“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.
An Open Label Study of Synthetic Psilocybin in Bipolar Type II Depression
Highlights from Posters Presented at the Society of Biological Psychiatry Meeting, April 27-29, 2023 in San Diego
Scott Aaronson reported on patients receiving a single dose of synthetic psilocybin. All subjects had three preparatory sessions prior to dosing and three integration sessions post dosing and were followed for 12 weeks.
“At the three week primary outcome measure, 11 of 14 participants (78.6%) met remission criteria.” They concluded: “Most subjects reported significant improvement in chronic depressive symptoms without hypomania or suicidality and durability lasting for three months follow-up.”
Cannabis Use Disorder Increases Risk of Subsequent Unipolar Depression and Bipolar Disorder
Jefsen et al report in JAMA Psychiatry. that in “[6,651,765] individuals in Demark, cannabis use disorder was associated with an increased risk of (subsequent) both psychotic and nonpsychotic unipolar depression and bipolar disorder….Associations between CUD and subsequent affective disorders were estimated as hazard ratios (HRs) using Cox proportional hazards regression with time-varying information on CUD, adjusting for sex; alcohol use disorder; substance use disorder; having been born in Denmark; calendar year; parental educational level (highest attained); parental cannabis, alcohol, or substance use disorders; and parental affective disorders….Cannabis use was associated with an increased risk of bipolar disorder in men (HR, 2.96; ) and women (HR, 2.54; )”, and was highest for psychotic bipolar disorder (HR, 4.05; 95% CI, 3.52-4.65).
Editors Note: Marijuana is not a benign substance. “In all, 60,?696 individuals received a diagnosis of (cannabis use disorder) during follow-up, and 260,?746 (3.9%) developed an affective disorder.”
DRAMATIC PROPHYLACTIC RESPONSE TO NIMODIPINE: A Case Report
(This is an invited contribution by Robert Westhead.)
This 50 year old man had a lifetime of incapacitating rapid cycling (10 days up and 10 days down) bipolar I disorder, but then for the past 4 years has had a complete remission on nimodipine (60mg QID). He remains on lithium (800mg), and of his other long-term medications, he has titrated quetiapine down from 800mg to 50mg and has discontinued phenelzine.
He had previously failed to respond to combinations of:
· Lithium
· Anticonvulsant mood stabilizers (including divalproex sodium, lamotrigine, carbamazepine and pregablin)
· Atypical antipsychotics (including quetiapine, aripiprazole and lurasidone)
· Antidepressants (including SSRIs eg citalopram and sertraline, NSRIs eg venlaflaxine and mirtazapine, and a MAOI eg phenelzine)
· Thyroxine
· Propranolol
· Clonazepam
He wanted to highlight this dramatic response to nimodipine in combination with lithium as this dihydropyridine calcium channel blocker is not well known or frequently used for its prophylactic effectiveness.
He noted that as well as stopping the rapid cycling, the nimodipine has provided complete relief from comorbid social anxiety symptoms and remediated cognitive and memory impairment.
This response to nimodipine potentially also has pathophysiological implications. Nimodipine directly blocks the CACNA1C calcium influx gene that has repeatedly been associated with vulnerability to depression, bipolar disorder, and schizophrenia in gene wide association studies. This patient does not know whether he carries this gene variant, but assays for it are routinely available as performed by the company Genomind.
Thus, it remains an open question as to whether those who have the CACNA1C variant would be more responsive to nimodipine compared to those without the variant. Certainly, the efficacy of this agent in treatment of patients with bipolar disorder deserves further consideration and study.
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.
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. “
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.
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.“
