A new meta-analysis presented at the 2015 meeting of the Society of Biological Psychiatry has clarified the efficacy of transcranial direct current stimulation (tDCS) in major depression. TDCS is a treatment in which electrodes deliver a steady low level of electrical stimulation to the brain. The meta-analysis presented by Andre Brunoni and colleagues used individual patient data from six recent studies comparing tDCS treatment to a sham treatment, totaling 289 patients. TDCS treatment was superior to the sham control in terms of antidepressant response (34% to 19%), remission rates (23.1% to 12.7%), and improvement in depression.
After adjusting for confounding factors, the researchers found that patients who had failed to respond to previous treatments were less likely to respond well to tDCS than other patients. They also found that higher doses of tDCS (in terms of current density, duration, and number of sessions) predicted a better response than lower doses.
Repeated transcranial magnetic stimulation (rTMS) is a treatment for depression in which magnets placed near the skull stimulate electrical impulses in the brain. In a poster presented at the 2015 meeting of the Society of Biological Psychiatry, Martin Lan and colleagues presented results of the first study of structural changes in the brain following rTMS.
In the study, 27 patients in an episode of major depression underwent magnetic resonance brain scans before and after receiving rTMS treatment over their left prefrontal cortices. Lan and colleagues reported that several cortical regions related to cognitive appraisal, the subjective experience of emotion, and self-referential processing increased in volume following rTMS treatment: the anterior cingulate, the cingulate body, the precuneous, right insula, and gray matter in the medial frontal gyrus. The increases ranged from 5.3% to 15.7%, and no regions decreased in volume. More than 92% of the participants showed increased gray matter in all of these regions.
The brain changes were not correlated with antidepressant response to rTMS, but suggest a possible mechanism by which rTMS is effective in some people. Lan and colleagues concluded that rTMS likely had neuroplastic effects in areas of the brain that are important for emotion regulation.
A new longitudinal study of 391 youth at risk for bipolar disorder revealed some predictors of the disorder. The study by Danella M. Hafeman and colleagues was presented at the 2015 meeting of the Society of Biological Psychiatry. The participants were aged 6–18 and each had a parent with bipolar disorder. Over the course of the study, 40 developed an illness on the bipolar spectrum, including 21 who developed bipolar I or II. The participants were assessed for various descriptive characteristics and those who developed bipolar disorder were compared to those who developed major depressive disorder.
The most important predictors of bipolar disorder were parental assessment of internalizing symptoms of anxiety or depression, self-assessment of mood changeability, and self-assessment of hostility. A diagnosis of bipolar disorder not otherwise specified (BP-NOS) was the only predictor of a later diagnosis of bipolar I or II.
Editors Note: These data resemble findings from a 2015 study by David Axelson and colleagues in the American Journal of Psychiatry that used the same cohort of participants. The Axelson study indicated that a categorical diagnosis of a major psychiatric disorder occurred in 74% of the offspring of a bipolar parent compared to about 50% in a control group from the community. Depression, anxiety, attention deficit hyperactivity disorder (ADHD), and oppositional disorders were even more common than bipolar disorder in the at-risk population.
The presence of a major psychiatric diagnosis in about three-quarters of the offspring of a parent with bipolar disorder suggests the importance of early vigilance. One way to track symptoms of depression, anxiety, ADHD, oppositional behavior, and bipolar disorder is to join the Child Network, a secure online platform for rating children’s moods, medications, and side effects. These weekly ratings can be collected longitudinally and printed out to help parents and clinicians assess mood difficulties in their children.
Dysregulation of the brain in early life can have lasting effects, and the effects of stress and depression can also accumulate. At the 2015 meeting of the Society of Biological Psychiatry, researcher Huda Akil explained that behavioral pathology can “take on a life of its own, leading to deteriorating course of illness and treatment resistance.” She illustrated how preclinical work in animals can help clarify the molecular biology of depression and develop new targets for therapeutics.
Early Life Experiences are Key
Akil discuss studies of rodents in which she used new molecular genetic techniques to increase the number of glucocorticoid receptors in the hippocampus early in life (prior to weaning). Glucocorticoid receptors mediate the effects of the stress hormone cortisol in people and corticosterone in rodents. More receptors help shut off cortisol secretion after a stressful event. People with post-traumatic stress disorder (PTSD) have high levels of glucocorticoid receptors while people with depression have low levels, leading to over-secretion of cortisol in depression.
The increased glucocorticoid receptors led to a long-term increase in anxiety behaviors and response to stimulants. When Akil carried out the same manipulation on rats that had already been weaned, it had no long-lasting effects, showing that there is a vulnerability window for some long-lasting effects on behavior.
CLOCK Genes and Circadian Rhythms
Akil also studied CLOCK genes in rodents. These genes, including BMAL-1, Per 1, Per 2, and Per3, play a role in circadian rhythms, and their transcription induces these 24-hour cycles. In rodents who were induced into a depression-like state, the CLOCK genes were dysregulated and did not correspond to normal circadian rhythms. These data show that depressive states can induce changes in CLOCK genes and circadian rhythms. Others have shown the converse, that abnormal CLOCK genes can induce behavioral abnormalities including mania-like behaviors.
Fibroblast Growth Factor
Levels of fibroblast growth factor 2 (FGF2) in the hippocampus are low in people with depression. In rodents, FGF2 inhibits anxiety. Decreases in FGF2 are seen in the hippocampus of animals in a depression-like state following repeated defeat by a larger animal. It appears that FGF2 is an endogenous antidepressant (i.e. one that is produced by the brain). When the rodent brain is manipulated to eliminate FGF2, the animals become anxious.
In addition, animals bred to have high stress, low social responsivity, and resistance to new learning also have low FGF2. Treatment with FGF2 reversed these behavioral abnormalities and also increased the production of new neurons. For the stressed rats, receiving FGF2 on their second day of life increased new neuron production, decreased anxiety, decreased proneness to social defeat stress and increased the bonding hormone oxytocin in the amygdala into adulthood.
FGF2 had no effect on rats bred for low stress and high social responsivity, indicating that it only worked for the rats that needed it. Akil compared FGF2 to “personalized medicine for rats.”
Defeat stress affects the way genes are transcribed, and FGF2 was able to reverse one of these specific transcriptional effects, suggesting it could potentially ameliorate some of the long-lasting effects of stress and depression.
The Human Brain
Akil also studied the brains of people who had died of depression, bipolar disorder, or schizophrenia. In bipolar disorder, the nucleus accumbens, the reward center of the brain, was enlarged.
In contrast, Akil described the brains of those people who had died with depression as being “low on fertilizer.” That is, they showed less cell growth, less production of new neurons, more abnormalities in cell shape, and more cell death. Akil said that by the time someone is severely ill, the pathology is all over the brain. The changes Akil saw in the brains of people who were depressed are also consistent with data indicating that several neuroprotective factors, including BDNF and VEG-F, are low in the frontal cortex and the hippocampus of depressed people (while BDNF is high in the nucleus accumbens).
A study currently in progress indicates that the anti-inflammatory COX-2 inhibitor celecoxib (better known as the arthritis treatment Celebrex) may aid in the treatment of bipolar depression. In a panel session on inflammation at the 2015 meeting of the Society of Biological Psychiatry, researcher Angelos Halaris reported results from the first 26 participants.
Participants were taking mood stabilizers for bipolar disorder and became depressed. They received either 20mg/day of the selective serotonin reuptake inhibitor antidepressant escitalopram (Lexapro) plus either 200mg twice a day of celecoxib or placebo for a total of eight weeks. Those participants who received celecoxib showed greater and more rapid reductions in depression symptoms than those who received placebo.
The study will continue, and Halaris and colleagues will also observe whether measures of inflammation in patients’ blood are correlated with the patients’ responsiveness to the combined treatment with escitalopram and celecoxib.
There is growing evidence of a link between inflammation of depression. At the 2015 meeting of the Society of Biological Psychiatry, researcher Jeff Meyer summarized past studies on inflammatory markers. These are measurements, for example of certain proteins in the blood, that indicate the presence of inflammation in the body.
Common inflammatory markers that have been linked to depression include IL-6, TNF-alpha, and c-reactive protein. At the meeting, Meyer reviewed the findings on each of these. Twelve studies showed that IL-6 levels are elevated in the blood of patients with depression. Four studies had non-significant results of link between IL-6 and depression, and Meyer found no studies indicating that IL-6 levels were lower in those with depression. Similarly, for TNF-alpha, Meyer found 11 studies linking elevated TNF-alpha with depression, four with non-significant results, and none showing a negative relationship between TNF-alpha and depression. For c-reactive protein, six studies showed that c-reactive protein was elevated in people with depression, six had non-significant results, and none indicated that c-reactive protein was lower in depressed patients.
Most studies that have linked inflammation to depression have done so by measuring inflammatory markers in the blood. It is more difficult to measure inflammation in the brain of living people, but Meyer has taken advantage of new developments in positron emission tomography (PET) scans to measure translocator protein binding, which illustrates when microglia are activated. Microglial activation is a sign of inflammation. Translocator protein binding was elevated by about 30% in the prefrontal cortex, anterior cingulate cortex, and insula in study participants who showed symptoms of a major depressive episode compared to healthy control participants. The implication is that the depressed people with elevated translocator protein binding have more brain inflammation, probably via microglial activation.
The antibiotic minocycline reduces microglial activation. It would be interesting to see if minocycline might have antidepressant effects in people with depression symptoms and elevated translocator protein binding.
At the 2015 meeting of the Society of Biological Psychiatry in May, researcher Daniel Blumberger reported to this editor (Robert M. Post) that he has found repeated transcranial magnetic stimulation (rTMS) to be effective for depression in late life. Blumberger noted that it may be necessary to use higher intensity stimulation (i.e. at 120% of motor threshold instead of the usual 110% of motor threshold) in the elderly in order to overcome the gap between the skull and the brain, which can grow with age due to brain atrophy.
Blumberger has also successfully used rTMS as a followup treatment to a successful course of electroconvulsive therapy (ECT), administering rTMS twice a week for up to 66 treatments in a given patient in order to maintain remission of their depression.
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.