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Metabolic dysregulation is quite common among psychiatric patients, especially those with psychotic or mood disorders. Obesity, diabetes, and dyslipidemia can be present at the onset of the illness, or as an iatrogenic complication. This often leads to premature mortality due to elevated cardiovascular and cerebrovascular risks.
Enter metformin. It is the most widely used hypoglycemic agent for type 2 diabetes (T2D), and it is frequently used by psychiatric clinicians. Discovered in 1922 and developed in France in the 1950s, metformin was approved for use in the United States in 1995, 3 decades after its launch in Europe. Its original trade name in the United States was Glucophage, and it is currently available from several companies in generic form. It is included on the World Health Organization list of essential medications.
T2D is currently an epidemic across the general populations globally, especially in the United States, where approximately 95% of the 37 million individuals with diabetes have been diagnosed with T2D.1 This is 300% higher than the prevalence in the 1970s. No wonder metformin is one of the most often-used drugs in all of medicine, and a staple in primary care and psychiatry. It has helped countless patients avoid the multisystem hazards of insulin resistance, which is the root cause of T2D.
Metformin exerts its hypoglycemic effects by:
- decreasing glucose production from the liver
- increasing insulin receptors’ sensitivity in various body tissues
- increasing secretion of growth differentiating factor, which reduces appetite and calorie intake.
In 2017, the American College of Physicians updated its guidelines to adopt metformin as the first-line treatment for T2D, especially because the class of sulfonylureas were associated with a more than 5-fold higher risk of severe low blood sugar events compared with metformin.2 In addition, metformin causes weight loss, while sulfonylureas are associated with weight gain. Metformin is particularly useful in gestational diabetes, where babies are born with less visceral fat and are less prone to insulin resistance later in life as adults.
The adverse effects of metformin are dose-related and mostly gastrointestinal (GI), including nausea, vomiting, cramps, diarrhea, and flatulence. Gradual titration or using the extended-release formulation can lower or avert GI discomfort. Metformin should not be used in patients with severe kidney or liver disease. With long-term use, metformin can cause malabsorption and eventual deficiency of vitamin B12.
The metabolic benefits of metformin listed below are why psychiatrists use it in clinical practice. However, this medication has several benefits that go beyond metabolic disorders. Clinicians should be aware of all of the following salutary physical and mental effects of metformin.
Metabolic benefits
- Decreasing glucose dysregulation with the use of clozapine and other antipsychotics.3
- Decreasing weight, body mass index, and waist circumference with the use of clozapine.4
- Decreasing triglycerides and total cholesterol.5
- Mitigating clozapine-induced obesity, especially if used prophylactically.6
- Lowering antipsychotic-induced weight gain.7
Continue on to: Nonmetabolic benefits...
Nonmetabolic benefits
- Lowering elevated serum prolactin levels to avert sexual dysfunction.8-10
- Increasing the production of neurons by inducing neurogenesis.11,12
- Activating the cerebral cortex to blunt the adverse effects of clozapine (such as deterioration of motivation, attention, cognition, and behavior) and increasing the activity of the dopamine D1 receptor, which is believed to be involved with cognition in schizophrenia.13
- Reducing the symptoms of anxiety and depression by increasing serotonin activity and hippocampal concentration of serotonin.14
- Decreasing the depressive symptoms known to be associated with uncontrolled diabetes.15
- Improving insulin resistance associated with polycystic ovary syndrome and helping with infertility.16
- Exerting multiple anti-aging effects (Table17). Metformin reduces several hallmarks of aging and may increase longevity.17
- Lowering the risks of cancer, dementia, and mortality in patients with and without diabetes18 due to its anti-aging effects. Scientists are actively studying metformin’s anti-aging effects and trying to develop drugs with similar effects.
- Counteracting inflammatory bowel disease, osteoporosis, neurodegeneration, inflammation, frailty, and senescence.19
Metformin may sound like a wonder drug or panacea, but most of its multiple beneficial effects have been reported and replicated. Its therapeutic effects on obesity, diabetes, and dyslipidemia can prevent early mortality, but its anti-aging effects are also important and may help reduce premature mortality, which is common in psychiatric patients.20 So, the question arises: At some point, will metformin be used for persons not afflicted by diabetes or metabolic syndrome? For now, psychiatrists should continue to use it on label, but in the future, our patients may benefit from its “fringe benefits.”
1. Centers for Disease Control and Prevention. Type 2 diabetes. Accessed January 28, 2022. https://www.cdc.gov/diabetes/basics/type2.html
2. Qaseem A, Barry MJ, Humphrey LL, et al; Clinical Guidelines Committee of the American College of Physicians. Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166(4):279-290.
3. Agarwal SM, Panda R, Costa-Dookhan KA, et al. Metformin for early comorbid glucose dysregulation and schizophrenia spectrum disorders: a pilot double-blind randomized clinical trial. Transl Psychiatry. 2021;11(1):219.
4. Hebrani P, Manteghi AA, Behdani F, et al. Double-blind, randomized, clinical trial of metformin as add-on treatment with clozapine in treatment of schizophrenia disorder. J Res Med Sci. 2015;20(4):364-371.
5. Jiang WL, Cai DB, Yin F, et al. Adjunctive metformin for antipsychotic-induced dyslipidemia: a meta-analysis of randomized, double-blind, placebo-controlled trials. Transl Psychiatry. 2020;10(1):117.
6. Siskind DJ, Leung J, Russell AW, et al. Metformin for clozapine associated obesity: a systematic review and meta-analysis. PLoS One. 2016;11(6):e0156208
7. de Silva VA, Suraweera C, Ratnatunga SS, et al. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry. 2016;16(1):341.
8. Zheng W, Yang XH, Cai DB, et al. Adjunctive metformin for antipsychotic-related hyperprolactinemia: a meta-analysis of randomized controlled trials. J Psychopharmacol. 2017;31(5):625-631.
9. Krysiak R, Kowalcze K, Szkrobka W, et al. The effect of metformin on prolactin levels in patients with drug-induced hyperprolactinemia. Eur J Intern Med. 2016;30:94-98.
10. Bo QJ, Wang ZM, Li XB, et al. Adjunctive metformin for antipsychotic-induced hyperprolactinemia: a systematic review. Psychiatry Res. 2016;237:257-263.
11. Wang J, Gallagher D, DeVito LM, et al. Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell. 2012;11(1):23-35.
12. Fatt M, Hsu K, He L, et al. Metformin acts on two different molecular pathways to enhance adult neural precursor proliferation/self-renewal and differentiation. Stem Cell Reports. 2015;5(6):988-995.
13. Horvath G, Kis G, Kekesi G, et al. Interaction of clozapine with metformin in a schizophrenia rat model. Sci Rep. 2021;11(1):16862.
14. Zemdegs J, Martin H, Pintana H, et al. Metformin promotes anxiolytic and antidepressant-like responses in insulin-resistant mice by decreasing circulating branched-chain amino acids. J Neurosci. 2019;39(30):5935-5948.
15. B˘adescu SV, T˘ataru C, Kobylinska L, et al. The association between diabetes mellitus and depression. J Med Life. 2016;9(2):120-125.
16. Erensoy H, Niafar M, Ghafarzadeh S, et al. A pilot trial of metformin for insulin resistance and mood disturbances in adolescent and adult women with polycystic ovary syndrome. Gynecol Endocrinol. 2019;35(1):72-75.
17. Kulkarni AS, Gubbi S, Barzilai N. Benefits of metformin in attenuating the hallmarks of aging. Cell Metab. 2020;32(1):15-30.
18. Campbell JM, Bellman SM, Stephenson MD, et al. Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. Ageing Res Rev. 2017;40:31-44.
19. Ala M, Ala M. Metformin for cardiovascular protection, inflammatory bowel disease, osteoporosis, periodontitis, polycystic ovarian syndrome, neurodegeneration, cancer, inflammation and senescence: what is next? ACS Pharmacol Transl Sci. 2021;4(6):1747-1770.
20. Nasrallah HA. Premature mortality across most psychiatric disorders. Current Psychiatry. 2019;8(10):9-10,12,34.
Metabolic dysregulation is quite common among psychiatric patients, especially those with psychotic or mood disorders. Obesity, diabetes, and dyslipidemia can be present at the onset of the illness, or as an iatrogenic complication. This often leads to premature mortality due to elevated cardiovascular and cerebrovascular risks.
Enter metformin. It is the most widely used hypoglycemic agent for type 2 diabetes (T2D), and it is frequently used by psychiatric clinicians. Discovered in 1922 and developed in France in the 1950s, metformin was approved for use in the United States in 1995, 3 decades after its launch in Europe. Its original trade name in the United States was Glucophage, and it is currently available from several companies in generic form. It is included on the World Health Organization list of essential medications.
T2D is currently an epidemic across the general populations globally, especially in the United States, where approximately 95% of the 37 million individuals with diabetes have been diagnosed with T2D.1 This is 300% higher than the prevalence in the 1970s. No wonder metformin is one of the most often-used drugs in all of medicine, and a staple in primary care and psychiatry. It has helped countless patients avoid the multisystem hazards of insulin resistance, which is the root cause of T2D.
Metformin exerts its hypoglycemic effects by:
- decreasing glucose production from the liver
- increasing insulin receptors’ sensitivity in various body tissues
- increasing secretion of growth differentiating factor, which reduces appetite and calorie intake.
In 2017, the American College of Physicians updated its guidelines to adopt metformin as the first-line treatment for T2D, especially because the class of sulfonylureas were associated with a more than 5-fold higher risk of severe low blood sugar events compared with metformin.2 In addition, metformin causes weight loss, while sulfonylureas are associated with weight gain. Metformin is particularly useful in gestational diabetes, where babies are born with less visceral fat and are less prone to insulin resistance later in life as adults.
The adverse effects of metformin are dose-related and mostly gastrointestinal (GI), including nausea, vomiting, cramps, diarrhea, and flatulence. Gradual titration or using the extended-release formulation can lower or avert GI discomfort. Metformin should not be used in patients with severe kidney or liver disease. With long-term use, metformin can cause malabsorption and eventual deficiency of vitamin B12.
The metabolic benefits of metformin listed below are why psychiatrists use it in clinical practice. However, this medication has several benefits that go beyond metabolic disorders. Clinicians should be aware of all of the following salutary physical and mental effects of metformin.
Metabolic benefits
- Decreasing glucose dysregulation with the use of clozapine and other antipsychotics.3
- Decreasing weight, body mass index, and waist circumference with the use of clozapine.4
- Decreasing triglycerides and total cholesterol.5
- Mitigating clozapine-induced obesity, especially if used prophylactically.6
- Lowering antipsychotic-induced weight gain.7
Continue on to: Nonmetabolic benefits...
Nonmetabolic benefits
- Lowering elevated serum prolactin levels to avert sexual dysfunction.8-10
- Increasing the production of neurons by inducing neurogenesis.11,12
- Activating the cerebral cortex to blunt the adverse effects of clozapine (such as deterioration of motivation, attention, cognition, and behavior) and increasing the activity of the dopamine D1 receptor, which is believed to be involved with cognition in schizophrenia.13
- Reducing the symptoms of anxiety and depression by increasing serotonin activity and hippocampal concentration of serotonin.14
- Decreasing the depressive symptoms known to be associated with uncontrolled diabetes.15
- Improving insulin resistance associated with polycystic ovary syndrome and helping with infertility.16
- Exerting multiple anti-aging effects (Table17). Metformin reduces several hallmarks of aging and may increase longevity.17
- Lowering the risks of cancer, dementia, and mortality in patients with and without diabetes18 due to its anti-aging effects. Scientists are actively studying metformin’s anti-aging effects and trying to develop drugs with similar effects.
- Counteracting inflammatory bowel disease, osteoporosis, neurodegeneration, inflammation, frailty, and senescence.19
Metformin may sound like a wonder drug or panacea, but most of its multiple beneficial effects have been reported and replicated. Its therapeutic effects on obesity, diabetes, and dyslipidemia can prevent early mortality, but its anti-aging effects are also important and may help reduce premature mortality, which is common in psychiatric patients.20 So, the question arises: At some point, will metformin be used for persons not afflicted by diabetes or metabolic syndrome? For now, psychiatrists should continue to use it on label, but in the future, our patients may benefit from its “fringe benefits.”
Metabolic dysregulation is quite common among psychiatric patients, especially those with psychotic or mood disorders. Obesity, diabetes, and dyslipidemia can be present at the onset of the illness, or as an iatrogenic complication. This often leads to premature mortality due to elevated cardiovascular and cerebrovascular risks.
Enter metformin. It is the most widely used hypoglycemic agent for type 2 diabetes (T2D), and it is frequently used by psychiatric clinicians. Discovered in 1922 and developed in France in the 1950s, metformin was approved for use in the United States in 1995, 3 decades after its launch in Europe. Its original trade name in the United States was Glucophage, and it is currently available from several companies in generic form. It is included on the World Health Organization list of essential medications.
T2D is currently an epidemic across the general populations globally, especially in the United States, where approximately 95% of the 37 million individuals with diabetes have been diagnosed with T2D.1 This is 300% higher than the prevalence in the 1970s. No wonder metformin is one of the most often-used drugs in all of medicine, and a staple in primary care and psychiatry. It has helped countless patients avoid the multisystem hazards of insulin resistance, which is the root cause of T2D.
Metformin exerts its hypoglycemic effects by:
- decreasing glucose production from the liver
- increasing insulin receptors’ sensitivity in various body tissues
- increasing secretion of growth differentiating factor, which reduces appetite and calorie intake.
In 2017, the American College of Physicians updated its guidelines to adopt metformin as the first-line treatment for T2D, especially because the class of sulfonylureas were associated with a more than 5-fold higher risk of severe low blood sugar events compared with metformin.2 In addition, metformin causes weight loss, while sulfonylureas are associated with weight gain. Metformin is particularly useful in gestational diabetes, where babies are born with less visceral fat and are less prone to insulin resistance later in life as adults.
The adverse effects of metformin are dose-related and mostly gastrointestinal (GI), including nausea, vomiting, cramps, diarrhea, and flatulence. Gradual titration or using the extended-release formulation can lower or avert GI discomfort. Metformin should not be used in patients with severe kidney or liver disease. With long-term use, metformin can cause malabsorption and eventual deficiency of vitamin B12.
The metabolic benefits of metformin listed below are why psychiatrists use it in clinical practice. However, this medication has several benefits that go beyond metabolic disorders. Clinicians should be aware of all of the following salutary physical and mental effects of metformin.
Metabolic benefits
- Decreasing glucose dysregulation with the use of clozapine and other antipsychotics.3
- Decreasing weight, body mass index, and waist circumference with the use of clozapine.4
- Decreasing triglycerides and total cholesterol.5
- Mitigating clozapine-induced obesity, especially if used prophylactically.6
- Lowering antipsychotic-induced weight gain.7
Continue on to: Nonmetabolic benefits...
Nonmetabolic benefits
- Lowering elevated serum prolactin levels to avert sexual dysfunction.8-10
- Increasing the production of neurons by inducing neurogenesis.11,12
- Activating the cerebral cortex to blunt the adverse effects of clozapine (such as deterioration of motivation, attention, cognition, and behavior) and increasing the activity of the dopamine D1 receptor, which is believed to be involved with cognition in schizophrenia.13
- Reducing the symptoms of anxiety and depression by increasing serotonin activity and hippocampal concentration of serotonin.14
- Decreasing the depressive symptoms known to be associated with uncontrolled diabetes.15
- Improving insulin resistance associated with polycystic ovary syndrome and helping with infertility.16
- Exerting multiple anti-aging effects (Table17). Metformin reduces several hallmarks of aging and may increase longevity.17
- Lowering the risks of cancer, dementia, and mortality in patients with and without diabetes18 due to its anti-aging effects. Scientists are actively studying metformin’s anti-aging effects and trying to develop drugs with similar effects.
- Counteracting inflammatory bowel disease, osteoporosis, neurodegeneration, inflammation, frailty, and senescence.19
Metformin may sound like a wonder drug or panacea, but most of its multiple beneficial effects have been reported and replicated. Its therapeutic effects on obesity, diabetes, and dyslipidemia can prevent early mortality, but its anti-aging effects are also important and may help reduce premature mortality, which is common in psychiatric patients.20 So, the question arises: At some point, will metformin be used for persons not afflicted by diabetes or metabolic syndrome? For now, psychiatrists should continue to use it on label, but in the future, our patients may benefit from its “fringe benefits.”
1. Centers for Disease Control and Prevention. Type 2 diabetes. Accessed January 28, 2022. https://www.cdc.gov/diabetes/basics/type2.html
2. Qaseem A, Barry MJ, Humphrey LL, et al; Clinical Guidelines Committee of the American College of Physicians. Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166(4):279-290.
3. Agarwal SM, Panda R, Costa-Dookhan KA, et al. Metformin for early comorbid glucose dysregulation and schizophrenia spectrum disorders: a pilot double-blind randomized clinical trial. Transl Psychiatry. 2021;11(1):219.
4. Hebrani P, Manteghi AA, Behdani F, et al. Double-blind, randomized, clinical trial of metformin as add-on treatment with clozapine in treatment of schizophrenia disorder. J Res Med Sci. 2015;20(4):364-371.
5. Jiang WL, Cai DB, Yin F, et al. Adjunctive metformin for antipsychotic-induced dyslipidemia: a meta-analysis of randomized, double-blind, placebo-controlled trials. Transl Psychiatry. 2020;10(1):117.
6. Siskind DJ, Leung J, Russell AW, et al. Metformin for clozapine associated obesity: a systematic review and meta-analysis. PLoS One. 2016;11(6):e0156208
7. de Silva VA, Suraweera C, Ratnatunga SS, et al. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry. 2016;16(1):341.
8. Zheng W, Yang XH, Cai DB, et al. Adjunctive metformin for antipsychotic-related hyperprolactinemia: a meta-analysis of randomized controlled trials. J Psychopharmacol. 2017;31(5):625-631.
9. Krysiak R, Kowalcze K, Szkrobka W, et al. The effect of metformin on prolactin levels in patients with drug-induced hyperprolactinemia. Eur J Intern Med. 2016;30:94-98.
10. Bo QJ, Wang ZM, Li XB, et al. Adjunctive metformin for antipsychotic-induced hyperprolactinemia: a systematic review. Psychiatry Res. 2016;237:257-263.
11. Wang J, Gallagher D, DeVito LM, et al. Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell. 2012;11(1):23-35.
12. Fatt M, Hsu K, He L, et al. Metformin acts on two different molecular pathways to enhance adult neural precursor proliferation/self-renewal and differentiation. Stem Cell Reports. 2015;5(6):988-995.
13. Horvath G, Kis G, Kekesi G, et al. Interaction of clozapine with metformin in a schizophrenia rat model. Sci Rep. 2021;11(1):16862.
14. Zemdegs J, Martin H, Pintana H, et al. Metformin promotes anxiolytic and antidepressant-like responses in insulin-resistant mice by decreasing circulating branched-chain amino acids. J Neurosci. 2019;39(30):5935-5948.
15. B˘adescu SV, T˘ataru C, Kobylinska L, et al. The association between diabetes mellitus and depression. J Med Life. 2016;9(2):120-125.
16. Erensoy H, Niafar M, Ghafarzadeh S, et al. A pilot trial of metformin for insulin resistance and mood disturbances in adolescent and adult women with polycystic ovary syndrome. Gynecol Endocrinol. 2019;35(1):72-75.
17. Kulkarni AS, Gubbi S, Barzilai N. Benefits of metformin in attenuating the hallmarks of aging. Cell Metab. 2020;32(1):15-30.
18. Campbell JM, Bellman SM, Stephenson MD, et al. Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. Ageing Res Rev. 2017;40:31-44.
19. Ala M, Ala M. Metformin for cardiovascular protection, inflammatory bowel disease, osteoporosis, periodontitis, polycystic ovarian syndrome, neurodegeneration, cancer, inflammation and senescence: what is next? ACS Pharmacol Transl Sci. 2021;4(6):1747-1770.
20. Nasrallah HA. Premature mortality across most psychiatric disorders. Current Psychiatry. 2019;8(10):9-10,12,34.
1. Centers for Disease Control and Prevention. Type 2 diabetes. Accessed January 28, 2022. https://www.cdc.gov/diabetes/basics/type2.html
2. Qaseem A, Barry MJ, Humphrey LL, et al; Clinical Guidelines Committee of the American College of Physicians. Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166(4):279-290.
3. Agarwal SM, Panda R, Costa-Dookhan KA, et al. Metformin for early comorbid glucose dysregulation and schizophrenia spectrum disorders: a pilot double-blind randomized clinical trial. Transl Psychiatry. 2021;11(1):219.
4. Hebrani P, Manteghi AA, Behdani F, et al. Double-blind, randomized, clinical trial of metformin as add-on treatment with clozapine in treatment of schizophrenia disorder. J Res Med Sci. 2015;20(4):364-371.
5. Jiang WL, Cai DB, Yin F, et al. Adjunctive metformin for antipsychotic-induced dyslipidemia: a meta-analysis of randomized, double-blind, placebo-controlled trials. Transl Psychiatry. 2020;10(1):117.
6. Siskind DJ, Leung J, Russell AW, et al. Metformin for clozapine associated obesity: a systematic review and meta-analysis. PLoS One. 2016;11(6):e0156208
7. de Silva VA, Suraweera C, Ratnatunga SS, et al. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry. 2016;16(1):341.
8. Zheng W, Yang XH, Cai DB, et al. Adjunctive metformin for antipsychotic-related hyperprolactinemia: a meta-analysis of randomized controlled trials. J Psychopharmacol. 2017;31(5):625-631.
9. Krysiak R, Kowalcze K, Szkrobka W, et al. The effect of metformin on prolactin levels in patients with drug-induced hyperprolactinemia. Eur J Intern Med. 2016;30:94-98.
10. Bo QJ, Wang ZM, Li XB, et al. Adjunctive metformin for antipsychotic-induced hyperprolactinemia: a systematic review. Psychiatry Res. 2016;237:257-263.
11. Wang J, Gallagher D, DeVito LM, et al. Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell. 2012;11(1):23-35.
12. Fatt M, Hsu K, He L, et al. Metformin acts on two different molecular pathways to enhance adult neural precursor proliferation/self-renewal and differentiation. Stem Cell Reports. 2015;5(6):988-995.
13. Horvath G, Kis G, Kekesi G, et al. Interaction of clozapine with metformin in a schizophrenia rat model. Sci Rep. 2021;11(1):16862.
14. Zemdegs J, Martin H, Pintana H, et al. Metformin promotes anxiolytic and antidepressant-like responses in insulin-resistant mice by decreasing circulating branched-chain amino acids. J Neurosci. 2019;39(30):5935-5948.
15. B˘adescu SV, T˘ataru C, Kobylinska L, et al. The association between diabetes mellitus and depression. J Med Life. 2016;9(2):120-125.
16. Erensoy H, Niafar M, Ghafarzadeh S, et al. A pilot trial of metformin for insulin resistance and mood disturbances in adolescent and adult women with polycystic ovary syndrome. Gynecol Endocrinol. 2019;35(1):72-75.
17. Kulkarni AS, Gubbi S, Barzilai N. Benefits of metformin in attenuating the hallmarks of aging. Cell Metab. 2020;32(1):15-30.
18. Campbell JM, Bellman SM, Stephenson MD, et al. Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. Ageing Res Rev. 2017;40:31-44.
19. Ala M, Ala M. Metformin for cardiovascular protection, inflammatory bowel disease, osteoporosis, periodontitis, polycystic ovarian syndrome, neurodegeneration, cancer, inflammation and senescence: what is next? ACS Pharmacol Transl Sci. 2021;4(6):1747-1770.
20. Nasrallah HA. Premature mortality across most psychiatric disorders. Current Psychiatry. 2019;8(10):9-10,12,34.