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We’re back!
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.
Obesity is associated with reduce cortical thickness in bipolar disorders
Sean R. McWhinney et al reported in Psychological Medicine (2023) that obesity was associated with reduced cortical thickness (but not surface area) in most areas of the brain in 2832 participants.
Editors Note: Patients and clinicians should try to prevent and reduce weight gain using the best tolerated medications from the outset and helping with weight loss by various measures. These can include the anticonvulsants topiramated and zonisamine, the combination of bupropion and naltrexone, and the use of new anti-diabetic drugs such as Jardiance and Farxiga that have weight loss (greater than with metformin) as a side effect. Prescribing a good diet and regular exercise is also indicated. Reducing obesity will likely make you live longer and maybe could even make you smarter.
Single-dose psilocybin-assisted therapy in major depressive disorder: a placebo-controlled, double-blind, randomized clinical trial
von Rotz et al reported in eClinical Medicine (the Lancet) that a single dose of psilocybin produced a huge AD (anti-depressant) effect compared to placebo. A dose of 0.215mg Kg (about 15mg for a 70kg person) had a rapid onset AD effect that persisted for at least 14 days. Music was played and in a living room like environment. Psychological support was provided on 3 visits pretreatment and on days 8 and 14 for a total of 14 hours
Inflammatory marker CRP predicts worse course of adolescent bipolar disorder
Sudhir Karthikeyan in Ben Goldstein’s lab in Toronto reported in Brain Behav Immun (2022) that in 79 adolescents the inflammatory marker CRP (C-Reactive Protein) was higher and the anti-inflammatory cytokine Il-10 was lower during the most ill periods compared to normal volunteers. “Moreover, higher CRP levels (p = 0.009) at intake predicted greater time to recovery from the index symptomatic episode.” They concluded that: “In the first repeated-measures study on this topic in adolescents with BD, we found evidence that CRP, an inexpensive and ubiquitous blood test, may be useful in predicting the prospective course of BD symptoms. “
Adiposity and Cognitive Function Are Bidirectionally Related
Sakib et al reported in JAMA New Open that ” In this cohort study that included 11,103 adolescents, executive function and episodic memory were bidirectionally associated with adiposity, and this association was statistically mediated through the morphology of the lateral prefrontal cortex. Obesity (BMI) was associated worse executive functioning, episodic memory, and task performance. Thus preserving cognition is another reason beyond physical health to follow a good diet, get exercise, and use medications for weight loss if obesity is a problem.”
Familial Aggregation of Major Depression Predicts Risk of Major Depression
Gronemann et al reported in JAMA Psychiatry: “In this cohort study of 2,903,430 individuals, maternal, paternal, full sibling, or half-sibling with MD were associated with 2-fold higher risks of MD in men and women….(E)xposure to family MD during childhood and adolescence was associated with increased risk. The risk increased with number of affected family members; (however) individuals exposed when 30 years or older had markedly lower risk.”
Editors Note: Even depression in grandparents adds further to the risk of depression. When there is high familial loading for depression and other psychiatric illnesses, one should be alert to the possible onset of depression in young individuals and treat them early and well accordingly.
Abuse Histories Decrease Rate of Remission to Antidepressant Treatment
Harkness et al reported in The Canadian Journal of Psychiatry (2023) “Greater severity of emotional maltreatment perpetrated by the mother was a significant and direct predictor of lower odds of week 16 remission (odds ratio [OR]=1.68, P =0.02). In contrast, the relations of paternal-perpetrated emotional maltreatment and physical maltreatment to week 16 remission were indirect, mediated through greater severity of anhedonia at week 8.”
Editors note: Response to ADs is less good in those with a history of abuse in childhood. Therefore psychotherapy should be added to medications in such situations to attempt to enhance responsiveness.
Sleep Disturbances in Pediatric Bipolar NOS is the Same as in BP I
Gianni Faedda reported in Frontiers in Psychiatry (2012) that decreased need for sleep is as prominent in BP NOS children as in those with BP I. So it appears that with the exception of only brief periods of mania in BP NOS, these children have similar characteristics to those with full blown BP I. Thus in addition to the briefer periods of mania, one should be on the look out for all the symptoms of bipolar disorder that are not typical of ADHD, including brief or extended periods of euphoria, decreased need for sleep, more extreme degrees of irritability and poor frustration tolerance, hallucination, delusions, suicidal and homicidal ideation, more severe depression, and increases in sexual interest and actions. When these are present, the bipolar mood instability should be treated first and only then small doses of psychomotor stimulants can be used to treat what ever residual ADHD remains. The typical symptoms of ADHD are very of present and comorbid in childhood onset bipolar disorder and cannot be used to discriminate the two diagnoses. The children with BP NOS are as dysfunctional as those with BP I and take longer to stabilize, so pharmacological treatment may need to be intensive, multimodal, and supplemented by Family Focused Therapy (FFT) or a related family therapy. It is most often not conceptualized as such, but BP NOS as well as BP I should be considered as a medical emergency and handled by a sophisticated pediatrician and/or referred for psychiatric consultation and therapy. The longer bipolar disorder is not treated, the worse the outcome is in adulthood.
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.”
