Cognitive Function and White Matter Integrity in Individuals With Bipolar Disorder

Highlights from Posters Presented at the Society of Biological Psychiatry Meeting, April 27-29, 2023 in San Diego

Jennifer McDowell reported that they found “significantly reduced FA (fractional anisotropy) values in 85 bipolar probands compared to 66 controls” in multiple (n=8) white matter tracts. There were significantly lower scores in bipolar probands compared to controls on composite scores, ( p = 0.007), verbal fluency, ( p < 0.001), and symbol coding, (p = 0.023). They concluded that: “ Impacted connectivity in critical fiber tracts may be key to understanding the neural underpinnings of deficits, like cognition, observed in this clinical population.”

Editors note: It is of interest that lithium has been shown to normalize some white matter abnormalities in youngsters and help preserve cognitive function in older individuals. On this and many other accounts, way too little lithium is being used in the treatment of patients with bipolar disorder. Lithium not only increases neurogenesis (new grey matter neurons) and hippocampal volume, but also has positive effects on white matter tracts and even increases the length of one’s telomeres (which keeps you more healthy). In other ungrammatical words, “If your brain is not connected right, it don’t work right.”

Greater Severity of Depression in Youth With Bipolar Disorder versus Unipolar Depression

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

Aaron Silverman of the University of Toronto, CAMH found that “youth (age 13-21) with [Bipolar Disorders] compared to those with [unipolar] depression had significantly higher (more severe) ratings on depressed mood (p = .001), irritability (p = .037), anhedonia (p = .004), negative self-image (p < .001), hopelessness (p = .04), fatigue (p = .001), hypersomnia (p = .001), suicidal ideation (p = .04), and recurrent thoughts of death (p < .001).”

Intravenous Arketamine As Adjunctive Treatment for Bipolar Depression

Highlights from Posters Presented at the Society of Biological Psychiatry Meeting, April 27-29, 2023 in San Diego

I.D. Bandeira of Stanford University reported on the feasibility and safety of the (R)-enantiomer of ketamine (arketamine) in treating six patients with bipolar depression: “Subjects received two intravenous infusions of arketamine of 0.5mg/kg, followed by 1mg/kg one week later.” Patients improved after the first dose and after “1mg/kg dose, the mean MADRS [Montgomery–Åsberg Depression Rating Scale] total score before the second infusion was 32.0, which dropped to 17.66 after 24h (p<0.001).” All individuals tolerated both doses, exhibiting no dissociative or manic symptoms.

LITHIUM’S AMAZING DIVERSITY OF ASSETS

Editor’s Note: Lithium is vastly underutilized. There is wide spread ignorance about its many assets and misconceptions about its few side effects. Here is an update that should be of interest to potential users, family members, and clinicians.

Lithium:

  • Prevents unipolar and bipolar depression
  • Augments effects of antidepressants in unipolar depression
  • Potentiates the effects of atypical antipsychotics in treating mania and depression
  • Reduces inflammation
  • Normalizes some aspects of cardiovascular risk
  • Normalizes secretions for monocytes and leukocytes
  • Increases neurogenesis, BCl-2, and hippocampal and thalamic volumes
  • The increases in neuroprotective factors occurs at brain levels below typical therapeutic dosages
  • Protects against memory deterioration
  • Lowers dementia risk in old age
  • Reduces suicide clinically and at minute concentrations in the water supply
  • Lengthens telomeres and increases longevity
  • Reduces size of lesions in models of stroke, AIDS, and Huntington’s chorea
  • Normalizes circadian rhythms
  • Reduces manic-like behavior induced by clock gene mutations
  • Prevents calcium currents and increased firing rate in stem cells from bipolar patients
  • Induces minimal to no weight gain on long term follow up
  • Does not increase risk of kidney failure when given at blood levels of .6 to .8 blood levels
  • Protects against spine and hip osteoporosis

Conclusion: With so many assets and so few liabilities, physicians and patients should reconsider the benefits of lithium and use it more often, not only in the few who respond to it as a monotherapy, but as a adjunct to the many other treatments of bipolar disorder. This should be a “no brainer” as lithium will very likely help some have fewer problems from their illness and may even help them live longer.

Many of these points are summarized in the open access publication: Robert M Post, The New News About Lithium: An Underutilized Treatment in The United States, Neuropsychopharmacology accepted article preview 4 October 2017; several new updates have been added from the International Society on Bipolar Disorders meeting, Chicago, June, 2023.

Even Psychotic Mania Does Not Preclude Remarkable Success

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

Major (Two Star) General Gregg F. Martin described his lifetime hyperthermia (high energy) as a youngster morphing into full-blown mania and then a fulminatory psychotic mania. This was undiagnosed and untreated for almost 20 years and was accompanied by anxiety and Iraq war-induced PTSD and, eventually, terrifying delusions and hallucinations; all the while he was somehow functioning at a very high level and getting repeated promotions.

When finally and properly diagnosed, he was told he had to resign. He was treated with lithium and other agents, and achieved a complete recovery. He is now lecturing about his experience with bipolar illness and working on efforts directed at better illness recognition, treatment, and destigmatization. He is not only a war hero, but also an illness hero.

Effectiveness of Repeated Ketamine Infusions for Treatment Resistant Bipolar Depression

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

Farhan Fancy, of the University of Toronto, gave 66 highly treatment resistant (unselected) bipolar I or II patients four sub-anesthetic doses of IV ketamine (0.5-0.75mg/kg) over a two-week period. They saw significant reductions in depression, anxiety, suicidality, and disability. Response rates were 35% and remission rate was 20%. “Infusions were generally well tolerated with treatment-emergent hypomania observed in only three patients (4.5%) with zero cases of mania or psychosis.”

Disrupted Circadian Temperature Rhythm in Skin Temperature in Bipolar Mania

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

Andrea Stautland of University of Bergen studied the nocturnal temperature of sleeping participants in mania and during remission between 3:00am and 6:00am (n=12). In mania, but not in remission there were “highly significant mean changes (lack of night time decreases) between baseline and 4:30am and 6:00am, with p=0.012 and p=0.037, respectively.”

Editors Note: This data is of interest in light of the new subtype of unspecified bipolar disorder called Temperature and Sleep Dysregulation Disorder (TSDD) characterized by profound behavioral dyscontrol, marked sleep disturbance, and temperature dysregulation (red face and ears, being too hot, going out in the cold underdressed). This extremely dysfunctional syndrome responds to high dose lithium; melatonin, clonidine, and other cooling techniques; and ascending and then repeated doses of intranasal ketamine (as described by Papolos et al 2013; 2018).

“Pharmacotherapy of Bipolar Depression”

Roger McIntyre gave a talk on the “Pharmacotherapy of Bipolar Depression” at the International Society for Bipolar Disorders Conference in Chicago, June 22-25, 2023

He pointed out that, contrary to the many approved agents for mania, there were few FDA-approved drugs for depression in patients with Bipolar Disorders. These approved drugs included: cariprazine (Vraylar); lumateperone (Caplyta); lurasidone (Latuda); quetiapine (Seroquel); and the olanzapine-fluoxetine combination (Symbyax). Other non-approved agents include: lithium, lamotrigine, antidepressants, MAOIs, pramipexole, carbamazepine, ketamine, bupropion+dextromethorphan, amantadine, memantine, and possibly minocycline and celecoxib. Surprisingly, more than 3,000 bipolar depressed patients have been reported to be taking ketamine and that this was not associated with the induction of hypomania or mania.

McIntyre reported on the antidepressant (AD) effects of intra-nasal (i.n.) insulin. The insulin receptor sensitizer metformin had AD effects, but only in those who converted to insulin sensitivity.

McIntyre reported on the mixed effects of the GLP-1 agonists in the prevention of depression (Cooper et al J. Psychiatric Res, 2023). This is of interest in relationship to the bidirectional relationship of diabetes mellitus and depression.

Liraglutide appeared to have an anti-anhedonia effect. Semaglutide had AD and antianxiety effects in animal models of depression.

Recent studies have explored the antidepressant effect of psilocybin. Small studies have indicated that it has rapid onset of AD effects, and, in contrast to ketamine where rapid onset AD and anti-suicidal effects are short lived, the AD effect of psilocybin may be more prolonged.

Ketamine repairs structure and function of prefrontal cortical neurons via glutamate NMDA receptor blocking action, while psilocybin and other psychedelics act via stimulating 5HT2A receptors. One single case study suggested that blocking 5HT2A receptors with trazodone could achieve a rapid onset of AD effects of psilocybin without the psychedelic effects, a very interesting finding that requires replication.

Early Antidepressant Use is Associated with Rapid Cycling Bipolar Disorder

Highlights from Posters Presented at the Society of Biological Psychiatry Meeting, April 27-29, 2023 in San Diego

A.C. Courtes and Jair Soares reported that “Antidepressants were prescribed as the first psychiatry medication in 74/114 (65%) of BD patients.” This and alcohol use disorder were independent predictors of rapid cycling.

Higher Brain Temperature in Youth Bipolar Disorder Using a Novel Magnetic Resonance Imaging Approach

Highlights from Posters Presented at the Society of Biological Psychiatry Meeting, April 27-29, 2023 in San Diego

Ben Goldstein of the University of Toronto reported that “Brain temperature was significantly higher in BD (bipolar youth) compared to CG (control group) in the precuneus. Higher ratio of brain temperature-to-CBF [cerebral blood flow] was significantly associated with greater depression symptom severity in both the ACC [anterior cingulate cortex] and precuneus within BD.”

These finding are of particular interest in light of the Unspecified Bipolar Disorder subtype called Temperature and Sleep Dysregulation Disorder (TSDD), where patients are over heated and respond to clonidine and other cooling techniques along with lithium and repeated intranasal ketamine insufflations.

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