Cannabinoid Gel Treats Fragile X Syndrome

April 23, 2018 · Posted in Potential Treatments · Comment 
cannabidiol gel

Zynerba’s website depicts the gel

Fragile X syndrome is a genetic disorder characterized by developmental problems such as intellectual disabilities, cognitive impairment, and behavioral and learning challenges. Zynerba Pharmaceuticals announced in 2017 that a cannabinoid gel they have produced improved symptoms of fragile x syndrome in children and adolescents when applied daily to the upper arm.

Multiple cannabinoids are derived from cannabis plants, and include cannabidiol, which likely conveys some of the plant’s positive effects, and tetrahydrocannabinol (THC), which lends marijuana its psychoactive or psychomimetic effects, such as delusion or delirium. Cannabidiol is the active ingredient in the gel, and no THC was found in participants’ blood tests after using the gel.

The open study of 20 patients aged 6 to 17 years found that the participants showed improvement on a scale measuring anxiety, depression, and mood after 12 weeks of using the gel. The gel also appeared to improve aberrant behaviors including social avoidance, temper tantrums, repetitive movements, and hyperactivity. Treatment began at a dose of 50mg per day, and could be increased up to 250 mg per day within the first six weeks of the study. The dose then remained stable for the next six weeks.

Zynerba Pharmaceuticals hope to begin controlled clinical trials in 2018, with the goal of attaining approval for the drug from the US Food and Drug Administration. Other companies are also competing to garner the first FDA approval of a cannabis-based drug. Many of the drugs currently in development are intended to target neurological or behavioral conditions.

Clinical Vignettes from Dr. Elizabeth Stuller

April 11, 2018 · Posted in Potential Treatments · Comment 

Dr. Elizabeth Stuller, a staff psychiatrist at the Amen clinics in Washington, DC and CEO of private practice Stuller Resettings in Baltimore, MD, provided this editor (Robert M. Post) with several interesting anecdotal observations based on her wide clinical experience with difficult-to-treat mood disordered patients.

  1. Stuller has used low-dose asenapine (Saphris), e.g. half a pill placed under the tongue, for depressed patients with alcohol use problems who have trouble getting to sleep. She has also used asenapine for rapid calming of agitated patients in her office.
  2. Stuller has also had success with the use of the atypical antipsychotic drug brexpiprazole (Rexulti) for patients with bipolar depression and low energy. She typically uses 0.5 mg/day for women and 1 mg/day for men. Stuller finds that there is little weight gain or akathisia with brexpiprazole.
  3. She has had success with the drug Nuedexta, which is a combination of dextromethorphan and quinidine and is approved for the treatment of sudden uncontrollable bouts of laughing or crying, known as pseudobulbar affect, which can occur as a result of neurological conditions or brain injuries. It is a combination of an NMDA antagonist and a sigma receptor agonist. Stuller starts with the 20mg dextromethorphan/10 mg quinidine dose once a day and increases to twice a day in week two. She finds it useful for behavioral effects of traumatic brain injury (TBI), anxiety resulting from the use of synthetic marijuana (sometimes called spice), and psychosis not otherwise specified. Stuller also finds that some patients appear to respond well to Nuedextra but not minocycline, or vice versa.

Editor’s Note: Note that these are preliminary clinical anecdotes conveyed in a personal communication, and have not been studied in clinical trials, thus should not be relied upon in the making of medical decisions. All decisions about treatment are the responsibility of a treating physician.

Nutritional Supplement ALC Improves Depression

March 26, 2018 · Posted in Potential Treatments · Comment 

vitaminA meta-analysis of 12 studies suggests that the nutrient acetyl-l-carnitine (ALC), when taken as a nutritional supplement, has antidepressant effects. The meta-analysis by researcher Nicola Veronese and colleagues appeared in the journal Psychosomatic Medicine in 2017. Veronese and colleagues found that in nine randomized controlled trials, ALC reduced depressive symptoms significantly compared to placebo. In three randomized controlled trials that compared ALC with established antidepressants, ALC showed similar effectiveness at reducing depressive symptoms while producing 79% fewer side effects. Doses of ALC ranged from 1 to 4 grams per day, and higher doses led to greater improvement.

In the comparisons with antidepressants, the other treatments included fluoxetine (Prozac), duloxetine (Cymbalta), and amisulpride (which is not approved by the US Food and Drug Administration).

Low ALC has been linked to depression. According to Veronese and colleagues, ALC deficiency can dysregulate the transport of fatty acids across the inner membrane of mitochondria. The researchers suggest several ways that ALC might contribute to an improvement in depression. One is that is seems to promote neuroplasticity in cerebral regions implicated in depression, such as the hippocampus. It could also work by increasing brain-derived neurotrophic factor (BDNF), which protects neurons and is important for learning and memory. ALC decreases release of the neurotransmitter glutamate by increasing the production of the inhibitory metabotrophic glutamate receptor (mGluR-2) on presynaptic glutamate neurons . Another way ALC might work is by normalizing lipid metabolism. Or it could modulate neurotransmitters, increasing serotonin and dopamine and protecting against stress.

In the meta-analysis, ALC produced more improvement in older patients than in younger ones. The researchers stressed the need for better treatments for older people, which may experience falls, cardiovascular disease, or increased mortality from antidepressants.

ALC also seems to improve pain syndromes, making it a good option for patients with both depression and pain symptoms.

Veronese and colleagues cited another meta-analysis that found that taking ALC in addition to an antidepressant led to lower rates of adverse events than the antidepressants alone, which helped patients adhere to their drug regimen.

Management of Unipolar and Bipolar Depression During Pregnancy

March 5, 2018 · Posted in Current Treatments, Potential Treatments · Comment 

pregnancyAt the Maryland Psychiatric Research Society’s continuing medical education conference in November, Lauren Osbourne, Assistant Director of the Women’s Mood Disorders Clinic at Johns Hopkins Hospital, gave a presentation on the management of mood and anxiety during pregnancy and lactation. She had a number of important ideas for physicians and patients to consider in their decision-making process.

According to Osbourne, 60%-70% of pregnant women with unipolar depression who discontinue their antidepressants relapse. Of those with bipolar disorder who discontinue their mood stabilizers, 85% relapse, while 37% of those who stay on their medications relapse.

Something to consider when deciding whether to continue medication while pregnant is that depression in pregnancy carries its own risks for the fetus. These include preterm delivery, low birth weight, poor muscle tone, hypoactivity, increased cortisol, poor reflexes, and increased incidence of attention deficit hyperactivity disorder (ADHD) and other behavioral disorders.

The placenta makes an enzyme 11-BHSD2 that lowers the stress hormone cortisol in the baby. However, this enzyme is less active in depression, exposing the fetus to higher levels of cortisol.

Thus, the decision about whether to continue medications during pregnancy should consider the risks to the fetus of both the mother’s depression and the mother’s medications.

Most antidepressants are now considered safe during pregnancy. There have been reports of potential problems, but these data are often confounded by the fact that women with more severe depression are more likely to require antidepressants, along with other risk variables such as smoking or late delivery (after 42 weeks). When these are accounted for by using matched controls, the apparent risks of certain antidepressants are no longer significant. This includes no increased risk of persistent pulmonary hypertension, autism, or cardiac malformations.

There may be a possible increased risk of Neonatal Adaption Syndrome (NAS) in the first weeks of life in babies who were exposed to selective serotonin reuptake inhibitor (SSRI) antidepressants in the third trimester. This syndrome presumably results from antidepressant withdrawal, and can include respiratory distress, temperature changes, decreased feeding, jitteriness/irritability, floppiness or rigidity, hypoglycemia, and jaundice. There is not yet a robust literature on the syndrome, but Osbourne suggested that it disappears within 2 weeks of birth.

In her practice, Osbourne prefers to prescribe sertraline, which has the best safety data, along with fluoxetine. Sertraline is also OK for breastfeeding. There is less data on bupropion, but it also appears to be safe during pregnancy. Endocrine and enzyme changes in pregnancy typically cause a 40% to 50% decrease in concentrations of antidepressants, so doses of antidepressants typically must be increased in order to maintain their effectiveness.

Osbourne ranked mood stabilizers for bipolar disorder, from safest to most worrisome. Lamotrigine is safest. There is no evidence linking it to birth defects, but higher doses are required because of increased clearance during pregnancy. Lithium is next safest. There are cardiac risks for one in 1,200 patients, but these can be monitored. Carbamazepine is third safest. One percent of babies exposed to carbamazepine will develop spina bifida or craniofacial abnormalities. Valproate is least safe during pregnancy. Seven to ten percent of babies exposed to valproate will develop neural tube defects, other malformations, or developmental delay, with a mean decrease of 9 IQ points. The atypical antipsychotics all appear safe so far.

Alternatives and Adjuncts to Medications in Pregnancy

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30 Minutes of TDCS Better Than 20 Minutes in Patients with Unipolar Depression

March 2, 2018 · Posted in Potential Treatments · Comment 

tDCSTranscranial direct current stimulation (tDCS) has successfully been used to treat depression. In this treatment, electrodes applied to the scalp provide a constant low level of electricity that can modulate neuron activity. In a 2017 article in the journal Progress in Neuro-Psychopharmacology & Biological Psychiatry, researcher Elena L. Pavlova and colleagues report that both 20- and 30-minute sessions of tDCS improved mild to moderate depression when combined with the selective-serotonin reuptake inhibitor (SSRI) antidepressant sertraline. However, the 30-minute sessions produced more improvement in depression.

In the study, 69 right-handed patients (average age 37.6) received 50 mg of sertraline (Zoloft) per day and were randomized to one of three tDCS conditions: 10 daily 30-minute sessions, 10 daily 20-minute sessions, or 10 daily sham sessions with no tDCS treatment. The tDCS consisted of 0.5mA anodal current to the left dorsolateral prefrontal cortex.

Both 30-minute and 20-minute tDCS sessions produced greater benefit than the sham sessions. The 30-minute group showed significantly greater percentage improvement in depression scores than the 20-minute group, and included more participants who responded to treatment (89% compared to 68% of the 20-minute group and 50% of the sham group) and more whose depression remitted (70% compared to 27% of the 20-minute group and 35% of the sham group).

TDCS Effective in Bipolar Depression

February 28, 2018 · Posted in Potential Treatments · Comment 

tDCSA 2017 study in the journal JAMA Psychiatry reports that transcranial direct current stimulation (tDCS) is an effective add-on treatment for bipolar depression. In the study by researcher Bernardo Sampaio-Junior and colleagues, 59 patients taking medication for bipolar disorder and experiencing a depressive episode were randomized to receive either 10 daily half-hour sessions of tDCS (and then one every two weeks) or an inactive sham stimulation.

TDCS is a painless form of neurostimulation in which electrodes applied to the scalp provide a steady, low current of electricity that modulates neuron activity. Sampaio-Junior describes its low cost, portability and ease of use as some of its benefits. This is the first randomized, sham-controlled study of tDCS in bipolar disorder.

After six weeks of treatment, patients who received real tDCS treatment showed significantly more improvement in their depression than those who received the inactive sham stimulation. In the active group, 67.6% showed sustained response compared to 30.4% in the inactive group. TDCS was well tolerated, with skin redness at the application site the only side effect that was more common in the active group than in the sham group. Mood switching rates were similar across the two groups.

The research was completed as part of the Bipolar Depression Electrical Treatment Trial (BETTER) taking place in Brazil. The group of participants was 68% female with a mean age of 45.9 years. Sixty-one percent of participants had bipolar I disorder while the remainder had been diagnosed with bipolar II.

In Danish Study, Higher Trace Levels of Lithium in Drinking Water in Certain Regions Do Not Seem to Prevent Bipolar Disorder

February 21, 2018 · Posted in Potential Treatments · Comment 

man drinking water

Previous studies have found that trace levels of lithium that occur naturally in the drinking water of certain regions are associated with lower rates suicide. Preliminary studies have also shown that lithium in drinking water is associated with lower dementia rates. The trace levels seen in drinking water are many hundreds of times lower than clinical doses of lithium prescribed for bipolar disorder, but they vary greatly according to locality.

A new study by researcher Lars Kessing and colleagues investigated whether chronic exposure to lithium in drinking water might protect against bipolar disorder, but found no evidence that this is the case in Denmark.

In an article published in the journal Bipolar Disorders in 2017, Kessing and colleagues describe findings from their analysis of data on 14,820 patients with a diagnosis of mania or bipolar disorder and (for each participant with bipolar disorder) 10 other age- and gender-matched control participants totaling 140,311. The researchers were able to look longitudinally at the participants’ exposure to trace levels of lithium in drinking water based on their municipalities of residence.

The investigators hoped to find evidence that greater exposure to lithium was associated with lower rates of bipolar disorder. Kessing and colleagues concluded that trace lithium levels higher than those in Denmark might be needed to find such a result.

Editor’s Note: Clinical studies of lithium treatment for children at high risk for bipolar disorder could help clarify whether even conventional therapeutic levels of lithium could reduce or delay the appearance of bipolar disorder.

Naturally Occurring Lithium in Texas Drinking Water Reduced Alzheimer’s Mortality Rates

February 19, 2018 · Posted in Potential Treatments · Comment 

woman drinking water

Several studies have found that trace levels of lithium that naturally occur in the drinking water of certain regions are associated with reductions in dementia compared to regions with less lithium in the water. The latest such study found that higher trace levels of lithium in certain Texas counties were associated with less mortality from Alzheimer’s disease compared to Texas counties with lower levels of lithium in the water.

The research by Val Andrew Fajardo and colleagues was published in the Journal of Alzheimer’s Disease in 2017. Fajardo’s team obtained 6,180 water samples from 234 of Texas’ 254 counties. They also calculated that there was an increase in the Alzheimer’s mortality rate from the period 2000–2006 to the period 2009–2015. However, regions with higher trace levels of lithium were negatively correlated with this increase, suggesting that the lithium in the water had a protective effect on people in those counties.

The researchers controlled for gender, race, education, rural living, and air pollution. Physical inactivity, obesity, and type 2 diabetes seemed to be confounding factors. Obesity and type 2 diabetes were positively correlated with Alzheimer’s mortality and negatively correlated with lithium levels in drinking water, meaning that it is possible that lithium also protects against these conditions.

Lithium in Drinking Water May Reduce Dementia

February 16, 2018 · Posted in Potential Treatments · Comment 

New research suggests that higher trace levels of lithium in drinking water can reduce dementia rates in the general population. In a 2017 article in the Archives of General Psychiatry, researcher Lars Kessing and colleagues compared data on 73,731 patients in Denmark with a diagnosis of dementia to 733,653 control participants without this diagnosis between the years 1970 and 2013. They were able to match the data to recorded levels of trace lithium in the drinking water in participants’ municipalities of residence.

Lithium levels in the water ranged from 0.6 micrograms per liter to 30.7 micrograms per liter in 151 different locations throughout Denmark. Compared to those exposed to 2.0 to 5.0 micrograms of lithium per liter of water, those exposed to more than 15.0 micrograms per liter had a lower incidence rate of dementia. However, those exposed to 5.1 to 10.0 micrograms per liter had a higher incidence of dementia. The same relationship was also found between lithium exposure levels and both Alzheimer’s disease and vascular dementia.

The lithium levels in the water were approximately 10,000 to 300 times lower than typical clinical doses (typically 900–1500mg/day, which produce concentrations ranging from 0.6 to 1.2 meq/L in patients’ blood). The minute exposures to lithium in the drinking water occurred over decades in the Danish study, and suggest that there may be long-term positive effects to chronic lifetime exposure to very low lithium levels.

These data follow others regarding exposure to trace lithium. In 2011, researcher Orestes V. Forlenza and colleagues reported in the British Journal of Psychiatry that low dose lithium (150–600mg/day) over a period of one year decreased the progression of mild cognitive impairment compared to placebo, while researcher Marielza Andrade Nunes and colleagues reported in the journal Current Alzheimer’s Research in 2013 that an even smaller dose (0.3mg/day) over a period of 15 months slowed the progression of Alzheimer’s dementia. Thus, low or microscopic doses consumed over long periods could slow cognitive deterioration.

Exercise May Protect Against Breast Cancer

February 9, 2018 · Posted in Potential Treatments · Comment 

walkingEpidemiological evidence suggests that exercise reduces breast cancer rates and rates of breast cancer recurrence. However, it is not well understood why this is true.

Exercise that is intense enough to increase the heartrate and induce heavy breathing can increase the hormone epinephrine in the blood. A 2017 article by researcher Christine Dethlefson and colleagues in the journal Cancer Research reported that this elevated level of epinephrine in the blood of breast cancer patients after one intense exercise session stopped their breast cancer cells from growing in vitro and reduced tumor growth by half.

Senior author Pernille Hojman told Reuters that while exercise could not be expected to replace anti-cancer treatments, it is a great supportive strategy that has the added benefits of increasing patients’ quality of life and sense of empowerment.

The study looked at human breast cancer tumor cells in test tubes, and the same type of tumor cells implanted into mice. Only 45 percent of the mice implanted with the cancer cells collected after vigorous exercise developed tumors, compared to 90 percent of the mice who received cancer cells collected before exercise or with no exercise.

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