Many patients with bipolar disorder experience cognitive deficits that impede their recovery and that persist during times of wellness. In a double-blind placebo-controlled study by K. N. Roy Chengappa et al. published in the Journal of Clinical Psychiatry in 2013, the herb Withania somnifera (WSE, commonly called ashwagandha and sold under the name Sensoril) was significantly better than placebo at improving patients’ performance on three different cognitive tasks.
In the eight-week study, 53 patients took either 500 mg of WSE or placebo in addition to their regular medications.
The herb, which has traditionally been used in Ayurvedic medicine in India as an aid to resisting stress and disease, improved performance on digit span backwards (a test of short-term memory in which the subject must repeat a sequence of numbers backwards), Flanker neutral (a test of response time in which a subject must repress their instinct to give an incorrect response), and the Penn Emotional Acuity Test (which requires subjects to correctly identify facial emotions depicted in photographs).
Mood and anxiety levels were not different for the group taking WSE and the group taking placebo.
The researchers hope to continue their investigation of WSE with larger and longer-term studies that will explore the effects of different doses of WSE.
The combination of antidepressant bupropion (Wellbutrin) and naltrexone (Revia), a drug that helps alcoholics resist the craving for alcohol, can help patients keep their weight down. Last year we summarized an article by Smith et al. in the journal Diabetes, Obesity, and Metabolism that showed that obese patients with diabetes treated with the combination of bupropion and naltrexone had excellent weight loss and reduction in body fat compared to those treated with either drug alone or with placebo.
A more recent study by G. J. Wang et al. published in the International Journal of Obesity in 2013 shows that the combination of 360mg of bupropion sustained release and 32mg of naltrexone sustained release works by reducing patients’ response to food cues. Forty women were shown a video of their favorite food being prepared, which stimulated parts of the brain associated with visual stimuli and other functions. Those who received the combination of naltrexone and bupropion had lessened hypothalamic response to the videos compared to those who received placebo, and also showed activity in parts of the brain associated with inhibitory control (the anterior cingulate), internal awareness (the superior frontal cortex, the insula, and the superior parietal cortex), and memory (the hippocampus).
Editor’s Note: It looks like the drug combination prompts the brain to say, “Wow, that looks good, but maybe I shouldn’t take in any more calories today.”
An oral preparation of lavender oil called Silexan decreased anxiety significantly more than placebo in a study by S. Kasper et al. published in the International Journal of Neuropsychopharmacology in 2014.
This randomized double-blind study of 539 patients with Generalized Anxiety Disorder compared two different doses of Silexan (160 mg and 80 mg) with a 20 mg dose of the antidepressant paroxetine and placebo. Both doses of Silexan reduced anxiety significantly more than placebo did. While paroxetine performed better than placebo, that result did not reach statistical significance.
Sixty percent of the patients who received the 160 mg dose of Silexan showed reductions of 50% in scores on the Hamilton Anxiety Scale (HAMA). In addition to its anti-anxiety effects, Silexan was associated with an antidepressant effect, improved general mental health, and improvement in health-related quality of life.
Combination of N-acetylcysteine and Risperidone Improves Irritability in Autistic Disorders More Than Placebo and Risperidone
In a 2013 study of 40 children and adolescents with autism spectrum disorders published by Ahmad Ghanizadeh and Ebrahim Moghimi-Sarani in the journal BMC Psychiatry, the combination of the over-the-counter nutritional supplement n-acetylcysteine (NAC) and the atypical antipsychotic risperidone alleviated irritability more than the combination of placebo and risperidone. Side effects were mild. The data extend 2012 observations by A.Y. Hardan et al. in which NAC improved irritability and stereotypy (repeated behavior) in autism more than placebo did.
The two studies taken together support the effectiveness of NAC prescribed either alone or in conjunction with an atypical antipsychotic for the treatment of autism.
In a six-week study published by S.S. Qu et al. in the Journal of Psychiatric Research in 2013, participants with depression who received manual or electrical acupuncture along with the selective serotonin reuptake inhibitor (SSRI) antidepressant paroxetine (Paxil) improved more than those participants taking paroxetine alone.
More patients taking paroxetine alone needed increased doses to deal with symptom aggravation.
Patients who had received electrical acupuncture continued to show improvement four weeks after the treatment ended.
Intravenous scopolamine has shown promise as a rapid-acting antidepressant in studies by Carlos Zarate and colleagues at the National Institute of Mental Health (NIMH). Improvement on the drug can occur within 24 hours.
In a 6-week 2012 study, an oral preparation of scopolamine was more effective than placebo as an add-on medication to the selective serotonin reuptake intake (SSRI) antidepressant citalopram. Patients who received scopolamine and citalopram had higher rates of response and remission than those who received placebo and citalopram. The scopolamine group experienced more blurred vision and dizziness, which is to be expected from an anticholinergic drug, a drug that blocks the action of the neurotransmitter acetylcholine in the brain.
EMPowerPlus is a nutritional supplement marketed by the company Truehope as a way of correcting nutritional deficiencies that contribute to depression, anxiety, bipolar disorder, and attention-deficit hyperactivity disorder (ADHD). In 2014 Rucklidge et al. published the first controlled study of EMPowerPlus in the British Journal of Psychiatry showing that the supplement was more effective than placebo in adults with untreated ADHD.
EMPowerplus contains 36 ingredients, including 14 vitamins, 16 minerals, 3 amino acids, and 3 antioxidants. Patients were randomized to receive either 15 EMPowerPlus pills per day or 15 placebos per day for 8 weeks, and those patients receiving the supplement were rated as more improved by the end of the study. Effect sizes were moderately robust and side effects did not differ.
Editor’s Note: Multiple uncontrolled studies have suggested the efficacy of EMPowerPlus in childhood mania and related conditions, but this is the first formal placebo-controlled study of the supplement in adults with ADHD. A study in children with ADHD is planned, but it would also be important to study this micronutrient formulation in childhood bipolar disorder, where there is some anecdotal evidence (from Charles Popper at McLean Hospital in Boston and Mary Fristad at the Ohio State University) of excellent responses in children with highly treatment-resistant bipolar illness.
At the US Psychiatric Congress in 2013, researcher T. Ketter reported on two recent studies of armodafinal (Neuvigil), which is approved for the treatment of narcolepsy. Doses of 150mg/day did not perform significantly better than placebo in the treatment of bipolar depression (in contrast to an earlier positive study).
Editor’s Note: It appears that this drug will not play a major role in the treatment of bipolar depression, as some had hoped.
In a 2014 study published by Michael A. Yassa et al. in the journal Nature Neuroscience, a 200mg caffeine pill (about the equivalent of a strong cup of coffee) improved long-term recognition memory. One hundred sixty participants who were not regular coffee drinkers were shown a series of 200 pictures, and 24 hours later they were given a surprise test. Compared to participants who received a placebo, those participants who received 200mg of caffeine were better able to discriminate which pictures they had seen before and which ones were new. Participants who received 100mg of caffeine did not show this effect, while those who received 300mg showed the same improvement in memory but also experienced side effects such as headache and nausea.
As long as a cup of coffee does not make its drinker more anxious, it may help boost memory.
Editor’s Note: Coffee may have other benefits. In research collected by the Bipolar Collaborative Network (in which this editor is an investigator), patients who drank coffee were less likely to be overweight. Yassa also believes based on other research that caffeine is associated with a reduced risk for Alzheimer’s disease and that it increases longevity.
Unwanted recall and re-experiencing of traumatic memories is thought to be a crucial mechanism leading to the onset of post-traumatic stress disorder (PTSD). The inability to diminish (extinguish) those memories contributes to the persistence of PTSD. A new study suggests that the extinction of fear memories can be enhanced by a drug that acts epigenetically to alter the structure of DNA and subsequent gene expression.
DNA is wound around structures called histones, and chemical changes can affect how loosely or tightly the DNA is wound. Johannes Graff et al. reported in the journal Cell in 2014 that application of a histone deacetylase (HDAC) inhibitor, which keeps acetyl groups on histones, ensuring that DNA is wrapped more loosely and is easier to activate (or transcribe), helps rodents revise both new and old fear memories after they have been actively recalled.
When a memory is actively recalled, the trace of that memory in the brain becomes more amenable to revision over the proceeding five minutes to one hour (a period known as the reconsolidation window). New learning and extinction training (to get rid of the memory) lasts much longer when it takes place during the reconsolidation window than when the same procedures are performed 6 hours later (after the reconsolidation window has closed) or if the procedures are performed in the absence of active recall of the memory (when the reconsolidation window is never opened).
We have previously described the 2013 work of Xue et al. published in the journal Science, which showed that this specific procedure could yield long-lasting extinction of a patient’s craving for cocaine or heroin, and could reduce amygdala activation (as observed via functional magnetic resonance imaging) in response to an experiment that produces conditioned fear (Agren et al. Science, 2013).
Editor’s Note: This new work by Graff et al. adds another twist. Older long-term memories are more stable and less amenable to new learning than more recent (but still long-term) memories. The application of an HDAC inhibitor changes this and makes even very old memories amenable to lasting revision. The HDAC inhibitor that Graff et al. used was a specific inhibitor for HDAC type II. However, the anticonvulsant valproate (Depakote) is a potent although nonspecific HDAC inhibitor, and presumably could have the same facilitating effect as the more selective drug.
EMDR (Eye Movement Desensitization and Reprocessing), which has been widely used for the treatment of PTSD, includes active memory recall, immediately followed by an attempt to re-interpret and construct new memories of the trauma. These elements could open the reconsolidation window. However, EMDR works less well with older memories compared to more recent traumatic memories.
The Graff et al. data would suggest that adding an HDAC inhibitor such as valproate to EMDR-like work might make it more effective in revising more remote memories. Graff et al. encourage controlled clinical trials with a type II inhibitor to confirm that their findings in rodents would generalize to humans. While awaiting such validation through controlled clinical trials, it would not be surprising if clinicians started trying out the paradigm on their own using valproate.