BUPROPION’S POTENTIAL: WHAT WILL THEY THINK OF NEXT?


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

DEHYRATION DURING  TERMINAL  ILLNESSES            

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.

Food for Thought: Microbiome and Depression

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

ALUMINUM – IS IT A BRAIN TOXIN ?

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

For decades there have been concerns about whether aluminum is toxic for humans. Does it cause dementias? No conclusive answers, but many people have gotten rid of aluminum cookware, despite still using aluminum foil. Lots of us remember the past frequency of pots and pans made of aluminum. There were questions about whether aluminum incorporation into the body, by oral or dermal means, might induce cognitive declines or other neurological conditions, like parkinsonism, autism, or others.           

There are investigations suggesting that aluminum toxicity is related to early-onset dementia of an Alzheimer disease-like state. However, other research documents no clear etiological leakage. Studies provide no definitive answer. There is much speculation, but a literature review leaves one realizing how little we truly understand. Exposure is widespread because aluminum is the third commonest element in the earth’s crust, and thus, it is in our food supply, medications, and cosmetics.           

Aluminum, in acceptably low levels, is naturally present in many fruits, vegetables meats, fish, and cheeses, etc., but without noting dangerous consequences. Toxicity from this is not recognized. In addition, aluminum is used to facilitate some food preparations like in baking and/or pickling. Baking powder is one of the ingredients of concern, but fortunately aluminum-free baking powders that only contain sodium bicarbonate are ubiquitously available and safe. Exposure can also come through water purification processes and might leach into beverages via aluminum can containers.           

There are many industrial and medical applications. Besides widely available aluminum containing antacids, its hydroxide can also be a vaccine adjuvant. Fear of vaccines has long been an issue; yet, not all vaccines contain aluminum. Our currently available COVID-19 vaccinations contain no aluminum; good news now adays during this pandemic. Reportedly, there is no aluminum in Pfizer, Moderna, Johnson & Johnson, or AstraZeneca vaccines.           Aluminum has antibacterial and antiperspirant qualities, thus it is present in some underarm odor-suppression products. Antiperspirants diminish sweating and that differentiates them from deodorants. Some cosmetic and skin care products also contain aluminum traces, and that also includes styptic pencils or powders, because of their potential to diminish bleeding from small abrasions or cuts, like from razor shaving.           

What about the safety of antiperspirants that contain aluminum? Some marketed products, state clearly up-front in bold lettering that they do not contain aluminum chlorohydrate. That prominent disclosure is sometimes followed in small print on the back label, saying that this product contains potassium alum. Yes, alum is an aluminum salt with potassium, sulfate, sodium, or ammonium. Potassium alum is sometimes called potash alum, proclaimed to be safe, and used in place of aluminum chloride or chlorohydrate.Apparently, this form of chlorohydrate is a small molecule and is easily absorbed through skin, while alum is larger and is thus with less dermal penetration. The implications of these statements opens a question because the product labeling appears to be deceptive. It seemed that the marketers want to convey that their product contains no aluminum and counts on people not reading or understanding potassium alum’s relationship to this metallic element. It might still be safe, but the product labeling prompts concern.           

The pathophysiology of many neurodegenerative conditions remains unknown and proven aluminum toxicity is not obvious. One possible explanation from some sources suggests that aluminum-induced dementias may be due to a physiological predisposition to retain aluminum in the body and/or brain. Thus, vulnerable persons might become toxic while other people evidence no ill effects. However, anyone with a family history of early-onset dementia, probably ought to diminish aluminum exposures.           

Despite lack of clarity about brain toxicity, there are ways to reduce exposures. One can easily avoid aluminum-content antiperspirants, not employ aluminum cookware, even not cooking in its foil form, and not using aluminum-containing baking powders, antacids, and/or vaccinations. Patients and the public should be made aware that no current COVID-19 vaccinations in this country contain aluminum. Also, let people know that many popular antacid tablet brands contain aluminum salts, but calcium carbonate alone and/or with magnesium salt alternative antacids are very widely available. More difficult to identify and harder to rule out is exposure through packaged, prepared baking products. This may not be a major concern, but the degree of presence and risk is not widely known.           We should not become preoccupied with an unproven toxicity, but there are reasonable precautions to minimize adding high aluminum exposures. Time may settle this issue. For now, rely on awareness and prudence.

Telemedicine and COVID-19


Telemedicine technology has been around for a few decades but it was never optimally utilized until the COVID-19 pandemic. Insurance reimbursement was a big barrier in utilizing telemedicine along with other systems barriers. In March 2020, COVID-19 was declared a pandemic by WHO. After this, telemedicine was considered the preferred modality of treatment in the health care industry, and insurance supported the use of this technology. This was a big change for all of us as physicians. We all had to adapt to this new technology within days. This transition had its pros and cons, there was a lot of uncertainty about the usage of telemedicine at that time. When the pandemic started, we were worried if we would be able to continue to safely provide care for our patients or not. With telemedicine as a preferred modality, several of us started working from home. It’s been more than a year now since we have been doing Telemedicine and it has been an interesting experience. Some of us love it and some not so much.


Now most of us are comfortable with this technology and some of us prefer virtual over in-person visits. We never thought that we would be able to build therapeutic rapport and feel connected with patients via telemedicine but I have to say that I feel connected. Research supports this as well. A systematic review by Guaiana and et al published in October 2020 in the Community Mental Health journal showed that the efficacy of Telemedicine and in-person visits were similar (1). Several patients prefer using Telemedicine over in-person visits. There are several advantages of Telemedicine visits. From the patient perspective, 1) They can overcome the geographical barrier and save the transportation cost. 2) They don’t have to worry about bad weather. 3) Several patients are very anxious about waiting in the doctor’s office so they like virtual visits. 4) Mobility is another barrier. As with any technology, there are disadvantages of telemedicine as well. Some patients don’t have access to video technology, some patients are not tech-savvy and it intimidates them to use this platform. As physicians, we see several advantages and disadvantages as well. One of the biggest advantages has been the ability to continue patient care during the COVID- 19 pandemic. Patients’ show rate has been better as compared to in-person visits. Psychiatry is more equipped to do Telemedicine as compared to other specialties where physicals are needed to diagnose and treat patients. With the COVID-19 pandemic, research is showing worsening of mental health so demand for mental health treatment is increasing. Maxime. T et al did a retrospective cohort study on 236379 patients who were COVID survivors. They found out that estimated evidence of neurological and psychiatric diagnosis was 33.62 % in the following 6 months post-COVID (2). 


At this time Telemedicine continues to grow in Psychiatry but we still don’t know what would be the future of Telemedicine once the COVID-19 pandemic is over. Will we as physicians and our patients struggle with virtual “ fatigue” or will we continue to like this? Will this pandemic be over or is COVID- 19 here to stay? Will this be a “ new normal” or not? It is hard to answer these questions at this time. It would be appropriate to have a hybrid model where patients and physicians can have the choice to have either virtual or in-person visits depending on what’s best for the patient. As with any other decision-making in health care, we have to weigh the risks and benefits and make our best decision. 

 References-1.Guaiana, G., Mastrangelo, J., Hendrikx, S. et al. A Systematic Review of the Use of Telepsychiatry in Depression. Community Ment Health J 57, 93–100 (2021). https://doi.org/10.1007/s10597-020-00724-22.6-month neurological and psychiatric outcomes in 236379 survivors of COVID-19: a retrospective cohort study using electronic health records Maxime Taquet, John R Geddes, Masud Husain, Sierra Luciano, Paul J Harrison 

Ruchita Agrawal MD, FAPA
Board Certified Adult Psychiatrist
Associate Chief Medical Officer Adult Services
Seven Counties Services
708 Magazine Street
Phone no. 5025898926
Assistant Professor U of L