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December 7, 2022 · Posted in About the BNN · Comment 

All future posts will include a rating indicating their potential clinical importance.
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C – May become important in the future

D – Related to neurobiology or theory

We’re back!

February 23, 2022 · Posted in About the BNN · Comment 

After a pandemic-related hiatus, we’re back, and we hope to bring you articles regularly. For print subscribers, we hope to send out a single large issue in the coming months.

Bipolar I patient show dramatic reductions in white matter integrity

Thiel et al in Neuropsychopharmacology (2024) reported that “Compared with HC [healthy controls], BD-I patients exhibited lower FA [fractional anisotropy] in widespread clusters (ptfce-FWE?< 0.001), including almost all major projection, association, and commissural fiber tracts. BD-II patients also demonstrated lower FA compared with HC, although less pronounced (ptfce-FWE?=?0.049).”

Editors Note: These data once more emphasize the importance of using lithium (Li) in bipolar disorder as it can ameliorate the deficits in white matter integrity that are so prominent in the illness. Li also improve the loss of cortical grey matter volume that evolves with illness progression. Li prevents episodes of depression and mania and reduces the incidence of suicides. That Li can reverse or ameliorate brain abnormalities in bipolar disorder is one more piece of evidence that Li should be considered a disease modifying drug (DMD) and started early in the course of illness in almost all bipolar patients. The new mantra for patients and clinicians is: Use more lithium and prevent illness progression.

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.”

Antidepressant Use and Risk of Manic Episodes in Children and Adolescents With Unipolar Depression

Suvi Virtanen, PhD; et al in JAMA Psychiatry. September 27, 2023. report a low risk of switching in youngsters with unipolar depression. However, the odds ratio for a switch were significantly elevated when there was concomitant use of anticonvulsants and antipsychotics, and there was a four fold increased risk if a parent had bipolar disorder. Thus one should be particularly careful about treating depression with antidepressants (AD) when there is a positive parental history of bipolar disorder and one should think of other options, such as lamotrigine, an atypical with good AD effects, or lithium.

Smoking Pot While Pregnant is a No-No

Mom, Don’t Think Smoking Pot When Pregnant is Harmless for your Child

In a new article in Science, Jasmine Hurd reports on a large sample of mothers who smoked pot while pregnant. Their offspring were more anxious, hyperactive, and aggressive and had higher levels of the stress hormone cortisol in their hair at ages 3-6.

When Superstorm Sandy hit, mothers who were stressed and smoked pot while pregnant had children 31 times more like to have oppositional defiant disorder and 7 times more likely to have an anxiety disorder. Stress may interact negatively with the effects of pot.

In fetuses aborted after being exposed to pot while in utero had decreased dopamine receptors in the their amygdala and n. accumbens, a reward center in brain. In animal studies, pregnant mother rodents who were exposed to THC had offspring more likely to use heroin.


DADS’ BEHAVIOR COUNTS TOO. Dad’s exposure to THC as an adult also led to offspring who preferred opiates. This was based on epigenetic changes passed on in the sperm. To the extent that this also happens in humans, one could ask how much of the current opiate epidemic is based on parental use of marijuana. Mom’s and dad’s smoking pot could make their offspring more vulnerable to opiate addiction.

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.

Cannabis and Cannabinoids Don’t Work for Pain or Posttraumatic Stress Disorder

Aaron S. Wolfgang, MD and Charles W. Hoge, MD reviewed data on cannabis in JAMA Psychiatry and found that there were big placebo effects and no evidence for effectiveness of cannabis in military personal.

This negative data, along will all the liability of cannabis potentially causing or triggering psychosis, bipolar disorder, and schizophrenia (as well as possibly contributing to cognitive dysfunction, worsening anxiety and depression in patients with mood disorders) makes the use of pot for medical purposes an entirely foolhardy proposition, as well as a waste of money.

Legalization of pot has helped people avoid jail but precipitated a rash of use and over use.

So the bottom line from this editor is: Get Your Priorities Straight. Cannabis and Cannabinoids Don’t Work for Pain or Posttraumatic Stress Disorder and they Worsen Most Everything Else. Save your Money and Do Something Nice for Yourself and Others Instead.

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.)

More Data that Long Term Lithium Treatment Does NOT CAUSE RENAL TOXICITY (more than those on valproate).

In a recent meeting, Mark Weiser of Sheba Medical Center analysed data from “from the Clalit Health Services (CHS) database, the largest provider of health insurance in Israel, n=4.8 million, representing over 50% of the Israeli population. This study examined lithium use between the years 2000 and 2022, focusing on its impact on kidney and thyroid function…(and) compared all patients receiving lithium (n=19,433) to all patients receiving valproic acid (n=44,524). There was no different in the life-time rates of dialysis between patients treated with lithium and patients treated with valproic acid (1.03% vs 0.99%, p = 0.683). A lifetime diagnosis of hypothyroidism was more common in patients receiving lithium (21.84%) in comparison to patients treated with valproic acid (8.83%, p = <0.0001). Conclusions: In this large population study, treatment with lithium was not associated with decreased kidney function but was associated with a clinical diagnosis of hypothyroidism. These factors should be taken into account when considering treatment with lithium.”

Editors Note: In patients on lithium, overtime there are small decreases in estimated glomerular filtration rate (eGFR), but these do not differ from those seen in physiological age adjusted eGFR in the general population. These data are convergent with the large national studies of Kessing et al in Denmark and indicate that the long-held view of lithium causing undo renal toxicity are not accurate and are based on inappropriate suppositions without an adequate control group. They found more end-stage renal dysfunction in bipolar patients treated with anticonvulsants than with lithium.

THERE IS A GRAVE UNDERUTILIZATION OF LITHIUM DUE IN LARGE PART TO THE FALSE ASSUMPTION THAT IT CAUSES EXCESS RENAL TOXICITY. PATIENTS AND CLINICIANS SHOULD BE MADE AWARE OF THE NEW DATA THAT THIS IS LIKELY RELATED TO POOR METHODOLOGY AND BEGIN TO MORE FREQUENTLY THINK ABOUT USING LITHIUM — UNEQUIVOCALLY THE BEST DRUG FOR THE TREATMENT OF BIPOLAR DISORDER. LITHIUM ALSO HAS THE BEST DATA FOR REDUCING EPISODES OF BOTH DEPRESSION AND MANIA AND FOR HAVING POSITIVE EFFECTS IN PREVENTING SUICIDE. USING LITHIUM MORE OFTEN WILL UNDOUBTEDLY MARKEDLY IMPROVE PATIENTS WELL BEING AND SURVIVAL. THIS EDITOR BELIEVES THAT GIVEN LITHIUM’S MULTIFACETED ROLE IN AMELIORATING ALMOST ALL ASPECTS OF THE COURSE OF BIPOLAR DISORDER, IT SHOULD BE CONSIDERED A “DISEASE MODIFYING DRUG.” THERE ARE MULTIPLE DISEASE MODIFYING DRUGS FOR TREATMENT OF MULTIPLE SCLEROSIS, AND EXPERTS IN THAT FIELD BELIEVE THAT DISEASE MODIFYING SHOULD BE STARTED AS EARLY AS POSSIBLE AFTER FIRST DIAGNOSIS. A SIMILAR CONCLUSION WOULD NOW APPEAR APPROPRIATE FOR LITHIUM.

Of note is the other widely held reason for not using lithium more often is that it causes hypothyroidism. While this is clearly correct based on the Weiser study and many other data, patients should be aware that this well-known condition is readily correctable with thyroid hormone replacement and does not produce an undo burden on patients.

Since lithium has many other assets including: increasing hippocampal volume; protecting memory; and increasing the length of telomeres (critical to sustaining good medical and psychiatric health), its wider use in bipolar disorder should be a no brainer. However, it is likely (like most revisions in medical lore) to take 10 years or more before this re-evaluation of lithium has an impact on conventional treatment decisions, so physicians should make very active and conscious decisions about changing their routine choices of treatment for each patient with bipolar disorder.

FDA Warns of Potentially Lethal Reaction to Seizure Meds

Megan Brooks reports:

“The antiseizure drugs levetiracetam (Keppra, Keppra XR, Elepsia XR, Spritam, generic) and clobazam (Onfi, Sympazan, generic) can cause a rare but serious drug hypersensitivity reaction that can be life threatening if not detected and treated promptly, the US Food and Drug Administration (FDA) warns in an alert issued today.

Known as drug reaction with eosinophilia and systemic symptoms (DRESS), it may start as a rash but can quickly progress and cause injury to internal organs, the need for hospitalization, and death, the FDA notes.

Three cases occurred in the US, and 29 occurred abroad. In all 32 cases, the patients were hospitalized and received medical treatment; in two cases, the patients died.

The median time to onset of DRESS in the levetiracetam cases was 24 days; times ranged from 7 to 170 days. The reported signs and symptoms included skin rash (n = 22), fever (n = 20), eosinophilia (n = 17), lymph node swelling (n = 9), and atypical lymphocytes (n = 4). The median time to onset of DRESS in the levetiracetam cases was 24 days; times ranged from 7 to 170 days. The reported signs and symptoms included skin rash (n = 22), fever (n = 20), eosinophilia (n = 17), lymph node swelling (n = 9), and atypical lymphocytes (n = 4)…. DRESS symptoms resolved when levetiracetam was discontinued.”

NEW FINDINGS BY COLVIN AWARD WINNER ROGER MCINTYRE

There is a convergence of finding of the occurrence of cognitive dysfunction in diabetes, obesity, and bipolar and unipolar mood disorders. This is based on new evidence of insulin resistance in the CNS found in examination of exosomes. Insulin is neuroprotective and neurotrophic much like lithium. People on lithium do not have evidence of loss of grey and white matter that other’s with bipolar disorder who are not on lithium have. Intra-nasal insulin can improve cognition. The widely used insulin sensitizers GLP-1s for diabetes and weight loss appear to also decrease cognitive decline. The GLP-1 liraglutide improves cognition in mood disordered patients, and increases brain NAA in obesity. The GLP-1 semaglutide appears to increase motivation, cognition and overcome reward deficits. These agents could have anti-depressant and depression preventing properties which remain to be further confirmed in ongoing clinical trials.

McIntyre finds that 80% of Alzheimer’s patients are insulin resistant and the GLP-1s are being studied for this illness as well. There is also a convergence of deficits in cognition, motivation, normal mood in Alzheimer’s patients.

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