The Potential Utility of Ashwagandha for Improving Cognitive Dysfunction in Persons with Bipolar or Other Neurocognitive Disorders

  • K. N. Roy ChengappaEmail author
  • Jessica M. Gannon
  • Luna Acharya
  • Abhishek Rai


Bipolar Disorder is a mood disorder that can be quite severe for subgroups of patients, and often such patients manifest deficits in attention, concentration, memory, and executive functions that persist even when they are relatively well. Cognitive concerns can impair daily life functioning and impact employment, education, and interpersonal relationships. Main line treatments for bipolar disorder typically do not address cognitive impairments, and some treatments may actually worsen cognitive deficits. Treatment development for cognitive impairments in bipolar disorder is truly in its infancy; extracts of Ashwagandha (Withania somnifera) may hold promise as a potential treatment option. The bioactive constituents of Ashwagandha, including withanolides, indosides, Withaferin A, and others, possess anti-inflammatory-immunomodulatory, anti-oxidant, cortisol lowering, anti-stress, pro-cholinergic, anti-glutamatergic and neuroprotective properties, the very processes that are thought to underlie cognitive impairments not only in in bipolar disorder but also in other psychiatric disorders like schizophrenia and major depression. This chapter reviews this in detail and highlights the preliminary randomized controlled study assessing an extract of Ashwagandha for improving cognition in bipolar disorder. The chapter also explores the potential role of Ashwagandha extracts in the treatment of other neurocognitive disorders, and it concludes by summarizing additional future research needed to realize the potential of this ancient medicinal plant for the treatment of human ailments.


Bipolar disorder Ashwagandha Withanolides Randomized controlled study Improvement of cognitive dysfunction 


  1. Agarwal R, Diwanay S, Patki P, Patwardhan B (1999) Studies on immunomodulatory activity of Withania somnifera (Ashwagandha) extracts in experimental immune inflammation. J Ethnopharmacol 67:27–35PubMedCrossRefGoogle Scholar
  2. Ahmed ME, Javed H, Khan MM, Vaibhav K, Ahmad A, Khan A, Tabassum R, Islam F, Safhi MM, Islam F (2013) Attenuation of oxidative damage-associated cognitive decline by Withania somnifera in rat model of streptozotocin-induced cognitive impairment. Protoplasma 250:1067–1078PubMedCrossRefGoogle Scholar
  3. Akintola AA, Jansen SW, van Bodegom D, van der Grond J, Westendorp RG, de Craen AJ, van Heemst D (2015) Subclinical hypothyroidism and cognitive function in people over 60 years: a systematic review and meta-analysis. Front Aging Neurosci 11:7–150Google Scholar
  4. Alonso J, Petukhova M, Vilagut G, Chatterji S, Heeringa S, Üstün TB, Alhamzawi AO, Viana MC, Angermeyer M, Bromet E, Bruffaerts R, de Girolamo G, Florescu S, Gureje O, Haro JM, Hinkov H, Hu CY, Karam EG, Kovess V, Levinson D, Medina-Mora ME, Nakamura Y, Ormel J, Posada-Villa J, Sagar R, Scott KM, Tsang A, Williams DR, Kessler RC (2011) Days out of role due to common physical and mental conditions: results from the WHO World Mental Health surveys. Mol Psychiatry 16:1234–1246PubMedCrossRefGoogle Scholar
  5. Altshuler LL, Ventura J, van Gorp WG, Green MF, Theberge DC, Mintz J (2004) Neurocognitive function in clinically stable men with bipolar I disorder or schizophrenia and normal control subjects. Biol Psychiatry 56:560–569PubMedCrossRefGoogle Scholar
  6. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th edn (DSM-5). American Psychiatric Publishing, Washington, DCGoogle Scholar
  7. Anbalagan K, Sadique J (1981) Influence of an Indian medicine (Ashwagandha) on acute-phase reactants in inflammation. Indian J Exp Biol 19:245–249PubMedGoogle Scholar
  8. Anbalagan K, Sadique J (1985) Withania somnifera (ashwagandha), a rejuvenating herbal drug which controls a-2 macroglobulin synthesis during inflammation. Int J Crude Drug Res 23:177–183CrossRefGoogle Scholar
  9. Andallu B, Radhika B (2000) Hypoglycemic, diuretic and hypocholesterolemic effect of winter cherry (Withania somnifera, Dunal) root. Indian J Exp Biol 38:607–609PubMedGoogle Scholar
  10. Andrade C, Aswath A, Chaturvedi SK, Srinivasa M, Raguram R (2000) A double-blind, placebo-controlled evaluation of the anxiolytic efficacy of an ethanolic extract of Withania Somnifera. Indian J Psychiatry 42:295–301PubMedPubMedCentralGoogle Scholar
  11. Atre-Vaidya N, Taylor MA, Seidenberg M, Reed R, Perrine A, Glick-Oberwise F (1998) Cognitive deficits, psychopathology, and psychosocial functioning in bipolar mood disorder. Neuropsychiatry Neuropyschol Behav Neurol 11:120–126Google Scholar
  12. Auddy B, Hazra J, Mitra A, Abedon B, Ghosal S (2008) A standardized Withania somnifera Extract significantly reduces stress-related parameters in chronically stressed humans: A double-blind, randomized, placebo-controlled study. JANA 11:51–57Google Scholar
  13. Bauer M, Glenn T, Pilhatsch M, Pfennig A, Whybrow PC (2014a) Gender differences in thyroid system function: relevance to bipolar disorder and its treatment. Bipolar Disord 16:58–71PubMedCrossRefGoogle Scholar
  14. Bauer IE, Pascoe MC, Wollenhaupt-Aguiar B, Kapczinski F, Soares JC (2014b) Inflammatory mediators of cognitive impairment in bipolar disorder. J Psychiatr Res 56:18–27PubMedPubMedCentralCrossRefGoogle Scholar
  15. Bearden CE, Shih VH, Green MF, Gitlin M, Sokolski KN, Levander E, Marusak S, Hammen C, Sugar CA, Altshuler LL (2011) The impact of neurocognitive impairment on occupational recovery of clinically stable patients with bipolar disorder: A prospective study. Bipolar Disord 13:323–333PubMedPubMedCentralCrossRefGoogle Scholar
  16. Begum V, Sadique J (1988) Long term effect of herbal drug Withania somnifera on adjuvant induced arthritis in rats. Indian J Exp Biol 26:877–882PubMedGoogle Scholar
  17. Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Bush AI (2008) N-acetylcysteine for depressive symptoms in bipolar disorder – a double-blind randomized placebo-controlled trial. Biol Psychiatry 64:468–475PubMedCrossRefGoogle Scholar
  18. Besedovsky H, del Rey A, Sorkin E, Da Prada M, Burri R, Honegger C (1983) The immune response evokes changes in brain noradrenergic neurons. Science 221:564–566PubMedCrossRefGoogle Scholar
  19. Bhattacharya SK, Muruganandam AV (2003) Adaptogenic activity of Withania somnifera: An experimental study using a rat model of chronic stress. Pharmacol Biochem Behav 75:547–555PubMedCrossRefGoogle Scholar
  20. Brar JS, Chengappa KNR (2011) Does one shoe fill all? The Randomized Controlled Clinical Trial (RCT) as a model for assessing the efficacy or effectiveness of whole systems Ayurveda or other Traditional Medicine (TM) treatments. J Ayurveda Integr Med 2:91–93PubMedPubMedCentralCrossRefGoogle Scholar
  21. Brown NC, Andreazza AC, Young LT (2014) An updated meta-analysis of oxidative stress markers in bipolar disorder. Psychiatry Research 218:61–68PubMedCrossRefGoogle Scholar
  22. Burdick KE, Braga RJ, Nnadi CU, Shaya Y, Stearns WH, Malhotra AK (2012) A Placebo-controlled adjunctive trial of pramipexole in patients with bipolar disorder: Targeting cognitive dysfunction. J Clin Psychiatry 73:103–112PubMedCrossRefGoogle Scholar
  23. Cannon WB (1932) The wisdom of the body. WW Norton, New YorkGoogle Scholar
  24. Chandrasekhar K, Kapoor J, Anishetty S (2012) A prospective, randomized double-blind, placebo-controlled study of safety and efficacy of a high-concentration full-spectrum extract of Ashwagandha root in reducing stress and anxiety in adults. Indian J Psychol Med 34:255–262PubMedPubMedCentralCrossRefGoogle Scholar
  25. Cheng G, Huang C, Deng H, Wang H (2012) Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Intern Med J 42:484–491PubMedCrossRefGoogle Scholar
  26. Chengappa KN, Bowie CR, Schlicht PJ, Fleet D, Brar JS, Jindal R (2013) Randomized placebo-controlled adjunctive study of an extract of Withania Somnifera for Cognitive Dysfunction in Bipolar Disorder. J Clin Psychiatry 74:1076–1083PubMedCrossRefGoogle Scholar
  27. Chopra A, Lavin P, Patwardhan B, Chitre D (2000) Randomized Double-blind trial of an Ayurvedic Plant derived formulation for Treatment of Rheumatoid arthritis. Journal of Rheumatology 27:1365–1372PubMedGoogle Scholar
  28. Chopra A, Lavin P, Patwardhan B, Chitre D (2004) A 32-week randomized, placebo-controlled clinical evaluation of RA-11, and Ayurvedic drug, on osteoarthritis of the knees. J Clin Rheumatol 10:236–245PubMedCrossRefGoogle Scholar
  29. Choudhary MI, Yousuf S, Nawaz SA, Ahmed S, Atta-ur-Rahman (2004) Cholinesterase inhibiting withanolides from Withania somnifera. Chem Pharm Bull (Tokyo) 52:1358–1361CrossRefGoogle Scholar
  30. Choudhary D, Bhattacharyya S, Joshi K (2017) Body weight management in adults under chronic stress through treatment with Ashwagandha root extract: A double-blind, randomized, placebo-controlled trial. J Evid Based Complementary and Altern Med 22:96–106CrossRefGoogle Scholar
  31. Chrousos GP (1995) The Hypothalamic-Pituitary-Adrenal Axis and Immune-Mediated Inflammation. N Engl J Med 332:1351–1363PubMedCrossRefGoogle Scholar
  32. Clark L, Goodwin G (2008) Attentional and Executive Functioning in Bipolar Disorder. In: Goldberg JF, Burdick KE (eds) Cognitive dysfunction in bipolar disorder. A guide to clinicians. American Psychiatric Publishing Inc, Arlington, pp 23–47Google Scholar
  33. Clark L, Iverson SD, Goodwin GM (2001) A neuropsychological investigation of the prefrontal cortex involvement in acute mania. Am J Psychiatry 158:1605–1611PubMedCrossRefGoogle Scholar
  34. Clark L, Sarna A, Goodwin GM (2005) Impairment of executive function but not memory in first degree relatives of patients with bipolar I disorder and in euthymic patients with unipolar depression. Am J Psychiatry 162:1980–1982PubMedCrossRefGoogle Scholar
  35. Coogan AN, Wyse CA (2008) Neuroimmunology of the circadian clock. Brain Res 1232:104–112PubMedCrossRefGoogle Scholar
  36. Cooley K, Szczurko O, Perri D, Mills EJ, Bernhardt B, Zhou Q, Seely D (2009) Naturopathic care for anxiety: a randomized controlled trial ISRCTN78958974. PLoS One 4:e6628PubMedPubMedCentralCrossRefGoogle Scholar
  37. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: When the immune system subjugates the brain. Nat Rev Neurosci 9:46–56PubMedPubMedCentralCrossRefGoogle Scholar
  38. Dar NJ, Hamid A, Ahmed M (2015) Pharmacologic overview of Withania somnifera, the Indian Ginseng. Cell Mol Life Sci 72:4445–4460PubMedCrossRefGoogle Scholar
  39. Dargél AA, Godin O, Kapczinski F, Kupfer DJ, Leboyer M (2015) C-Reactive Protein Alterations in Bipolar Disorder: A meta-analysis. J Clin Psychiatry 76:142–150PubMedCrossRefGoogle Scholar
  40. Demant KM, Vinberg M, Kessing LV, Miskowiak KW (2015) Effects of short-term cognitive remediation on cognitive dysfunction in partially or fully remitted individuals with bipolar disorder: Results of a randomised controlled trial. PLoS One 10:e0127955PubMedPubMedCentralCrossRefGoogle Scholar
  41. Dickerson FB, Boronow JJ, Stallings CR, Origoni AE, Cole S, Yolken RH (2004) Association between cognitive functioning and employment status of persons with bipolar disorder. Psychol Serv 55:54–58CrossRefGoogle Scholar
  42. Dupont RM, Jernigan TL, Butters N, Delis D, Hesselink JR, Heindel W, Gillin JC (1990) Subcortical abnormalities detected in bipolar affective disorder using magnetic resonance imaging. Clinical and neuropsychological significance. Arch Gen Psychiatry 47:55–59PubMedCrossRefGoogle Scholar
  43. Durg S, Dhadde SB, Vandal R, Shivakumar BS, Charan CS (2015) Withania somnifera (Ashwagandha) in neurobehavioral disorders induced by brain oxidative stress in rodents: a systematic review and meta-analysis. J Pharmacy Pharmacol 67:879–899CrossRefGoogle Scholar
  44. Elgamal L, Sokolowska M, MacQueen G (2008) Memory deficits associated with Bipolar Disorder. In: Goldberg JF, Burdick KE (eds) Cognitive dysfunction in bipolar disorder. A guide to clinicians. American Psychiatric Publishing Inc, Arlington, pp p49–p67Google Scholar
  45. Ferrier IN, Chowdhury R, Thompson JM, Watson S, Young AH (2004) Neurocognitive function in unaffected first-degree relatives of patients with bipolar disorder: a preliminary report. Bipolar Disord 6:319–322PubMedCrossRefGoogle Scholar
  46. Frangou S, Donaldson S, Hadjulis M, Landau S, Goldstein LH (2005) The Maudsley bipolar disorder project: executive dysfunction in bipolar disorder I and its clinical correlates. Biol Psychiatry 58:859–864PubMedCrossRefGoogle Scholar
  47. Frank E, Swartz HA, Kupfer DJ (2000) Interpersonal and social rhythm therapy: managing the chaos of bipolar disorder. Biol Psychiatry 48:593–604PubMedCrossRefGoogle Scholar
  48. Gajarmal AA, Shende MB (2015) A clinical evaluation of antistress activity of Ashwagandha (Withania somnifera Dunal) on employees experiencing mental stress at work place. Int J Ayur Pharma Res 3:37–45Google Scholar
  49. Ganguli R, Brar JS, Rabin BS (1994) Immune abnormalities in schizophrenia: evidence for the autoimmune hypothesis. Harv Rev Psychiatry 2:70–83PubMedCrossRefGoogle Scholar
  50. Ganguli R, Brar JS, Chengappa KR, DeLeo M, Yang ZW, Shurin G, Rabin BS (1995) Mitogen-stimulated interleukin-2 production in never-medicated, first-episode schizophrenic patients. The influence of age at onset and negative symptoms. Arch Gen Psychiatry 52:668–672PubMedCrossRefGoogle Scholar
  51. Gannon JM, Forrest PE, Chengappa KNR (2014) Subtle changes in thyroid indices during a placebo-controlled study of an extract of Withania somnifera in persons with bipolar disorder. J Ayurveda Integr Med 5:241–245PubMedPubMedCentralCrossRefGoogle Scholar
  52. Gershon S, Chengappa KNR (2009) Contemporary diagnosis and management of bipolar disorders. Handbooks in Health Care Company, NewtownGoogle Scholar
  53. Ghosal S, Kaur R, Srivatsava RS (1988) Sitoindosides IX and X, two new withanolide glycosides from Withania Somnifera. Indian J Nat Prod 4:12–13Google Scholar
  54. Glahn DC, Burdick KE, Bearden CE (2008) The Endophenotye concept. In: Goldberg JF, Burdick KE (eds) Cognitive dysfunction in bipolar disorder. A guide to clinicians. American Psychiatric Publishing Inc, Arlington, pp 69–88Google Scholar
  55. Goldberg JF (2008) Adverse cognitive effects of psychotropic medications. In: Goldberg JF, Burdick KE (eds) Cognitive dysfunction in bipolar disorder. A guide to clinicians. American Psychiatric Publishing Inc, Arlington, pp 137–158Google Scholar
  56. Goldberg JF, Burdick KE (eds) (2008) Cognitive dysfunction in bipolar disorder. A guide to clinicians. American Psychiatric Publishing, Inc. ArlingtonGoogle Scholar
  57. Goldberg JF, Chengappa KNR (2009) Identifying and treating cognitive impairment in bipolar disorder. Bipolar Disord 11(Suppl 2):123–137PubMedCrossRefGoogle Scholar
  58. Goodwin FK, Jamison KR (2007) Manic depressive illness, 2nd edn. Oxford University Press, New YorkGoogle Scholar
  59. Gorelick J, Rosenberg R, Smotrich A, Hanuš L, Bernstein N (2015) Hypoglycemic activity of withanolides and elicitated Withania somnifera. Phytochemistry 116:283–289PubMedCrossRefGoogle Scholar
  60. Grande I, Berk M, Birmaher B, Vieta E (2015) Bipolar Disorder. The Lancet 387:1561–1572CrossRefGoogle Scholar
  61. Green MF (1996) What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 153:321–330PubMedCrossRefGoogle Scholar
  62. Grover A, Shandilya A, Agrawal V, Bisaria VS, Sundar D (2012) Computational evidence to inhibition of human acetyl cholinesterase by withanolide a for Alzheimer treatment. J Biomol Struct Dyn 29:651–562PubMedCrossRefGoogle Scholar
  63. Heckers S, Stone D, Walsh J, Shick J, Koul P, Benes FM (2002) Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia. Arch Gen Psych 59:521–529CrossRefGoogle Scholar
  64. Hibberd C, Yau JLW, Seckyl JR (2000) Glucocorticoids and the ageing hippocampus. J Anat 197:553–562PubMedPubMedCentralCrossRefGoogle Scholar
  65. Jain S, Shukla SD, Sharma K, Bhatnagar M (2001) Neuroprotective Effects of Withania somnifera Dunn in Hippocampal Sub-regions of Female Albino Rat. Phytother Res 15:544–548PubMedCrossRefGoogle Scholar
  66. Jayaprakasam B, Nair MG (2003) Cyclooxygenase-2 enzyme inhibitory withanolides from Withania Somnifera leaves. Tetrahedron 59:841–849CrossRefGoogle Scholar
  67. Joyashiki E, Matsuya Y, Tohda C (2011) Sominone improves memory impairments and increases axonal density in Alzheimer’s disease model mice, 5XFAD. Int J Neurosci 121:181–190PubMedCrossRefGoogle Scholar
  68. Kataria H, Wadhwa R, Kaul SC, Kaur G (2012) Water extract from the leaves of Withania somnifera protect RA differentiated C6 and IMR-32 cells against glutamate-induced excitotoxicity. PLoS One 7:e37080PubMedPubMedCentralCrossRefGoogle Scholar
  69. Keck PE Jr, Mintz J, McElroy SL, Freeman MP, Suppes T, Frye MA, Altshuler LL, Kupka R, Nolen WA, Leverich GS, Denicoff KD, Grunze H, Duan N, Post RM (2006) Double-blind, randomized, placebo-controlled trials of ethyl-eicosapentanoate in the treatment of bipolar depression and rapid cycling bipolar disorder. Biol Psychiatry 60:1020–1022PubMedCrossRefGoogle Scholar
  70. Khan ZA, Ghosh AR (2010) Possible nitric oxide modulation in protective effects of withaferin A against stress induced neurobehavioral changes. J Medicinal Plants Res 4:490–495Google Scholar
  71. Khan B, Ahmad SF, Bani S, Kaul A, Suri KA, Satti NK, Athar M, Qazi GN (2006) Augmentation and proliferation of T lymphocytes and Th-1cytokines by Withania somnifera in stressed mice. Int Immunopharmacol 6:1394–1403PubMedCrossRefGoogle Scholar
  72. Konar A, Shah N, Singh R, Saxena N, Kaul SC, Wadhwa R, Thakur MK (2011) Protective role of Ashwagandha leaf extract and its component withanone on scopolamine-induced changes in the brain and brain derived cells. PloS One 6:e27265PubMedPubMedCentralCrossRefGoogle Scholar
  73. Kour K, Pandey A, Suri KA, Satti NK, Gupta KK, Bani S (2009) Restoration of stress-induced altered T cell function and corresponding cytokines patterns by Withanolide A. Intl Immunopharmacol 9:1137–1144CrossRefGoogle Scholar
  74. Kronfol Z, Remick DG (2000) Cytokines and the brain: Implications for clinical psychiatry. Am J Psychiatry 157:683–694PubMedCrossRefGoogle Scholar
  75. Kuboyama T, Tohda C, Komatsu K (2005) Neuritic regeneration and synaptic reconstruction induced by withanolide A. Br J Pharmacol 144:961–971PubMedPubMedCentralCrossRefGoogle Scholar
  76. Kuboyama T, Tohda C, Komatsu K (2006) Withanoside IV and its active metabolite, sominone, attenuate Aβ(25-35)-induced neurodegeneration. Eur J Neurosci 23:1417–1426PubMedCrossRefGoogle Scholar
  77. Kuboyama T, Tohda C, Komatsu K (2014) Effects of Ashwagandha (Roots of Withania somnifera) on neurodegenerative diseases. Biol Pharm Bull 37:892–897PubMedCrossRefGoogle Scholar
  78. Kulkarni SK, Dhir A (2008) Withania somnifera: an Indian ginseng. Progress in Neuro-Psychopharmacol Biol Psychiatry 32:1093–1105CrossRefGoogle Scholar
  79. Kulkarni RR, Patki PS, Jog VP, Gandage SG, Patwardhan B (1991) Treatment of osteoarthritis with a herbomineral formulation: a double blind, placebo-controlled, crossover study. J Ethno Pharmacol 33:91–95CrossRefGoogle Scholar
  80. Kumar P, Kumar A (2008) Effects of root extract of Withania somnifera in 3-Nitropropionic acid-induced cognitive dysfunction and oxidative damage in rats. Int J Health Res 1:139–149Google Scholar
  81. Kumar P, Kumar A (2009) Possible neuroprotective effect of Withania somnifera root extract against 3-nitropropionic acid-induced behavioral, biochemical, and mitochondrial dysfunction in an animal model of Huntington’s disease. J Medicinal Food 12:591–600CrossRefGoogle Scholar
  82. Kurapati KR, Atluri VS, Samikkannu T, Nair MP (2013) Ashwagandha (Withania somnifera) reverses beta-amyloid1-42 induced toxicity in human neuronal cells: implications in HIV-associated neurocognitive disorders (HAND). PLoS One 8:e77624PubMedPubMedCentralCrossRefGoogle Scholar
  83. Lupien SJ, Gillin CJ, Hauger RL (1999) Working memory is more sensitive than declarative memory to the acute effects of corticosteroids: a dose–response study in humans. Behav Neurosci 113:420–430PubMedCrossRefGoogle Scholar
  84. Malhi GM, Cahill CM, Mitchell P (2008) Impact of Mood, Anxiety, and Psychotic Symptoms on Cognition in Patients with Bipolar Disorder. In: Goldberg JF, Burdick KE (eds) Cognitive dysfunction in bipolar disorder. A guide to clinicians. American Psychiatric Publishing Inc, Arlington, pp 89–111Google Scholar
  85. Malik F, Singh J, Khajuria A, Suri KA, Satti NK, Singh S, Kaul MK, Kumar A, Bhatia A, Qazi GN (2007) A standardized root extract of Withania somnifera and its major constituent withanolide-A elicit humoral and cell-mediated immune responses by up regulation of Th1-dominant polarization in BALB/c mice. Life Sci 80:1525–1538PubMedCrossRefGoogle Scholar
  86. Mann-Wrobel MC, Carreno JT, Dickinson D (2011) Meta-analyses of neuropsychological functioning in euthymic bipolar disorder: an update and investigation of moderator variables. Bipolar Disord 13:334–342PubMedCrossRefGoogle Scholar
  87. Martínez-Arán A, Penadés R, Vieta E, Colom F, Reinares M, Benabarre A, Salamero M, Gastó C (2002) Executive function in patients with remitted bipolar disorder and schizophrenia and its relationship with functional outcome. Psychother Psychosom 71:39–46PubMedCrossRefGoogle Scholar
  88. Martínez-Arán A, Vieta E, Colom F, Torrent C, Sánchez-Moreno J, Reinares M, Benabarre A, Goikolea JM, Brugué E, Daban C, Salamero M (2004a) Cognitive Impairment in euthymic bipolar patients: implications for clinical and functional outcomes. Bipolar Disord 6:224–232PubMedCrossRefGoogle Scholar
  89. Martínez-Arán A, Vieta E, Reinares M, Colom F, Torrent C, Sánchez-Moreno J, Benabarre A, Goikolea JM, Comes M, Salamero M (2004b) Cognitive function across manic or hypomanic, depressed, and euthymic states in bipolar disorder. Am J Psychiatry 161:262–270PubMedCrossRefGoogle Scholar
  90. McIntosh AM, Harrison LK, Forrester K, Lawrie SM, Johnstone EC (2005) Neuropsychological impairments in people with schizophrenia or bipolar disorder and their unaffected relatives. Br J Psychiatry 186:378–385PubMedCrossRefGoogle Scholar
  91. Michael N, Erfurth MN, Ohrmann P, Gossling M, Arrolt V, Heindel W, Pfliederer B (2003) Acute mania is accompanied by elevated levels of glutamate/glutamine levels within the left dorsolateral prefrontal cortex. Psychopharmacol 168:344–346Google Scholar
  92. Mikolai J, Erlandsen A, Murison A, Brown KA, Gregory WL, Raman-Caplan P, Zwickey HL (2009) In vivo effects of Ashwagandha (Withania somnifera) extract on the activation of lymphocytes. J Altern Complement Med 15:423–430PubMedCrossRefGoogle Scholar
  93. Miller AH (2010) Depression and immunity: a role for T cells? Brain Behav Immun 24:1–8PubMedCrossRefGoogle Scholar
  94. Miller A, Maletic V, Raison C (2009) Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 65:732–741PubMedPubMedCentralCrossRefGoogle Scholar
  95. Miskowiak KW, Ehrenreich H, Christensen EM, Kessing LV, Vinberg M (2014) Recombinant human erythropoietin to target cognitive dysfunction in bipolar disorder: a double-blind, randomized, placebo-controlled phase 2 trial. J Clin Psychiatry 75:1347–1355PubMedCrossRefGoogle Scholar
  96. Moore PB, Shepherd DJ, Eccleston D, Macmillan IC, Goswami U, McAllister VL, Ferrier IN (2001) Cerebral white matter lesions in bipolar affective disorder: relationship to outcome. Br J Psychiatry 178:172–176PubMedCrossRefGoogle Scholar
  97. Morrens M, Wezenberg E, Verkes RJ, Hulstijn W, Ruigt GS, Sabbe BG (2007) Psychomotor and memory effects of haloperidol, olanzapine, and paroxetine in healthy subjects after short term administration. J Clin Psychopharmacol 27:15–21PubMedCrossRefGoogle Scholar
  98. Mulabagal V, Subbaraju GV, Rao CV, Sivaramakrishna C, Dewitt DL, Holmes D, Sung B, Aggarwal BB, Tsay HS, Nair MG (2009) Withanolide sulfoxide from Aswagandha roots inhibits nuclear transcription factor-Kappa-B, cyclooxygenase and tumor cell proliferation. Phytother Res 22:987–992CrossRefGoogle Scholar
  99. Muller N, Schwarz M (2006) Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission. Neurotoxicity Res 10:131–148CrossRefGoogle Scholar
  100. Müller N, Krause D, Dehning S, Musil R, Schennach-Wolff R, Obermeier M, Möller HJ, Klauss V, Schwarz MJ, Riedel M (2010) Celecoxib treatment in an early stage of schizophrenia: results of a randomized, double-blind, placebo-controlled trial of celecoxib augmentation of amisulpride treatment. Schizophrenia Res 121:118–124CrossRefGoogle Scholar
  101. Nagashayana N, Sankarankutty P, Nampoothiri MR, Mohan PK, Mohanakumar KP (2000) Association of L-DOPA with recovery following Ayurveda medication in Parkinson’s disease. J Neurol Sci 176:124–127PubMedCrossRefGoogle Scholar
  102. Naidu PS, Singh A, Kulkarni SK (2006) Effect of Withania somnifera root extract on reserpine-induced orofacial dyskinesia and cognitive dysfunction. Phytotherapy Res 20:140–146CrossRefGoogle Scholar
  103. Nashine K, Srivastava DN, Sahni YP (1995) Role of inflammatory mediators in anti-inflammatory activity of Withania somnifera. Indian Veterinary Medical J 19:286–288Google Scholar
  104. Nery FG, Monkul ES, Hatch JP, Fonseca M, Zunta-Soares GB, Frey BN, Bowden CL, Soares JC (2008) Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, randomized placebo-controlled study. Hum Psychopharmacol 23:87–94PubMedCrossRefGoogle Scholar
  105. Özerdem A, Tunca Z, Çımrın D, Hıdıroğlu C, Ergör G (2014) Female vulnerability for thyroid function abnormality in bipolar disorder: role of lithium treatment. Bipolar Disord 16:72–82PubMedCrossRefGoogle Scholar
  106. Padmos RC, Hillegers MH, Knijff EM, Vonk R, Bouvy A, Staal FJ, de Ridder D, Kupka RW, Nolen WA, Drexhage HA (2008) A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes. Arch Gen Psychiatry 65:395–407PubMedCrossRefGoogle Scholar
  107. Panda S, Kar A (1997) Evidence for Free radical scavenging activity of Ashwagandha root powder in mice. Indian J Physiol Pharmacol 41:424–426PubMedGoogle Scholar
  108. Panda S, Kar A (1998) Changes in thyroid hormone concentrations after administration of Ashwagandha root extract to adult male mice. J Pharm Pharmacol 50:1065–1068PubMedCrossRefGoogle Scholar
  109. Panda S, Kar A (1999) Withania somnifera and bauhinia purpurea in the regulation of circulating thyroid hormone concentrations in female mice. J Ethnopharmacol 67:233–239PubMedCrossRefGoogle Scholar
  110. Pasqualetti G, Pagano G, Rengo G, Ferrara N, Monzani F (2015) Subclinical hypothyroidism and cognitive impairment: systematic review and meta-analysis. J Clin Endocrinol Metab 100:4240–4248PubMedCrossRefGoogle Scholar
  111. Resmini E, Santos A, Gómez-Anson B, López-Mourelo O, Pires P, Vives-Gilabert Y, Crespo I, Portella MJ, de Juan-Delago M, Webb SM (2013) Hippocampal dysfunction in cured Cushing’s syndrome patients detected by (1) H-MR-spectroscopy. Clin Endocrinol 79:700–707Google Scholar
  112. Robinson LJ, Thompson JM, Gallagher P, Goswami U, Young AH, Ferrier IN, Moore PB (2006) A meta-analyses of cognitive deficits in euthymic patients with bipolar disorder. J Affect Disord 93:105–111PubMedCrossRefGoogle Scholar
  113. Rosenblat JD, Brietzke E, Mansur RB, Maruschak NA, Lee Y, McIntyre RS (2015) Inflammation as a neurobiological substrate of cognitive impairment in bipolar disorder: evidence, pathophysiology and treatment implications. J Affect Disord 188:149–159PubMedCrossRefGoogle Scholar
  114. Rosenthal NE, Sack DA, Gillin JC, Lewy AJ, Goodwin FK, Davenport Y, Mueller PS, Newsome DA, Wehr TA (1984) Seasonal affective disorder. A description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 41:72–80PubMedCrossRefGoogle Scholar
  115. Rush AJ, Giles DE, Schlesser MA, Orsulak PJ, Parker CR Jr, Weissenburger JE, Crowley GT, Khatami M, Vasavada N (1996) The dexamethasone suppression test in patients with mood disorders. J Clin Psychiatry 57:470–484PubMedCrossRefGoogle Scholar
  116. Sapolsky R, Rivier C, Yamamoto G, Plotsky P, Vale W (1987) Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science 238:522–524PubMedCrossRefGoogle Scholar
  117. Schiepers OJ, Wichers MC, Maes M (2005) Cytokines and major depression. Progr Neuropsychopharmacol Biol Psychiatry 29:201–217CrossRefGoogle Scholar
  118. Schliebs R, Liebmann A, Bhattacharya SK, Kumar A, Ghosal S, Bigl V (1997) Systemic administration of defined extracts from Withania somnifera (Indian Ginseng) and Shilajit differentially affects cholinergic but not glutamatergic or GABAergic markers in rat brain. Neurochem Int 30:181–190PubMedCrossRefGoogle Scholar
  119. Sehgal N, Gupta A, Valli RK, Joshi SD, Mills JT, Hamel E, Khanna P, Jain SC, Thakur SS, Ravindranath V (2012) Withania somnifera reverses Alzheimer’s disease pathology by enhancing low-density lipoprotein receptor-related protein in liver. Proc Natl Acad Sci U S A 109:3510–3515PubMedPubMedCentralCrossRefGoogle Scholar
  120. Selye H (1956) The stress of life. McGraw-Hill, New YorkGoogle Scholar
  121. Singh D, Aggarwal A, Maurya R, Naik S (2007) Withania somnifera inhibits NF-kappaB and AP-1 transcription factors in human peripheral blood and synovial fluid mononuclear cells. Phytother Res 10:905–913CrossRefGoogle Scholar
  122. Sloan RP, McCreath H, Tracey KJ, Sidney S, Liu K, Seeman T (2007) RR interval variability is inversely related to inflammatory markers: the CARDIA study. Mol Med 13:178–184PubMedPubMedCentralGoogle Scholar
  123. Starkman MN, Giordani B, Berent S, Schork MA, Schteingart DE (2001) Elevated cortisol levels in Cushing’s disease are associated with cognitive decrements. Psychosom Med 63:985–993PubMedCrossRefGoogle Scholar
  124. Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, Marangell LB (1999) Omega 3 fatty acids in bipolar disorder: a preliminary, double-blind, placebo-controlled trial. Arch Gen Psychiatry 56:407–412PubMedCrossRefGoogle Scholar
  125. Subbaraju GV, Vanisree M, Rao CV, Sivaramakrishna C, Sridhar P, Jayaprakasam B, Nair MG (2006) Ashwagandhanolide, a bioactive dimeric thiowithanolide isolated from the roots of Withania somnifera. J Nat Prod 12:1790–1792CrossRefGoogle Scholar
  126. Szentivanyi A (1989) The discovery of immune-neuroendocrine circuits in the fall of 1951. In: Hadden JW, Masek K, Nistico G (eds) Interactions among central nervous system, neuroendocrine and immune systems. Pythagora Press, Rome-Milan, pp 1–3Google Scholar
  127. Thompson JM, Gallagher P, Hughes JH, Watson S, Gray JM, Ferrier IN, Young AH (2005) Cognitive Impairment in euthymic patients with bipolar affective disorder. Br J Psychiatry 186:32–40PubMedCrossRefGoogle Scholar
  128. Tighe SK, Reading SA, Rivkin P, Caffo B, Schweizer B, Pearlson G, Potash JB, Depaulo JR, Bassett SS (2012) Total white matter hyperintensity volume in bipolar disorder patients and their healthy relatives. Bipolar Disord 14:888–893PubMedPubMedCentralCrossRefGoogle Scholar
  129. Tohda C, Joyashiki E (2009) Sominone enhances neurite outgrowth and spatial memory mediated by the neurotrophic factor receptor, RET. British J Pharmacol 157:1427–1440CrossRefGoogle Scholar
  130. Torrent C, Martínez-Arán A, Daban C, Sánchez-Moreno J, Comes M, Goikolea JM, Salamero M, Vieta E (2006) Cognitive impairment in bipolar II disorder. Br J Psychiatry 189:254–259PubMedCrossRefGoogle Scholar
  131. Torres IJ, Boudreau VG, Yatham LN (2007) Neuropsychological functioning in euthymic bipolar disorder: a meta-analysis. Acta Psychiatr Scand 116(suppl):17–26CrossRefGoogle Scholar
  132. Torres IJ, DeFreitas CM, Yatham LN (2008) Cognition and functional outcome in bipolar disorder. In: Goldberg JF, Burdick KE (eds) Cognitive dysfunction in bipolar disorder. A guide to clinicians. American Psychiatric Publishing Inc, Arlington, pp 217–234Google Scholar
  133. Tremont G, Stern RA (1997) Use of thyroid hormone to diminish the cognitive side effects of psychiatric treatment. Psychopharmacol Bull 33:273–280PubMedGoogle Scholar
  134. Udayakumar R, Kasthurirengan S, Vasudevan A, Mariashibu TS, Rayan JJ, Choi CW, Ganapathi A, Kim SC (2010) Antioxidant effect of dietary supplement Withania somnifera L. Reduce blood glucose levels in alloxan-induced diabetic rats. Plant Foods Hum Nutr 65:91–98PubMedCrossRefGoogle Scholar
  135. van der Hooft CS, Hoekstra A, Winter A, de Smet PA, Stricker BH (2005) Thyrotoxicosis following the use of Ashwagandha. Ned Tijdschr Geneeskd 149:2637–2638PubMedGoogle Scholar
  136. Veronese N, Solmi M, Luchini C, Lu RB, Stubbs B, Zaninotto L, Correll CU (2016) Acetylcholinesterase inhibitors and memantine in bipolar disorder: a systematic review and best evidence synthesis of the efficacy and safety for multiple disease dimensions. J Affect Disord 197:268–280PubMedCrossRefGoogle Scholar
  137. Vieta E, Martinez-Aran A, Goldberg JF (2008) Cognition across the life span. In: Goldberg JF, Burdick KE (eds) Cognitive dysfunction in bipolar disorder. A guide to clinicians. American Psychiatric Publishing Inc, Arlington, pp 235–255Google Scholar
  138. Wehr TA, Sack DA, Rosenthal NE (1987) Sleep reduction as a final common pathway in the genesis of mania. Am J Psychiatry 144:201–204PubMedCrossRefGoogle Scholar
  139. Wehr TA, Turner EH, Shimada JM, Lowe CH, Barker C, Leibenluft E (1998) Treatment of rapidly cycling bipolar patient by using extended bed rest and darkness to stabilize the timing and duration of sleep. Biol Psychiatry 43:822–828PubMedCrossRefGoogle Scholar
  140. Whelan TB, Schteingart DE, Starkman MN, Smith A (1980) Neuropsychological deficits in Cushing’s syndrome. J Nerv Ment Dis 168:753–757PubMedCrossRefGoogle Scholar
  141. Wingo AP, Harvey PD, Baldessarini RJ (2009) Neurocognitive impairment in bipolar disorder patients: functional implications. Bipolar Disord 11:113–125PubMedCrossRefGoogle Scholar
  142. Wingo AP, Baldessarini RJ, Compton MT, Harvey PD (2010) Correlates of recovery of social functioning in type I and II bipolar disorder patients. Psychiatry Res 177:131–134PubMedPubMedCentralCrossRefGoogle Scholar
  143. Wirz-Justice A, Bromundt V, Cajochen C (2009) Circadian disruption and psychiatric disorders: the importance of entrainment. Sleep Med Clin 4:273–284CrossRefGoogle Scholar
  144. Yadav CS, Kumar V, Suke SG, Ahmed RS, Mediratta PK, Banerjee BD (2010) Propoxur-induced acetylcholine esterase inhibition and impairment of cognitive function: attenuation by Withania somnifera. Indian J Biochem Biophys 47:117–120PubMedGoogle Scholar
  145. Young AH, Sahakian BJ, Robbins TW, Cowen PJ (1999) The effects of chronic administration of hydrocortisone on cognitive function in normal male volunteers. Psychopharmacol (Berl) 145:260–266CrossRefGoogle Scholar
  146. Young AH, Gallagher P, Watson S, Del-Estal D, Owen BM, Ferrier IN (2004) Improvements in neurocognitive function and mood following adjunctive treatment with mifepristone in bipolar disorder. Neuropsychopharmacol 29:1538–1545CrossRefGoogle Scholar
  147. Zalcman S, Green-Johnson JM, Murray L, Nance DM, Dyck D, Anisman H, Greenberg AH (1994) Cytokine specific central monoamine alterations induced by IL-1, IL-2 and IL-6. Brain Res 643:40–49PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • K. N. Roy Chengappa
    • 1
    Email author
  • Jessica M. Gannon
    • 1
  • Luna Acharya
    • 2
  • Abhishek Rai
    • 3
  1. 1.Western Psychiatric Institute and ClinicUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Icahn School of Medicine at Mount Sinai (Bronx) ProgramJames J. Peters VA Medical CenterBronxUSA
  3. 3.University of Pittsburgh Medical Center – NorthwestSenecaUSA

Personalised recommendations