Nimodipine Decreases Frontal and Parietal Cortical Activity During Working Memory in Healthy Subjects

January 30, 2019 · Posted in Genetics, Potential Treatments · Comment 

brain

At a recent scientific meeting, researcher Kristin Bigos and colleagues described the effects of nimodipine, a treatment for brain hemorrhage, on the brain during working memory tasks. Nimodipine is a dihydropyridine L-type calcium channel blocker. Calcium channel blockers prevent calcium from entering cells in the heart and blood vessel walls, and they are often used to treat high blood pressure.

Nimodipine acts on the CACNA1C calcium influx gene. Certain genetic variations in this gene (particularly the rs1006737 A allele) have been linked to vulnerability to bipolar disorder, schizophrenia, depression, and autism. Carriers of the risk allele also have higher CACNA1C mRNA expression in the dorsolateral prefrontal cortex and exhibit more activity in the frontal and parietal regions of the brain during working memory tasks, suggesting inefficient brain processing in these regions. Bigos and colleagues found that 60mg/day of nimodipine decreased frontal and parietal cortical activity by 39.1% and 42.8%, respectively, during a working memory task, suggesting that nimodipine improved the efficiency of memory processing. Nimodipine’s positive effects were greater in those participants who had the CACNA1C risk allele.

Editor’s Note:  Using a placebo-controlled off-on-off-on study design (meaning patients took placebo for a period, then nimodipine, then placebo again and nimodipine again), this editor (Robert M. Post), Peggy J. Pazzaglia and colleagues found that nimodipine had positive effects in both mania and depression in patients with bipolar disorder (described in the 2008 book Treatment of Bipolar Disorder: A Casebook for Clinicians and Patients by Robert M. Post and Gabriele S. Leverich). In a large randomized study of patients with bipolar disorder presented by Haroon R. Chaudhry at the 2010 meeting of the Society of Biological Psychiatry, lithium was associated with about a 50% response rate while the combination of lithium and nimodipine was associated with a 73% response rate.

It remains to be seen whether people with bipolar disorder who have the CACNA1C risk gene would respond better to nimodipine than those without the risk gene, and whether it would improve working memory more in the subgroup with the risk gene.

Ketamine May Enhance the Effects of Cognitive Training Therapy

January 28, 2019 · Posted in Potential Treatments · Comment 
group therapy

Woman receiving cognitive training

Rebecca B. Price, a professor of Psychiatry and Psychology at the University of Pittsburgh, and colleagues reported at a recent scientific meeting that the combination of intravenous ketamine treatment and four days of cognitive training to enhance positive self-representations improved depression better than either intervention alone (IV ketamine plus a sham training or a non-medicated saline drip plus 4 days of cognitive work).

Price and colleagues suggested that priming brain plasticity with ketamine could enhance cognitive training focused on increasing positive self-representations. Psychologists have theorized that self-representations (or assessments of one’s strengths and other qualities) can be a resource that helps people cope with life stress.

Il-6 Inhibitor Sirukumab May Improve Anhedonia, But Not General Depression

January 25, 2019 · Posted in Potential Treatments · Comment 

cyclingAt a 2018 scientific meeting, researcher Giacomo Salvadore and colleagues reported that the drug sirukumab, a monoclonal antibody that targets the inflammatory marker Il-6 and that was originally developed to treat rheumatoid arthritis, did not have a statistically significant effect on overall depression compared to placebo. However, by the twelfth week of treatment, sirukumab did have a significant effect on anhedonia (loss of interest or pleasure in activities that one previously enjoyed).

The degree of improvement in anhedonia was significantly correlated with patients’ baseline levels of the inflammatory marker CRP. Since the inflammatory marker that sirukumab targets, Il-6, is one of those most often elevated in depression, it appears that more study of sirukumab would be warranted.

Vitamin D3 Improves Depression in Older Adults

December 3, 2018 · Posted in Potential Treatments · Comment 

vitamin D

Researcher Negin Masoudi Alavi and colleagues reported in the journal Clinical Nutrition in 2018 that compared to placebo, 50,000 IU of vitamin D3 taken weekly for eight weeks improved depression in depressed patients over the age of 60.

Although the literature about vitamin D3’s effects on depression are mixed, a 2014 meta-analysis by Simon Spedding in the journal Nutrients found that in studies of vitamin D-deficient depressed participants whose vitamin D levels were restored to normal levels by the end of the study, vitamin D significantly improved depression. (Spedding attributed earlier mixed results to studies that did not clearly correct a vitamin D deficiency.) A 2013 study by Nayereh Khoraminya and colleagues in the Australian and New Zealand Journal of Psychiatry suggested that a 1500 IU dose of vitamin D3 combined with the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine improved depression more than fluoxetine plus placebo in depressed patients who were not necessarily deficient in vitamin D. Another study by Jacqueline A. Pettersen in the journal Experimental Gerontology found that in healthy adults, 4,000 IU of vitamin D3 improved cognitive functioning (namely visual memory) more than 400 IU.

Editor’s Note: Given these promising studies, the safety of D3, and fact that psychiatric patients are often deficient in vitamin D3, taking vitamin D3 supplements to improve depression might be worth trying.

Supplements for the Treatment of Schizophrenia

November 16, 2018 · Posted in Potential Treatments · Comment 

supplements

At the 2018 meeting of the North Carolina Psychiatric Association, researcher Karen Graham reviewed evidence for adjunctive treatments that may help treat schizophrenia when added to antipsychotic medications.

Graham endorsed omega-3-fatty acids, saying that they may delay the conversion to schizophrenia in young people at high risk for the illness. Data in chronic schizophrenia are more equivocal.

Data on the effects of vitamin D3 in schizophrenia are mixed, but D3 is often low in patients with psychotic disorders, and supplementation with vitamin D3 in the general population has been associated with decreases in cancer and all-cause mortality.

Graham indicated that in three studies vitamin B6 (pyridoxine) decreased tardive dyskinesia, a side effect of antipsychotic medication that is characterized by repetitive or jerky involuntary movements of the face and body. B6 also reduced the severity of akathisia or restless legs, which is comparable to the effects of 40mg/day of the beta blocker drug propranolol. Graham recommended a dose of 300mg/day of B6 that could be increased up to 600mg twice per day. The onset of effects usually begins by week three, and the cost ranges from 25 to 80 cents per day.

The antioxidant supplement N-acetylcysteine (NAC) may also help. Graham described six studies that found NAC had positive effects on negative symptoms (apathy, blunted emotions, etc.) and/or cognition in patients with schizophrenia. The dosage in these studies was usually 2 grams/day for 24 weeks. The cost was 50 cents per day.

Two 8-week trials of L-theanine (an amino acid found in green and black tea) at doses of 400mg/day improved negative symptoms and anxiety in 40 patients with schizophrenia. The rationale for the study was that L-theanine increases inhibitory neurotransmitters, modulates the amino acid 5-HTP and the neurotransmitter dopamine, increases brain-derived neurotrophic factor (BDNF), and may be neuroprotective after a heart attack or a traumatic brain injury. The cost is 40 cents per day.

Graham reported that the supplement ginkgo biloba produced significant improvement in negative symptoms and total symptoms in eight clinical trials that included a total of 1,033 patients with schizophrenia. Doses ranged from 240 to 360 mg/day. These supplements (usually extracted from leaves of the ginkgo tree) have not been found to have many side effects, but they can reportedly increase post-operative bleeding. Gingko biloba supplements cost 20 to 80 cents per day. There is also at least one positive study of ginkgo biloba in tardive dyskinesia.

Three of four studies of cannabidiol in schizophrenia have been positive (at doses of 600, 800, and 1,000 mg/day in studies that lasted four to six weeks). There are now six additional ongoing studies listed on the website clinicaltrials.gov. There is little of this diol component in regular marijuana, and the cost of pure cannabidiol is unfortunately an exorbitant $60 to $100/day.

There is a positive controlled study of the herb ashwagandha in 66 patients with schizophrenia.

Not included in Dr. Graham’s review was the prenatal treatment of women with phosphatidylcholine (900mg/day) followed by supplements in the newborn, which normalized an aspect of sensory gating known as P50 in patients with schizophrenia. Healthy individuals show a reduced response to an auditory cue when it is repeated 50 milliseconds after the initial cue. In people with schizophrenia, response to the repeated cue is not suppressed. This has been suggested by researchers Robert Freedman and Randal G. Ross in a 2015 article in the Shanghai Archives of Psychiatry as a possible primary preventive approach to schizophrenia.

Pregnant women in their second and third trimesters should at least consume foods high in choline, especially if the fetus is at high risk for schizophrenia because of a family history of schizophrenia.

Beef liver is very high in choline, providing 420mg per slice. Other animal products provide significant choline, such as eggs (120 mg/egg), beef (90mg/100g), chicken liver (85mg/liver), fish (85mg/100g), bacon (35mg/strip) or other pork, chicken (67mg/100g). Tofu (36mg/half cup) and cereal (22mg/half cup) are also sources of choline.

Foods High in Choline

Beef liver 1 slice 420mg choline;
Egg 1 egg 120;
Beef 100 gm 90;
Chicken liver 1 liver 85;
Fish 100 gm 85;
Bacon or pork 2 strips bacon 70;
Chicken 100 gm 67;
Tofu 120 ml (0.5 cup) 36;
Cereal 120 ml (0.5 cup) 22

 

Pilot Study Finds Intravenous Ketamine Improves Tough-to-Treat Adolescent Depression

November 1, 2018 · Posted in Potential Treatments · Comment 

teen depression

A 2018 open study by Kathryn R. Cullen and colleagues in the Journal of Child and Adolescent Psychopharmacology suggests that intravenous ketamine may improve depression in adolescents who have not responded to at least two antidepressants.
Thirteen patients ranging in age from 12 to 18 with treatment-resistant depression were given six ketamine infusions over a period of two weeks, at doses of 0.5 mg/kg of body weight. A 50% drop in scores on the Children’s Depression Rating Scale-Revised (CDRS-R) was considered a good response, and the average drop in participants’ scores was 42.5%. Five of the thirteen participants (38%) met the criteria for a good response. Three of these participants were still in remission at six weeks, while the other two relapsed within two weeks.

Ketamine was fairly well-tolerated by the young participants. Some had temporary dissociative symptoms or blood pressure changes. Higher absolute doses of ketamine were linked to better response.

The response rates in this group were not as good as in some studies of adults. More research using larger sample sizes and placebo controls is needed to optimize dosing and clarify the safety and efficacy of intravenous ketamine in adolescents with tough-to-treat depression, but this is a promising finding in a small number of adolescents.

Curcumin Improves Memory and Depression

October 2, 2018 · Posted in Potential Treatments · Comment 

curcumin

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.

Cannabidiol May Help Treat Schizophrenia

September 28, 2018 · Posted in Potential Treatments · Comment 

marijuanaA 2017 article by researcher Philip McGuire and colleagues in the American Journal of Psychiatry reports that when added to antipsychotic medication, cannabidiol, a component of marijuana, improved positive symptoms of schizophrenia, such as hallucinations and delusions, more than did the addition of a placebo.

In the double-blind, parallel-group study, 43 participants received 1000 mg/day of cannabidiol in addition to their regular antipsychotic medication, while 45 participants received a placebo alongside their regular medication.

Side effects were minimal, and after six weeks those who received cannabidiol had decreased positive symptoms and were more likely to be considered improved and not severely unwell.

Editor’s Note: It is important to emphasize that cannabidiol is only a minor component of marijuana, which contains much more tetrahydrocannabinol (THC), which is psycho-mimetic, i.e. it can worsen psychosis. Pure cannabidiol is not readily available to the public.

Withania Somnifera Herb Normalizes Sensory Processing Measure in Schizophrenia

September 26, 2018 · Posted in Potential Treatments · Comment 

One of the best biomarkers of schizophrenia is low auditory mismatch negativity. Auditory mismatch negativity describes the pattern of electrical activity that occurs in the brain when a repeated sound is interrupted by a mismatched sound, such as a change in pitch or volume.

At the International Congress on Schizophrenia Research, Paulina S. Marell and colleagues described their pilot study of the antioxidant and anti-inflammatory herb Ashwagandha or Withania Somnifera (also known as Indian ginseng, poison gooseberry, or winter cherry). In 11 patients with schizophrenia, the herb normalized mismatch negativity compared to placebo.

Marell and colleagues wrote that the herb “recover[ed] some of the impaired early sensory/cognitive potentials in schizophrenia.” Since normal cognition relies on sensory processing, normalizing these functions in people with schizophrenia could improve their symptoms.

A 2018 study by researcher K.N. Roy Chengappa and colleagues in the Journal of Clinical Psychiatry reports that adding Withania Somnifera to patients’ regular antipsychotic medication improved negative symptoms of schizophrenia and total symptoms compared to adding placebo.

Editor’s Note: These studies, taken together, suggest the utility of adding this supplement to the treatment regimen for schizophrenia.

Sodium Benzoate Helps Treat Schizophrenia When Added to Clozapine

September 24, 2018 · Posted in Potential Treatments · Comment 

schizophrenia

In a 2017 article in the journal Biological Psychiatry, Chieh-Hsin Lin and colleagues reported that sodium benzoate, a common food preservative, may augment the effects of clozapine in patients with schizophrenia.

Clozapine is the most effective antipsychotic available, but as many as 40–70% of patients with treatment-resistant schizophrenia do not respond to it. For those with a poor response to clozapine, sodium benzoate may offer some hope.

In a randomized, double-blind trial, sixty inpatients taking clozapine for schizophrenia were divided into three groups. One group received an additional 1 g/day of sodium benzoate, another received 2 g/day, and the third received placebo in addition to clozapine. Both groups taking sodium benzoate and clozapine showed improvements in negative symptoms of schizophrenia (which can include apathy and inability to experience pleasure) compared to the group taking only clozapine. The larger 2g dose also improved positive symptoms of schizophrenia (such as hallucinations or delusions) and quality of life. Changes in levels of the antioxidant catalase were linked to the total improvement in symptoms and the improvement in positive symptoms. Sodium benzoate did not seem to cause any side effects.

Editor’s Note: Sodium benzoate is a D-amino acid oxidase inhibitor that activates NMDA receptors and increases levels of the amino acid D-serine in the brain by preventing it from breaking down. D-serine can reverse the effects of the illicit drug PCP, and very high doses of D-serine have improved the effectiveness of atypical antipsychotics in people with schizophrenia. By increasing levels of D-serine, sodium benzoate may offer new benefits to people with schizophrenia, especially those who have not responded to other treatments.

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