Two studies published in the Journal of Clinical Psychiatry in 2015 suggest that the new atypical antipsychotic brexpiprazole (trade name Rexulti) safely improves depression when added to antidepressant treatment. The 6-week studies, both by Michael E. Thase and colleagues, compared brexpiprazole to placebo in people who had not responded adequately to one to three antidepressants and were taking at least one antidepressant at the time of the study.
The studies examined the effectiveness of different doses of brexpiprazole. Doses of 2mg/day and 3mg/day were more effective than placebo, while a dose of 1mg/day was not. The drug was well-tolerated by patients at each of these doses, although those taking the 3mg/day reported more side effects than those taking 2mg/day. The side effects included restless legs, weight gain, and headaches.
Like the atypical antipsychotic aripiprazole (Abilify), brexpiprazole partially blocks and partially stimulates dopamine receptors. While aripiprazole allows 61% activity at dopamine D2 receptors, brexpiprazole allows 43%. It is not yet clear how the new drug’s effects may differ from those of aripiprazole.
Another relatively new atypical antipsychotic drug, cariprazine (Vraylar) is approved by the Food and Drug Administration for schizophrenia and mania, but not yet for bipolar depression or as an add-on treatment to antidepressants in unipolar depression, although there are placebo-controlled trials showing that cariprazine can also treat these conditions.
Like aripiprazole and brexpiprazole, cariprazine also partially blocks and partially stimulates dopamine receptors. Unlike them, cariprazine is more potent at dopamine D3 receptors, which are linked to mood, motivation, and drug reward, than at D2 receptors, which are linked to motor control. It is not yet clear how these differences may change treatment outcomes or side effects.
At the 2015 meeting of the International Society for Bipolar Disorders, researcher Martin McInnis described how stem cells can be used to identify biochemical abnormalities in patients with bipolar disorder. In this research, the stem cells, or IPSCs (for induced pluripotential stem cells), are created when cells from skin fibroblasts, which produce connective tissue, are treated with chemicals that cause them to de-differentiate back into stem cells.
McInnis identified several abnormalities in the stem cells of patients with bipolar disorder. Stem cells with the gene CACNA1C, which is associated with vulnerability to bipolar disorder, fired more rapidly than non-CACNA1C stem cells. There were other abnormalities at the NMDA glutamate receptor and an imbalance of the neurotransmitter GABA in the cells. When the cells were treated with lithium, some of these abnormalities were reversed. In the cells with the CACNA1C gene, lithium normalized the firing rate. Lithium aslo re-balanced the distribution of GABA in the cells.
McInnis hopes that this stem cell research will shed light on the abnormalities associated with bipolar disorder, help explain how lithium corrects some of these, and lead to the development of new therapeutic approaches.
A new double-blind, randomized clinical trial has shown that transcranial direct current stimulation (tDCS) can reduce negative symptoms of schizophrenia. TDCS, a treatment in which an anode and a cathode electrode placed on the skull are used to apply a steady, low-level current of electricity to the brain, has been shown to improve neuroplasticity, such as neuronal remodeling, by depolarizing or hyperpolarizing neurons. People with schizophrenia have neuroplasticity deficits in parts of the cortex, so a few case reports and one previous randomized clinical trial have explored the use of tDCS in schizophrenia.
The current study, presented by Ulrich Palm at the 2015 meeting of the Society of Biological Psychiatry, included 20 patients with primarily negative symptoms of schizophrenia, such as thought disorders, poverty of speech, and withdrawal. The patients, who had stable medication regimes for at least three weeks, were randomized to receive either a sham procedure or tDCS with the anode over the left dorsolateral prefrontal cortex and the cathode over the right eye. TDCS stimulation was delivered at a current of 2 mA ten times over two weeks. The patients continued to take their medication and also received functional connectivity magnetic resonance imaging (fcMRI) before and after tDCS treatment.
Two weeks following the stimulation, scores on a scale of positive symptoms (hallucinations and delusions) and negative symptoms of schizophrenia had decreased significantly in those who received tDCS compared to the sham procedure. A measure of negative symptoms was significantly lower among the tDCS group throughout the study period and at the 2-week followup. The fcMRI revealed that those who received tDCS had a deactivated cluster in the brain region that includes the nucleus accumbens, the subgenual cortex, and the striatum.
This study suggests that tDCS is a promising treatment for otherwise difficult-to-treat symptoms of schizophrenia.
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.
Certain nutritional supplements may help people cope following natural disasters. Following a 7.1 magnitude earthquake in Christchurch, New Zealand, in 2010, researchers there who were working on a clinical trial of a broad spectrum mineral and vitamin formula for ADHD realized that they could compare participants who had been taking the nutritional supplements at the time of the earthquake with those who had either already completed the trial or had not yet begun it. Two weeks after the quake, those who had been taking the multivitamin at the time of the quake were less anxious and stressed than those who hadn’t been taking the formula.
When another large earthquake struck five months later, the researchers implemented a randomized trial comparing two doses of the same broad spectrum supplement with a B Complex vitamin formula that had previously shown efficacy for stress and anxiety. Those participants taking any supplement showed fewer symptoms of post-traumatic stress disorder (PTSD) a month after the second quake compared to controls, and those taking the higher dose of the broad spectrum formula had greater improvements in mood and anxiety than those taking the B Complex supplement.
More recently, in Alberta, Canada, flooding forced many people from their homes. Researchers there who were studying the effects of micronutrients on stress and anxiety realized they had the opportunity to replicate the research from New Zealand in a different type of environmental disaster.
Researcher Bonnie J. Kaplan and colleagues recruited adults who had been affected by the flood, and randomized the participants to receive different types of supplements: vitamin D (1 pill/day); a B complex vitamin containing B6, B12, and several other nutrients (1 pill/day); or a broad spectrum supplement containing 24 vitamins and minerals and several botanical extracts (4 pills/day). No placebo was used—it was considered unethical to deny participants access to a potentially helpful treatment.
In a 2015 article in the journal Psychiatry Research, the Alberta team reported that while all of the nutrient supplements minimized stress after the flood, patients randomized to the B complex vitamin or the broad spectrum formula had less stress and anxiety following the flood than those randomized to vitamin D.
We have previously described a broad spectrum vitamin preparation called EMPowerplus, used by psychiatrist Charles Popper and psychologist Mary A. Fristad to treat children with treatment-resistant bipolar disorder. This may be the same formula used in the Alberta study. We await larger trials of this preparation in children with bipolar disorder.
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.
Obsessive compulsive disorder (OCD) occurs in about 2% of the population worldwide. Selective serotonin reuptake inhibitor (SSRI) antidepressants are the most commonly used treatment for OCD, but not all patients respond adequately to them.
At the 2015 meeting of the Transcranial Magnetic Stimulation Society, researcher Joseph Zohar presented evidence that deep transcranial magnetic stimulation (deep TMS) targeted over the medial prefrontal cortex may reduce OCD symptoms. In TMS treatment, an electromagnetic coil is placed against the patient’s head and magnetic pulses that can penetrate the scalp are converted into small electrical currents that stimulate neurons in the brain. In Zohar’s study, patients with OCD were randomized to receive deep TMS at frequencies of either 20 Hz or 1 Hz, or a sham procedure. The 20 Hz deep TMS resulted in a 28% reduction in OCD symptoms compared to the other two groups, indicating that the 20 Hz treatment had a large effect size.
In addition to the deep TMS procedures, all patients also received cognitive behavioral therapy, high doses of SSRIs, and relapse prevention training.
Editor’s Note: It is interesting that 20 Hz deep TMS, which activates the prefrontal cortex, was more effective than 1 Hz, which decreases activity there. Other attempts to treat OCD have focused on suppressing frontal-striatal-thalamic circuits, which are overactive in the disorder. Since the medial prefrontal cortex is an important area for the new learning required for the extinction of anxiety symptoms in a variety of disorders, increasing activity in this medial prefrontal target area with 20 Hz may activate that extinction process allowing new learning rather than nonspecifically suppressing hyperactive frontal-striatal-thalamic circuits as 1 Hz TMS would do.
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.