Skip to main content
SpringerLink
Log in

Role of Inositol in the Treatment of Psychiatric Disorders

Basic and Clinical Aspects

  • Leading Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Summary

Myo-inositol is a ubiquitous carbohydrate that is present in large amounts in brain tissue and is involved in neuronal signalling and osmoregulation. This sugar is an essential component of the inositol signalling system, which is a post-receptor second messenger signalling system found in many cells. Myo-inositol is the precursor of membrane inositol phospholipids, which are critically linked to a number of CNS receptor signalling systems, including muscarinic, serotonergic, adrenergic, metabotropic and histaminergic systems, and those linked to cholecystokinin, tachykinins, neurotensin, platelet activating factor and other transmitters.

Upon stimulation of these receptors, a signal is transmitted through a guanosine triphosphate (GTP)-binding protein (Gq), which then activates the enzyme phospholipase C. This results in the release of a second messenger, inositol 1,4,5-trisphosphate (InsP3), from membrane inositol phospholipids. InsP3 then causes the release of free intracellular calcium into the cytosol, activating a number of enzymes or receptors.

Myo-inositol in the brain is derived from 3 sources: (i) receptor stimulation (a salvage pathway); (ii) de novo synthesis from glucose; and (iii) uptake of dietary myo-inositol through plasma membrane myo-inositol transporters. Most myo-inositol is probably derived from the first 2 sources, which are controlled through the lithium-sensitive enzyme myo-inositol monophosphatase (IMPase). This enzyme acts upon myo-inositol monophosphates, hydrolysing them to release free myo-inositol. Recent biochemical, molecular and crystallographic studies have demonstrated that the overall metabolism of brain inositol is closely modulated by this enzyme. Lithium salts, which are commonly used in various psychiatric conditions, inhibit this enzyme, and this action has been implicated as a therapeutic mechanism of action of lithium.

A change in the availability of CNS inositol may lead to altered brain cell signalling pathways and, eventually, to the development of a neuropsychiatric disorder. Recent evidence indicates that myo-inositol has psychoactive effects, with initial studies demonstrating effectiveness in the treatment of depression, panic disorder and obsessive-compulsive disorder. At present, the exact mechanism of these clinical effects is uncertain. The development of various inositol system-based drugs may lead to future psychoactive drugs designed to modulate a second messenger cascade of events rather than a receptor system, and will lead to further understanding of CNS disease from a post-receptor second messenger perspective.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Levine J, Barak Y, Gonzales M, et al. Double-blind, controlled trial of inositol treatment of depression. Am J Psychiatry 1995; 152: 792–4

    PubMed  CAS  Google Scholar 

  2. Benjamin J, Levine J, Fux M, et al. Double-blind placebo-controlled, crossover study of inositol treatment for panic disorder. Am J Psychiatry 1995; 152: 1084–6

    PubMed  CAS  Google Scholar 

  3. Fux M, Levine J, Aviv A, et al. Inositol treatment of obsessive compulsive disorder. Am J Psychiatry 1996; 153: 1219–21

    PubMed  CAS  Google Scholar 

  4. Hokin LE, Hokin MR. Effects of acetylcholine on the turnover of phosphoryl units in individual phospholipids of pancreas slices and brain cortex slices. Biochim Biophys Acta 1955; 18: 102–10

    Article  PubMed  CAS  Google Scholar 

  5. Berridge MJ, Irvine RF. Inositol phosphates and cell signaling. Nature 1989; 341: 197–205

    Article  PubMed  CAS  Google Scholar 

  6. Majerus PW. Inositol phosphate biochemistry. Annu Rev Biochem 1992; 61: 225–50

    Article  PubMed  CAS  Google Scholar 

  7. Fisher SK, Heacock AM, Agranoff BW. Inositol lipids and signal transduction in the nervous system: an update. J Neurochem 1992; 58: 18–38

    Article  PubMed  CAS  Google Scholar 

  8. Rhee SG, Choi KD. Regulation of inositol phospholipid specific phospholipase C isozymes. J Biol Chem 1992; 267: 12393–6

    PubMed  CAS  Google Scholar 

  9. Downes CP, MacPhee CH. Myo-inositol metabolites as cellular signals. Eur J Biochem 1990; 193: 1–18

    Article  PubMed  CAS  Google Scholar 

  10. Bansal S, Majerus PW. Phosphatidyl-derived precursors and signals. Annu Rev Cell Biol 1990; 6: 41–68

    Article  PubMed  CAS  Google Scholar 

  11. Parthasarathy R, Eisenberg Jr F. The inositol phospholipids: a stereochemical view of biological activity. Biochem J 1986; 235: 313–22

    PubMed  CAS  Google Scholar 

  12. Parthasarathy R, Eisenberg Jr F. Biochemistry, stereochemistry and nomenclature of the inositol phosphates. In: Reitz AB, editor. Inositol phosphates and derivatives: synthesis, biochemistry, and therapeutic potential. Washington, DC: American Chemical Society, 1991: 1–19

    Chapter  Google Scholar 

  13. Thurston JH, Sherman WR, Hauhart RE, et al. Myo-inositol: a newly identified non-nitrogenous osmoregulatory molecule in mammalian brain. Pediatr Res 1989; 26: 482–5

    Article  PubMed  CAS  Google Scholar 

  14. Kwon HM, Yamaguchi A, Uchida S, et al. Cloning of the cDNA for Na+/myo-inositol cotransporter a hypertonicity stress protein. J Biol Chem 1992; 267: 6297–301

    PubMed  CAS  Google Scholar 

  15. Spector R. Myo-inositol transport through the blood-brain barrier. Neurochem Res 1988; 13: 785–7

    Article  PubMed  CAS  Google Scholar 

  16. Strange K, Emma F, Paredes A, et al. Osmoregulatory changes in myo-inositol content and Na+-myo-inositol cotransport in rat cortical astrocytes. Glia 1994; 12: 35–43

    Article  PubMed  CAS  Google Scholar 

  17. Bersudsky Y, Kaplan Z, Shapiro Y, et al. Behavioral evidence for the existence of two pools of cellular inositol. Eur Neuropsychopharmacol 1994; 4: 463–7

    Article  PubMed  CAS  Google Scholar 

  18. Levine J, Rapaport A, Lev L, et al. Inositol treatment raises CSF inositol levels. Brain Res 1993; 627: 168–70

    Article  PubMed  CAS  Google Scholar 

  19. Baraban JM, Worley PF, Snyder SH. Second messenger systems and psychoactive drug action: focus on the phosphoinositide system and lithium. Am J Psychiatry 1989; 146: 1251–60

    PubMed  CAS  Google Scholar 

  20. Berridge MJ, Downes CP, Hanley MR. Neural and developmental actions of lithium: a unifying hypothesis. Cell 1989; 59: 411–9

    Article  PubMed  CAS  Google Scholar 

  21. Pollack SJ, Atack JR, Knowles MR, et al. Mechanism of inositol monophosphatase, the putative target of lithium therapy. Proc Natl Acad Sci U S A 1994; 91: 5766–70

    Article  PubMed  CAS  Google Scholar 

  22. Atack JR, Broughton HB, Pollack SJ. Inositol monophosphatase — a putative target for Li+ in the treatment of bipolar disorder. Trends Neurosci 1995 18: 343–9

    Article  PubMed  CAS  Google Scholar 

  23. Allison JH, Stewart MA. Reduced brain inositol in lithium treated rats. Nature New Biol 1971; 233: 267–8

    Article  PubMed  CAS  Google Scholar 

  24. Hallcher LM, Sherman WR. The effects of the lithium ion and other agents on the activity of myo-inositol 1-phosphatase from bovine brain. J Biol Chem 1980; 255: 10896–901

    PubMed  CAS  Google Scholar 

  25. Parthasarathy L, Vadnal RE, Ramesh TG, et al. Myo-inositol monophosphatase from rat testes: purification and properties. Arch Biochem Biophys 1993; 304: 94–101

    Article  PubMed  CAS  Google Scholar 

  26. Nahorski SR, Ragan CI, Challis RAJ. Lithium and the phosphoinositide cycle: an example of uncompetitive inhibition and its pharmacological consequences. Trends Pharmacol Sci 1991; 12: 297–303

    Article  PubMed  CAS  Google Scholar 

  27. Holub BJ. The nutritional importance of inositol and the phosphoinositides. New Engl J Med 1992; 326: 1285–7

    Article  PubMed  CAS  Google Scholar 

  28. Holub BJ. Metabolism and function of myo-inositol and inositol phospholipids. Annu Rev Nutr 1986; 6: 563–7

    Article  PubMed  CAS  Google Scholar 

  29. Holub BJ. Nutritional, biochemical and clinical aspects of inositol and phosphatidylinositol metabolism. Can J Physiol Pharmacol 1984; 62: 1–8

    Article  PubMed  CAS  Google Scholar 

  30. Hegsted DM, Gallagher A, Hanford H. Inositol requirement of the gerbil. J Nutr 1974; 104: 588–92

    PubMed  CAS  Google Scholar 

  31. National Research Council. Recommended dietary allowances. 10th ed. Washington, DC: National Academy Press, 1989: 266–7

    Google Scholar 

  32. Clements Jr RS, De Jesus PV, Winegard AI. Raised plasma myo-inositol levels in uraemia and experimental neuropathy. Lancet 1973; I: 1137–41

    Article  Google Scholar 

  33. Romero G, Larner J. Insulin mediators and the mechanism of insulin action. Adv Pharmacol 1993; 24: 21–50

    Article  PubMed  CAS  Google Scholar 

  34. Asplin I, Galasko G, Larner J. Chiro-inositol deficiency and insulin resistance: a comparison of the chiro-inositol- and the myo-inositol containing insulin mediators isolated from urine, hemodialysate, and muscle of control and type II diabetic subjects. Proc Natl Acad Sci U S A 1993; 90: 7759–63

    Article  Google Scholar 

  35. Watson S, Girdlestone D. Receptor and ion channel nomenclature supplement. Trends Pharmacol Sci 1995; 15: 1–51

    Article  Google Scholar 

  36. Freissmuth M, Casey PJ, Gilman AG. G proteins control diverse pathways of transmembrane signaling. FASEB J 1989; 3: 2125–31

    PubMed  CAS  Google Scholar 

  37. Rana RS, Hokin LE. Role of phosphoinositides in transmem-brane signaling. Physiol Rev 1990; 70: 115–64

    PubMed  CAS  Google Scholar 

  38. Vadnal RE, Parthasarathy R. The identification of a novel inositol lipid, phosphatidyl inositol trisphosphate in rat cerebrum using in vivo techniques. Biochem Biophys Res Commun 1989; 163: 995–1001

    Article  PubMed  CAS  Google Scholar 

  39. Kucera GL, Rittenhouse SE. Human platelets form 3-phosphorylated phosphoinositides in response to alpha-thrombin, U46619 or GTP-S. J Biol Chem 1990; 259: 267–76

    Google Scholar 

  40. Ruderman NB, Kapeller R, White MF, et al. Activation of phosphatidylinositol 3-kinase by insulin. Proc Natl Acad Sci U S A 1990; 87: 1411–5

    Article  PubMed  CAS  Google Scholar 

  41. Serunian LA, Haber MT, Fukui T. Polyphosphoinositides produced by phosphatidylinositol 3-kinase are poor substrates for phospholipase C from rat liver and bovine brain. J Biol Chem 1989; 264: 17809–15

    PubMed  CAS  Google Scholar 

  42. Vadnal R, Parthasarathy R. The identification of a novel inositol lipid, phosphatidyl-inositol trisphosphate (PIP3), in rat cerebrum using in vivo techniques. Biochem Biophys Res Comm 1989; 163: 995–1001

    Article  PubMed  CAS  Google Scholar 

  43. Streb H, Irvine RF, Berridge MJ, et al. Release of calcium from a non-mitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate. Nature 1983; 306: 67–9

    Article  PubMed  CAS  Google Scholar 

  44. Irvine RF. Inositol tetrakisphosphate as a second messenger: confusions, contradictions, and a potential resolution. Bioessays 1991; 13: 419–25

    Article  PubMed  CAS  Google Scholar 

  45. Vadnal RE, Bazan NG. Electroconvulsive shock stimulates polyphosphoinositide degradation and inositol trisphosphate accumulation in rat cerebrum: lithium pre-treatment does not potentiate these changes. Neurosci Lett 1987; 80: 75–9

    Article  PubMed  CAS  Google Scholar 

  46. Batty I, Nahorski R. Lithium inhibits muscarinic-receptor-stimulated inositol tetrakisphosphate accumulation in rat cerebral cortex. Biochem J 1987; 247: 797–800

    PubMed  CAS  Google Scholar 

  47. Vallejo M, Jackson T, Lightman S, et al. Occurrence and extracellular actions of inositol pentakis- and hexakisphosphate in mammalian brain. Nature 1987; 330: 656–8

    Article  PubMed  CAS  Google Scholar 

  48. Parthasarathy L, Vadnal RE, Parthasarathy R, et al. Biochemical and molecular properties of lithium-sensitive myo-inositol monophosphatase. Life Sci 1994; 54: 1127–42

    Article  PubMed  CAS  Google Scholar 

  49. Parthasarathy R, Eisenberg Jr F. Lack of differential lethality of lithium isotopes in mice. Ann N Y Acad Sci 1984; 435: 463–5

    Article  CAS  Google Scholar 

  50. Vadnal R, Parthasarathy R. Myo-inositol monophosphatase: diverse effects of lithium, carbamazepine, and valproate. Neuropsychopharmacology 1995; 12: 277–85

    Article  PubMed  CAS  Google Scholar 

  51. Sherman WR, Munsell LY, Gish BG, et al. Effects of systematically administered lithium on phosphoinositide metabolism in rat brain, kidney, and testis. J Neurochem 1985; 44: 798–807

    Article  PubMed  CAS  Google Scholar 

  52. Baker GR, Billington DC, Gani D. Synthesis of D- and L-myo-inositol 1-phosphothiorate substrates for inositol monophosphatase. Tetrahedron 1991; 47: 3895–908

    Article  CAS  Google Scholar 

  53. Pachter J. Noncompetitive inhibition of inositol monophosphatase by K-76 monocarboxylic acid. Mol Pharmacol 1991; 40: 107–11

    PubMed  CAS  Google Scholar 

  54. Lam YKT, Wichmann CF, Meinz MS, et al. A novel inositol monophosphatase inhibitor from Memnoniella echinata. J Antibiot (Tokyo) 1992; 45: 1397–403

    Article  CAS  Google Scholar 

  55. Kulagowski J, Baker R, Fletcher SR. Inhibitors of myo-inositol monophosphatase containing methylenebisphosphonic acid as a replacement for a phosphate group. J Chem Soc Chem Commun 1991; 1649-50

  56. Atack JR, Prior AM, Fletcher SR. et al. Effects of L-690,488, a prodrug of the bisphosphonate inositol monophosphatase inhibitor L-690,330, on phosphatidylinositol cycle markers. J Pharmacol Exp Ther 1994; 270: 70–6

    PubMed  CAS  Google Scholar 

  57. McAllister G, Whiting P, Hammond EA, et al. cDNA cloning of human and rat brain myo-inositol monophosphatase. Biochem J 1992; 284: 749–54

    PubMed  CAS  Google Scholar 

  58. Bone R, Springer JP, Atack JR. Structure of inositol monophosphatase, the putative target of lithium therapy. Proc Natl Acad Sci U S A 1992; 89: 10031–5

    Article  PubMed  CAS  Google Scholar 

  59. Leech AP, Baker GR, Shute JK, et al. Chemical and kinetic mechanism of the inositol monophosphate reaction and its inhibition by Li+. Eur J Biochem 1993; 212: 693–704

    Article  PubMed  CAS  Google Scholar 

  60. Whitworth P, Kendall DA. Effects of lithium on inositol phospholipid hydrolysis and inhibition of dopamine D1 receptor-mediated cyclic AMP formation by carbachol in rat brain slices. J Neurochem 1989; 53: 536–41

    Article  PubMed  CAS  Google Scholar 

  61. Kofman O, Belmaker RH. Biochemical, behavioral, and clinical studies of the role of inositol in lithium treatment and depression. Biol Psychiatry 1993; 34: 839–52

    Article  PubMed  CAS  Google Scholar 

  62. Williams MB, Jope RS. Modulation by inositol of cholinergic and serotonergic-induced seizures in lithium-treated rats. Brain Res 1995; 685: 169–78

    Article  PubMed  CAS  Google Scholar 

  63. Renshaw PF, Joseph NE, Leigh JS. Chronic dietary lithium induces increased levels of myo-inositol 1-phosphatase activity in rat cerebral cortex homogenates. Brain Res 1986; 380: 401–4

    Article  PubMed  CAS  Google Scholar 

  64. Honchar MP, Ackerman KE, Sherman WR. Chronically administered lithium alters neither myo-inositol monophosphatase activity nor phosphoinositide levels in rat brain. J Neurochem 1989; 53: 590–4

    Article  PubMed  CAS  Google Scholar 

  65. Moscovich D, Belmaker RH, Agam G, et al. Inositol 1-phosphatase in red blood cells of manic-depressive patients before and during treatment with lithium. Biol Psychiatry 1990; 27: 552–5

    Article  PubMed  CAS  Google Scholar 

  66. Molchan SE, Atack JR, Sunderland T. Decreased inositol monophosphatase activity after lithium treatment. Psychiatry Res 1994; 53: 103–5

    Article  PubMed  CAS  Google Scholar 

  67. Levine J, Umansky R, Ezrielev G, et al. Lack of effect of inositol treatment in chronic schizophrenia. Biol Psychiatry 1993; 33: 673–5

    Article  PubMed  CAS  Google Scholar 

  68. Levine J, Ring A, Barak Y, et al. Inositol may worsen attention deficit disorder with hyperactivity. Hum Psychopharmacol 1995; 10: 481–4

    Article  CAS  Google Scholar 

  69. Kaplan Z, Amir M, Swartz M, et al. Inositol treatment of post- traumatic stress disorder. Anxiety 1996; 2: 51–2

    Article  PubMed  CAS  Google Scholar 

  70. Barkai A, Dunner DL, Gross HA, et al. Reduced myo-inositol levels in cerebrospinal fluid from patients with affective disorder. Biol Psychiatry 1978; 13: 65–72

    PubMed  CAS  Google Scholar 

  71. Arendrup K, Gregerseng G, Hawley J, et al. High-dose dietary myo-inositol supplementation does not alter the ischemia phenomenon in human diabetics. Acta Neurol Scand 1989; 8: 99–102

    Article  Google Scholar 

  72. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 3rd ed, rev. Washington, DC: American Psychiatric Association, 1987

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular Neuroscience Laboratory, Mental Health and Behavioural Science Service, VA Medical Center (116), 800 Zorn Avenue, Louisville, Kentucky, 40206, USA

    Robert Vadnal (Chief), Lathakumari Parthasarathy & Ranganathan Parthasarathy

Authors
  1. Robert Vadnal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lathakumari Parthasarathy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ranganathan Parthasarathy
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vadnal, R., Parthasarathy, L. & Parthasarathy, R. Role of Inositol in the Treatment of Psychiatric Disorders. CNS Drugs 7, 6–16 (1997). https://doi.org/10.2165/00023210-199707010-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00023210-199707010-00002

Keywords

Search

Navigation