GLP-1s Might Decrease the Incidence of Depression and Anxiety

Lisa O’Mary of WebMD wrote: “People taking a popular type of drug for weight loss or to manage diabetes have a lower likelihood of being newly diagnosed with depression or anxiety, according to an analysis of millions of people’s health records.

The findings were published this week by researchers from the electronic health record company Epic. Researchers looked for new diagnoses of depression or anxiety among people who started taking drugs from a class called GLP-1 agonists that can help manage blood sugar or treat obesity by mimicking hormone levels in the body that can affect appetite and blood sugar. Many people who take the drugs experience significant weight loss.

The researchers found that people with diabetes who started taking most versions of GLP-1 agonists were between 11% and 65% less likely to be newly diagnosed with depression than people with diabetes who didn’t take one of the drugs. The greatest reduction in likelihood of a new depression diagnosis was observed among people taking tirzepatide, which is sold under the brand names Mounjaro and Zepbound.”

Vitamin B6 Plus Lithium Helps Ease Mania Symptoms in Patients With Bipolar Disorder

Daily vitamin B6 (40mg/day), but not B1 (100mg/day), as an adjunctive therapy to lithium was associated with the improvement of mood symptoms in hospitalized patients with bipolar disorder experiencing a manic episode, according to a study published in the Journal of Affective Disorders 2024; 345 103-111: Zandifar et al.

NEW DATA ON EXTENDING THE EFFFECTS OF IV KETAMINE: Implications for countering the effects of stigma.

John Krystal of Yale U. in an article in Proceedings of the National Academy of Sci. (2023) gave new information about the anatomical and physiological effects of ketamine and about how to extend its effects. Ketamine in animals acutely (in a matter of hours) increases spines, synapses, and dendrites and physiological connectivity in neurons in the prefrontal cortex. Data now support these findings in humans with depression, but AD effects of ketamine tend to dissipate over a period of 3 to 5 days and require repeated infusions to maintain the improvement. Synaptic density can be measured with SV2A and this can be enhanced with a Navitor Pharmaceuticals drug acting on mTORC1. Surprisingly low doses of rapamycin, an inhibitor of mTOR1, extends the duration of AD effects of ketamine, increasing the response rate at 2 weeks of 13% to 41%. Ketamine restores only the spines that have been reduced in depression and rapamycin is thought to extend the duration of the restored spines. It may do this by increasing the neurotropic effects of microglia. The tripartite synapse of pre and post synaptic neurons and astrocytes, may now be better described as the tetrapartite synapse with the inclusion of microglial.

Adding psychotherapy to the effects of ketamine in PTSD increases and extends efficacy.

AD effects of ketamine can be extended with cognitive behavioral therapy. Thus, ketamine increases synaptic efficacy, synaptic density, glutamate homeostasis, and experience-dependent neuroplasticity. Extending the persistence of these effects by various chemical and psychotherapeutic mechanisms may give new ways of enhancing and prolonging the therapeutic effects of this rapidly acting agent.

Interestingly, Kaye at Yale U. reports that in contrast to transient effects of ketamine, the AD effects of therapy-assisted psilocybin appear to be very long lasting and the associated increases in spines persist for longer than 37 days. Another psychedelic MDMA that is effective in PTSD causes large increases in spines, although they are less persistent and are gone by 34 days.

Editors Note: As we have previously highlighted in the BNN, these data on ketamine and other psychedelics reversing the anatomical and physiological deficits in prefrontal neurons of depressed animals and humans (spines, dendrites, synapses and intercellular communication), give a new view of the real, reliable, and replicable neurological defects accompanying depression. The rapid correction of these neural abnormalities in conjunction with the rapid induction of antidepressant effects are not only paradigm shifting from a treatment perspective, but have major implications for the assertion that there is a neurobiological basis of depression and its treatment.

As such, these data should do much to counter the continuing stigma too often accompanying the term “mental” illness that it is somehow not as real as other medical and neurological conditions, and as it is often asserted that “it is just all in one’s head.”  This picks up on the unfortunate associations and definitions of “mental” as imaginary, all in the mind, and evanescent and that mental illness can readily be countered with effort and will power such as “pulling oneself up by the bootstraps,” (the latter of which is in itself a logical impossibility.)

A Case Report: Good Effect of Psilocybin Even with No Psychedelic Effects

Highlights from the International Society for Bipolar Disorders Conference Posters and Presentations, Chicago, June 22-25, 2023

Marisa Leon-Carlyle reported on a 43 yr. old man with chronic treatment refractory depression who was given psilocybin 25mg (a 5HT2A agonist) at 8:00 AM after receiving trazodone 200mg HS (which should be enough to block 80% of 5HT2A receptors). He had an excellent antidepressant response, was able to feel emotion and new love for his wife, and finally felt that doing one’s best is good enough. Obviously further systematic study is needed.

Assets of Exercise

Highlights from the International Society for Bipolar Disorders Conference Posters and Presentations, Chicago, June 22-25, 2023

Ben Goldstein of the University of Toronto gave a plenary talk on the benefits of exercise.

He found poor aerobic fitness in 19 of 20 young bipolar patients. They had low cerebral blood flow in proportion to the severity of their exhaustion after exercise. He noted the importance of stressing an endpoint of fitness for exercise rather than weight loss. Using an exercise coach and running with family and friends was helpful in motivating patients for consistent exercise.

Long COVID ‘Brain Fog’ Confounds Doctors, but New Research Offers Hope

James C. Jackson, PsyD, a licensed psychologist specializing in neuropsychology and rehabilitation, at Vanderbilt University School of Medicine and author of a new book, Clearing the Fog: From Surviving to Thriving With Long COVID ? A Practical Guide, reports in Medscape July, 2023 : “There’s not a lot of imprecision in the term (brain fog) because it might mean different things to different patients,”

Jackson, who began treating [a patient] in February 2023, said that it makes more sense to call brain fog a brain impairment or an acquired brain injury (ABI) because it doesn’t occur gradually. COVID damages the brain and causes injury. For those with long COVID who were previously in the intensive care unit and may have undergone ventilation, hypoxic brain injury may result from the lack of oxygen to the brain.

An April 2022 study published in the journal Nature found strong evidence that SARS-CoV-2 infection may cause brain-related abnormalities, for example, a reduction in gray matter in certain parts of the brain, including the prefrontal cortex, hypothalamus, and amygdala.

Additionally, white matter, which is found deeper in the brain and is responsible for the exchange of information between different parts of the brain, may also be at risk of damage as a result of the virus, according to a November 2022 study published in the journal SN Comprehensive Clinical Medicine.
Thus, new data suggest that long COVID is associated with inflammation and both reduced volume of several brain structures and decreases in white matter. These data suggest several novel approaches to therapy that require further study. One is low dose lithium which both increases gray matter volume and white matter integrity. Lithium also has some antiviral properties. This could be combined with anti-inflammatories that could be bought over the counter such as N-acetylcysteine (NAC), acetyl-L-carnitine, and celecoxib.

Note of caution. This is only an untested hypothesis and would need to be discussed with one’s physician before any of these options are considered.

High Response Rate to Psilocybin in Bipolar II Depression

Highlights from the International Society for Bipolar Disorders Conference Posters and Presentations, Chicago, June 22-25, 2023

Scott Aaronson gave 15 medication-free BP II patients (off all medications) 25mg of psilocybin with extensive therapeutic support. He saw rapid onset and persistent AD effects, such that at the end of 12 weeks 12 of the 15 patients were still in remission. Quality of life increased and suicidal ideation decreased. He indicated that others found that serum BDNF increased 1000 fold greater than baseline.

Antidepressant Effects of Psilocybin in Unipolar Depression

Highlights from the International Society for Bipolar Disorders Conference Posters and Presentations, Chicago, June 22-25, 2023

Alan Young reported on 233 patients with treatment refractory depression who were given 10mg then 25mg of psilocybin, 1 week apart.

There was intensive therapeutic support before, during, and after the ingestions. Patients experienced it as a waking dream. Response was rapid in onset and 20% response persisted at least through week 12.

Preliminary data on ketogenic diet

Highlights from the International Society for Bipolar Disorders Conference Posters and Presentations, Chicago, June 22-25, 2023

Georgia Ede gave a talk on the first results of 12 bipolar patients using a ketogenic diet (composed of 75% fat; 5% carbohydrates; 20% protein) as a adjunct to about 5 medications that were insufficiently effective. She saw improvement by week 3, 58% remitted, and some lost weight. She indicated that some could revert to a regular diet after the improvement achieved by children, but not in adults.

Sebari Sethi talked about 26 of 27 bipolar patients who achieved 1.3 mmole/L ketones and lost weight and showed increases in glutamate in brain measured by Glx and decreases of 11.2% in the ACC

Positive Effects of Low-Dose Lithium (LDL)

Highlights from the International Society for Bipolar Disorders Conference Posters and Presentations, Chicago, June 22-25, 2023

Rebecca Strawbridge of the Institute of Psychiatry, Psychology & Neuroscience, King’s College London reported on 18 articles that were examined and grouped according to outcome domain (cognition, depression, mania, and related constructs e.g., suicidality). Significant benefits (versus placebo) were identified for attenuating cognitive decline, and potentially as an adjunctive therapy for people with depression/mania. Across studies, LDL (~serum level ?0.6 mmol/L) was reported to be safe.

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