At the 2015 meeting of the Transcranial Magnetic Stimulation Society in May, researcher Stephanie Ameis discussed the dearth of medication studies in children, particularly for depression but also for schizophrenia and autism spectrum disorders, which share the symptom of impaired executive functioning, which can include skills such as planning and problem solving.
Ameis noted that in a literature review, there were a total of 1046 controlled pharmacological treatment studies in adults compared to only 106 in children, which reflects a relative absence of treatment knowledge, especially for depression (where there were 303 studies in adults versus only 17 in children) and bipolar disorder (where there were 174 studies of adults and 24 of children).
Ameis then reviewed the few studies of rTMS for depression in young people. She identified several series with only a total of 33 children and adolescents who had been treated with rTMS. She is beginning to study rTMS in patients with high-functioning autism (40 patients aged 16 to 25 have been randomized in her study). Ameis also described a 2013 study of rTMS in which patients with schizophrenia showed improved performance on a test of working memory published by Mera S. Barr and colleagues in the journal Biological Psychiatry. Ameis cited this as a rationale for studying rTMS’s effect on cognitive performance in people with autism.
At the 3rd Annual Meeting of the Transcranial Magnetic Stimulation Society, Canadian researcher Frank MacMaster discussed his study of repeated transcranial magnetic stimulation (rTMS) in 50 children with depression. RTMS is a non-invasive procedure in which an electromagnetic coil is placed against the side of the forehead and magnetic pulses that can penetrate the scalp are converted into small electrical currents that stimulate neurons in the brain. The study was designed to identify biomarkers, or characteristics that might indicate which patients were likely to respond to the treatment. All of the patients received rTMS at a frequency of 10 Hz. Using magnetic resonance spectroscopy (MRS) technology, MacMaster found that children who responded well to rTMS treatment had low levels of the neurotransmitter glutamate at the beginning of the study, but their glutamate levels increased as their depression improved. Children who didn’t improve had higher glutamate levels at the beginning of the study, and these fell during the rTMS treatment.
MacMaster hopes that glutamate levels and other biological indicators such as inflammation will eventually pinpoint which treatments are likely to work best for children with depression. At the meeting, MacMaster said that in Canada, only a quarter of the 1,200,000 children with depression receive appropriate treatment for it. Very little funding is devoted to research on children’s mental health, a serious deficit when one considers that most depression, anxiety, attention deficit hyperactivity disorder (ADHD), bipolar disorder, oppositional behavior, conduct disorder, and substance abuse begins in childhood and adolescence, and early onset of these illnesses has been repeatedly linked to poorer outcomes.
Editor’s Note: The strategy of identifying biomarkers is an important one. MacMaster noted that this type of research is possible due to the phenomenal improvements in brain imaging techniques that have occurred over the past several decades. These techniques include magnetic resonance imaging (MRI) to a resolution of 1 mm; functional MRI; diffusion tensor imaging (DTI), which can depict the connectivity of white matter tracts; and spectroscopy, which can be used to identify chemical markers of neuronal health and inhibitory and excitatory neurotransmitters, and analyze membrane integrity and metabolic changes. These methods provide exquisite views of the living brain, the most complicated structure in the universe. The biomarkers these techniques may identify will allow clinicians to predict how a patient will respond to a given treatment, to choose treatments more rapidly, and to treat patients more effectively.
At the May meeting of the Society of Biological Psychiatry, researcher Deborah Kim gave a talk on the use of repeated transcranial magnetic stimulation (rTMS) for depression in women who are pregnant. In rTMS treatment, an electromagnetic coil is placed against the side of the forehead and magnetic pulses that can penetrate the scalp are converted into small electrical currents that stimulate neurons in the brain. Kim had recently completed an open study of rTMS in pregnant women, in which 70% of the women responded to rTMS. In another controlled randomized study of 30 women (also by Kim), 75% responded to active rTMS and 50% responded to a sham procedure. None of the women included had problems with the fetus or during delivery.
RTMS offers an alternative to women who are reluctant to take antidepressants during pregnancy. Kim cited data by Lee S. Cohen and colleagues in which women taking antidepressants show a 68% relapse rate if they stop taking these medications during pregnancy compared to a 26% relapse rate among those who continue taking antidepressants during pregnancy. Concerns about antidepressants’ potential effects on a fetus may have been overemphasized. Kim summarized the literature on antidepressants in pregnancy, concluding that there is a preponderance of evidence that antidepressants are safe for the mother and fetus, with few serious effects having been observed. Some researchers have been concerned about risks of persistent pulmonary hypertension or autism among offspring of women who took antidepressants during pregnancy, but studies have shown that the absolute risk of either is small. Stay tuned—on Wednesday we’ll discuss a new large and comprehensive study in which most SSRIs showed no link to birth defects, but fluoxetine and paroxetine were associated with risks of certain birth defects.
Editor’s Note: For mild depression during pregnancy, exercise and psychotherapy might be optimal, along with folate and vitamin D3. For moderate depression, omega-3 fatty acids might also be helpful, but it now appears that rTMS would be less risky than electroconvulsive therapy (ECT), which in the past has been a typical recommendation for pregnant women, but which exposes the fetus to the effects of anesthesia and seizure. In her summary Kim recommended that women with a pattern of recurrent depression continue antidepressant treatment, especially since a mother’s depression itself poses non-trivial risks to the fetus.
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.