S15 – Treatment-Resistant Bipolar Disorder: Underlying Mechanisms and Novel Treatments

S15 – Treatment-Resistant Bipolar Disorder: Underlying Mechanisms and Novel Treatments

Le samedi 21 octobre
10:45 – 11:45 (1 hr)
Salle de réunion : Pavilion Ballroom D (3rd floor – North Tower)
Cynthia Calkin*, MD, CCFP, FRCPC; KN Roy Chengappa, MD; Cynthia Calkin, MD; Jessica Gannon, MD

Rôles CanMEDS :

  1. Expert médical
  2. Érudit
  3. Promoteur de la santé

À la conclusion de cette activité, les participants seront en mesure de : 1) Understand the importance of recognizing and treating insulin resistance (IR) in treatment-resistant bipolar depression (TRBD); 2) Review potential mechanisms underlying TRBD associated with IR; and 3) Discuss the measurement of IR and the clinical predictive models to predict IR reversal with metformin in patients withTRBD.

Treatment-resistant bipolar depression (TRBD) remains highly recalcitrant to pharmacological and somatic interventions. The first speaker will review recent definitions and economic costs of TRBD and introduce an intriguing mechanism that may underlie TRBD in a significant proportion of patients (i.e., insulin resistance [IR]). He will then review how the development of IR and diabetes changes a responsive bipolar illness course to one of poor clinical outcomes and is further complicated by comorbidities and treatment resistance. Our second speaker will present the results of a 26-week, proof-of-concept, quadruple-blind randomized placebo-controlled clinical trial, using adjunctive metformin as an insulin sensitizer in TRBD patients who also met predefined IR resistance criteria. She will review the two-step hypothesis that underscored the study design, the rationale for using metformin, and present data showing improvements in depression and general functioning among those who converted (i.e., switched from IR to insulin sensitive). She will provide suggestive evidence for why improvements in blood-brain barrier disruptions may underlie these positive clinical outcomes. Our third speaker will address improvements noted among converters in anxiety, clinical global impressions, and lack of emergence of suicidality or mania. She will then discuss how front-line psychiatrists might screen for IR in TRBD patients and use office-based clinical and laboratory tools at their disposal to predict which of their TRBD patients might respond to metformin. Finally, future clinical directions, including the use of alternative insulin sensitizers (e.g., semaglutide), and mechanistic underpinnings will be reviewed with the audience.

S15a – Definition and Costs of Treatment-Resistant Bipolar Depression: A Practical and Novel Approach to Successful Treatment by Screening and Reversing Insulin Resistance
KN Roy Chengappa, MD

À la conclusion de cette activité, les participants seront en mesure de : 1) Review a recently-put-forth consensus definition of treatment-resistant bipolar depression (TRBD); 2) Consider economic costs associated with TRBD; and 3) Consider screening patients in their practice for insulin resistance who meet criteria for TRBD.

The lack of evidence-based pharmacological interventions for treatment-resistant bipolar depression (TRBD) remains one the most glaring unmet treatment needs in psychiatric practice. In fact, only recently have consensus-based definitions of TRBD begun to emerge. In the absence of modern data, the lifetime economic cost for a chronic or nonresponsive patient with bipolar disorder (BP) was nearly 625,000 $US in 1988, compared to a single manic episode estimated to cost nearly 12,000 US dollars. A 2020 study estimated the annual cost of BP I disorder in the USA was greater than 195 billion dollars. The clinical trajectory of a non-responsive BP patient is invariably accompanied by emergent medical and psychiatric comorbidity, the use of combinations of medications with little evidence to support their use and eventually poor clinical outcomes. In this doom and gloom scenario has emerged an intriguing finding that may underlie treatment-resistance in TRBD, i.e. Insulin Resistance. The emergence of Insulin resistance and type 2 diabetes mellitus in BP disorder results in a switch from being treatment responsive to treatment resistant. Unsurprisingly, the next step would be to test whether reversal of insulin resistance would lead to reversal of treatment-resistance. Metformin is a quintessential insulin sensitizer, and psychiatrists use it in practice to promote weight loss. The data from a proof-of-concept study provides the initial evidence to i) screen for insulin resistance in TRBD and b) seriously consider metformin adjunctive treatment to reverse IR. Finally, these data provide a platform to further investigate an innovative treatment approach in TRBD.

Références :

  1. Hidalgo-Mazzei D, Berk M, Cipriani A, et al. Treatment-resistant and multi-therapy-resistant criteria for bipolar depression: consensus definition. Br J Psychiatry 2019;214:27–35.
  2. Bessonova L, Ogden K, Doane MJ, et al. The economic burden of bipolar disorder in the United States: a systematic literature review. Clinicoecon Outcomes Res 2020;12:481–492.

S15b – Mechanisms Underlying Treatment Resistant Bipolar Disorder (TRBD): New Targets for Treatment
Cynthia Calkin, MD

À la conclusion de cette activité, les participants seront en mesure de : 1) Review clinical trial results demonstrating that reversal of insulin resistance improves outcome in TRBD depressed patients; 2) Consider insulin resistance as the potential mechanism underlying treatment-resistant bipolar depression; and 3) Understand the importance of identifying and treating insulin resistance in treatment resistant bipolar patients.

Insulin resistance (IR) is an underdiagnosed condition frequently comorbid with bipolar disorder (BD) and has been associated with a chronic course of illness, rapid cycling, and treatment non-responsiveness. As such, IR has emerged as a promising treatment target in BD, including for treatment resistant bipolar depression (TRBD). We recruited 45 subjects with IR and non-remitting bipolar depression into a 26-week randomized, quadruple-masked, parallel group prospective study examining the efficacy of metformin as add-on treatment in TRBD. Subjects were 18 years or older, diagnosed with BD I or II, and had non-remitting bipolar depression as defined by the presence of moderate depressive symptoms (Montgomery-Ǻsberg Depression Rating Scale [MADRS] score ≥ 15 despite optimal, guideline compatible treatment. IR was defined by a HOMA-IR≥ 1.8. Ten metformin treated patients (50%) no longer met IR criteria by week 14 compared to one (4%) placebo assigned patient (Fisher exact p= 0.0009). These converters achieved a significantly greater reduction in MADRS scores and increase in global functioning scores as compared to non-converters, beginning at week 6, with improvement maintained through end of study. Nearly 82% of metformin treated TRBD patients met depression response criteria by 14 weeks. Effect sizes for the depression treatment effect and the improvement in functioning were large. Results from the first study imaging the blood-brain barrier (BBB) in BD will also be presented, demonstrating an association between BBB leakage, IR and poor outcomes in BD. BBB leakage may be a further mechanism to target in the treatment of TRBD.

Références :

  1. Kamintsky L, Cairns KA, Veksler R, Bowen C, Beyea SD, Friedman A, Calkin C. Blood-brain barrier imaging as a potential biomarker for bipolar disorder progression. Neuroimage Clin. 2020;26:102049. doi: 10.1016/j.nicl.2019.102049. Epub 2019 Oct 22. PMID: 31718955; PMCID: PMC7229352.
  2. Calkin C, McClelland C, Cairns K, Kamintsky L, Friedman A. Insulin Resistance and Blood-Brain Barrier Dysfunction Underlie Neuroprogression in Bipolar Disorder. Front Psychiatry. 2021 May 25;12:636174. doi: 10.3389/fpsyt.2021.636174. PMID: 34113269; PMCID: PMC8185298.

S15c – Insulin Resistance in Treatment Resistant Bipolar Depression: Beyond Core Symptoms and Predicting Clinical Response
Jessica Gannon, MD

À la conclusion de cette activité, les participants seront en mesure de : 1) Review potential improvements in anxiety scores as well as in overall functioning in TRBD with reversal of insulin resistance; 2) Discuss clinical strategies for identifying TRBD patients with insulin resistance; and 3) Review known predictors of response to conversion to insulin sensitive with metformin in TRBD patients.

Treatment resistant bipolar depression (TRBD) is frequently accompanied by significant psychiatric comorbidity, particularly anxiety disorders, and can markedly impact the quality of life of patients. TRIO-BD findings suggesting that reversal of insulin resistance (IR) with metformin in TRBD patients can reduce anxiety and improve measures of overall functioning will be presented. Importantly, IR reversal and clinical improvements were not accompanied by serious adverse events; trial safety data highlighting a lack of emergence of suicidality and mania will be presented. Despite promising findings demonstrated with IR reversal, only 50% of TRIO-BD metformin subjects became insulin sensitive. The astute clinician may wonder which IR TRBD patients would most likely benefit from a trial of metformin. Given strong external evidence for their association with IR, we thus developed a predictive tool using easily obtained body mass index (BMI) and homeostatic model assessment -insulin resistance (HOMA-IR). The predictive performance of BMI and HOMA-IR at baseline was tested with a logistic regression model utilizing known metrics: area under the receiver operating curve (AUC), sensitivity, and specificity. In view of the high benefit to low risk of metformin in reversing IR, high sensitivity was favored over specificity. For each unit increase in BMI or HOMA-IR, there was a 15% (OR = 0.85, 95% CI [0.71 – 0.99]) or 43 % (OR = 0.57, CI [0.18 – 1.36]) decrease in the odds of conversion respectively. This suggests that early introduction of metformin, when patients have relatively lower BMI and HOMA-IR values, would be recommended.

Références :

  1. Calkin CV, Chengappa KNR, Cairns K, Cookey J, Gannon J, Alda M, O’Donovan C, Reardon C, Sanches M, Růzicková M. Treating Insulin Resistance With Metformin as a Strategy to Improve Clinical Outcomes in Treatment-Resistant Bipolar Depression (the TRIO-BD Study): A Randomized, Quadruple-Masked, Placebo-Controlled Clinical Trial. J Clin Psychiatry. 2022;83(2):21m14022
  2. Giménez-Palomo A, Gomes-da-Costa S, Dodd S, et al. Does metabolic syndrome or its component factors alter the course of bipolar disorder? A systematic review. Neurosci Biobehav Rev. 2022;132:142-153. doi: 10.1016/j.neubiorev.2021.11.026.