|Year : 2019 | Volume
| Issue : 1 | Page : 4-7
Insulin resistance and depression: Relationship and treatment implications
Vijender Singh1, Bhavuk Garg2
1 Department of Psychiatry, Institute of Human Behaviour and Allied Sciences, NABH Accredited Hospital Based Autonomous Institute Under Government of Delhi, Delhi, India
2 Department of Psychiatry and Drug De-Addiction Centre, Lady Hardinge Medical College and SSK Hospital, Delhi, India
|Date of Web Publication||4-Jun-2020|
Department of Psychiatry, Institute of Human Behaviour and Allied Sciences, NABH Accredited Hospital Based Autonomous Institute Under Government of Delhi, G.T. Road, Dilshad Garden, Delhi - 110 095
Source of Support: None, Conflict of Interest: None
Insulin resistance has been associated with depressive symptoms and depressive syndrome. Studies have attempted to assess the relationship between metabolic syndrome and depression and more specifically insulin resistance and depression. Studies have also been carried out to assess the direction of this relationship. This brief review is purported to present and discuss the currently available literature evidence about relationship of insulin resistance with depression and the treatment implications of this relationship. The presence of insulin resistance in an individual is positively associated with increased depressive symptoms and the presence of depressive symptoms is found to be associated with insulin resistance. However, a causal relationship could not be established. Prospective study designs can help to enhance our knowledge in finding a causal relationship. Intervention studies that will further help in treatment decisions are required.
Keywords: Depression, depressive symptoms, diabetes, insulin resistance, insulin sensitivity, metabolic syndrome
|How to cite this article:|
Singh V, Garg B. Insulin resistance and depression: Relationship and treatment implications. J Mental Health Hum Behav 2019;24:4-7
|How to cite this URL:|
Singh V, Garg B. Insulin resistance and depression: Relationship and treatment implications. J Mental Health Hum Behav [serial online] 2019 [cited 2022 Jun 28];24:4-7. Available from: https://www.jmhhb.org/text.asp?2019/24/1/4/285995
| Introduction|| |
Major depression is a common psychiatric disorder with a prevalence of 2.6%–5.9%. It is characterized by low mood, reduced interest in activities, sleep and appetite disturbances, feelings of worthlessness, and guilt and impaired concentration. Insulin resistance is a state in which insulin is not able to show the desired effect in the body; as a result, cells in the body fail to respond to the action of insulin, and a given concentration of insulin is not able to produce the expected biological effect. The International Diabetes Federation defines insulin resistance in the additional metabolic measurements for research while defining metabolic syndrome. It mentions the following as parameters to establish insulin resistance: fasting insulin/proinsulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), insulin resistance by Bergman minimal model, elevated free fatty acids (fasting and during oral glucose tolerance test), and M value from clamp.
While searching for neurobiological basis of depression, many factors have been studied from structural to functional imaging, neurotransmitters to cytokines, and immunological to endocrinal factors. The association between metabolic syndrome and depression and diabetes and depression has been studied extensively. More specifically, research is moving in the direction of studying the relationship between insulin resistance and depression. In a systematic review and meta-analysis of 21 studies, a small but significant cross-sectional association was found between insulin resistance and depression. The authors also found that there is substantial heterogeneity in the studies and there was a possibility of publication bias.
The relationship can be studied under different heads. In this review, the authors have attempted to find the possibility of a bidirectional relationship of insulin resistance and depression and the treatment implications of the relationship.
PubMed and Google Scholar search was done using two sets of keywords combined using AND operator. The first set of keywords included terms related to insulin resistance – insulin resistance, insulin sensitivity, diabetes, and metabolic syndrome. The second set included depression-related terms – depression, stress, anxiety, and depressive symptoms.
| Relationship between Insulin Resistance and Depression|| |
Many studies have found a positive relationship between insulin resistance and depression. An important point to consider here is that there have been a number of studies, reviews, and meta-analyses on the relationship between diabetes and depression,,,, and the overall conclusion points toward a positive association. While studying for the relationship between insulin resistance and depression, it is important that the study participants are not diagnosed with diabetes and their insulin resistance status is independent of diabetes. A common confounder in the studies is diagnosed or undiagnosed diabetes. Studies have tried to keep appropriate inclusion and exclusion criteria to be free of this confounding effect. Other common confounders in assessing this relationship are smoking status, alcohol consumption, physical activity levels, and waist circumference. In these studies, insulin resistance has been assessed using fasting insulin levels, HOMA-IR, hyperinsulinemic-euglycemic clamp, and quantitative insulin sensitivity check index. The hyperinsulinemic-euglycemic clamp is considered the gold standard but is not suitable for large-scale cross-sectional studies. The different techniques used to assess insulin resistance in different studies also lead to an impact on the findings. In a large population-based study including both young men and women, it was found that depressive disorder (according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria) was significantly related to insulin resistance. The authors adjusted for demographic, behavioral, and dietary factors in their methodology. Pyykkönen et al. also found a positive association between insulin resistance and depressive symptoms. They further studied the effect of antidepressant medications and found that their use did not augment or explain these effects. In a study done on Chinese population, it was found that a positive association was found between depressive symptoms and insulin resistance. They also recommended that prospective studies are needed to find a temporal and causal relationship.
Depression leading to insulin resistance has been studied in a longitudinal study. In this study, depressive symptoms in children were found to be a risk factor for greater insulin resistance after 6 years while accounting for known additional risk factors.
It has not been clearly established whether the state of insulin resistance leads to depressive symptoms or the depressive state leads to insulin resistance. Due to the lack of prospective studies, the directionality of the two is not clear. Determining this directionality can have important implications. Theoretically, treating depression in individuals with a risk of diabetes might prevent or delay the onset of diabetes.
A 6-year prospective study to assess the directionality of this relationship found that depressive symptoms increased insulin resistance over time, but in the other direction, insulin resistance at baseline did not increase depressive symptoms over follow-up.
A study carried out on around 4000 women found an inverse association between insulin resistance and depression, i.e., with increasing insulin resistance, the prevalence of depression decreased. This finding was seen in women without diabetes. In women with diabetes, the prevalence of depression increased with increasing insulin resistance. Emotional abuse during childhood was found as a risk factor for developing insulin resistance.
Some studies have found no association between insulin resistance and depression. A prospective study did not find a significant relationship between insulin resistance and depressive symptoms in men. Similar findings were obtained in another study done in Swedish women. Another study found only a weak association between depressive symptoms and insulin resistance. A recent genetic association study done using genotypic and phenotypic data from the UK Biobank cohort did not find a causal relationship between insulin resistance and depression.
| What Is the Underlying Basis of Relationship?|| |
Different mechanisms have been proposed for the association of depressive symptoms with insulin resistance. It has been proposed that the state of insulin resistance leads to raised levels of free fatty acids in the blood which has an impact on tryptophan metabolism and the brain serotonin concentration. This impact on brain serotonin levels may be responsible for an association between insulin resistance and depression. Conversely, the state of depression may lead to insulin resistance. Depression is associated with the activation of the hypothalamic–pituitary–adrenal (HPA) axis. Activation of the HPA axis leads to corticosteroid release which further leads to a state of insulin resistance., Depression is also associated with an increase in inflammatory mediators such as cytokines. This pro-inflammatory state leads to apoptosis and cell damage which may lead to a state of insulin resistance., The sedentary lifestyle, lack of physical activity, and exercise associated with depressive symptoms may also lead to an increase in central obesity which, in turn, leads to insulin resistance. Insulin resistance was also found associated with smaller brain volumes in a study done in depressed and obese children.
| Treatment Implications of Relationship|| |
There can be different treatment implications of the relationship between insulin resistance and depression. The questions which come forward are (a) whether treatment of depression leads to the improvement of insulin resistance and (b) whether improvement of insulin resistance leads to amelioration of depression.
The first question has been studied by a few researchers. Okamura et al. found that patients with depression had impaired insulin sensitivity and resultant hyperinsulinemia and that these abnormalities could be resolved after recovery from depression.
Wagner et al. found that insulin sensitivity was found to be lower in individuals with untreated depression and that insulin sensitivity increased in individuals on antidepressant medication.
An intervention study found that insulin sensitivity was related to the severity of depression. It was also found that the treatment of depression with an antidepressant (escitalopram) enhanced insulin sensitivity. In another such study, successful treatment of depression with either a selective serotonin reuptake inhibitor or a tricyclic antidepressant agent increased the sensitivity to insulin in nondiabetic patients. Similar findings were obtained with studies using other antidepressants such as mirtazapine and venlafaxine. Among nonpharmacological treatment strategies, lower decreased fasting insulin levels were found at 1 year in adolescent girls with depression receiving cognitive behavioral therapy in a randomized controlled trial. Similar findings were reported in a study done by Shomaker et al. in 2017. Mindfulness-based group intervention in adolescent girls was also found to lead to better insulin resistance.
In the other direction, researchers have also tried to study the effect of insulin sensitizers such as thiazolidinediones on depression. In a pilot study carried out on patients with major depressive disorder, it was found that pioglitazone improved depressive symptoms during the acute treatment period of 12 weeks which was maintained over 3 months. The antidepressant effect of pioglitazone has been studied extensively, and beneficial effects have been found in a systematic review and meta-analysis. Similar improvement has also been reported with rosiglitazone. Metformin has also been studied for its antidepressant effect. Mechanisms that may explain the antidepressant effect of metformin include raising insulin-like growth factor 2 expression in the dorsal hippocampus and regulating DNA hydroxymethylation.
To summarize, both pharmacological and nonpharmacological treatments of depression improve insulin sensitivity in patients with depression. Effective treatment of depression is helpful in managing insulin resistance. Insulin sensitizers also lead to an improvement in depressive symptoms. It is important to keep these aspects in mind while managing patients in real-world settings.
| Conclusion and Future Recommendations|| |
In this review, it is found that there is a bidirectional relationship between insulin resistance and depression. The presence of insulin resistance in an individual is positively associated with increased depressive symptoms, and the presence of depressive symptoms is found to be associated with insulin resistance. However, a causal relationship could not be established. If the Bradford Hill criteria (strength, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy) are applied to look for causality, the criteria of strength, specificity, and biological gradient need to be established more firmly between insulin resistance and depression. The research trends are mainly showing that most of the studies done in this field are cross-sectional in nature. Cross-sectional studies have been able to provide evidence of the relationship between the two entities. However, it is important to search for some causal relationship between insulin resistance and depression. Prospective study designs can help to enhance our knowledge in this direction. Even while studying the relationship between diabetes and depression, longitudinal and prospective study designs have been recommended to look for causality. Large-scale studies on individuals at risk of diabetes or insulin resistance need to be carried out. Intervention studies that will further help in treatment decisions are required. With the growing trends toward biological psychiatry, this is an important field wherein further research is required.
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Conflicts of interest
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| References|| |
World Health Organization. Depression and other Common Mental Disorders-Global Health Estimates. Geneva: World Health Organization; 2017.
Wilcox G. Insulin and insulin resistance. Clin Biochem Rev 2005;26:19-39.
Maletic V, Robinson M, Oakes T, Iyengar S, Ball SG, Russell J. Neurobiology of depression: An integrated view of key findings. Int J Clin Pract 2007;61:2030-40.
Kan C, Silva N, Golden SH, Rajala U, Timonen M, Stahl D, et al
. A systematic review and meta-analysis of the association between depression and insulin resistance. Diabetes Care 2013;36:480-9.
Mezuk B, Eaton WW, Albrecht S, Golden SH. Depression and type 2 diabetes over the lifespan: A meta-analysis. Diabetes Care 2008;31:2383-90.
Simon GE, Von Korff M, Saunders K, Miglioretti DL, Crane PK, van Belle G, et al
. Association between obesity and psychiatric disorders in the US adult population. Arch Gen Psychiatry 2006;63:824-30.
Eaton WW, Armenian H, Gallo J, Pratt L, Ford DE. Depression and risk for onset of type II diabetes. A prospective population-based study. Diabetes Care 1996;19:1097-102.
Ali S, Stone MA, Peters JL, Davies MJ, Khunti K. The prevalence of co-morbid depression in adults with Type 2 diabetes: A systematic review and meta-analysis. Diabet Med 2006;23:1165-73.
Svenningsson I, Björkelund C, Marklund B, Gedda B. Anxiety and depression in obese and normal-weight individuals with diabetes type 2: A gender perspective. Scand J Caring Sci 2012;26:349-54.
Pearson S, Schmidt M, Patton G, Dwyer T, Blizzard L, Otahal P, et al
. Depression and insulin resistance: Cross-sectional associations in young adults. Diabetes Care 2010;33:1128-33.
Pyykkönen AJ, Räikkönen K, Tuomi T, Eriksson JG, Groop L, Isomaa B. Depressive symptoms, antidepressant medication use, and insulin resistance: The PPP-Botnia Study. Diabetes Care 2011;34:2545-7.
Pan A, Ye X, Franco OH, Li H, Yu Z, Zou S, et al
. Insulin resistance and depressive symptoms in middle-aged and elderly Chinese: Findings from the Nutrition and Health of Aging Population in China Study. J Affect Disord 2008;109:75-82.
Shomaker LB, Tanofsky-Kraff M, Stern EA, Miller R, Zocca JM, Field SE, et al
. Longitudinal study of depressive symptoms and progression of insulin resistance in youth at risk for adult obesity. Diabetes Care 2011;34:2458-63.
Khambaty T, Stewart JC, Muldoon MF, Kamarck TW. Depressive symptom clusters as predictors of 6-year increases in insulin resistance: Data from the Pittsburgh Healthy Heart Project. Psychosom Med 2014;76:363-9.
Lawlor DA, Smith GD, Ebrahim S; British Women's Heart and Health Study. Association of insulin resistance with depression: Cross sectional findings from the British Women's Heart and Health Study. BMJ 2003;327:1383-4.
Nasca C, Watson-Lin K, Bigio B, Robakis TK, Myoraku A, Wroolie TE, et al
. Childhood trauma and insulin resistance in patients suffering from depressive disorders. Exp Neurol 2019;315:15-20.
Lawlor DA, Ben-Shlomo Y, Ebrahim S, Davey Smith G, Stansfeld SA, Yarnell JW, et al
. Insulin resistance and depressive symptoms in middle aged men: Findings from the Caerphilly prospective cohort study. BMJ 2005;330:705-6.
Roos C, Lidfeldt J, Agardh CD, Nyberg P, Nerbrand C, Samsioe G, et al
. Insulin resistance and self-rated symptoms of depression in Swedish women with risk factors for diabetes: The Women's Health in the Lund Area study. Metabolism 2007;56:825-9.
Adriaanse MC, Dekker JM, Nijpels G, Heine RJ, Snoek FJ, Pouwer F. Associations between depressive symptoms and insulin resistance: The Hoorn Study. Diabetologia 2006;49:2874-7.
Frangou S, Shirali M, Adams MJ, Howard DM, Gibson J, Hall LS, et al
. Insulin resistance: Genetic associations with depression and cognition in population based cohorts. Exp Neurol 2019;316:20-6.
Frayn KN, Kingman SM. Dietary sugars and lipid metabolism in humans. Am J Clin Nutr 1995;62:250S-261S.
Brown ES, Varghese FP, McEwen BS. Association of depression with medical illness: Does cortisol play a role? Biol Psychiatry 2004;55:1-9.
Weber-Hamann B, Hentschel F, Kniest A, Deuschle M, Colla M, Lederbogen F, et al
. Hypercortisolemic depression is associated with increased intra-abdominal fat. Psychosom Med 2002;64:274-7.
Black PH. The inflammatory response is an integral part of the stress response: Implications for atherosclerosis, insulin resistance, type II diabetes and metabolic syndrome X. Brain Behav Immun 2003;17:350-64.
Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: A meta-analysis. Psychosom Med 2009;71:171-86.
Phillips OR, Onopa AK, Zaiko YV, Singh MK. Insulin resistance is associated with smaller brain volumes in a preliminary study of depressed and obese children. Pediatr Diabetes 2018;19:892-7.
Okamura F, Tashiro A, Utumi A, Imai T, Suchi T, Tamura D, et al
. Insulin resistance in patients with depression and its changes during the clinical course of depression: Minimal model analysis. Metabolism 2000;49:1255-60.
Wagner J, Allen NA, Swalley LM, Melkus GD, Whittemore R. Depression, depression treatment, and insulin sensitivity in adults at risk for type 2 diabetes. Diabetes Res Clin Pract 2009;86:96-103.
Asghar S, Magnusson A, Hussain A, Diep LM, Bhowmik B, Thorsby PM. Depression and Insulin resistance in non-diabetic subjects: An intervention study with insulin clamp technique. Int J Clin Med 2012;3:575-81.
Weber-Hamann B, Gilles M, Lederbogen F, Heuser I, Deuschle M. Improved insulin sensitivity in 80 nondiabetic patients with MDD after clinical remission in a double-blind, randomized trial of amitriptyline and paroxetine. J Clin Psychiatry 2006;67:1856-61.
Weber-Hamann B, Gilles M, Schilling C, Onken V, Frankhauser P, Kopf D, et al
. Improved insulin sensitivity in 51 nondiabetic depressed inpatients remitting during antidepressive treatment with mirtazapine and venlafaxine. J Clin Psychopharmacol 2008;28:581-4.
Gulley LD, Shomaker LB, Kelly NR, Chen KY, Stice E, Olsen CH, et al
. Indirect Effects of a Cognitive-Behavioral Intervention on Adolescent Weight and Insulin Resistance Through Decreasing Depression in a Randomized Controlled Trial. J Pediatr Psychol 2019. pii: Jsz064.
Shomaker LB, Kelly NR, Radin RM, Cassidy OL, Shank LM, Brady SM, et al
. Prevention of insulin resistance in adolescents at risk for type 2 diabetes with depressive symptoms: 1-year follow-up of a randomized trial. Depress Anxiety 2017;34:866-76.
Shomaker LB, Bruggink S, Pivarunas B, Skoranski A, Foss J, Chaffin E, et al
. Pilot randomized controlled trial of a mindfulness-based group intervention in adolescent girls at risk for type 2 diabetes with depressive symptoms. Complement Ther Med 2017;32:66-74.
Kemp DE, Ismail-Beigi F, Ganocy SJ, Conroy C, Gao K, Obral S, et al
. Use of insulin sensitizers for the treatment of major depressive disorder: A pilot study of pioglitazone for major depression accompanied by abdominal obesity. J Affect Disord 2012;136:1164-73.
Moulton CD, Hopkins CW, Ismail K, Stahl D. Repositioning of diabetes treatments for depressive symptoms: A systematic review and meta-analysis of clinical trials. Psychoneuroendocrinology 2018;94:91-103.
Rasgon NL, Kenna HA, Williams KE, Powers B, Wroolie T, Schatzberg AF. Rosiglitazone add-on in treatment of depressed patients with insulin resistance: A pilot study. ScientificWorldJournal 2010;10:321-8.
Guo M, Mi J, Jiang QM, Xu JM, Tang YY, Tian G, et al
. Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus. Clin Exp Pharmacol Physiol 2014;41:650-6.
Poggini S, Golia MT, Alboni S, Milior G, Sciarria LP, Viglione A, et al
. Combined Fluoxetine and Metformin Treatment Potentiates Antidepressant Efficacy Increasing IGF2 Expression in the Dorsal Hippocampus. Neural Plast 2019;2019:1-12.
Wang Y, Liu B, Yang Y, Wang Y, Zhao Z, Miao Z, et al
. Metformin exerts antidepressant effects by regulated DNA hydroxymethylation. Epigenomics 2019;11:655-67.
Hill AB. The environment and disease: Association or causation? Proc R Soc Med 1965;58:295-300.
Rustad JK, Musselman DL, Nemeroff CB. The relationship of depression and diabetes: Pathophysiological and treatment implications. Psychoneuroendocrinology 2011;36:1276-86.