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.
Disruptions to circadian rhythms are common in mood disorders, leading some researchers to believe that normalizing these daily rhythms may improve the illnesses. Several genes, called CLOCK genes, are implicated in circadian rhythms. In animal studies, researcher Marco Riva and colleagues are examining the expression of CLOCK genes in different brain regions as a result of chronic stress that is meant to produce behaviors resembling human depression.
Male rats were exposed to chronic mild stress for two weeks, and divided into those that were susceptible to stress (identified by their loss of interest in sucrose) and those who were not. Then the rats were randomized to receive either a placebo treatment or 3 mg/kg/day of the atypical antipsychotic lurasidone (trade name Latuda), which has been effective in bipolar depression, during five more weeks of the stress procedure.
The researchers observed the expression of clock genes Clock/Bmal1, Per1, Per2, Cry1, and Cry2. In susceptible rats, the chronic mild stress decreased the clock genes Per1, Per2, and Cry2 in the prefrontal cortex. Lurasidone reversed these CLOCK gene abnormalities and the rats’ depression-like behaviors, which may explain some of the drug’s efficacy in bipolar depression.
Editor’s Note: Lurasidone is also a potent inhibitor of 5HT7 serotonin receptors, an effect that has been linked to antidepressant efficacy. Lurasidone also increases brain-derived neurotrophic factor (BDNF), which is important for learning and memory, and prevents stress from decreasing BDNF. Now it seems that lurasidone’s normalization of CLOCK genes may be another mechanism that explains the drug’s antidepressant effects.
In a recent randomized, controlled clinical study comparing two types of omega-3 fatty acid supplements (one with EPA and one with DHA) with placebo in 196 adults with major depression, there were no statistically significant differences in outcomes across the three groups. The participants received the treatments for eight weeks, and response and remission rates were 40-50% in those receiving either omega-3 preparation (at doses of 1000mg/day) and 30% for placebo. The research was published by David Mischoulon and colleagues in the Journal of Clinical Psychiatry.
In 2012 we reported on an open study by Athanasios Koukopoulos and colleagues that explored whether the NMDA glutamate receptor antagonist memantine (Namenda), which is used to treat dementia, could be helpful to people with treatment-resistant bipolar disorder. In an update of that study, the researchers, led by Giulia Serra, compared patients’ symptoms during three years of treatment as usual, followed by three years with memantine added to their stable medication regime (at doses of 20–30 mg/day). Patients improved progressively over the three years of taking memantine.
Improvements in symptoms included decreased time ill, decreased severity of symptoms, decreased duration of new episodes, and fewer episodes per year. Memantine was particularly helpful for those patients who had had rapid or continuous cycling. Side effects were minimal.
Given the success of this open study, randomized controlled trials are needed to explore this much-needed option for people with treatment-resistant bipolar disorder.
Women are more likely than men to experience depression, and this difference begins in adolescence, when girls show more sensitivity to stress. Researchers are studying how animals react to stress in the hopes of learning what mediates these gender differences in mental illness.
At a recent scientific meeting, researcher Jodi Lukkes and colleagues presented a recent study of stress and inflammation in female rats. The rats were exposed to different types of stressors. Some were separated from their mothers for four hours a day during the first 20 days of their lives. Later, some rats were exposed to an acute stressor, witnessing another rat receiving shocks. All the rats were placed in a box in which they could escape a shock by jumping to the other end of the box, in order to measure their motivation. Because drugs that inhibit the inflammatory enzyme COX-2 had reversed the effects of maternal separation in earlier studies, the researchers also treated some rats with these anti-inflammatories.
The researchers found that anti-inflammatory treatment could prevent behavioral consequences of stress in adolescent female rats. Witnessing another rat being shocked brought about deficits in motivation (a depression-like behavior), but in rats that had received treatment with a COX-2 inhibitor, these deficits were reduced. The COX-2 treatment was only helpful to rats that had experienced an acute stressor in their lifetime, either maternal separation in infancy, or witnessing another rat receive the shocks. A history of stress was required for the anti-inflammatories to improve motivation.
Lukkes and colleagues hope that this research begins to clarify the relationship between stress, inflammation, and gender. This may eventually lead to new targets in the treatment of depression.
While it can sometimes take weeks for the effects of antidepressant treatments to appear, intravenous ketamine can produce antidepressant effects in as little as two hours. However, ketamine’s effects fade after three to five days. New animal research by Chi-Tso Chiu et al. explores whether adding lithium to ketamine treatment can produce more sustained antidepressant effects.
Mice who are restrained by being placed in a tube for several hours (chronic restraint stress) exhibit a behavioral and neurochemical profile that resembles human depression. When Chiu and colleagues pretreated these stressed mice with sub-therapeutic doses of lithium (600 mg/L) in their drinking water for several weeks, a sub-therapeutic dose of ketamine (2.5 mg/kg of body weight) was enough to produce robust antidepressant effects in the mice, while neither drug alone was effective at these doses.
The combination of ketamine and lithium also restored the density of spines on the dendrites of neurons in the medial prefrontal cortex. Post-treatment with lithium (1200 mg/L) for several weeks was also successful in extending the effects of a single (50 mg/kg) ketamine injection.
Both lithium and ketamine affect the intracellular signaling pathway mTOR. Ketamine activates the pathway, increasing levels of synaptic proteins and dendritic spine density. It also increases brain-derived neurotrophic factor (BDNF) and the BDNF receptor TrkB. BDNF is important for learning and memory.
When lithium was added to the treatment of the mice with ketamine, the mTOR and BNDF pathways were further activated. Lithium also inhibits the receptor GSK-3, supporting ketamine’s rapid-acting antidepressant effects.
Ketamine treatment can produce oxidative stress, in which toxic free radicals can endanger cells, and the addition of low doses of lithium also completely prevented this neurochemical side effect.
Chiu and colleagues hope that the findings of this study in mice can eventually be applied to research in humans in the hopes of finding a clinical option that would sustain the rapid-onset antidepressant effects of ketamine for the long term.
At a recent scientific meeting, researcher John Geddes and colleagues reported that compared to adding placebo to the treatment of bipolar depressed patients already receiving the atypical antipsychotic quetiapine, adding the mood stabilizing drug lamotrigine led to significant improvements in their illness. Lamotrigine was slowly titrated to doses of 200mg/day. (Slowly increasing dosage is important because a serious rash is a possible side effect of lamotrigine, occuring in about one in 5,000 individuals exposed.)
Researcher Charles Bowden found in 2000 that adding lamotrigine to valproate improved its effectiveness, as Marc van der Loos found in 2008 with lamotrigine and lithium. Thus it appears that adding lamotrigine to a mood stabilizer or to an atypical antipsychotic like quetiapine is a good second-line option in the treatment of bipolar depression. While lamotrigine is not FDA-approved for the acute treatment of depression, this approach is worthy of consideration, and could be of immediate clinical use. It provides an alternative to adding a unimodal antidepressant, which recent meta-analyses have indicated is not effective and which can increase switches into mania, cycle acceleration, or even treatment resistance in patients with bipolar disorder.
At the 2014 meeting of the American Academy of Child and Adolescent Psychiatry, researcher Robert Findling reported on a double blind, placebo controlled 36-week study of lamotrigine for children and adolescents with bipolar I disorder. The doses designed for maintenance treatment averaged about 225 mg/day, achieved by very slow increases over time in order to reduce the risk of a serious rash.
Findling found that lamotrigine was more effective than placebo in extending the time until a patient required an intervention for a new mood episode among the older children in the study (aged 13 to 17). Among the younger children in the study (aged 10 to 12), lamotrigine’s effects were not statistically significant compared to placebo. Findling and colleagues concluded that lamotrigine appeared effective in delaying time to onset of a new episode in adolescents with bipolar I disorder.
Lamotrigine is approved by the Federal Drug Administration (FDA) for bipolar disorder in adults only.
At the 2014 meeting of the American Academy of Child and Adolescent Psychiatry, researcher Adelaine Robb reported that in 81 children with mania (aged 7-17), lithium was superior to placebo in reducing the severity of mania measured on the Young Mania Rating Scale. There had been some debate about the efficacy of lithium in young children with mania, but this study clearly indicates lithium’s effectiveness. The drug is approved by the Federal Drug Administration (FDA) for use in patients with bipolar disorder aged 12 and up.
Another researcher, Vivian Kafrantaris, found that in children who averaged 14.5 years of age, lithium increased the volume of the corpus callosum, a bundle of neural fibers that connects the brain’s right and left hemispheres. Lithium also normalized white matter integrity in other neural fiber tracts—the cingulum bundle and the superior longitudinal fasciculus. The authors concluded that lithium may “facilitate microstructural remodeling of white matter tracts involved in emotional regulation.”
Editor’s Note: There is much research showing that in adults, lithium has positive effects on the brain, including increases in hippocampal and cortical grey matter volume. Now it appears that lithium can improve white matter integrity in the developing brain as well.
Researcher Charles Popper gave a talk at the 2014 meeting of the American Academy of Child and Adolescent Psychiatry on the benefits of nutritional supplements designed to provide multiple vitamins and minerals to children with bipolar disorder and other dyscontrol syndromes, such as attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder. Popper reviewed the literature on the substantial incidence of vitamin and mineral deficiencies among these children.
A modicum of data support the effectiveness of supplements for children with these disorders. One of these supplements is called EMPowerPlus and is sold online. It is moderately expensive and must be given under the supervision of a knowledgeable treating physician. While it is relatively safe in medication-free children, Popper says it can exacerbate withdrawal reactions from some psychotropic medications.
In addition, EMPowerPlus greatly increases lithium-related side effects, in patients taking lithium, the dose must be reduced to about one-tenth of a normal dose for those who are adding EMPowerPlus.
Popper and another researcher, Mary Fristad, have both seen excellent responses to this type of supplementation in children with bipolar disorder who have been unresponsive to more traditional drugs.
In another study by Rita Aouad et al., 72.3% of 980 children with a variety of psychiatric diagnoses had insufficient vitamin D levels (values < 30 nanograms/ml) and 26.7% had vitamin D deficiency (values < 20 nanograms/ml). These data support the rationale for vitamin D supplementation, especially in those who have low levels to start with.