“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.

Risk of Attempted or Completed Suicide in Borderline Personality Disorder: Reduced with ADHD meds; Increased with Benzodiazepines

Johannes Lieslehto et al 2023 reported in JAMA New. Open on the comparative effectiveness in 22,601 individuals with BPD that “ADHD medication was the only pharmacological treatment associated with reduced risk of suicidal behavior among patients with BPD. Conversely, the findings suggest that benzodiazepines should be used with care among patients with BPD due to their association with increased risk of suicide.” Mood stabilizers had no effect while antipsychotics minimally and antidepressants moderately increased risk of suicide attempts or completed suicide.

The Cognitive Effects of Electroconvulsive Therapy in Community Settings

Harold Sackeims’ review in Neuropsychopharmacology, 32, 244-254 (2007) remains one of the best updates indicating that the cognitive effects of Electroconvulsive Therapy (ECT) are not always benign. They followed 347 patients from seven facilities in New York city and tested them after their last session of ECT and then again 6 months later. They reported that “Electrical waveform and electrode placement had marked cognitive effects. Sine wave stimulation resulted in pronounced slowing of reaction time, both immediately and 6 months following ECT. Bilateral (BL) ECT resulted in more severe and persisting retrograde amnesia than right unilateral ECT. Advancing age, lower premorbid intellectual function, and female gender were associated with greater cognitive deficits. Thus, adverse cognitive effects were detected 6 months following the acute treatment course. Cognitive outcomes varied across treatment facilities and differences in ECT technique largely accounted for these differences. Sine wave stimulation and BL electrode placement resulted in more severe and persistent deficits.”

Editors note: This is why it is important to recommend right unilateral ultra brief pulse (RUUBP) ECT both for acute and continuation treatment if necessary. Continuing RUUBP ECT rather than converting to bilateral ECT would appear to be preferable.

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.

U.S. FDA Approves VRAYLAR® (cariprazine) as an Adjunctive Treatment for Major Depressive Disorder

“A Phase 3 Study 3111-301-001 showed a clinically and statistically significant change from baseline to week six in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score for patients treated with cariprazine at 1.5 mg/day + ADT compared with placebo + ADT. A second registration-enabling study, RGH-MD-75, showed a clinically and statistically significant change from baseline to week eight in the MADRS total score for patients treated with cariprazine at 2-4.5 mg/day (mean dose 2.6 mg) + ADT compared with placebo + ADT.

Cariprazine was generally well tolerated in 6- and 8-week studies. Mean weight change was < 2lbs and ? 3% of patients had a weight increase of ? 7%.

The starting dosage of VRAYLAR is 1.5 mg once daily. Depending upon clinical response and tolerability, the dosage can be increased to 3 mg once daily on Day 15. In clinical trials, dosage titration at intervals of less than 14 days resulted in a higher incidence of adverse reactions. The maximum recommended dosage is 3 mg once daily.

Most common adverse reactions observed in the adjunctive MDD studies (? 5% and at least twice the rate of placebo) were:

Akathisia, nausea, and insomnia at the recommended doses in 6-week, fixed-dose trials

Akathisia, restlessness, fatigue, constipation, nausea, increased appetite, dizziness, insomnia, and extrapyramidal symptoms in one 8-week flexible-dose trial at a titration of less than 14 days”

Lithium is a Lifesaver in Bipolar Disorder

Batya Swift Yasgur MA, LSW reported in Medscape Medical News on November 28, 2022 that “Mood stabilizers protect against suicide and all-cause mortality in patients with bipolar disorder (BD), including natural mortality, with lithium emerging as the most protective agent, new research suggests.

Investigators led by Pao-Huan Chen, MD, of the Department of Psychiatry, Taipei Medical University Hospital, Taiwan, evaluated the association between the use of mood stabilizers and the risks for all-cause mortality, suicide, and natural mortality in over 25,000 patients with BD and found that those with BD had higher mortality.

However, they also found that patients with BD had a significantly decreased adjusted 5-year risk of dying from any cause, suicide, and natural causes. Lithium was associated with the largest risk reduction compared with the other mood stabilizers.

Intermittent theta burst magnetic stimulation (iTBS) is FDA approved.

As reported in Psych. News:?The Food and Drug Administration (FDA) has cleared the SAINT Neuromodulation System for the treatment of refractory depression in adults, Magnus Medical Inc. (the manufacturer of the product)?announced?Tuesday. SAINT is a?modified form of transcranial magnetic stimulation?(TMS) that compresses weeks of conventional TMS therapy into just five days”. ?Regular TMS takes 20-30 minutes per daily session while iTBS takes about 5 minutes and thus can be applied many times in a single day. ?”As demonstrated in a clinical trial?published?in?The American Journal of Psychiatry, Montgomery-Åsberg Depression Rating Scale (MADRS) scores dropped by 62% among participants following five days of SAINT stimulation compared with a 14% drop among participants receiving sham stimulation. These improvements were sustained over a four-week follow-up.” ?The method was developed by Nolan Williams and he used MRI to best target the site of stimulation 

Cannabidiol (CBD) does not make cannabis safer

Amir Englund et al reported in Neuropsychopharmacology in A randomised, double-blind, cross-over trial of cannabis with four different CBD:THC ratios that CBD did not protect against the adverse effect of THC. These included impaired delayed verbal recall ( p?=?0.001) and induced positive psychotic symptoms on the PANSS ( p?=?2.41?×?10–5).

Editors Note: Not only does marijuana impair memory, it is a risk factor the onset of bipolar disorder and schizophrenia. When pot is used by a person with a unipolar or bipolar mood disorder, there are increases in depression and anxiety and an overall less favorable course of illness. If a person with a mood disorder uses heavy amounts of marijuana, they could consider buying N-acetylcysteine (NAC) 500mg and increasing the dose to 1,000mg twice a day within a week as this has been shown to decrease drug use compared to placebo in adolescents and young adults using and abusing pot. Most people who sell pot, are not well-informed about its dangers and just want to make money.

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