About a year ago we reported that exercise was recommended for patients with fibromyalgia and chronic fatigue syndrome. The case for exercise has been bolstered by a 2013 analysis published by the Cochrane Collaboration, a nonprofit research network. The authors reviewed five randomized clinical trials that compared resistance training with a control or another type of physical activity in a total of 219 women. Resistance training is exercise that is performed against resistance with the intention of improving muscle strength, and can include weights, resistance machines, or elastic resistance bands. The authors found that in the studies they analyzed, resistance training was both beneficial and safe for women with fibromyalgia, and that aerobic exercise helped reduce pain.
As reported in Medscape Medical News, lead author Angela Busch said, “It appears that people with fibromyalgia can benefit from this form of exercise, but we noted that the programs we examined involved supervised exercise and started low and gradually increased the resistance. There are particular health benefits associated with resistance exercise (e.g. increasing bone strength, which is important for preventing osteoporosis), so it is good to know that clinicians can safely [recommend] this form of exercise.”
Whether patients will widely accept this recommendation remains to be seen since some doctors have advised only rest. The key to avoiding pain exacerbation while adding an exercise regimen may be, like in much of medicine, to start slow.
Editor’s Note: The antidepressant milnacipran (Savella) is the most recent drug to receive Federal Drug Administration approval for the treatment of fibromyalgia. Pregabalin (Lyrica) and duloxetine (Cymbalta) were approved for fibromyalgia in 2007 and 2008, respectively.
Iron deficiency is the most prevalent nutritional deficiency in industrialized countries and can cause problems with cognitive and intellectual development. New research published in the journal BMC Psychiatry shows that it has psychiatric ramifications as well. Children and adolescents with iron deficiency anemia are at greater risk for psychiatric disorders, including depression, bipolar disorder, anxiety, and autism.
Iron supplementation should be implemented in children with iron deficiency anemia in order to prevent any possible psychiatric repercussions, and similarly, psychiatrists should check iron levels in young patients with psychiatric disorders.
Iron provides myelin for white matter in the brain and plays a role in the function of neurotransmitters.
In a 2014 study published by Michael A. Yassa et al. in the journal Nature Neuroscience, a 200mg caffeine pill (about the equivalent of a strong cup of coffee) improved long-term recognition memory. One hundred sixty participants who were not regular coffee drinkers were shown a series of 200 pictures, and 24 hours later they were given a surprise test. Compared to participants who received a placebo, those participants who received 200mg of caffeine were better able to discriminate which pictures they had seen before and which ones were new. Participants who received 100mg of caffeine did not show this effect, while those who received 300mg showed the same improvement in memory but also experienced side effects such as headache and nausea.
As long as a cup of coffee does not make its drinker more anxious, it may help boost memory.
Editor’s Note: Coffee may have other benefits. In research collected by the Bipolar Collaborative Network (in which this editor is an investigator), patients who drank coffee were less likely to be overweight. Yassa also believes based on other research that caffeine is associated with a reduced risk for Alzheimer’s disease and that it increases longevity.
Lithium treatment is associated with a moderate incidence of hyperparathyroidism, usually observed as an elevated concentration of calcium in the blood in addition to elevated parathormone levels, and often associated with the development of a tumor (adenoma) of the parathyroid gland.
In a recent study by Van Melick et al. published in the International Journal of Geriatric Psychiatry, among 111 patients with an average age of 75 years, 24-hour calcium excretion was elevated in only 3% of the patients, but levels of parathormone were elevated in 48%. Duration of lithium treatment was associated with lower vitamin 25OH D. Vitamin D is important for healthy bones and good cognitive functioning.
Editor’s Note: Lithium-induced hyperparathyroid should be investigated in those with elevated calcium levels, and if found, surgical removal of the parathyroid gland may be indicated. Low vitamin D is common in the US population. It is also particularly low in patients with mania and elderly patients on who have been on lithium for more than ten years. (Levels are below normal in 77% of these elderly individuals.) Assessment of vitamin D levels in those on long-term lithium is advisable, in addition to monitoring the thyroid, kidney function, and calcium metabolism.
Exercise increases brain-derived neurotrophic factor (BDNF), a protein that protects neurons and is important for learning and memory. In a study of mice who were trained to find objects, sedentary mice could not discriminate between familiar object locations and novel ones 24 hours after receiving weak training, while mice who had voluntarily taken part in exercise over a 3-week period could easily distinguish between these locations after the weak training.
Mice who received sodium butyrate (NaB) after training behaved similarly well to those who had exercised. Sodium butyrate is a histone deacetylase (HDAC) inhibitor, meaning it helps keep acetyl groups on histones, around which DNA is wrapped, making the DNA easier to transcribe. In this case the easy transcription of DNA enables learning under conditions in which it might not usually take place.
Both sodium butyrate and exercise promote learning through their effects on BDNF in the hippocampus. They make the DNA for BDNF easier to transcribe, suggesting that exercise can put the brain in a state of readiness to create new or more lasting memories.
Unwanted recall and re-experiencing of traumatic memories is thought to be a crucial mechanism leading to the onset of post-traumatic stress disorder (PTSD). The inability to diminish (extinguish) those memories contributes to the persistence of PTSD. A new study suggests that the extinction of fear memories can be enhanced by a drug that acts epigenetically to alter the structure of DNA and subsequent gene expression.
DNA is wound around structures called histones, and chemical changes can affect how loosely or tightly the DNA is wound. Johannes Graff et al. reported in the journal Cell in 2014 that application of a histone deacetylase (HDAC) inhibitor, which keeps acetyl groups on histones, ensuring that DNA is wrapped more loosely and is easier to activate (or transcribe), helps rodents revise both new and old fear memories after they have been actively recalled.
When a memory is actively recalled, the trace of that memory in the brain becomes more amenable to revision over the proceeding five minutes to one hour (a period known as the reconsolidation window). New learning and extinction training (to get rid of the memory) lasts much longer when it takes place during the reconsolidation window than when the same procedures are performed 6 hours later (after the reconsolidation window has closed) or if the procedures are performed in the absence of active recall of the memory (when the reconsolidation window is never opened).
We have previously described the 2013 work of Xue et al. published in the journal Science, which showed that this specific procedure could yield long-lasting extinction of a patient’s craving for cocaine or heroin, and could reduce amygdala activation (as observed via functional magnetic resonance imaging) in response to an experiment that produces conditioned fear (Agren et al. Science, 2013).
Editor’s Note: This new work by Graff et al. adds another twist. Older long-term memories are more stable and less amenable to new learning than more recent (but still long-term) memories. The application of an HDAC inhibitor changes this and makes even very old memories amenable to lasting revision. The HDAC inhibitor that Graff et al. used was a specific inhibitor for HDAC type II. However, the anticonvulsant valproate (Depakote) is a potent although nonspecific HDAC inhibitor, and presumably could have the same facilitating effect as the more selective drug.
EMDR (Eye Movement Desensitization and Reprocessing), which has been widely used for the treatment of PTSD, includes active memory recall, immediately followed by an attempt to re-interpret and construct new memories of the trauma. These elements could open the reconsolidation window. However, EMDR works less well with older memories compared to more recent traumatic memories.
The Graff et al. data would suggest that adding an HDAC inhibitor such as valproate to EMDR-like work might make it more effective in revising more remote memories. Graff et al. encourage controlled clinical trials with a type II inhibitor to confirm that their findings in rodents would generalize to humans. While awaiting such validation through controlled clinical trials, it would not be surprising if clinicians started trying out the paradigm on their own using valproate.
In a recent study by Ghasemi et al. published in the journal Psychiatric Research, 18 patients with unipolar depression were divided into two groups, one that received intravenous infusions of ketamine hydrochloride (0.5 mg/kg over 45 minutes) three times (every 48 hours), and another that received electroconvulsive therapy (ECT) on the same schedule.
Ketamine produced antidepressant effects more quickly than ECT, and these effects were significantly better than baseline for the duration of the study, but not significantly different from those achieved through ECT by the end of the study.
Editors Note: These data continue to add to the already strong findings that ketamine produces rapid-onset antidepressant effects. When and where ketamine should be incorporated into routine clinical treatment of depression remains to be further clarified.
There is mounting evidence that inflammation and metabolic problems are related to depression. A recent study by Vogelzangs et al. in the journal Neuropsychopharmacology examined 313 patients being treated for depression to see whether levels of inflammatory markers in the blood and metabolic factors such as cholesterol, blood pressure, and waist circumference predicted whether those patients would still (or again) be diagnosable with depression two years later.
Several factors predicted later depression, including high levels of the inflammatory marker interleukin-6, low HDL (“good”) cholesterol, higher than normal triglycerides, and high blood glucose (hyperglycemia).
People who had four or more types of inflammatory or metabolic abnormalities had almost twice the odds of having chronic depression. Among those study participants who had only recently begun taking antidepressant medication, having four or more of these risk factors made them almost 7 times more likely to be depressed during follow-up.
One explanation for the connection between inflammatory and metabolic dysregulation and depression is that inflammation and metabolic problems worsen and complicate a patient’s depression and reduce the patient’s responsiveness to traditional antidepressants. Alternative ways of treating these patients aimed at their inflammation and metabolism may be necessary.
Transcranial Direct Current Stimulation Plus Zoloft Has Better Antidepressant Effects Than Either Treatment Alone
Transcranial direct current stimulation (tDCS), in which a barely perceptible level of electrical current is applied directly from one side of a patient’s scalp to the other, is a promising treatment for patients with tought-to-treat depression. A 2013 study by Brunoni et al. in JAMA Psychiatry examined whether combined treatment using tDCS and the selective-serotonin reuptake inhibitor (SSRI) antidepressant sertraline (Zoloft) would be a safe and effective treatment for unipolar depression. The combination was better than either treatment alone and better than placebo.
The six-week study used what is called a 2×2 factorial design, in which 120 patients with unipolar depression received either 50 mg/day of sertraline or placebo and also received either real tDCS or a sham procedure. The tDCS was administered in twelve 30-minute sessions, one per day Monday through Friday during the first two weeks, followed by one every other week. TDCS consists of an anodal (positive) and cathodal (negative) current placed at particular positions on the head. This study used 2 microamps of anodal left/cathodal right prefrontal stimulation for the tDCS treatment.
While the combination of sertraline and tDCS was significantly better than all three other treatment options (sertraline plus sham procedure, placebo plus tDCS, and placebo plus sham procedure), sertraline by itself and tDCS by itself resulted in similar efficacies. However, TDCS by itself was also significantly better than placebo, while sertraline by itself was not.
Side effects among the different treatment options were similar, except those who received tDCS had more scalp redness. There were seven instances of patients developing mania or hypomania during the study, five of which occurred in the combined tDCS and sertraline treatment group, higher than the 1–2% rate that would be expected in a study of unipolar depression.
In 2008, the Federal Drug Administration approved the Neuronetics company’s Neuro-Star system for delivering repeated transcranial magnetic stimulation to patients with treatment-resistant depression. In rTMS treatment, an electromagnetic coil is placed against the forehead and magnetic pulses that can penetrate the scalp are converted into small electrical currents that stimulate neurons in the brain. Now the FDA has approved a second device manufactured by Brainsway Ltd.
In 2012, Brainsway released data from their double-blind, multicenter controlled trials of the device. After five weeks of treatment, 30.4% of the patients who received the rTMS treatment achieved remission of their depression, twice the rate of remission among the patients who received a sham procedure instead.
Editor’s Note: These data showing slightly higher response rates than seen in two trials by Neuronetics confirm the efficacy of rTMS in patients whose depression persists after one or more trials with antidepressant medications. The efficacy of rTMS in those patients who have failed to respond to multiple antidepressant medications remains to be further defined, as do the optimal stimulation parameters to achieve the best results in this difficult-to-treat sub-group of patients.