, researcher Seva G. Khambadkone and colleagues reported that a history of eating nitrated dry cured meat, such as beef jerky, was associated with a more than threefold increase in the risk of current mania. Eating other types of meat and fish products was not linked to mania.

The study included 217 people with mania, 91 with bipolar depression, 79 with unipolar depression, and 371 with schizophrenia, plus 343 control participants without a psychiatric disorder. Each participant responded to a questionnaire assessing whether they had ever eaten certain foods. The researchers had the idea that eating foods such as undercooked meat or fish, which might carry infectious agents, could be connected with mania, since inflammation seems to be linked to psychiatric illness. To the researchers’ surprise, their analysis found an independent link between eating nitrated dry cured meat (such as beef jerky, turkey jerky, or meat sticks) and being admitted to a hospital with acute mania.

Having eaten other cured meats such as salami or prosciutto was not linked to mania, nor was having eaten any other food.

Following these findings, Khambadkone and colleagues designed a study in which rats were given meat with added nitrate. The rats showed hyperactivity that resembled human mania, alterations in brain pathways that have been linked to bipolar disorder, and changes to gut microbes.

Antioxidant Supplement Coenzyme Q10 Looks Promising for Bipolar Depression

April 8, 2019 · Posted in Potential Treatments · Comment 

lithium

Coenzyme Q10 (CoQ10) is an antioxidant that occurs naturally in the human body, but its levels decline with age, medical illness, and depression. In a randomized, controlled trial that was published in the Journal of Clinical Psychopharmacology in 2018, researcher Maryam Mehrpooya and colleagues found that adding coenzyme Q10 supplements to a treatment regimen improved bipolar depression compared to adding placebo.

The pathophysiology of bipolar disorder involves mitochondrial dysfunction, oxidative stress, and inflammation, and coenzyme Q10 can affect all of these pathways. It is also neuroprotective, and may help prevent the degeneration of neurons in people with Alzheimer’s, Parkinson’s, or Huntington’s diseases.

The study included a final total of 69 participants who were randomly assigned to receive either 200 mg/day of coenzyme Q10 supplements or placebo in addition to their normal treatment regimen, which had been stable for at least two months at the time of the study. Participants’ bipolar depression was rated at the beginning of the study, after four weeks, and after eight weeks. At the eight-week mark, coenzyme Q10 showed a statistically significant benefit over placebo with a large effect size. Three participants who received coenzyme Q10 experienced full remission of their depression, and 72% of those in the coenzyme Q10 group improved compared to only 12% of those who received placebo.

The study had some limitations. It was small, and twenty participants dropped out of the study before its completion, which may have inflated the findings.

Previous research found that coenzyme Q10 had benefits in specific populations. In two non-blind studies (studies in which participants know that they are receiving the treatment in question rather than possibly a placebo), 29 older patients with bipolar disorder improved when taking 800 mg to 1200 mg/day of coenzyme Q10. A randomized, controlled trial of coenzyme Q10 in people with multiple sclerosis and depression found that 500 mg/day reduced fatigue symptoms and depression. Coenzyme Q10 has also improved well-being and energy in small, controlled trials in people with breast cancer, Gulf War veterans, and elderly populations.

Taking coenzyme Q10 is low-risk. It had no adverse effects in the study by Mehrpooya and colleagues. Gastrointestinal reactions are possible, but can be managed by taking coenzyme Q10 with food and spreading out dosing throughout the day. Insomnia is also possible, but is less likely when coenzyme Q10 is taken early in the day. One effect to note is that coenzyme Q10 can interact badly with the blood-thinner warfarin.

Editor’s Note: The study by Mehrpooya and colleagues is interesting. Another antioxidant, N-acetylcysteine (NAC), also took 2 months to work in trichotillomania and bipolar depression, so patients should be warned not to expect a quick response with either coenzyme Q10 or NAC. Other potentially useful supplements include: Vitamin D3 (1500–5000 IU/day), folate or L-methylfolate, and acetyl-L-carnitine. Acetyl-L-carnitine may work more quickly, based on its presumed mechanism (increasing the production of the inhibitory metabotrophic glutamate receptor mGluR-2, which inhibits glutamate release).

Inflammation Associated With Duration of Untreated Unipolar Depression

February 14, 2019 · Posted in Brain Imaging, Course of Illness, Neurobiology · Comment 

depressed woman

Researcher Sophia Attwells and colleagues reported at a 2018 scientific meeting that the longer the time that a patient went without treatment for depression, the more inflammation they exhibited on positron emission tomography (PET) scans. Attwells and colleagues used the PET scans to assess the total distribution volume of TSPO, which is a marker of brain microglial activation, a form of inflammation.

Strikingly, in participants who had untreated major depressive disorder for 10 years or longer, TSPO distribution volume was 29–33% greater in the prefrontal cortex, anterior cingulate cortex, and insula than in participants who were untreated for 9 years or less. TSPO distribution volume was 31–39% greater in these three important regions of gray matter in participants with long durations of untreated major depressive disorder than in healthy control participants.

Editor’s Note: In schizophrenia, the duration of untreated interval (DUI) is associated with a poor prognosis, but not with inflammation. Researcher Yvette Sheline has also reported that less time on antidepressants compared to more time treated with them was associated with greater hippocampal volume loss with aging in patients with major depression.

Given Attwells and colleagues’ remarkable finding about the adverse effects of the DUI in depression, including inflammation and brain volume loss, and other findings that associate more episodes with poorer functioning, cognition, and treatment responsiveness, physicians and patients should think hard about committing to long-term antidepressant treatment to prevent episodes, beginning early in the course of illness.

This editor (Robert M. Post) would propose that if a second depressive episode occurs after a first depression that responded well to treatment, this would be an appropriate time to start antidepressant prophylaxis. Most guidelines suggest that prophylaxis be started after a third episode, but these recommendations generally do not account for newer data on the pernicious effects of experiencing repeated depressive episodes. In addition to causing dysfunction and disability, going through four depressive episodes doubles the risk of dementia in old age, and this risk increases further with each successive episode, according to researcher Lars Kessing.

Having too many depressions is bad for the brain. In Kessing’s studies, two episodes of unipolar or bipolar depression did not increase the risk of dementia compared to the general population, while four depressions did. One could compare the effects of repeated depressions on the brain to the effects of heart attacks on the heart muscle. A heart might still function well after one or even two heart attacks, but the chances of significant loss of function and the risk of congestive heart failure increase as a function of the number of heart attacks. After even one heart attack, most patients change their lifestyle and/or go on prophylactic medications to reduce risk factors such as elevated blood pressure, cholesterol, triglycerides, weight, blood sugar, and smoking. The benefits of reducing heart attacks are a no brainer. Trying to prevent recurrent depression with pharmacotherapy and adjunctive psychotherapy after a second depressive episode should be a no brainer too.

In addition, if antidepressants are not effective enough in preventing depressions, lithium is an option, even in unipolar depression, for preventing both episodes and suicide. The evidence of efficacy in both instances is very strong according to an article by Mohammed T. Abou-Saleh in the International Journal of Bipolar Disorders in 2017.  The renowned psychiatrist Jules Angst’s recommendation as to when to start lithium treatment was that if a patient had had one episode or more in the previous five years in addition to the present episode, then they were likely to have two further episodes in the following five years, and lithium prophylaxis would be recommended.

Family History of Lithium Response A Potent Predictor of Lithium Effectiveness

February 11, 2019 · Posted in Current Treatments · Comment 

family

Researcher Martin Alda and colleagues reported at a 2018 scientific meeting that a family history of good response to lithium is highly predictive of response to lithium in a current bipolar patient. A good prospective response to lithium was seen in 68.6% of patients with a family member who responded well to lithium. Only 22% of those without a family member with a positive lithium response responded well to lithium.

Editor’s Note: Other predictors of a good response to lithium include: a family history of mood disorder, classical euphoric mania with clear-cut well intervals between episodes, lack of a simultaneous anxiety or substance abuse disorder, starting lithium early rather than late in the course of illness after many episodes or rapid cycling has occurred, and a sequential pattern of episodes of mania followed by depression, and then an interval of wellness (i.e. M-D-I rather than D-M-I). Even in those without these characteristics, lithium has many benefits including neuroprotection, reduction of suicide risk, and improved medical health (perhaps through its ability to increase the length of telomeres which are bits of DNA at the end of each chromosome). Longer telomeres are protective, while people with shorter ones may be vulnerable to some medical and psychiatric illnesses.

Risk Gene for Bipolar Disorder Implicated in Depressed Behaviors and Abnormal Firing of GABA Neurons

February 8, 2019 · Posted in Genetics, Neurobiology · Comment 

DNA

At a 2018 scientific meeting and in a 2017 article in the journal PNAS, researcher Shanshan Zhu and colleagues reported that mice genetically engineered to lack the protein Ankyrin-G in certain neurons showed increases in depression- and mania-like behavior after being exposed to defeat stress (by repeatedly being placed in physical proximity to a larger, more aggressive mouse), which is often used to model human depression.

The researchers targeted the gene ANK3, which is responsible for the production of Ankyrin-G, and has been linked to bipolar disorder in genome-wide association studies. By manipulating the gene, they could eliminate Ankyrin-G in pyramidal neurons in the forebrain, a region relevant to many psychiatric disorders. Pyramidal neurons perform key brain functions, sending nerve pulses that lead to movement and cognition.

The missing Ankyrin-G affected sodium channels (which allow for the flow of sodium ions in and out of cells) and potassium channels. The neurochemical GABA (which typically inhibits nerve impulses) was also dysregulated, resulting in the kind of disinhibition seen in psychosis. Mice showed dramatic behavioral changes ranging from hyperactivity to depression-like behavior (e.g. giving up in a forced swimming test). The hyperactivity decreased when the mice were given treatments for human mania, lithium or valproic acid.

While mutations in the ANK3 gene may disturb sodium channels, another gene linked to depression and bipolar disorder, CACNA1C, affects calcium channels.

In a related study by researcher Rene Caballero-Florán and colleagues that was also presented at the meeting, mice were genetically engineered in such a way that interactions between Ankyrin-G and GABA Type A Receptor-Associated Protein (GABARAP) were disrupted, leading to deficits in inhibitory signaling. These deficits were partially corrected when the mice were treated with lithium.

The study by Caballero-Florán and colleagues used mice with a mutation known as W1989R in the ANK3 gene. Through a program that examines the genes of people with bipolar disorder, the researchers also identified a family with this genetic mutation, including a patient with type I bipolar disorder with recurrent mania and depression who has responded well to lithium treatment.

Baseline Levels of CRP Could Help Predict Clinical Response to Different Treatments

February 5, 2019 · Posted in Current Treatments · Comment 
CRP

C-reactive protein (CRP)

C-reactive protein, or CRP, is a marker or inflammation that has been linked to depression and other illnesses. People with high levels of CRP respond differently to medications than people with lower CRP, so assessing CRP levels may help determine which medications are best to treat a given patient.

High baseline levels of CRP (3–5pg/ml) predict a poor response to selective serotonin reuptake inhibitor antidepressants (SSRIs) and to psychotherapy, and are associated with increased risk of recurrent depression, heart attack, and stroke.

However, high baseline CRP predicts a better response to the antidepressants nortriptyline and bupropion. High CRP is also associated with better antidepressant response to infliximab (a monoclonal antibody that inhibits the inflammatory cytokine TNF alpha), while low levels of CRP predict worsening depression upon taking infliximab.

High baseline CRP also predicts good antidepressant response to intravenous ketamine (which works rapidly to improve treatment-resistant depression), minocycline (an anti-inflammatory antibiotic that decreases microglial activation), L-methylfolate (a supplement that can treat folate deficiency), N-acetylcysteine (an antioxidant that can improve depression, pathological habits, and addictions), and omega-3 fatty acids (except in people with low levels of DHA).

High baseline CRP also predicts a good response to the antipsychotic drug lurasidone (marketed under the trade name Latuda) in bipolar depression. In people with high baseline CRP, lurasidone’s positive results have a huge effect size of 0.85, while in people with low CRP (<3pg/ml) the improvement on lurasidone has a smaller effect size (0.35).

In personal communications with this editor (Robert M. Post) in 2018, experts in the field (Charles L. Raison and Vladimir Maletic) agreed that assessing baseline CRP levels in a given patient could help determine optimal strategies to treat their depression and predict the patient’s responsiveness to different treatment approaches.

At a 2018 scientific meeting, researchers Cynthia Shannon, Thomas Weickert, and colleagues reported that high baseline levels of CRP were associated with symptom improvement in patients with schizophrenia when they were treated with the drug canakinumab (marketed under the trade name Ilaris). Canakinumab is a human monoclonal antibody that targets the inflammatory cytokine interleukin-1 beta (Il-1b). Il-1b is elevated in a subgroup of patients with depression, bipolar disorder, or schizophrenia, and CRP levels are an indication of the associated inflammation.

Lithium Superior to Other Mood Stabilizers in a Longitudinal Study of Bipolar Youth

February 1, 2019 · Posted in Current Treatments · Comment 

teenagers

At a late-2018 scientific meeting, researcher Danella Hafeman and colleagues reported some results of the Course and Outcome of Bipolar Youth (COBY) study. The study includes long-term follow up of 413 youth with bipolar disorder, who ranged in age from 7 to 17 years old. Hafeman and colleagues reported that taking lithium more than 75% of the time was linked to fewer suicide attempts, fewer depressive symptoms, and fewer psychosocial difficulties than taking another mood stabilizer (such as an atypical antipsychotic, lamotrigine, or valproic acid) more than 75% of the time after adjusting for demographic variables.

Despite the limitations of observational studies such as this one, the authors concluded, “Our findings are consistent with studies in adult populations, showing that lithium (compared to other mood stabilizers) is associated with decreased suicidality, less depression, and better psychosocial functioning. Given the paucity of evidence regarding lithium in children and adolescents, these findings have important clinical implications for the pharmacological management of youth with [bipolar disorder].”

Editor’s Note: These observations are consistent with several other studies. Researcher Barbara Geller and colleagues observed in eight years of follow up of children diagnosed with bipolar disorder that those who were treated with lithium spent more time in remission than those who took other medicines. A randomized controlled study by researcher Robert Findling and colleagues documented that maintenance lithium treatment was more effective than placebo at preventing bipolar episodes. Together, these data suggest that lithium should be used more often in the long-term treatment of children with bipolar disorder.

Way ahead of his time in about 1993, the renowned child psychiatrist Dennis Cantwell said something like this: “If I had an adolescent child with a first manic episode, I would have him stay on lithium for the rest of his life.” He seems to have been prescient, as evidence of the many benefits of lithium over other alternatives in the treatment of both children and adults has been accumulating.

An open-access review article this editor (Robert M. Post) published in the journal Neuropsychopharmacology in 2017, “The New News about Lithium: An Underutilized Treatment in the United States,” argues that lithium’s many benefits have been underestimated, while its side effects have been overestimated. It is my view that it would be beneficial if lithium were more often included in the treatment regimen of adults as well as children and adolescents with bipolar disorder.

Lithium has an astounding range of effectiveness. It prevents recurrent depressions and suicide (even in those with unipolar depression), increases hippocampal and cortical volume, protects memory, and increases the length of telomeres (the end portions of chromosomes that protect them as they replicate). In multiple animal models of neurological diseases, it has also been found to be neuroprotective and to reduce the size of brain lesions.

Nimodipine Decreases Frontal and Parietal Cortical Activity During Working Memory in Healthy Subjects

January 30, 2019 · Posted in Genetics, Potential Treatments · Comment 

brain

At a recent scientific meeting, researcher Kristin Bigos and colleagues described the effects of nimodipine, a treatment for brain hemorrhage, on the brain during working memory tasks. Nimodipine is a dihydropyridine L-type calcium channel blocker. Calcium channel blockers prevent calcium from entering cells in the heart and blood vessel walls, and they are often used to treat high blood pressure.

Nimodipine acts on the CACNA1C calcium influx gene. Certain genetic variations in this gene (particularly the rs1006737 A allele) have been linked to vulnerability to bipolar disorder, schizophrenia, depression, and autism. Carriers of the risk allele also have higher CACNA1C mRNA expression in the dorsolateral prefrontal cortex and exhibit more activity in the frontal and parietal regions of the brain during working memory tasks, suggesting inefficient brain processing in these regions. Bigos and colleagues found that 60mg/day of nimodipine decreased frontal and parietal cortical activity by 39.1% and 42.8%, respectively, during a working memory task, suggesting that nimodipine improved the efficiency of memory processing. Nimodipine’s positive effects were greater in those participants who had the CACNA1C risk allele.

Editor’s Note:  Using a placebo-controlled off-on-off-on study design (meaning patients took placebo for a period, then nimodipine, then placebo again and nimodipine again), this editor (Robert M. Post), Peggy J. Pazzaglia and colleagues found that nimodipine had positive effects in both mania and depression in patients with bipolar disorder (described in the 2008 book Treatment of Bipolar Disorder: A Casebook for Clinicians and Patients by Robert M. Post and Gabriele S. Leverich). In a large randomized study of patients with bipolar disorder presented by Haroon R. Chaudhry at the 2010 meeting of the Society of Biological Psychiatry, lithium was associated with about a 50% response rate while the combination of lithium and nimodipine was associated with a 73% response rate.

It remains to be seen whether people with bipolar disorder who have the CACNA1C risk gene would respond better to nimodipine than those without the risk gene, and whether it would improve working memory more in the subgroup with the risk gene.

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