Antidepressant Brintellix Renamed Trintellix
A new label: Brintellix is now Trintellix.
You may notice the label on your prescription bottle changing. As of June, the antidepressant vortioxetine (formerly Brintellix) is now called Trintellix. The US Food and Drug Administration approved the change to reduce any possible confusion of the antidepressant with a blood-thinning medication called Brilinta.
Weight Gain is a Common Issue with Antidepressants, But Buproprion is an Exception
A 2016 study by researcher David Arterburn and colleagues in the Journal of Clinical Medicine suggests that taking an antidepressant for two years is associated with an increase in body weight. Luckily, bupropion (trade name Wellbutrin) is an exception that may be a good choice for obese or overweight patients.
The researchers analyzed links between which antidepressants patients in a large health system in Washington State were prescribed and their body weight two years later.
The researchers used fluoxetine (Prozac) as a reference. Most antidepressants did not differ significantly from fluoxetine in terms of the weight gain experienced by people taking the drug.
There were a few exceptions. Compared to non-smoking fluoxetine users, who gained an average of 4.6 pounds in two years, non-smoking bupropion users actually lost weight—an average of 2.4 pounds. (Smokers taking bupropion still gained an average of 6.9 pounds.)
Sertraline (Zoloft) was another exception. Sertraline users gained more than users of other antidepressants—an average of 10.5 pounds over two years.
Intranasal Ketamine Produces Long-Lasting Antidepressant Effects
It has been known for years that ketamine, an anesthetic at higher doses, can quickly produce anti-depressant effects when delivered intravenously. However, these effects typically last only a few days. New research is exploring how to extend the antidepressant effects of ketamine.
Researcher Ella Daly and colleagues recently compared a form of ketamine called esketamine, this time delivered intranasally, to placebo in people with tough-to-treat depression that had resisted other treatments. Daly and colleagues randomized participants to receive one of three different doses of intranasal esketamine (28mg, 56mg, or 84mg) or placebo twice a week.
All of the doses of intranasal esketamine improved participants’ depression compared to placebo, with higher doses producing more sustained improvement. After the 2-week double-blind study, participants could choose to continue (or begin) taking esketamine for another nine weeks, tapering dosage slowly from twice a week to once every other week by the end. The participants were then monitored for another eight weeks. The intranasal esketamine doses they received led to sustained improvements in depression that lasted, in some cases, through the eight weeks following their final dose.
Side effects were not severe. Ketamine can produce dissociative sensations, but these tended to dissipate with two hours of administration.
Johnson and Johnson Pharmaceuticals funded this research, which was presented at a scientific meeting in 2015, and they plan to continue researching intranasal esketamine in the hopes of getting Food and Drug Administration approval for the drug.
Ketamine: Equal Efficacy When Given With Lithium Or Valproate
Studies of rodents with depression-like behaviors revealed that the combination of low (sub-therapeutic) doses of lithium and infusions of ketamine produced antidepressant-like effects. Researchers believed this might mean that in humans, lithium might have a unique effect potentiating the effects of ketamine.
In a small study by Mark J. Niciu presented at the 2015 meeting of the Society for Biological Psychiatry, patients with bipolar depression taking lithium or valproate mood stabilizers were given ketamine infusions or control infusions. In the 23 patients taking lithium and the 13 taking valproate, ketamine’s antidepressant effects were significantly better than placebo, but there was no difference between lithium and valproate with regard to these antidepressant effects. These preliminary data in a small number of subjects do not support the proposition that lithium augments the effects of ketamine in depression.
Ketamine Temporarily Reduces Suicidal Thoughts
Intravenous ketamine can bring about rapid improvement in depressive symptoms among people with treatment-resistant depression. Because of its rapid effects, which can appear after only two hours, ketamine is being investigated as a treatment for people with suicidal thoughts.
At the 2015 meeting of the Society of Biological Psychiatry, Laili Soleimani and colleagues presented a poster about their recent double blind, randomized, controlled pilot study of ketamine inpatients and outpatients who scored highly on a measure of suicidal ideation. The 24 participants were randomized to receive either a single intravenous infusion of ketamine (0.5mg/kg) or a single infusion of midazolam (0.045 mg/kg), which shares ketamine’s anxiety-reducing effects but does not have antidepressant effects. They reported suicidal thoughts at 24 hours post-infusion, 48 hours, 72 hours, and 7 days. At 48 hours, those who received ketamine reported significantly reduced suicidal ideation compared to those who received midazolam, but this effect was no longer significant at the 72-hour mark.
The findings show that ketamine can briefly reduce suicidal ideation, and that the treatment is safe and tolerable for patients. This pilot study paves the way for further study of ketamine to reduce suicidal thinking in people who are at high risk for suicidal behavior.
Meta-Analysis Shows Effectiveness of Ketamine for Bipolar and Unipolar Depression
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.
Lavender Oil Has Anti-Anxiety Effects and Possibly Antidepressant Effects
An oral preparation of lavender oil called Silexan was previously found to reduce anxiety in people with generalized anxiety disorders or subthreshold anxiety symptoms without causing sedation. It seems to work by inhibiting voltage dependent calcium channels in a manner similar to the anti-anxiety drug pregabalin. Unlike pregabalin, the lavender oil treatment also reduced depression in the people with subthreshold anxiety. Researchers are now exploring lavender oil’s effects on rats who exhibit behaviors that resemble human depression, and on rat and human cells in vitro.
Silexan had positive effects on rats with depression-like behaviors, increasing the time they would swim before giving up in a forced swim test. It also increased the growth of rat and human neurons in a lab setting. These effects are usually connected with activation of a protein called CREB that turns on some genes that affect mood. The researchers, led by Walter Mueller, were able to clarify the pathway for this activation by inhibiting specific kinases, enzymes responsible for transferring phosphates across different molecules. The kinases involved included PKA, PI3K, MAPK and CaMK IV.
Editor’s Note: Oral lavender supplements may help improve anxiety and depression without sedation.
New Data on Vortioxetine for Cognition in Unipolar Depression
A 5mg dose of the antidepressant vortioxetine (Brintellix) was previously reported to have positive cognitive effects in elderly depressed patients. In a 2014 article in the International Journal of Neuropsychopharmacology, researcher Roger S. McIntyre et al. presented data from FOCUS, a study of cognition in depressed patients. The eight-week double-blind study included 18- to 65-year-olds (who were not selected for having cognitive problems per se).
McIntyre and colleagues used two tests of cognition, the Digit Symbol Substitution Test (DSST), which measures attention, psychomotor speed, and executive function, and the Rey Auditory Verbal Learning Test (RAVLT), which measures memory and acute and delayed recall. The researchers found that both the 195 patients taking 10mg/day of vortioxetine and the 207 patients taking 20mg/day of vortioxetine had better performance on both tests than the 196 patients who received placebo.
Response rates (meaning a patient achieved a 50% improvement on a scale of depression) were 47.7% on 10mg of vortioxetine, and 58.8% on 20mg of vortioxetine, compared to 29.4% on placebo. Remission rates were 29.5% on 10mg of vortioxetine and 38.2% on 20mg of vortioxetine versus 17% on placebo. McIntyre suggested that the drug worked both directly and indirectly, improving depression in some, but also improving cognition even in those whose depression did not improve.
The mechanism that could account for vortioxetine’s cognitive effects has not yet been identified. Like other selective serotonin reuptake inhibitor (SSRI) antidepressants, vortioxetine is a potent blocker of serotonin (5HT) reuptake, which it does by inhibiting the serotonin transporter (5HT-T). Unlike other SSRIs, vortioxetine is also a blocker of 5HT3 and 5HT7 receptors, an agonist at 5HT1A and 5HT1B and a partial agonist at 5HT1D receptors. It could be considered a polymodal 5HT active drug in contrast to the more selectively active 5HT-T–inhibiting SSRIs.
Agomelatine in an Animal Model of PTSD
At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Joseph Zohar presented a poster on the effects of early post-stressor intervention with the drug agomelatine in animals who showed behavioral and molecular responses to stress that served as a model of post-traumatic stress disorder (PTSD).
Agomelatine is available clinically as an antidepressant in Canada and Europe (but not in the US), and can also reduce anxiety and re-synchronize circadian rhythms. Agomelatine is a melatonin (MT1/MT2) receptor agonist and a serotonin 5HT2C antagonist (increasing dopamine and norepinephrine in the frontal cortex).
Long-term behavioral, molecular and structural effects of the drug were assessed in animals. Adult male Sprague-Dawley rats were exposed to the scent of a predator for 10 minutes, and one hour later they were treated acutely for this stress with agomelatine (50mg/kg i.p.) or placebo.
Agomelatine decreased the prevalence of extreme, PTSD-like behavioral and molecular responses to the stressor, such as freezing in place and increased corticosterone. Agomelatine also normalized decreases in brain-derived neurotrophic factor (BDNF) observed in the dentate gyrus of the hippocampus, the cortex (layer III), and the basolateral amygdala. In line with this, agomelatine-treated stressed animals displayed significantly increased number and length of dendrites at glutamate synapses in the hippocampus (including the dentate gyrus and CA1) and reversed the hippocampal neuronal retraction observed in the rats who were given the placebo.
Agomelatine also affected the expression of clock genes in the rats, which regulate biorhythms. These genes lead to the production of the major clock gene proteins Per1 and Per2. Agomelatine normalized Per1 increases in three parts of the brain: the CA3, another glutamate synapse near the dentate gyrus; the suprachiasmatic nucleus over the optic chiasm, important for circadian rhythms; and the basolateral amygdala. Per2, a protein that also drives circadian rhythms, increased in the CA1 synapse of the hippocampus, the suprachiasmatic nucleus and the basolateral amygdala of the stressed rats.
The researchers concluded that the data provide “initial evidence that a single dose of agomelatine administered in the acute aftermath of stress promotes recovery while promoting enhanced neuronal and synaptic plasticity and connectivity in the secondary prevention of PTSD in this model.”
TDCS Promising for a Range of Illnesses
Transcranial direct current stimulation (tDCS) shows promise for a range of problems. In new research presented at the 2014 meeting of the Society of Biological Psychiatry, it was reported to be effective for improving cognition in bipolar disorder, alleviating depression, and reducing hallucinations.
How TDCS Works
At the meeting, researcher Marom Bikson discussed tDCS technology. The treatment can be delivered with a 12-volt battery. The anode directs current inward and is excitatory, while the cathode directs current outward and is inhibitory. The dendrites at the top of neurons under the anode are hyperpolarized by the tDCS, leading to relative depolarization of the cell soma, thus increasing excitation. TDCS, unlike repetitive transcranial magnetic stimulation (rTMS), which causes cells to fire, is only neuromodulatory, inducing minor changes in membrane polarization.
TDCS Improved Cognition in Bipolar Disorder
At the 2014 meeting of the American Psychiatric Association, Roberto Delle Chiaie et al. reported that two mA tDCS for 20 minutes for 15 days (anode over the left prefrontal cortex and cathode over the right cerebellum) improved immediate and delayed recall, trail making with a pointer, and motor coordination in 17 euthymic bipolar patients. This very promising result deserves further study and replication.
Antidepressant Effects of TDCS
At the 2014 meeting of the Society of Biological Psychiatry, Collen Loo reported that tDCS had positive effects in depressed patients compared to sham treatment. This complements a 2013 article by Brunoni et al. in JAMA Psychiatry that tDCS plus the selective serotonin reuptake inhibitor (SSRI) antidepressant sertraline (Zoloft) was more effective than either treatment alone.
TDCS for Treatment-Resistant Hallucinations
Jerome Brunelin et al. reported at the meeting that tDCS had positive effects in patients with schizophrenia who had hallucinations that resisted treatment. The positive electrode (anode) was placed over the left prefrontal cortex and the negative electrode (cathode) over the left temperoparietal area, where hallucinations are thought to originate. Stimulation was at two mA for 20 minutes, five days per week for two weeks. Effects lasted as long as 30 days and were associated with reduced functional connectivity of these brain regions.
Low frequency (1Hz) rTMS, which decreases neural activity, also improves refractory hallucinations when applied over the temperoparietal area, which is important for language. Placing the cathode over this area in tDCS is also inhibitory, so comparisons of rTMS with tDCS for suppressing hallucinations would be of great interest and importance.
