Inflammation has been linked to both unipolar and bipolar depression. New research shows that anti-inflammatory treatments may reduce bipolar depression, for which few treatments exist.
Researchers led by Jonathan Savitz divided people with bipolar depression into four groups. One group received two placebos, another received minocycline (a drug with neuroprotective and immune-modulating properties) plus a placebo, the third received aspirin plus a placebo, and the final group received both minocycline and aspirin. Of the 64 participants, those who took both minocycline and aspirin were most likely to respond to treatment and to enter remission. In people with body mass indexes (BMIs) above the median of 30, a sign of greater inflammation, 100% of those who received both anti-inflammatory drugs responded to treatment, compared to 36% of those who received aspirin alone, 33% of those who received minocycline alone, and 25% of those who received two placebos.
Dosages of the drugs were 100mg twice a day for minocycline and 81mg twice a day for aspirin. Savitz and colleagues believe that aspirin and minocycline must work particularly well together, and are modifying their study to more directly compare use of the two anti-inflammatory drugs together to the absence of anti-inflammatory treatments.
Studies have found that inflammatory molecules play a role in depression. A recent study by researcher Yu Sun and colleagues used data from clinical trials of anti-inflammatory drugs to show that these drugs also reduced depressive symptoms. The two drugs, which are administered either by a shot or injection into the skin, each consist of antibodies that target the inflammatory molecule IL-6. Sirukumab is being looked at as a possible treatment for rheumatoid arthritis, while siltuximab is a potential treatment for Castleman’s disease, an illness characterized by enlarged lymph nodes. As part of the clinical trials for these drugs, patients with these illnesses responded to survey questions that assessed symptoms of depression and fatigue.
Among patients who reported that they have at least one depressive symptom most of the time and another symptom at least part of the time, the anti-inflammatory drugs significantly improved depressive symptoms compared to placebo. Even when the patients’ inflammatory illnesses did not respond to the anti-inflammatory treatments, their depressive symptoms did improve (symptoms of fatigue did not). An improvement in depressive symptoms was observed after 6 weeks in patients with Castleman’s disease taking siltuximab, and after 12 weeks in patients with rheumatoid arthritis taking sirukumab.
In the sirukumab study, the level of the inflammatory molecule IL-6 in participants’ blood before the study was linked to the magnitude of improvement in their depressive symptoms during the study. IL-6 is elevated in many patients with unipolar and bipolar depression. It is possible that antibodies that target IL-6 could be used to treat primary depression (in the absence of other inflammatory disorders).
Many psychiatric illnesses, including bipolar disorder, schizophrenia, autism, attention deficit hyperactivity disorder (ADHD), and anxiety disorders may stem from abnormalities in brain development that begin before birth. Researchers are trying to determine whether dietary supplements taken by pregnant mothers or infants can reduce the risk of such illnesses. At a recent scientific meeting, researcher Randal Ross and colleagues reported that compared to placebo, choline supplements reduced problems with a brain process called sensory gating in one-month-old infants and also improved the children’s attention span and social skills at age 3.
Sensory gating is the process by which the brain filters out unimportant information, to avoid flooding higher cortical centers with irrelevant stimuli. Deficits in the way the brain inhibits response to this type of irrelevant information are associated with mental illnesses such as schizophrenia.
In Ross’s study, healthy pregnant mothers received either a placebo or 6300 mg of choline, a nutrient found in liver, egg yolks, and meat. After delivery, the infants also received 700 mg of supplemental choline per day. In children who carried CHRNA7, a risk gene for schizophrenia discovered by Ross’s colleague Robert Freedman, choline reversed the associated risk of sensory gating problems and normalized their behavior at age 3.
Stress increases the risk of psychiatric illnesses such as major depression and post-traumatic stress disorder. Not everyone who experiences stress goes on to develop these illnesses, though. Researchers are currently trying to find out why, exploring treatments that might increase resilience and prevent mental illnesses.
Animal research is often used to study depression. Mice exposed to certain stressors behave in ways that resemble human depression—like giving up faster when they’re forced to tread water, or withdrawing from activities they once enjoyed, like eating sucrose. In a recent study by researcher Christine Denny and colleagues, mice were injected with either saline or ketamine, a rapid-acting antidepressant, and one week later they were exposed to triggers that typically produce a depressive response. Mice who received the saline injection still got depressed when, for example, they were repeatedly forced to confront a dominant mouse. But mice who received ketamine injections did better, maintaining their motivation and not showing signs of depressive behavior following the stress. The researchers concluded that ketamine may have a protective effect against stress.
Editor’s Note: These results are remarkable because ketamine’s effects are typically short-lived.
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.
There is currently no Food and Drug Administration–approved treatment for cocaine addiction. One reason may be that in studies of treatments for cocaine use, participants may have a wide variety of exposure to cocaine. Some may be regularly using cocaine, while others may have gone some time without using the drug. A recent study by Margaret Haney and colleagues addressed some of these challenges by comparing the addiction treatment modafinil to placebo in different scenarios—such as when cocaine users have access to cheap cocaine versus expensive cocaine—and determining under which circumstances modafinil reduces the use of smoked cocaine.
In the study, presented at a scientific meeting in 2015, Haney and colleagues reported that among people who were not currently smoking cocaine, modafinil reduced cocaine use compared to placebo, but modafinil did not reduce cocaine use among people who had recently smoked cocaine. Modafinil also reduced cocaine use when the drug was expensive, but not when participants had access to cheap $5 cocaine. According to the researchers, these findings suggest that modafinil may be more useful at preventing relapse than at helping current users of cocaine achieve abstinence.
Editor’s Note: While they are not FDA-approved, two other treatments can reduce cocaine use, according to placebo-controlled studies: the antioxidant N-acetylcysteine (NAC) and the anticonvulsant topiramate.
The antioxidant N-acetylcysteine (NAC) has been found to reduce many types of habitual behavior, from gambling to drug use to compulsive hair-pulling. A recent study by researcher Gihyun Yoon and colleagues, which was presented at a 2015 scientific meeting, found that while NAC and placebo reduced days of heavy drinking by about the same rates, NAC significantly reduced alcohol cravings and quality of life compared to placebo among participants with alcohol dependence.
In the 8-week study, 44 participants aged 18–65 received either 3600mg/day of NAC or a placebo. This dose of NAC was higher than the 600mg–2400mg doses that have typically been used in research settings, and there were few side effects, confirming that NAC is a safe treatment.
The authors are not sure how NAC produces this effect, but it may be by regulating the neurotransmitter glutamate.
Glia are brain cells that surround neurons and synapses, protecting and insulating them. Chronic cocaine use and withdrawal changes the way certain glial cells, called astrocytes, interact with neurons. In particular, chronic cocaine use and withdrawal can shrink astrocytes and cause them to pull away from neurons. Cocaine use and withdrawal also interfere with the way the neurotransmitter glutamate is cleared from synapses and transported into astrocytes.
New research shows that certain medications that regulate and increase the movement of glutamate from the synapse into glial cells can reduce cravings for cocaine.
In studies of rats chronically exposed to cocaine and then denied access to it, treatment with these glutamate-targeting medications reduces the rats’ cocaine-seeking behaviors. The medications include N-acetylcysteine (NAC), an antioxidant that can reduce habitual behaviors, including addictive behaviors; riluzole, a treatment for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease; the antibiotic ceftriaxone; and propentofylline, which has been explored as a possible treatment for dementia and stroke.
The antioxidant N-acetylcysteine (NAC) has been found to be an effective treatment for a variety of habit-based behaviors—substance abuse, including cocaine, alcohol, marijuana, and nicotine; gambling; obsessive-compulsive behaviors; trichotillomania (compulsive hair-pulling), and repetitive behaviors among people with autism. Recent research by researcher Jon Grant and colleagues revealed that NAC can also treat skin-picking disorder.
At a 2015 scientific meeting, Grant reported that 1200–3000mg of NAC per day led to improvement in 47.1% of patients with a skin-picking disorder, compared to 19.2% improvement in patients who received placebo.
In addition to its positive effects in people with addictions and habit-based behaviors, NAC has also improved mood and anxiety in bipolar disorder and treated negative symptoms of schizophrenia, such as withdrawal and lack of motivation.
Editor’s Note: Given NAC’s effectiveness in such a wide range of disorders and behaviors, it could be a particularly useful treatment for people with major psychiatric disorders, such as bipolar disorder or schizophrenia, with co-occurring substance abuse.
Post-partum depression affects 13% of new mothers, but little is known about how to prevent it. Doctors are researching ways of reducing post-partum blues, which can occur 4–6 days after delivery, when levels of the enzyme monoamine oxidase-A are high. At a 2015 scientific meeting, researchers led by Yekta Dowlati of the Centre for Addiction and Mental Health at the University of Toronto reported that a nutritional supplement designed to counteract the high levels of monoamine oxidase-A improved depression among 17 healthy women who had recently given birth, compared to 16 new mothers who did not receive the supplement. The supplement contained 2g of tryptophan and 10g of tyrosine, both amino acids found in protein-rich foods, plus blueberry juice and a blueberry extract.