People with chronic fatigue syndrome, or myalgic encephalomyelitis, as it has also been called, suffer from extreme exhaustion and unrefreshing sleep. The condition has been considered mysterious, but new research is clarifying its symptoms and leading to more useful treatments. In 2015, a committee convened by the Institute of Medicine at the National Academy of Sciences decided to change the name of the condition to systemic exertion intolerance disease (SEID) to better reflect its symptoms and reduce stigma around the illness.
In recent years it had been determined that exercise regimens and cognitive behavioral therapy helped up to 60% of patients. Some new small studies show great results when patients are treated with anti-viral medications such as valacyclovir (Valtrex). Researcher Theodore Henderson reports that he has seen response rates as high as 85% in adults and 92% in adolescents.
Researchers now believe that some patients diagnosed with depression may actually have SEID. Symptoms like fatigue, exertion-induced malaise, brain fog, and impaired academic performance could be the result of the body’s reaction to a virus.
In a proof-of-concept study presented at the 2015 meeting of the Society of Biological Psychiatry, Charles R. Conway and Peter Nagele showed that an hour of 50% oxygen/50% nitrous oxide reduced depression more than placebo as measured 2 hours and 24 hours later. Twenty patients were randomized to receive the laughing gas combination or a placebo combination made up of 50% oxygen/50% nitrogen. In the laughing gas group, four patients responded to the treatment and three patients achieved remission, compared to only one patient responding in the placebo group.
Like the anesthetic ketamine, which can bring about rapid but temporary antidepressant effects when delivered intravenously, nitrous oxide is an NMDA receptor antagonist.
Vagal nerve stimulation (VNS) is an FDA-approved treatment for both seizures and depression that has resisted other treatments. It requires an operation for the insertion of a stimulator in the chest wall and electrodes on the left vagus nerve in the neck. A new study by Scott T. Aaronson and colleagues presented at the 2015 meeting of the Society of Biological Psychiatry observed severely depressed patients, 494 who received VNS and 301 who received treatment as usual in the community, over a period of five years. The patients who received VNS had greater response rates, they were more likely to have experienced remission, and their remissions lasted longer than those who received treatment as usual. Overall the patients who received VNS had lower mortality rates and suicide rates as well. VNS might be a good option for patients with depression that has not responded to most other treatments.
Patients with rheumatoid arthritis have high levels of the inflammatory proteins known as interleukin-6 (IL-6), which have been implicated in depression and stress. Rheumatoid arthritis is sometimes characterized by depressive symptoms as well. New research by Dai Wang and colleagues presented at the 2015 meeting of the Society of Biological Psychiatry suggests that treating the high levels of IL-6 in rheumatoid arthritis with the human anti–interleukin-6 antibody sirukumab can reduce symptoms of depression and anhedonia (loss of capacity to experience pleasure).
In the study, patients with rheumatoid arthritis and symptoms of depression or anhedonia were randomized to receive either placebo or sirukumab. After 12 weeks, those who received sirukumab had significantly reduced depression.
Editor’s Note: These data are consistent with meta-analyses showing that IL-6 is elevated in depression and with a study by Scott Russo showing that in animals, interfering with IL-6 blocks the development of depression-like behaviors that typically occur after repeated defeat stress (when an animal is subjected to attacks from a larger, more dominant animal).
One-third of people who have strokes face depression afterward. New research is looking to expand the safe options for the treatment of depression following strokes. At the 2015 meeting of the Society of Biological Psychiatry, researchers led by Leandro Valiengo presented their successful randomized, sham-controlled double-blind study of transcranial direct current stimulation for post-stroke depression. Forty-eight people who had depression following a stroke were randomized to receive either a sham procedure or tDCS in twelve 30-minute sessions over a period of six weeks. After the six weeks, those who received tDCS had fewer symptoms of depression, more remission, and better response. There were no serious side effects.
TDCS is very low-level electrical current that has a positive (anode) or negative (cathode) electrode. Anodal stimulation of the cortex is usually associated with positive effects on mood and cognition. TDCS sessions in this study consisted of 2-mA anodal left/cathodal right dorsolateral prefrontal stimulation.
Editor’s Note: Placebo-controlled studies have repeatedly indicated that patients who have a stroke show better neurological and psychiatric response afterward when they are given an selective serotonin reuptake inhibitor (SSRI) antidepressant, whether or not they have depression or a prior history of depression. If a neurologist does not suggest treatment with an SSRI after a stroke, ask why not. Since antidepressants increase brain levels of brain-derived neurotrophic factor (BDNF) and increase neurogenesis, they could help with post-stroke recovery.
The hypoglycemic drug pioglitazone is typically used to treat diabetes, but a 2015 study by A. Zeinoddini and colleagues shows that it may improve depressive symptoms in patients with bipolar disorder who do not have type 2 diabetes or the metabolic syndrome (characterized by high weight, cholesterol, triglycerides, and blood pressure).
Forty-four patients with bipolar disorder and a major depressive episode were randomized to receive either 30 mg/day of pioglitazone or placebo as an adjunctive treatment to lithium. Depressive symptoms were lower in the pioglitazone group at weeks 2, 4, and 6 of the six-week study.
No serious side effect occurred in the study, but pioglitazone use is associated with some risks in those using it for diabetes treatment. People taking pioglitazone for longer than a year have shown increased rates of bladder cancer. There is an increased risk of fractures of the upper arms, hands, and feet in female patients. The drug lowers blood sugar, but not enough to be a problem in people not taking other drugs that lower blood sugar. Pioglitazone can also cause fluid retention, worsening congestive heart failure. It can also cause mild weight gain, anemia, and sinus problems.
Borderline personality disorder is characterized by mood instability, cognitive symptoms, impulsive or risky behavior, and disturbed interpersonal relationships. There are no Federal Drug Administration–approved treatments, but several small open studies of the atypical antipsychotic quetiapine (trade name Seroquel) have been promising. Rapid mood shifts in borderline personality disorder resemble to some extent those in bipolar disorder, for which quetiapine is an approved treatment. The drug may also curb impulsivity and self-harm. A blind, placebo-controlled study by Donald W. Black and colleagues published in the American Journal of Psychiatry in 2014 compared a low dose of quetiapine (150mg/day) with a moderate dose (300mg/day) and with placebo for the treatment of borderline personality disorder. The low dose of quetiapine led to significant improvement over the other doses, particularly reducing verbal and physical aggression.
The study included 95 participants randomized to each of the three treatment groups. All met DSM-IV criteria for borderline personality disorder, and each participant received eight weeks of active treatment. (One week of 50mg/day followed by seven weeks of 150md/day for the low dose group, and one week of 50mg/day followed by 3 weeks of 150mg/day and 4 weeks of 300mg/day for the moderate dose group.)
Eighty-eight percent of the participants experienced an adverse event during the study, including sedation, dry mouth, increased heart rate, or decrease in blood pressure. None were serious. Sedation was most common in the group receiving moderate doses of quetiapine.
All groups improved over the 8-week study, particularly during weeks 2–6. Response rates of participants who completed the study were 82% for the low dose group, 74% for the moderate dose group, and 48% for placebo. (Large benefits from placebo are common in studies of borderline personality.) Improvement in symptoms was greatest in the low dose quetiapine group, significantly higher than the moderate dose quetiapine group. Time to improvement was shorter on quetiapine than on placebo.
Ketamine, an anesthetic sometimes used intravenously in the treatment of depression, can bring about rapid onset of antidepressant effects. A new meta-analysis by researcher Michael Bloch and colleagues presented at a recent conference showed that ketamine’s maximum antidepressant effects occur within one day of administration, and its effects remain significant (compared to control conditions) one week following infusion. Ketamine’s effects were diminished in patients taking other medications. There was a trend for better response in patients with bipolar disorder than with unipolar disorder.
Bloch and colleagues analyzed eight earlier studies including a total of 180 participants. In each study, ketamine had been compared to a control condition, either an infusion of saline solution or of midazolam, which mimics ketamine’s sensory effects but does not have antidepressant effects. The researchers are calling for more meta-analyses of ketamine studies to determine which patients respond best to ketamine and how to sustain ketamine’s effects.
Editor’s Note: In another poster presented at the same conference, James Murrough reported that patients with slower processing speed responded best to ketamine. Other findings have shown that those with a history of alcohol abuse and a common genetic variant of brain-derived neurotrophic factor (BDNF), the val-66-val allele of proBDNF, are more likely to respond to ketamine.
Prazosin, an alpha-1 adrenoreceptor antagonist, has been found to be effective at reducing symptoms of post-traumatic stress disorder (PTSD), including nightmares. Researchers led by Murray Raskind hypothesized that there may be a link between blood pressure and response to prazosin, since resting blood pressure can be used to measure alpha-1 adrenoreceptor responsiveness. In a study of active duty combat soldiers with PTSD, higher resting blood pressure and smaller drop in blood pressure when going from lying down to standing up predicted a better response to prazosin.
The researchers believe that blood pressure can be used to estimate the central nervous systems’s responsiveness to norepinephrine, which prazosin blocks. In patients with PTSD who received placebo instead of prazosin, blood pressure did not predict improvement. Raskind and colleagues hope to be better able to predict response to prazosin in PTSD by measuring patients’ baseline blood pressure.
In a new study of patients with major depressive disorder who did not improve after eight weeks of the selective serotonin reuptake inhibitor (SSRI) antidepressant escitalopram, the addition of the atypical antipsychotic ziprasidone improved their depression more than did placebo. Patients took the combination of escitalopram (20mg/day on average) and ziprasidone twice a day at doses of 20–80 mg.
This was the first randomized, double-blind placebo controlled trial of ziprasidone as an adjunct treatment for unipolar depression. While ziprasidone was more efficacious than placebo, discontinuation of the study due to intolerance was higher among the patients who received ziprasidone.
Editor’s Note: Two atypical antipsychotics (quetiapine and aripiprazole) have been approved by the Federal Drug Administration for augmentation of antidepressants in unipolar depression. Now there have also been placebo-controlled positive trials of two others (ziprasidone and cariprazine).
These findings are of particular interest as the studies of ziprasidone monotherapy in bipolar depression not only failed, but response to ziprasidone and placebo was virtually identical (and negligible).