Chesika J. Crump, M.D. – PGY-3 Psychiatry Resident

Steven Lippmann, M.D. – Emeritus Professor of Psychiatry, University of Louisville School of Medicine, Louisville, Kentucky

Bupropion was approved for clinical prescribing in 1985. This antidepressant medication has been widely prescribed for treating adults with major depression, seasonal affective disorder, and promotion of smoking cessation. It is prescribed also for many off-label indications, such as antidepressant drug-induced sexual dysfunction, attention-deficit/hyperactivity disorder, bipolar depression, and obesity.¹ Bupropion evidences a pharmacology that may target alternative applications.
           While bupropion’s mechanism of action is not fully clear, it inhibits norepinephrine-dopamine reuptake by blocking the norepinephrine and dopamine reuptake pumps. It does not inhibit monoamine oxidase or the reuptake of serotonin. Metabolized by cytochrome P-2D6 enzymes, active metabolites are excreted in urine.¹
           Beyond psychiatry, bupropion pharmacotherapies are also prescribed by neurologists and internists. Recently approved is a combined dextromethorphan-bupropion medicine indicated for patients with major depression, agitation during Alzheimer’s disease, and mitigating nicotine withdrawal. Dextromethorphan is a N-methyl-D-aspartate (NMDA) receptor antagonist, serotonin norepinephrine reuptake inhibitor, and may induce many other actions. Abnormal glutamate levels are identified in the cortex among depressed subjects using magnetic resonance spectroscopy. This pharmaceutical also affects the glutamatergic system by blocking the NMDA receptor.²
           A combination drug of bupropion and naltrexone is being investigated for usefulness during methamphetamine abuse. One randomized trial measuring methamphetamine-negative urine samples evidenced little difference compared to placebo treatment.³ Further research is ongoing.
Another drug study combining bupropion and naltrexone has revealed efficacy in helping people diminish binge eating disorders and assisting others with weight loss. One trial comparing this combination versus placebo, with and without behavioral weight loss therapy (BWT), revealed that bupropion/naltrexone with BWT resulted in significantly greater remission rates and more weight loss than alternative therapies.⁴
Other studies document that this same combination medication is effective as an augmenting agent for antidepressant drug effects, including decreasing antidepressant agent-induced weight gain. These trials evidenced some efficacy, but the results were not significant.⁵ Bupropion with naltrexone investigations were inconclusive at managing antipsychotic drug-induced weight gain in patients with psychotic disorders.⁶
The pharmacology of bupropion is still being investigated. The results of these studies remain undetermined.

References

1.    Huecker MR, Smiley A, Saadabadi A. Bupropion. [Updated 2022 Oct 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470212/ . Date last accessed 11/28/2022
2.    Iosifescu DV, Jones, A, O’Gorman C, et al. Efficacy and safety of AXS-05 (dextromethorphan-bupropion) in patients with major depressive disorder: a phase 3 randomized clinical trial (GEMINI). J Clin Psychiatry. 2022;83(4):21m14345. Date last accessed 11/28/2022
3.    Trivedi MH, Walker R, Ling W, et al. Bupropion and Naltrexone in Methamphetamine Use Disorder. N Engl J Med. 2021;384(2):140-153. doi:10.1056/NEJMoa2020214. Date last accessed 11/29/2022
4.    Grilo CM, Lydecker JA, Fineberg SK, et al. Naltrexone-Bupropion and Behavior Therapy, Alone and Combined, for Binge-Eating Disorder: Randomized Double-Blind Placebo-Controlled Trial [published online ahead of print, 2022 Oct 26]. Am J Psychiatry.2022;appiajp20220267. doi:10.1176/appi.ajp.20220267. Date last accessed 11/28/2022
5.    McIntyre RS, Paron E, Burrows M, et al. Psychiatric Safety and Weight Loss Efficacy of Naltrexone/bupropion as Add-on to Antidepressant Therapy in Patients with Obesity or Overweight. J Affect Disord. 2021;289:167-176. doi:10.1016/j.jad.2021.04.017. Date last accessed 11/28/2022
6.    Lee K, Abraham S, Cleaver R. A systematic review of licensed weight-loss medications in treating antipsychotic-induced weight gain and obesity in schizophrenia and psychosis. Gen Hosp Psychiatry. 2022;78:58-67. doi:10.1016/j.genhosppsych.2022.07.006. Date last accessed 11/28/2022

Steven Lippmann, M.D., Emeritus Professor of Psychiatry, University of Louisville School of Medicine 

This past year was difficult and with much lifestyle adjustment. There was an increased infectious disease death rate and considerable COVID-19 social and medical morbidity. Influenza-related mortality declined, but other causes of death continue. Among my family, friends, colleagues, and coworkers, about half a dozen died – none directly from coronavirus infections. Some lingered-long in vegetative states at nursing facilities and were suffering, without hope of recovery. I thought society was unwillingly tormenting them by prolonging their deaths, without facilitating meaningful life. And all that at great financial and social cost. Many of us were uncomfortable witnesses; that prompted me to think about dehydration during terminal illness.
           Once the balance of joy with meaningful life versus suffering goes negative for someone with terminal conditions, dehydration emerges as a reasonable comfort care treatment option. Our healthcare system should aim to preserve good life, not extend an uncomfortable demise.
           First-of-all, some degree of dehydration can facilitate pain relief by augmenting the efficacy of analgesic medications, shrinking tumors, and diminishing ascites or edema. Being under hydrated can diminish nausea, vomiting, and diarrhea; that, in cases of incontinence is a benefit at less bedsores and/or skin breakdown. It could also improve breathing with less coughing, choking, or dyspnea, also adding comfort and mobility.
           In addition, many decisional people in such difficult circumstances might voluntarily wish to shorten their lives, but not wanting to commit suicide. That choice should be their own unstigmatized selection, and not coerced by the wishes of others. It is done in consultation with their doctor. Electing to deliberately not eat or drink, will result in dehydration and death, even rather quickly in seriously ill individuals. It becomes a personal choice that can be reversed back-and-forth at their own control, with dignity, and not as suicide. To maintain comfort, some fluid access helps keep a moist mouth.
Families might elect therapeutic dehydration on behalf of no longer decisional relatives, who are suffering at the end of their lives. Electing this form of comfort care requires discussion between patients, family, and physicians and knowing about the life and death wishes of the ill relative. Doctors can initiate such a plan without facilitating suicide. The main benefits are to enhance comfort, diminish suffering, and that it is easily be reversed at any time for any reason.
Everybody can be beneficiaries. Please keep this treatment option in mind.

Induja Nimma, B.A.,MS – 4, University of Louisville School of Medicine

Depression is a severe global health problem. According to the Anxiety and Depression Association of America, 264 million people live with depression globally.  The gut biome can influence the brain’s functions through the microbiota-gut-brain axis.¹ A meta-analysis of randomized controlled trials on the effects of probiotics on depression showed a significant reduction in depression in both a healthy population and in patients with major depressive disorder (MDD).² However, all probiotics may not be beneficial for people with mood disorders. Specific organisms have been associated with improving and worsening symptoms of depression. 

In a parallel study on probiotic formulation, daily administration of Lactobacillus helveticus (R0052) and Bifidobacterium longum (R0175) significantly reduced anxiety-like behavior in rats and reduced psychological distress in healthy human volunteers.³ Additionally, Faecalibacterium, Coprococcus bacteria, and Dialister were depleted in patients with depression even after accounting for the confounding variable of antidepressant effects.⁴ 

However, Firmicutes, Actinobacteria, and Bacteroidetes seem to be associated with an increase in depressive symptoms. In a gut microbiome remodeling study, compared to healthy individuals, patients with MDD had an increase in the afore mentioned bacteria. Fecal transplant in healthy mice with this ‘depression microbiota’ taken from patients with MDD, resulted in “depression-like behaviors” that were not seen in mice transplanted with microbiota from healthy control individuals.⁵ 

Some microbiota seem to confer a positive effect while others a negative effect. This is important to consider since the probiotic supplement industry is not well regulated. If probiotics are to be implemented in the treatment regimen for depression, it is imperative to assess the efficacy and composition of commercially available products that are marketed for depression. This is something to further explore as probiotic use becomes more widely accepted as an adjunct therapy for the treatment of depression.  

References

1. Cryan JF, O’Riordan KJ, Cowan CSM, et al. The Microbiota-Gut-Brain Axis. Physiol Rev. 2019; 99(4):1877-2013. doi: 10.1152/physrev.00018.2018

2. Huang R, Wang K, Hu J. Effect of Probiotics on Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients. 2016 6;8(8):483. doi: 10.3390/nu8080483   

3. Messaoudi M, Lalonde R, Violle N, et al. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr. 2011;105(5):755-64. doi: 10.1017/S0007114510004319  

4. Valles-Colomer M, Falony G, Darzi Y, et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nature Microbiolo 2019;4:623-632.    

5. Zheng P, Zeng B, Zhou C, et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol Psychiatry. 2016; 21(6):786-96. doi: 10.1038/mp.2016.44