Michael E. Hoffer et al. reported in the journal PLosOne in 2013 that veterans with blast-induced mild traumatic brain injury had a better acute outcome when they were given the antioxidant N-acetylcysteine (NAC) within the first 24 hours after the trauma versus when they were given placebo during the same period. Forty-two percent of those receiving placebo had a good acute outcome, while 86% of those receiving N-acetylcysteine had a good acute outcome. Memory loss, sleep disturbance, dizziness, and headaches all improved more in the N-acetylcysteine group. NAC’s benefits diminished when it was given 3 or 7 days after the trauma.
Editor’s Note: These data add to the growing list of neuropsychiatric syndromes in which NAC has shown efficacy. These include schizophrenia, bipolar depression, unipolar depression, cocaine and heroin addiction, gambling addiction, trichotillomania (compulsive hair-pulling), obsessive-compulsive disorder (as an adjunctive treatment to SSRIs), and improvement in irritability and stereotypy (repetitive behaviors) in children with autism.
Given what appears so far to be a relatively benign side effects profile for NAC, and the potential for severe consequences from traumatic brain injury (TBI), a case for wider use of NAC (for example in emergency rooms) might be made.
The mechanisms of action of NAC in different syndromes remains to be clarified. Researcher Michael Berk used NAC in schizophrenia and bipolar disorder and more recently in unipolar depression because it has antioxidant properties. Peter Kalivas found that NAC can normalize glutamate in the reward area of the brain through actions on the cystine-glutamate exchanger, and it also increases clearance of glutamate by increasing the glutamate transporter in glial cells. NAC decreases the amount of cued glutamate release in a part of the brain called the nucleus accumbens, which may be helpful in recovery from pathological habits. NAC also has anti-inflammatory and perhaps neuroprotective effects, and it increases brain-derived neurotrophic factor (BDNF), which protects neurons and is important for long-term learning and memory. Which of these many actions is important in the treatment of PTSD is not yet known.
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.
Here are some suggestions from BNN Editor-in-Chief Robert M. Post, MD for preventing cognitive decline in patients with bipolar disorder.
1. Prevent Episodes with Long-term Prophylaxis
2. Remove Sedating or Impairing Drugs
3. Add Folate to Decrease Homocysteine
4. Treat Depression to Remission
5. Consider Adding:
a. Bupropion (Wellbutrin) for Mood and ADHD
b. Modafinil (Provigil) for Attention and ADHD
c. A Stimulant for ADHD
6. Add Lithium at 150mg/day for Neuroprotection in Mild Cognitive Impairment
7. Add Levitiracetam at 125mg/day to Decrease Hippocampal Hyperactivity
8. Treat Dementia Symptoms Early with:
a. Memantine (Namenda) AND/OR
b. Acetylcholine Esterase Inhibitors Such As Donepezil (Aricept)
9. Consider Adding an Anti-inflammatory Agent
A study published in the Lancet reports that even mild iodine deficiency during pregnancy can have adverse effects on IQ and cognitive development in the fetus. This occurs because of the deficiency’s effects on thyroid function.
Editor’s Note: Eat fish, drink milk and take a vitamin supplement with 140 to 150mcg of iodine.
Very dark chocolate made mostly from cocoa beans may be good for you. Cocoa is high in flavanols, which belong to a class of antioxidants called flavonoids. Dark chocolate has been associated with lowered risk of heart attack and stroke, improvements in cognition, lower body mass index (BMI, a weight to height ratio), dilation of blood vessels and lower blood pressure, and improved cholesterol profiles. This is despite containing a lot of saturated fat (a good trick, indeed). Among a study of 37,000 Swedish men, individuals who ate at least 1.8oz of dark chocolate a week had a 17% lower risk of stroke than those who ate less than 0.4oz a week.
Moderation is important. Two ounces of dark chocolate contain about 440 calories, so while a little may be good, a lot may not be so good. Watch out for milk chocolate and highly processed chocolates with great quantities of sugar added, they contain more calories and fewer health benefits.
A balanced diet and regular exercise are keys to good health, but don’t feel too badly if you top off a balanced meal with a tantalizing piece of the dark stuff.
There is some evidence that lithium can affect brain structure, particularly the size of various parts of the brain. A study by Hajek et al. presented at the 2013 meeting of the International Society of Bipolar Disorders examined patients with bipolar disorder who had either received lithium for at least two years (37 patients) or had received under three months of treatment with lithium (19 patients), and compared the size of the hippocampus in these two groups and one control group (50 people). The patients with bipolar disorder all had the disorder for at least 10 years (25 years on average) and had had a minimum of five episodes.
Those treated with lithium long-term had greater hippocampal volume than the non-lithium patients (despite having spent more time in episodes of illness), and equal volume to healthy controls. Measurements were collected via magnetic resonance imaging (MRI), and analyses were done two different ways to avoid being confounded by the changes lithium may have on water balance in the brain, a phenomenon that was recently found to affect MRI images.
Editor’s Note: These data add to the large number of studies in animals and humans indicating that lithium, in addition to preventing episodes and suicides, may have neurotrophic and neuroprotective effects.
Oxidative stress has been implicated in a wide range of illnesses, but what is it exactly? Our bodies use the oxygen we breathe to burn the fuel we get from food, and while this is a natural process, it produces byproducts known as free radicals, which are unstable molecules that can strip electrons from other molecules in a process called oxidation. Antioxidants (such as vitamin C) act as a source of electrons, helping keep other cells stable and healthy. Oxidative stress refers to the stress on our bodies from the normal effects of free radicals combined with environmental stressors like tobacco smoke or radiation.
In work presented at the 2013 meeting of the Society of Biological Psychiatry, Anna Andreason showed that over-activity of neurons increases oxidative stress through the production of reactive oxygen species (ROS). These are a type of free radicals that can damage cells in two ways: nitrosylation of proteins (adding nitric oxide to a thiol molecule), and oxidation, which results in more lasting effects on synaptic structures. The chemical compound rotenone damages mitochondria by producing ROS, and Andreason found that lithium was able to reverse this production and reverse the adverse effects of oxidative stress.
Lithium Has an Amazing Array of Positive Effects
Editor’s Note: The ability of lithium to protect mitochondria (the energy storehouse of a cell) adds to an increasingly long list of lithium’s neurotropic and neuroprotective benefits. Lithium increases cell survival factors BDNF and Bcl-2, increases markers of neuronal integrity such as N-Acetylaspartic acid (NAA), increases the volume of the hippocampus and cortex, and now helps protect mitochondria from oxidative stress. Lithium also increases the length of telomeres, which cap the ends of chromosome and protect them from damage during the DNA replication that occurs each time a cell divides. Short telomeres are associated with many kinds of medical and psychiatric diseases, as well as shorter life spans. No wonder that in addition to preventing mania and depression it has other clinical benefits, such as preventing memory deterioration, medical mortality, and suicide.
In an abstract presented at the 2013 meeting of the Society of Biological Psychiatry, Iosifescu et al. reported that the antibiotic minocycline, which has showed anti-inflammatory, neuroprotective, and mitochondrial-sparing effects in animal models, brought about improvement in patients with bipolar depression. Doses of 100mg to 300mg per day were successful in this small open study.
There are some positive placebo-controlled data in patients with schizophrenia who were prescribed this antibiotic. However, until now it had not been studied in bipolar disorder. The preliminary data reported here suggest that controlled double-blind studies of this agent are needed in bipolar depression.
The abstract (#497) can be found in the 2013 convention supplement (9S) to the journal Biological Psychiatry.
Too many depressions in unipolar and bipolar disorder are associated with multiple risks. These include social and employment losses, dysfunction and disability, cognitive dysfunction, reduction in hippocampal volume (in unipolar depression), increases in medical comorbidity, increased risk of cardiovascular disease, and endocrine abnormalities (see the 2012 article by this author Post et al. in the Journal of Psychiatric Research).
To this list we can now add short telomeres. Telomeres sit at the end of DNA strands and shorten with each cell replication. A person’s percentage of short telomeres increases with aging. The number of depressions a patient with bipolar II disorder has had is also associated with a higher percentage of short telomeres. The magnitude of the difference in telomeres is equivalent to 10 years of aging.
An article by Cohen et al. published by the Journal of the American Medical Association (JAMA) in 2013 suggests that short telomeres can even be linked to increased vulnerability to viral infections causing the common cold. Depression has also been linked to various immune deficiencies. Whether direct alteration in immune function is responsible or whether this is mediated via telomere length remains to be determined.
Editor’s Note: The moral of this story is that patients should stay on effective treatment long-term to prevent depression in the recurrent affective disorders. This means antidepressants for unipolar depression, and mood stabilizers and atypical antipsychotics for bipolar depression. Prevent depressions and protect your brain and your telomeres (and as a bonus, you may not get so many colds).
Research has previously shown a link between stress, inflammation, and mood diorders. Anti-inflammatory treatments are now being explored for depression. In an abstract presented at the 2013 meeting of the Society of Biological Psychiatry, Nadia Alvi et al. reported that the commonly used anti-inflammatory COX-2 inhibitor celecoxib (Celebrex) showed better antidepressant effects than placebo when added to the selective serotonin reuptake inhibitor (SSRI) antidepressant escitalopram (Lexapro) in an 8-week study.
While this research has not yet been peer-reviewed, it can be found in the 2013 convention supplement (9S) to the journal Biological Psychiatry as abstract #661.
Editor’s Note: These data are consistent with an emerging literature that shows there are increases in signs of inflammation in both unipolar and bipolar depression. It remains to be determined whether those patients whose blood shows markers of inflammation (such as increases in C-reactive protein (CRP), interleukins 1 and 6, and TNF-alpha) are more likely to respond to anti-inflammatory treatment than patients in general.