Two different subtypes of early onset unspecified bipolar disorder (USBD)
The first subtype is classical BP NOS (Not Otherwise Specified) having all the characteristics of full-blown bipolar disorder except for only having brief durations of mania and responding to conventional treatment. The second is what is now called Temperature and Sleep Dysregulation Disorder (TSDD) and was formerly described by D. Papolos as the Fear of Harm (FOH) syndrome, and requires a different treatment approach.
Clinicians should be alert to unique symptoms in children who might have TSDD as such a diagnosis would lead to a unconventional treatment paradigm. We emphasize the importance of specifically asking parents about evidence of over heating (red face and red ears) and high tolerance for cold (going outside markedly under-dressed) and the presence of fear of sleep and horrific nightmares, as these may lead one to consider the diagnosis of TSDD.
If these two novel aspects (temperature and sleep dysregulation) occur in the presentation of a highly fearful and behaviorally dysregulated child with bipolar-like symptoms, these may lead to the consideration of an unconventional treatment paradigm. It utilizes 1) high dose lithium; 2) clonidine and other practical approaches to achieve cooling and relieve over heating; and 3) ascending doses of intranasal ketamine (as described by Papolos et al 2013; 2018). This may be of considerable clinical importance as a large group of children with this unique presentation respond very poorly to conventional treatments for bipolar disorder and remain highly impaired and dysfunction throughout their childhood and adolescence.
If these children instead are treated with: lithium (to achieve blood levels of 1.0 meq/L or higher); clonidine (0.1- 0.3mg IR and 0.1mg ER at noon and HS) and other practical ways to achieve cooling; followed by ascending intranasal doses of ketamine (starting at 20mg and increasing toward 80-260mg/day, repeated every 2-3 days), marked improvement can be achieved. This occurs in conjunction with ketamine’s positive effects on fear and aggressive behaviors in association with its ability to reduce core body temperature.
We highlight this potential alternative treatment approach as long term positive effects have been achieved with it in open case series (Papolos et al 2013; 2018 ). The efficacy of this treatment approach has not been validated in controlled clinical trials, but we believe wider recognition of the two subtypes of USBD– BPNOS and TSDD,– will lead to more systematic research on treatment. Actively looking for the unique features of TSDD and pursuing its unconventional treatment may lead to long term positive effects in a child previously viewed as having an intractable psychiatric illness.
Antihypertensives That Stimulate vs Inhibit Type 2 and 4 Angiotensin II Receptors Decrease Dementia
Marcum et al in JAMA New Open (2023) found that in “57,773 Medicare beneficiaries, initiation of antihypertensive medications that stimulate vs inhibit type 2 and 4 angiotensin II receptors was associated with a statistically significant 16% lower risk of incident dementia, over a median of 6.9 years of follow-up.”
“Angiotensin II receptor type 2 and 4–stimulating antihypertensive medications (hereafter, stimulating medications) included: Angiotensin II receptor type 1 blockers, dihydropyridine calcium channel blockers, and thiazide diuretics.
Angiotensin II receptor type 2 and 4–inhibiting antihypertensive medications (hereafter, inhibiting medications) included: angiotensin-converting enzyme (ACE) inhibitors, ?-blockers, and nondihydropyridine calcium channel blockers.”
Editors Note: If you have hypertension and are at risk for cognitive decline, know that your choice of effective antihypertensive drugs can lead to better cognitive outcomes. Drugs that stimulate the angiotensin II receptor type 2 and 4 help prevent dementia. These drugs include:
ARB type 1, dihydropyridine calcium channel blockers, and thiazide diuretics. (Good guys)
Those that inhibit Angiotensin II receptors types 2 and 4 do not prevent dementia. These drugs include:
ACE inhibitors, beta blockers, and non-dihydropyridine calcium channel blockers. (Bad guys)
Talk with your doc about drugs equally for blood pressure control but those that also have benefits for ultimate preservation of cognition.
Hyperinsulinemia Associated Depression
Haider Sarwar writes in Clinical Medicine Insights (2022) that “Hyperinsulinemia promotes fat accumulation, causing obesity. Being an inflammatory state, obesity can induce further inflammation and is a risk factor for HPA (hypothalamic pituitary axis) dysregulation through hypercortisolism-related hyperglycemia….A disruption on SNS (sympathetic nervous system) activity increases insulin levels, and induces glycogenolysis in the liver and lipolysis in adipose tissue during hypoglycemia. Hyperglycemia-hyperinsulinemia exacerbates inflammation and increases the oxidative stress along with regulating the levels of norepinephrine in the brain sympathetic system. Increased inflammatory cytokines have also been shown to disrupt neurotransmitter metabolism and synaptic plasticity which play a role in the development of depression via inhibiting serotonin, dopamine, melatonin, and glutamate signaling. An increased level of plasma insulin over time in the absence of exercising causes …an increase in insulin resistance due to obesity and further culminates into depression….. Triple therapy with SSRI, bupropion, and cognitive behavioral therapy aids in improving glycemic control, lowering fasting blood glucose, decreasing the chances of relapse, as well as decreasing cortisol levels to improve cognition and the underlying depression.”
6 Minutes of Intense Cycling Produces Major Increases in BDNF
Brain derived neurotrophic factor (BDNF) is necessary for new synapses and call survival. A new study in J. Physiology (2023) reports that the increases in BDNF from short intense cycling exercise are much greater than from prolonged (90-minute) light cycling. The authors think that this is cause by the increases in lactate produced which helps up regulate BDNF production. This could be good for fighting depression and Alzheimer’s disease, where BDNF levels are low.
Bottom line: If you don’t have much time, bust your buns.
Chronic Fatigue, Depression and Anxiety Symptoms in Long COVID Are Strongly Predicted by Neuroimmune and Neuro- Oxidative Pathways Which Are Caused by the Inflammation during Acute Infection
HK Al-Hakeim et al in Michael Maes’ lab report in J. Clinical Medicine (2023) on very important findings about immune and oxidative changes in long COVID with “physio- somatic (chronic fatigue syndrome and somatic symptoms) and affective (depression and anxiety) symptoms. The severity of the long COVID physio-affective phenome is largely predicted by increased peak body temperature (BT) and lowered oxygen saturation (SpO2) during the acute infectious phase….. We recruited 86 patients with long COVID (3–4 months after the acute phase) and 39 healthy controls and assessed serum C-reactive protein (CRP), caspase 1, interleukin (IL) 1?, IL-18, IL-10, myeloperoxidase (MPO), advanced oxidation protein products (AOPPs), total antioxidant capacity (TAC), and calcium (Ca), as well as peak BT and SpO2 during the acute phase. Results: Cluster analysis revealed that a significant part (34.9%) of long COVID patients (n = 30) show a highly elevated NT (neurotoxicity) index as computed based on IL-1?, IL-18, caspase 1, CRP, MPO, and AOPPs. Partial least squares analysis showed that 61.6% of the variance in the physio-affective phenome of long COVID could be explained by the NT index, lowered Ca, and peak BT/SpO2 in the acute phase and prior vaccinations with AstraZeneca or Pfizer. The most important predictors of the physio-affective phenome are Ca, CRP, IL-1?, AOPPs, and MPO. Conclusion: The infection–immune–inflammatory core of acute COVID-19 strongly predicts the development of physio-affective symptoms 3–4 months later, and these effects are partly mediated by neuro-immune and neuro-oxidative pathways.”
Editors Note: These finding are important as they may lead to new treatment interventions. BNN readers are reminded of a previous BNN article by investigators from Yale (written by by Isabella Backman on Dec. 13, 2022) that in a new case study, they found that guanfacine plus N-acetylcysteine (which is an anti-inflammatory, anti-oxidant, and glutathione precursor) “mitigated and sometimes eliminated the cognitive impairment known as “brain fog” that often accompanies long COVID.
Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naïve Social Phobia Patients
M M Bergamaschi, et al reported in Neuropsychopharmacology volume 36, pages 1219–1226 (2011) that the one of the ingredient in cannabis, the diol or cannabidiol (CBD), containing none of the usual THC which make up the vast majority of plant-based marijuana, reduces the anxiety Induced by simulated public speaking in treatment-naïve social phobia patients. They used “CBD (600?mg) in powder, ?99.9% pure (kindly supplied by STI-Pharm, Brentwood, UK and THC-Pharm, Frankfurt, Germany),… dissolved in corn oil.” This CBD has shown efficacy in other anxiety disorders and is FDA approved for one form of seizure disorder. This pure form of CBD is very expensive and usual preparations of available cannabis contain mostly THC and only minute amounts of CBD. Thus, the generalizability of these results to people using the widely available preparations of cannabis is extremely unlikely.
