Neuregulin I: A Gene Linking Mental Illness and Creativity?

Caleb He1

Steven Lippmann, M.D.2

  1. University Student, University of Louisville, School of Arts and Sciences, Louisville, KY
  2. Emeritus Professor, University of Louisville, School of Medicine, Louisville, KY

Corresponding Author

Steven Lippmann, M.D.

University of Louisville School of Medicine

401 East Chestnut Street, #610

Louisville, KY 40202

502-681-6788

steven.lippmann@louisville.edu

The neuregulin 1 (NRG1) gene has associations with psychotic symptoms in individuals with schizophrenia.1High levels of creativity and intelligence are other possible polymorphisms associated with this gene. This may partially explain the persistence of schizophrenia in the gene pool despite adverse health effects affecting patients with this condition.

Among 200 subjects with high intellectual achievement (mean IQ = 124.7, SD = 9.5), those with the promoter gene for the NRG1 genotype had higher creativity scores as compared to controls.2 This may be the only known experiment demonstrating a correlation between positive psychological function and polymorphisms associated with severe mental illness.2

Low latent inhibition (LI), which refers to the inability to distinguish the relevance between novel and familiar stimuli, is associated with NRG1. People with schizophrenia demonstrated a low or absent LI.3 There is also a link between high IQ and low LI with greater creativity; high-IQ university students with excellent creative achievement were seven times more likely to have low LI.4 Creative achievement and psychotic tendencies might be positively correlated.

Persons with schizophrenia and also high intelligence often have less disorganization and better-preserved functioning. Patients with schizophrenia and superior premorbid and current IQ (mean = 120) performed just as well on neurocognitive tests as healthy controls with similar scores.5

 Individuals affected by schizophrenia have elevated levels of NRG1 and receptor ERBB4 activity in the prefrontal cortex.6 NRG1 and ERBB4 receptors play a significant role in regulating neurotransmission within the prefrontal cortex.7,8 The prefrontal cortex has a critical role in creativity;9,10 individuals with decreased prefrontal cortex function due to focal brain injury can have evidence of creative activity. This may be explained by the prefrontal cortex’s association with LI capabilities.11

Schizophrenia affects approximately 1% of all populations, but an elevated risk of schizotypal symptoms exists in first-degree relatives of individuals with schizophrenia.12 Genes coding for serious illnesses in homogeneous carriers may confer beneficial, adaptive traits to relatives who are heterozygous carriers.13 Perhaps increased creativity and intelligence is one of these traits. Parallels include that sickle-cell anemia can confer tolerance to malarial infection,14 Ashkenazi Jewish carriers of Tay-Sachs genes have elevated resistance against tuberculosis,15 and heterozygote carriers of cystic fibrosis have decreased susceptibility to cholera.16,17

These observations indicate the need for further research into the role of beneficial traits for survival of people with schizophrenia as a condition counter to evolutionary selection. Any correlation between increased creativity and heterozygous carriers of schizophrenia remains yet unclarified.

References

  1. Yang JZ, Si TM, Ruan Y, et al: Association study of neuregulin 1 gene with schizophrenia. Molecular Psychiatry 2003; 8:706–709.
  2. Kéri S: Genes for psychosis and creativity: a promoter polymorphism of the neuregulin 1 gene is related to creativity in people with high intellectual achievement. Psychological Science 2009; 20(9):1070-1073.
  3. Rascle C, Mazas O, Vaiva G, et al: Clinical features of latent inhibition in schizophrenia. Schizophrenia Research 2001; 51:149-161.
  4. Carson SH, Peterson JB, Higgins DM: Decreased latent inhibition is associated with increased creative achievement in high-functioning individuals. Journal of Personality and Social Psychology 2003; 85(3):499-506.
  5. Černis E, Vassos E, Brébion G, et al: Schizophrenia patients with high intelligence: A clinically distinct sub-type of schizophrenia? European Psychiatry 2015; 30(5):628-632.
  6. MacCabe J, Brébion G, Reichenberg A: Superior intellectual ability in schizophrenia: neuropsychological characteristics. Neuropsychology 2012; 26(2):181-190.
  7. Chong VZ, Thompson M, Beltaifa S, et al: Elevated neuregulin-1 and ErbB4 protein in the prefrontal cortex of schizophrenic patients. Schizophrenia Research 2008; 100(1-3):270-280.
  8. Woo RS, Li XM, Tao YM, et al: Neuregulin-1 Enhances Depolarization-Induced GABA Release. Neuron 2007; 54(4):599-610.
  9. Stefansson H, Petursson H, Sigurdsson E, et al: Neuregulin 1 and Susceptibility to Schizophrenia. American Journal of Human Genetics 2002; 71(4):877-892.
  10. Dietrich A: The cognitive neuroscience of creativity. Psychonomic Bulletin & Review 2004; 11:1011-1026.
  11. Wei DT, Yang JY, Li WF, et al: Increased resting functional connectivity of the medial prefrontal cortex in creativity by means of cognitive stimulation. Cortex 2014; 51:92-102.
  12. Walter EE, Fernandez F, Snelling M, et al: Genetic Consideration of Schizotypal Traits: A Review. Frontiers in Psychology 2016; 7:1769.
  13. Withrock IC, Anderson SJ, Jefferson MA, et al: Genetic diseases conferring resistance to infectious diseases. Genes & Diseases 2015; 2(3):247-254.
  14. Ferreira A, Marguti I, Bechmann I, et al: Sickle Hemoglobin Confers Tolerance to Plasmodium Infection. Cell 2011; 145(3):398-309.
  15. Spyropoulos B, Moens PB, Davidson J, et al: Heterozygote advantage in Tay-Sachs carriers? American Journal of Human Genetics 1981; 33(3):375-380.
  16. Gabriel SE, Brigamn KN, Koller BH, et al: Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model. Science 1994; 266(5182):107-109.
  17. Asimi A: “Cystic fibrotics could survive cholera, choleraics could survive cystic fibrosis”; hypothesis that explores new horizons in treatment of cystic fibrosis. Medical Hypotheses 2015; 85(6):715-717.

REFUGEE DOCTORS: PTSD AND DISCRIMINATION WITH US RESIDENCY REQUIREMENTS

 Sumeyra Baskoy, M.D., Volunteer Physician, VCare Family Practice, Vernon, CT

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

Refugee physicians are an asset to the healthcare system in the U.S.A. They often bring medical skills, knowledge, and experience; they also could thus contribute to healthcare for underserved communities. To obtain a medical license in this country, refugee doctors must complete at least two years of post-graduate residency training in this country.

Residency programs, however, usually favor applicants who graduated from medical school within the last 3–5 years. This timing is a barrier for refugee physicians who completed medical education in their home country years ago. The recent medical school graduation stipulation makes it difficult for many of them to gain admission to residency. And without that, becoming medically licensed is not possible.1 Unlicensed doctors are not able to practice clinical medicine; that results in frustration and disappointment for many trained and qualified practitioners. It also deprives our population of an opportunity to fill physician-storages.

Additionally, the stressful uncertainty associated with the residency application process can exacerbate the posttraumatic stress disorder (PTSD) symptoms that many refugee doctors already experience due to the past trauma that made them become refugees.2,3 Indeed, some programs discriminate against these doctors based on the age of their medical degree instead of individually evaluating qualifications and experiences.4 Such discrimination has mental health consequences, especially for individuals with already established trauma. That can worsen isolation, anxiety, and depression, aggravating PTSD issues, and compromise their ability to qualify at the competitive process of applying for residency.

The medical community, policymakers, and our citizens ought to recognize these challenges. Hopefully, they could create an inclusive, alternative pathway that is supportive for refugee doctors to qualify for restarting their medical careers in the U.S.A. Training programs could begin by offering new educational options for refugee doctors. For example, they might allow extended timelines following medical school graduation. Training also could focus on an encouraging understanding of our medical system and language, with less emphasis on basic medical education. These doctors often also nicely bring experiential knowledge from their past to our trainees and patients. Besides that, they require less supervision than needed by new, inexperienced physicians.

Subsequently, lots of international graduates who became US-licensed physicians seek citizenship by performing clinical services at medically under-served areas. Such doctors move to and work in parts of our country with a dearth of healthcare options; they help us provide attention to our people and that aids those doctors at gaining citizenship. That is a means of obtaining permanent resident status with insurance of a so-called Green Card that authorizes someone to stay, live, and work in the U.S.A. Secondarily, it might mitigate some of our society’s various prejudices against individuals perceived as “different” or “other”.

By providing refugee physicians with the what they need, we can help overcome official challenges, mitigate their PTSD aspects, and though that facilitate better healthcare to our population and communities.5,6 Once political and medical education decision-makers recognize the potential contributions of these doctors it can improve our healthcare system. By providing more opportunities and adding a measure of respect, we all can harness their skills and experiences into our healthcare system. Yes, everyone could benefit.

References

1-Bell SB, Walkover L. The case for refugee physicians: Forced migration of International Medical Graduates in the 21st century. Social Science & Medicine. 2021;277:113903. Date accessed April 29, 2021.

2-Nickerson A, Hoffman J, Keegan D, et al. Intolerance of uncertainty, posttraumatic stress, depression, and fears for the future among displaced refugees. Journal of Anxiety Disorders. 2023;94:102672. Date accessed March 30, 2023.

3-Jou YC, Pace-Schott EF. Call to action: Addressing sleep disturbances, a hallmark symptom of PTSD, for refugees, asylum seekers, and internally displaced persons. Sleep Health. 2022;8(6):593-600. Date accessed March 30, 2023.

4-Franklyn G. “We’re IMGs, and we’re often seen as human garbage outside of primary care”: A qualitative investigation of dynamic status hierarchy construction online by medical trainees. Social Science & Medicine. 2023;317:115611. Date accessed March 30, 2023.

5-Burgess AM. Resettlement of refugee physicians in the United States. The New England Journal of Medicine. 1952;247(12):419-423. Date accessed March 30, 2023.

6-Kureshi S, Namak SY, Sahhar F, Mishori R. Supporting the Integration of Refugee and Asylum Seeking Physicians Into the US Health Care System. Journal of Graduate Medical Education. 2019;11(4):22-29. Date accessed March 17, 2023.

Reflection: 2023 KPMA Annual Meeting

By Ali Farooqui, MD

Chair, Scientific Research Committee

At the conclusion of the KPMA annual meeting on March 10, I was left with a deep feeling of gratitude, accomplishment, and pride. We held the meeting at a new venue to attract psychiatrists from multiple areas of the Commonwealth. The enthusiasm and dedication of our presenters and panelists was palpable. Our presenters volunteered their time to educate our membership on the topics of eating disorders, pharmacology, ADHD, neurodivergence, cannabis, and covid-19. In addition to invaluable knowledge that was shared, we were able to reconnect with our colleagues from across the state and experience camaraderie and fellowship. I am grateful for the selfless service of our presenters and panelists, and for the participation and attendance of our members.

I am particularly grateful for the hard work and dedication of Dr. Mark Wright, the outgoing chairperson of the scientific committee. His leadership and guidance is irreplicable, and I hope to rely on his advice, mentorship, and guidance as the incoming chair.

The landscape of mental health care is rapidly evolving in both press and practice. Psychiatric disorders are becoming a topic of discussion nationwide, and interest in novel psychiatric therapies is gaining momentum. As we look into the future, I hope to humbly follow in the footsteps of my predecessor and provide the psychiatrists of Kentucky an avenue for sharing opinions and ideas, and a platform for education on mental health issues that are relevant and of interest to the practicing psychiatrist.

We could not have held this meeting without the tireless efforts of our executive director, Miranda Sloan, who was the glue that held us together and navigated the schedules of our busy physicians. Thank you to our president Dr. Suleman, the scientific committee, and the executive council, for their leadership and dedication to organized psychiatry. I would also like to personally thank each member of KPMA for trusting us with your time, and for your continued involvement in our meeting. I look forward to being of service to you all as we move toward planning our next scientific meeting in 2024.

Sincerely,

Ali A. Farooqui, MD

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.