Danish researcher Lars Kessing recently performed the first randomized controlled study of the efficacy of early intervention in bipolar disorder.
Patients who had been hospitalized for a first episode of mania were randomly assigned to two years of treatment in a specialized clinic versus two years with treatment as usual in the community (the control condition). The researchers predicted that then specialized clinic would decrease subsequent hospitalizations, and increase adherence to medication and patient satisfaction compared to treatment as usual over the subsequent six years.
Treatment at the special clinic began with a phase of post-hospitalization settling in, followed by psychoeducation (15 weeks of 1 session/week). Emphasis was placed on the recognition of breakthrough symptoms—early warning signals of an impending mood episode.
All three outcomes were better in the group who were treated at the specialized clinic than in control group who received treatment as usual. Hospitalizations were reduced 40%, medication compliance was enhanced, and patients were more satisfied. Patients younger than age 36 showed greater improvement and greater differences from the control group than were seen among older patients.
One striking observation was that the difference observed after patients had spent two years in the specialized clinic compared to the control group persisted and grew over the following four years, even though these patients left the specialized clinic after the first two years.
The specialized clinic was not only successful, but was also cost-effective. Clinic patient care led to a savings of €3,194 per patient. The costs for clinic patients were 11% of those for control patients.
Editor’s Note: We already know that treatment delay is related to poor outcome. (See article by this editor Robert Post et al. in the Journal of Clinical Psychiatry in 2010.) This study is groundbreaking in demonstrating that the quality of care in a specialized clinic has enormous personal, societal, and financial benefits, and can render the course of illness more benign over a sustained period of at least 6 years.
This means that a revolution in the care and treatment of patients with bipolar disorder is needed throughout the world, but especially in the US, where the typical treatment paradigm is as bad or worse than the treatment as usual condition in Kessing’s Danish study. When patients are discharged from the hospital, they are immediately at increased risk for relapses and, most alarmingly, at 200-fold increased risk of suicide. This post-hospitalization gap in treatment between episodes needs to be better managed. Transitional care is rarely handled well, psychoeducation is rarely given for a sufficient duration, therapy is often unavailable, and medication non-compliance is high. These factors lead to increased illness, re-hospitalizations, and skyrocketing personal and societal costs. Moreover, only 20% of bipolar patients identified in epidemiological studies in the US are in any kind of treatment.
Treatment guidelines must be changed to better address these issues. A first episode of mania should trigger a cascade of sequential treatments: Read more
Methylene blue is a chemical compound that has been used to treat a variety of medical conditions. This drug has some actions that resemble lithium’s: it inhibits guanylate cyclase, which generates second messenger cyclic GMP, and decreases nitric oxide. New evidence shows it may help depression and anxiety in bipolar disorder when added to lamotrigine.
In patients with bipolar disorder who were all treated with lamotrigine, an active 65mg dose of methylene blue three times per day (for a daily total of 195mg) versus 15mg/day (an inactive dose that produces the same side effect of blue urine) was more effective at treating depression and anxiety in a 12-week crossover study. Side effects, in addition to blue urine, included infrequent nausea, diarrhea, headache, and a burning sensation in the urinary tract. Of the 37 randomized study participants, 27 completed both phases of the entire six-month study. Martin Alda, a researcher who presented the double-blind randomized crossover data at the 2014 meeting of the International Society for Bipolar Disorders, indicated that he has also used this preparation clinically with success, although the pharmacy staff who prepared the capsules were not too happy, because everything the drug touches turns blue.
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 with 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.