Turmeric and its potential benefits for Depression

Turmeric — or rather, its active component curcumin — is known for processing potent anti-inflammatory, anti-cancer, anti-microbial and antioxidant properties and the last decade has seen a surge of research surrounding the health benefits of this bright, South Asian spice1. More recently, research has begun to investigate the potential benefits of curcumin for depression and, although still in its infancy, the findings are promising.

The impact of depression and issues with current treatment

Depression affects approximately 322 million people worldwide and is considered to be a major contributor to the overall global health burden of disease by the World Health Organisation2. Tens of millions of antidepressants are prescribed each year in the UK alone3. Although many patients depend on their therapeutic effects, their efficacy is far from optimal with 30-50% of patients failing to achieve complete remission following long-term treatment and issues such as delayed onset, non-responsiveness and unpleasant side effects1.

Changing theories of depression

Commonly prescribed antidepressants follow the monoaminergic theory of depression. This theory states that, depression is the result of changes in the activity of specific neurotransmitters in the brain. These neurotransmitters are noradrenaline, serotonin and dopamine — collectively termed monoamines — and are chemical messengers of the brain associated with changes in mood. For example, serotonin reuptake inhibitors (SSRIs), — a commonly prescribed antidepressant — increase the activity of serotonin in the brain by blocking the reuptake of serotonin into the pre-synaptic neuron (Figure 1).

However, beyond the dysfunction of the monoaminergic pathways, depression is now associated with several other pathophysiological changes. A growing body of research suggests that these changes are associated with an increased inflammatory immune response 4-6. In fact, elevated levels of several pro-inflammatory mediators (such as inflammatory cytokines) have been found in the serum of depressed patients. These pro-inflammatory mediators can cross the blood brain barrier and impact the brain and behaviour in several ways (Figure 2).

For example, not only does inflammation decrease monoamine activity but it also has a negative impact on neuroplasticity and neurogenesis. Neuroplasticity is the brains ability to rewire itself through a process of creating and strengthening neural connections. Neurogenesis is the process in which new neurons are formed. Growth factors, such as brain-derived neurotrophic factor (BDNF), play a crucial role in both of these processes and reduced levels of these are associated with inflammation. Interestingly, depression is also associated with reduced levels of several growth factors, including BDNF, particularly in patients presenting with high serum levels of proinflammatory markers 7.

Therefore, given that decreased monoamine activity may be but the tip of the iceberg (not to mention the limitations of antidepressants) there is a growing need to find treatments which are better able to target the inflammation and consequently, impact more of the down-stream effects associated with depression.

Curcumin’s ability to attenuate inflammation and associated changes in the brain

Extensive research has shown that curcumin — the active component of turmeric — can attenuate inflammation and modulate several of the biological mechanisms associated with depression. For example, animal studies and in vitro studies show that curcumin is able to; alter the release and uptake of serotonin, dopamine and noradrenaline, reduce HPA axis activity and associated rises in cortisol levels, improve neuroplasticity and neurogenesis by increasing growth factors including BDNF, reduce inflammatory markers whilst increasing anti-inflammatory markers, and protect against oxidative stress 8-10. These impressive abilities of curcumin make it a promising pharmacological target for treating depression.

Emerging clinical trials don’t live up to the promise of preclinical studies

Given the promising findings of pre-clinical studies there was a call for robust clinical trials to investigate the potential therapeutic effects of curcumin for depressed patients. To date there are only nine short term trials which investigate curcumins benefits as a stand-alone treatment or a combined treatment and their findings are somewhat mixed 11-19. Four of the nine trials found a significant benefit for curcumin versus placebo. One found benefits only emerged after 4 weeks of treatment and the last four found no difference between curcumin versus placebo. However, a lack of observed benefit of curcumin could be a consequence of study limitations such as:

  • Low dose of curcumin — studies ranged from 500 – 1,500 mg/day, but other research would suggest doses as high as 12 g/day are safe for humans 20.
  • No investigations into dose-response curves, i.e. does a higher dose infer a greater therapeutic benefit?
  • Limited numbers of patients with studies ranging from 30-123 patients.
  • Open-label as opposed to double-blind designs.
  • Issues of bioavailability not addressed.
  • Lack of inflammatory biomarker measurements.

Therefore, at present, clinical data is insufficient to recommend the use of curcumin as a treatment for depression. As is often the case, we need more research to fully understand whether curcumin can play a role in the treatment of depression. One area for future research that is vital, though often overlooked, is bioavailability. Research would suggest that curcumin’s bioavailability – that is, its ability to enter the blood stream and locate target tissue in its active form – is poor 20. It may be no wonder then that the potential therapeutic benefits seen in vitro are not realised in human trials. Furthermore, not all depressed patients present with inflammation and hence, the potential for curcumin may only extend to a subgroup of depressed patients. As only two of the nine clinical trials measured any biomarkers of inflammation it is hard to tell if these patients were experiencing an increased inflammatory immune response. Therefore, given its potent anti-inflammatory properties there is still hope that curcumin may have some therapeutic benefits for depressed patients who present with increase pro-inflammatory markers.

Limitations and things to keep in mind

  • Type 2 diabetes, obesity and cardiovascular disease are often present in depressed patients 21-23. These metabolic disorders contribute to a chronically elevated inflammatory state which further feeds depression; creating a vicious cycle. It is unlikely that curcumin alone will tackle these disorders. What may be more beneficial is the incorporation of anti-inflammatory interventions such as exercise and a healthy, balanced diet. Although these arguably, are of greater effort to the patient and may take longer to effect, they may have more significant long-term benefits versus purely pharmacological treatment.
  • Curcumin is found within turmeric in small amounts (approx. 3%) 24 and although turmeric as a whole is associated with several health benefits there is so far no evidence to suggest a turmeric rich diet has therapeutic effects for depression (at present there are no such studies). However, research has suggested that consuming a healthy, balanced diet and frequent exercise have beneficial effects for depression 25.
  • Depression is a highly complex disorder, the aetiology of which is still not well understood and it is unlikely that one ‘miracle pill’ exists. A combination of pharmacological treatments, psycho-therapies and life-style changes which suit the specific symptomatology and biology of each individual patient may be of greater therapeutic benefit.

References

  1. Ghisleni, G., Bastos, C.R., Kaufmann, F.N. and Kaster, M.P. (2019) Curcumin in Depressive Disorders. In Curcumin for Neurological and Psychiatric Disorders (pp. 459-477). Academic Press.
  2. Friedrich, M.J. (2017) ‘Depression is the leading cause of disability around the world.’ Jama317(15), pp.1517-1517.
  3. Iacobucci, G. (2019) ‘NHS prescribed record number of antidepressants last year’ BMJ364, pp.1508. DOI: https://doi.org/10.1136/bmj.l1508
  4. Dantzer, R., O’Connor, J.C., Lawson, M.A. and Kelley, K.W. (2011) ‘Inflammation-associated depression: from serotonin to kynurenine’ Psychoneuroendocrinology36(3), pp.426-436.
  5. Gałecki, P. and Talarowska, M. (2018) ‘Inflammatory theory of depression’ Psychiatr. Pol.52(3), pp.437-47.
  6. Miller, A. H. (2018) ‘Five things to know about inflammation and depression’ Psychiatric Times. 30th April. Available at: https://www.psychiatrictimes.com/special-reports/five-things-know-about-inflammation-and-depression
  7. Allison, D.J., Ditor, D.S. (2014) ‘The common inflammatory etiology of depression and cognitive impairment: a therapeutic target’ Journal of Neuroinflammation, 11(1), pp. 151.
  8. Arora, V., Kuhad, A., Tiwari, V., Chopra, K. (2011) ‘Curcumin ameliorates reserpine-induced pain-depression dyad: behavioural, biochemical, neurochemical and molecular evidences.’ Psychoneuroendocrinology, 36(10) pp. 1570-1581.
  9. Bhutani, M.K., Bishnoi, M., Kulkarni, S.K. (2009) ‘Anti-depressant like effect of curcumin and its combination with piperine in unpredictable chronic stress-induced behavioral, biochemical and neurochemical changes.’ Pharmacology Biochemistry and Behaviour, 92(1), pp. 39-43.
  10. Wang, R., Xu, Y., Wu, H.L. (1998) ‘The antidepressant effects of curcumin in the forced swimming test involve 5-HT1 and 5-HT2 receptors.’ European Journal of Pharmacology, 578(1), pp. 43-50. 
  11. Bergman, J., Miodownik, C., Bersudsky, Y., Sokolik, S., Lerner, P.P., Kreinin, A., Polakiewicz, J. and Lerner, V. (2013) ‘Curcumin as an add-on to antidepressive treatment: a randomized, double-blind, placebo-controlled, pilot clinical study.’ Clinical neuropharmacology36(3), pp.73-77.
  12. Yu, J.J., Pei, L.B., Zhang, Y., Wen, Z.Y. and Yang, J.L. (2015) ‘Chronic supplementation of curcumin enhances the efficacy of antidepressants in major depressive disorder: a randomized, double-blind, placebo-controlled pilot study.’ Journal of clinical psychopharmacology35(4), pp.406-410.
  13. Sanmukhani, J., Satodia, V., Trivedi, J., Patel, T., Tiwari, D., Panchal, B., Goel, A. and Tripathi, C.B. (2014) ‘Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trial.’ Phytotherapy research28(4), pp.579-585.
  14. Lopresti, A.L., Maes, M., Maker, G.L., Hood, S.D. and Drummond, P.D. (2014) ‘Curcumin for the treatment of major depression: a randomised, double-blind, placebo controlled study.’ Journal of affective disorders167, pp.368-375.
  15. Lopresti, A.L., Maes, M., Meddens, M.J., Maker, G.L., Arnoldussen, E. and Drummond, P.D. (2015) ‘Curcumin and major depression: a randomised, double-blind, placebo-controlled trial investigating the potential of peripheral biomarkers to predict treatment response and antidepressant mechanisms of change.’ European Neuropsychopharmacology25(1), pp.38-50.
  16. Lopresti, A.L. and Drummond, P.D. (2017) ’Efficacy of curcumin, and a saffron/curcumin combination for the treatment of major depression: A randomised, double-blind, placebo-controlled study.’ Journal of affective disorders207, pp.188-196.
  17. Kanchanatawan, B., Tangwongchai, S., Sughondhabhirom, A., Suppapitiporn, S., Hemrunrojn, S., Carvalho, A.F. and Maes, M. (2018) ‘Add-on treatment with curcumin has antidepressive effects in Thai patients with major depression: results of a randomized double-blind placebo-controlled study.’ Neurotoxicity research33(3), pp.621-633.
  18. Esmaily, H., Sahebkar, A., Iranshahi, M., Ganjali, S., Mohammadi, A., Ferns, G. and Ghayour-Mobarhan, M. (2015) ’An investigation of the effects of curcumin on anxiety and depression in obese individuals: A randomized controlled trial.’ Chinese journal of integrative medicine21(5), pp.332-338.
  19. Panahi, Y., Badeli, R., Karami, G.R. and Sahebkar, A. (2015) ’Investigation of the efficacy of adjunctive therapy with bioavailability‐boosted curcuminoids in major depressive disorder.’ Phytotherapy Research29(1), pp.17-21.
  20. Anand, P., Kunnumakkara, A.B., Newman, R.A. and Aggarwal, B.B. (2007) ‘Bioavailability of curcumin: problems and promises.’ Molecular pharmaceutics4(6), pp.807-818.
  21. Simon, G.E., Ludman, E.J., Linde, J.A., Operskalski, B.H., Ichikawa, L., Rohde, P., Finch, E.A., Jeffery, R.W. (2008) ‘Association between obesity and depression in middle-aged women.’ General Hospital Psychiatry, 30(1), pp.32-39.
  22. Menezes Zanoveli, J., de Morais, H., Caroline da Silva Dias, I., Karoline Schreiber, A., Pasquini de Souza, C., Maria da Cunha, J. (2016) ‘Depression associated with diabetes: from pathophysiology to treatment.’ Current diabetes reviews12(3), pp.165-178.
  23. Nemeroff, C.B. and Goldschmidt-Clermont, P.J. (2012) ‘Heartache and heartbreak—the link between depression and cardiovascular disease’ Nature Reviews Cardiology9(9), p.526.
  24. Tayyem, R.F., Heath, D.D., Al-Delaimy, W.K. and Rock, C.L. (2006) ‘Curcumin content of turmeric and curry powders.’ Nutrition and cancer55(2), pp.126-131.
  25. García-Toro, M., Ibarra, O., Gili, M., Serrano, M.J., Oliván, B., Vicens, E. and Roca, M. (2012) ‘Four hygienic-dietary recommendations as add-on treatment in depression: a randomized-controlled trial.’ Journal of affective disorders140(2), pp.200-203.

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