Bipolar I patient show dramatic reductions in white matter integrity

Thiel et al in Neuropsychopharmacology (2024) reported that “Compared with HC [healthy controls], BD-I patients exhibited lower FA [fractional anisotropy] in widespread clusters (ptfce-FWE?< 0.001), including almost all major projection, association, and commissural fiber tracts. BD-II patients also demonstrated lower FA compared with HC, although less pronounced (ptfce-FWE?=?0.049).”

Editors Note: These data once more emphasize the importance of using lithium (Li) in bipolar disorder as it can ameliorate the deficits in white matter integrity that are so prominent in the illness. Li also improve the loss of cortical grey matter volume that evolves with illness progression. Li prevents episodes of depression and mania and reduces the incidence of suicides. That Li can reverse or ameliorate brain abnormalities in bipolar disorder is one more piece of evidence that Li should be considered a disease modifying drug (DMD) and started early in the course of illness in almost all bipolar patients. The new mantra for patients and clinicians is: Use more lithium and prevent illness progression.

Antidepressant Use and Risk of Manic Episodes in Children and Adolescents With Unipolar Depression

Suvi Virtanen, PhD; et al in JAMA Psychiatry. September 27, 2023. report a low risk of switching in youngsters with unipolar depression. However, the odds ratio for a switch were significantly elevated when there was concomitant use of anticonvulsants and antipsychotics, and there was a four fold increased risk if a parent had bipolar disorder. Thus one should be particularly careful about treating depression with antidepressants (AD) when there is a positive parental history of bipolar disorder and one should think of other options, such as lamotrigine, an atypical with good AD effects, or lithium.

More Data that Long Term Lithium Treatment Does NOT CAUSE RENAL TOXICITY (more than those on valproate).

In a recent meeting, Mark Weiser of Sheba Medical Center analysed data from “from the Clalit Health Services (CHS) database, the largest provider of health insurance in Israel, n=4.8 million, representing over 50% of the Israeli population. This study examined lithium use between the years 2000 and 2022, focusing on its impact on kidney and thyroid function…(and) compared all patients receiving lithium (n=19,433) to all patients receiving valproic acid (n=44,524). There was no different in the life-time rates of dialysis between patients treated with lithium and patients treated with valproic acid (1.03% vs 0.99%, p = 0.683). A lifetime diagnosis of hypothyroidism was more common in patients receiving lithium (21.84%) in comparison to patients treated with valproic acid (8.83%, p = <0.0001). Conclusions: In this large population study, treatment with lithium was not associated with decreased kidney function but was associated with a clinical diagnosis of hypothyroidism. These factors should be taken into account when considering treatment with lithium.”

Editors Note: In patients on lithium, overtime there are small decreases in estimated glomerular filtration rate (eGFR), but these do not differ from those seen in physiological age adjusted eGFR in the general population. These data are convergent with the large national studies of Kessing et al in Denmark and indicate that the long-held view of lithium causing undo renal toxicity are not accurate and are based on inappropriate suppositions without an adequate control group. They found more end-stage renal dysfunction in bipolar patients treated with anticonvulsants than with lithium.

THERE IS A GRAVE UNDERUTILIZATION OF LITHIUM DUE IN LARGE PART TO THE FALSE ASSUMPTION THAT IT CAUSES EXCESS RENAL TOXICITY. PATIENTS AND CLINICIANS SHOULD BE MADE AWARE OF THE NEW DATA THAT THIS IS LIKELY RELATED TO POOR METHODOLOGY AND BEGIN TO MORE FREQUENTLY THINK ABOUT USING LITHIUM — UNEQUIVOCALLY THE BEST DRUG FOR THE TREATMENT OF BIPOLAR DISORDER. LITHIUM ALSO HAS THE BEST DATA FOR REDUCING EPISODES OF BOTH DEPRESSION AND MANIA AND FOR HAVING POSITIVE EFFECTS IN PREVENTING SUICIDE. USING LITHIUM MORE OFTEN WILL UNDOUBTEDLY MARKEDLY IMPROVE PATIENTS WELL BEING AND SURVIVAL. THIS EDITOR BELIEVES THAT GIVEN LITHIUM’S MULTIFACETED ROLE IN AMELIORATING ALMOST ALL ASPECTS OF THE COURSE OF BIPOLAR DISORDER, IT SHOULD BE CONSIDERED A “DISEASE MODIFYING DRUG.” THERE ARE MULTIPLE DISEASE MODIFYING DRUGS FOR TREATMENT OF MULTIPLE SCLEROSIS, AND EXPERTS IN THAT FIELD BELIEVE THAT DISEASE MODIFYING SHOULD BE STARTED AS EARLY AS POSSIBLE AFTER FIRST DIAGNOSIS. A SIMILAR CONCLUSION WOULD NOW APPEAR APPROPRIATE FOR LITHIUM.

Of note is the other widely held reason for not using lithium more often is that it causes hypothyroidism. While this is clearly correct based on the Weiser study and many other data, patients should be aware that this well-known condition is readily correctable with thyroid hormone replacement and does not produce an undo burden on patients.

Since lithium has many other assets including: increasing hippocampal volume; protecting memory; and increasing the length of telomeres (critical to sustaining good medical and psychiatric health), its wider use in bipolar disorder should be a no brainer. However, it is likely (like most revisions in medical lore) to take 10 years or more before this re-evaluation of lithium has an impact on conventional treatment decisions, so physicians should make very active and conscious decisions about changing their routine choices of treatment for each patient with bipolar disorder.

Preliminary data on ketogenic diet

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

Georgia Ede gave a talk on the first results of 12 bipolar patients using a ketogenic diet (composed of 75% fat; 5% carbohydrates; 20% protein) as a adjunct to about 5 medications that were insufficiently effective. She saw improvement by week 3, 58% remitted, and some lost weight. She indicated that some could revert to a regular diet after the improvement achieved by children, but not in adults.

Sebari Sethi talked about 26 of 27 bipolar patients who achieved 1.3 mmole/L ketones and lost weight and showed increases in glutamate in brain measured by Glx and decreases of 11.2% in the ACC

Pediatric Bipolar Disorder is Associated with Neurocognitive Deficits

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

Maria Paula Maziero of The University of Texas Health Science Center At Houston reported that while euthymic youths with BD (bipolar disorder) exhibited significant dysfunction in working memory (WM), verbal learning, and memory domains, fluctuation between the mood states affected the type of cognitive dysfunction. They concluded: “Pediatric bipolar disorder patients have marked cognitive dysfunction involving multiple domains, especially executive measures. The severity of mood symptoms influences cognitive performance, but even euthymic persons perform lower than matched controls.

Childhood Bullying and Maltreatment Yield A Worse Course of Bipolar Illness

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

Georgina Hosang of Bart’s & The London, Queen Mary’s School of Medicine reported that bullying and maltreatment together were associated with more suicidal behaviors than either childhood experience alone.

Lumateperone for Bipolar I or Bipolar II Depression: Few Extrapyramidal and Motor Symptoms

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

Tobie Escher of Intra-Cellular Therapies, Inc. reported on the excellent tolerability of lumateperone (42mg/day) in a “short-term population comprised 746 patients in pooled monotherapy trials (placebo, 374; lumateperone, 372) and 352 patients in the adjunctive study (adjunctive placebo, 175; adjunctive lumateperone, 177). Reported EPS [extrapyramidal symptom]-related TEAEs [treatment-emergent adverse events] were 1 patient (0.3%) with mild dyskinesia (lumateperone monotherapy), 1 (0.6%) with mild akathisia (adjunctive lumateperone), and 1 (0.3%) with severe akathisia (placebo monotherapy).”

Patterns of Pharmacotherapy for Bipolar Disorder

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

Balwinder Singh of the Mayo Clinic College of Medicine reported on “10,351 individuals from North America (n=3,985), Europe (n=3,822), and Australia (n=2,544), predominantly with cross-sectional data (80%)….They found that “Cross-sectionally, mood-stabilizing anticonvulsants (44%), second-generation antipsychotics (42%), and antidepressants (38%) were most prescribed. Lithium was prescribed in 29% of patients, primarily in Australian (31%) and European (36%) cohorts.” Lithium is remarkedly underutilized in North American cohorts.

Both Obesity and Bipolar Disorders in 2249 Individuals Show White Matter Microstructure Abnormalities

Lorielle Dietze of Dalhousie University “obtained body mass index (BMI) and diffusion tensor imaging derived fractional anisotropy (FA) values from 930 individuals with bipolar disorders (BD), and 1319 control individuals from 20 cohorts in the ENIGMA-BD Working Group.”

They “found that lower FA was associated with both BD and BMI, in five white matter tracts, including the corpus callosum and thalamic radiation. Nine ROIs were correlated with only BD, while higher BMI was uniquely correlated with lower FA in four white matter ROIs.”

They concluded: “For the first time we showed that both obesity and BD demonstrated lower FA in some of the same regions. The impact of obesity may be greater in some tracts in BD individuals.”

Beneficial Cognitive Effects of Transcranial Infrared Laser Stimulation (TILS) in Bipolar Disorder

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

Michael Gentry of The University of Texas At Austin reported on 30 individuals with remitted bipolar disorder (type I or type II). TILS was administered weekly to each participant over six consecutive weeks (1064 nm wavelength; bilaterally to the frontal poles; 10 minutes per weekly session)….. after six weeks of TILS administration, participants demonstrated decreased impulsivity on the Stop Signal Task and improved abilities to select correct responses on the Multitasking Test.

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