Cannabidiol Drug Approved For Rare and Severe Types of Epilepsy
In June, the US Food and Drug Administration (FDA) for the first time approved a drug derived completely from the cannabis plant. The drug, Epidiolex, a syrup, contains cannabidiol, the cannabis component that has been found to treat certain ailments. In a news release, the FDA stated that cannabidiol does not cause intoxication or a ‘high’. Tetrahydrocannabinol, or THC, is the cannabis component that makes people high, impairs cognition, and can induce paranoia.
The approval led, in September, to the Drug Enforcement Agency re-classifying FDA-approved drugs containing cannabidiol derived from cannabis and less than 0.1% THC as schedule V controlled substances. So far only Epidiolex meets these criteria. Cannabis had previously been classified as a schedule I controlled substance, in the same legal category as heroin, LSD, or ecstasy.
Epidiolex is now approved to treat two rare, severe types of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, in patients aged two years and older. It is the first FDA-approved treatment for Dravet syndrome, a genetic condition that appears in the first year of life when babies develop fever-related seizures. Other types of seizures, even including a continuous seizure state, can occur later.
Lennox-Gastaut syndrome also develops in young children, usually between the ages of three and five. They have multiple types of seizures with debilitating consequences.
In three randomized, double-blind, placebo-controlled clinical trials that included a total of 516 patients with either Lennox-Gastaut syndrome or Dravet syndrome, the drug reduced the frequency of patients’ seizures compared to placebo.
Side effects of Epidiolex include sleepiness, sedation and lethargy; elevated liver enzymes; decreased appetite; diarrhea; rash; fatigue, malaise and weakness; insomnia, sleep disorder and poor quality sleep; and infections. The FDA also warned in its approval that “[a]s is true for all drugs that treat epilepsy, the most serious risks include thoughts about suicide, attempts to commit suicide, feelings of agitation, new or worsening depression, aggression and panic attacks.” The drug is produced by GW Pharmaceuticals, which has already gained approval outside the US for a cannabis-based drug to treat multiple sclerosis.
Editor’s Note: It is important for readers to know that most marijuana available in the US contains mostly THC with minimal cannabidiol.
Early Intervention Works in Schizophrenia: Also Needed in Bipolar Disorder
For twenty years, evidence has shown that early intervention can ameliorate many of the adverse consequences of schizophrenia. In a 2018 article in the journal Annual Review of Clinical Psychiatry titled “Transforming the treatment of schizophrenia in the United States: The RAISE Initiative,” Lisa B. Dixon and colleagues described the importance of early intervention in schizophrenia. RAISE stands for Recovery After an Initial Schizophrenia Episode. Dixon and colleagues emphasize that shortening the time that a patient’s psychosis goes untreated, which averages 74 months, is critical to achieving good outcomes. In parallel to these consistent findings, researchers of bipolar disorder (including this editor Robert M. Post and colleagues) have found that an increased length of the interval before treatment is initiated in childhood-onset bipolar disorder is associated with a poor outcome in adulthood.
The RAISE program consists of four interventions: personalized psychopharmacology using a computerized decision support system, individual resilience therapy, family psychoeducation and therapy, and supportive employment and education. Compared with patients receiving standard treatments, patients who participated in the RAISE program showed greater improvements on almost all measures, including the Heinrichs-Carpenter Quality of Life Scale (main outcome), the Calgary Depression Scale for Schizophrenia, the Positive and Negative Syndrome Scale, treatment duration, and engagement in work and school. Moreover, the improvements were more substantial among patients with a shorter duration of untreated psychosis.
Editor’s Note: These findings are of great importance in their own right, but they also have great implications for treatment and research efforts in bipolar disorder. A 2013 randomized study by Lars Kessing and colleagues published in the British Journal of Psychiatry found that in bipolar patients hospitalized for a first or second episode of mania, two years of comprehensive treatment with psychotherapy, pharmacotherapy, and illness education that included mood monitoring and early symptom recognition was vastly superior to typical treatment, and this held true even six years later. In a 2014 article in the Journal of Clinical Psychiatry and a 2016 article in the journal Bipolar Disorders, researcher Jan Marie Kozicky and colleagues reported that in patients hospitalized with a first episode of mania, cognitive functioning and brain imaging abnormalities, respectively, returned to normal over the next year only if the patients experienced no further mood episodes. The message is clear: we must treat the first episode of mania comprehensively to avoid long-term deterioration, which occurs as a function of the number of episodes of mania or depression a patient experiences. However, this early multimodal approach is rarely taken in the US.
In schizophrenia, Dixon and colleagues noted that: “After the RAISE study reports were made available, Congress allocated additional funding to the community mental health …program, leading to growth in the number of…programs across the United States; they were expected to reach 48 states in 2018.”
The contrast between these efforts in schizophrenia and their virtual absence in bipolar disorder is incomprehensible and tragic. Studies in early schizophrenia have been funded for 25 years, while almost none have been funded in bipolar disorder, even in recent years. Community mental health programs for early schizophrenia will soon exist in 48 states; for patients with bipolar disorder there are no programs available in any state that I am aware of. The incidence of bipolar is about three times that of schizophrenia, and the long-term outcomes are often as devastating in bipolar disorder as in schizophrenia. There is a high incidence of drug abuse; social, educational and occupational deficits; and suicide in bipolar disorder. Early intervention with the many safe supplements, nutraceuticals, and well-tolerated drugs that are currently available to adult patients should be studied in young people with bipolar disorder, but such studies neither being funded nor conducted.
The reality is that childhood-onset bipolar disorder is poorly recognized and treated in the US, largely because of a paucity of treatment-related studies and knowledge about the best options for these young patients. If a reader of the BNN knows how to influence advocacy groups, leaders in the Substance Abuse Mental Health Services Administration (SAMHSA) and the National Institutes of Mental Health (NIMH), or influential politicians, it would be useful to take the initiative in bringing some of these deficits and disparities to their attention. Something must be done; ideas about how to do it are welcome. My own efforts to get funding for a childhood-onset bipolar research network in collaboration with such luminaries in the field as David Miklowitz (UCLA), Kiki D. Chang (Stanford University), Boris Birmaher (University of Pittsburg), Benjamin Goldstein (Stonybrook Research Institute), Eric Youngstrom (UNC, Chapel Hill), Soledad Romero (Hospital Clinic of Barcelona), and Josefina Castro Fornieles (University of Barcelona) have not been successful. We will keep trying, but the field needs to reach beyond the many investigators who are advocating for more treatment research to other people with more influence.
Curcumin Improves Memory and Depression
Recent studies suggest that curcumin, the micronutrient in turmeric that gives Indian curry its bright color, may reduce depression and improve memory.
A 2018 study published in the American Journal of Geriatric Psychiatry by Gary Small, director of geriatric psychiatry at UCLA’s Longevity Center, and colleagues found that a curcumin supplement improved mild, age-related memory loss in people without dementia.
Forty adults between the ages of 50 and 90 received either placebo or 90 mg of Theracumin, a bioavailable form of curcumin, twice daily for 18 months. The participants took cognitive tests at the beginning of the study and every 6 months during the study. Thirty of the participants also received positron emission tomography (PET) scans upon beginning and ending the study to evaluate the appearance of plaques and tangles in their brains.
Participants who received curcumin saw improvements in verbal and visual memory and attention over the course of the study compared to those who received placebo. The curcumin participants also saw mild improvements in mood, and less accumulation of amyloid plaques and tau tangles in the amygdala and hypothalamus, brain areas that play a role in memory and emotion. A few participants had mild gastrointestinal effects after taking Theracumin.
In India, where diets are high in curcumin, there is a lower incidence of Alzheimer’s than in the west, and older people also have better cognitive performance than in the west.
Curcumin has anti-inflammatory, antioxidant, and neuroprotective properties. Researchers speculate that curcumin may reduce brain inflammation, which has been implicated in both depression and Alzheimer’s disease.
A 2017 meta-analysis by Qin Xiang Ng and colleagues of 6 studies of curcumin including a total of 377 patients found that the substance has significant antidepressant effects compared to placebo. Half of the studies also reported improvements in anxiety. No adverse events were reported. Ng’s meta-analysis was published in the Journal of the American Medical Directors Association.
