Inositol as a treatment for psychiatric disorders: a scientific evaluation of its clinical effectiveness
Gina L. Nick
Inositol is a naturally occurring isomer of glucose, though it is generally considered to be a member of the B vitamin family. It is a key intermediate in the intracellular phosphatidyl inositol second messenger pathway activated by numerous serotonergic, cholinergic, and noradrenergic receptors. (1) In this capacity it serves as an important signal transduction molecule, but inositol is also a structural component of cellular membrane phospholipids. (2) Research indicates that inositol is an effective and safe option in the treatment of panic disorder, obsessive-compulsive disorder (OCD), bulimia nervosa, binge eating and/or depression. (3-9) Inositol’s efficacy, in the absence of side effects, makes this nutrient an attractive addition to treatment plans for specific mood disorders. Following is a scientific review of inositol for the treatment of mood disorders, including a discussion of its anecdotal use for the treatment of insomnia and its cautioned use by pregnant women for the prevention of neural tube defects and embryopathies.
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Inositol occurs naturally as phytic acid in the fiber component of numerous plant foods, especially whole grains, citrus fruit, nuts, and seeds, and as myoinositol in meat. In the intestinal tract, bacteria break down phytic acid into bioavailable inositol that is easily absorbed via the intestinal epithelium. Myoinositol is found to bioaccumulate most abundantly in the central nervous system, supporting a role for it in neurological function.
Depression
Depressive patients generally have decreased levels of inositol in their cerebrospinal fluid. (3) Researchers now theorize that inositol produces positive clinical results in patients with depression due to intracellular phosphatidyl inositol serving as a second messenger for 5-hydroxytryptamine (5-H[T.sub.2]) receptor signaling mechanisms. Serotonin selective reuptake inhibitors (SSRIs), a family of drugs commonly used to treat depression, have a similar therapeutic profile to inositol in that they inhibit serotonin reuptake in the synaptic cleft. (10)
Levine et al. (4) performed a double-blind, placebo-controlled trial for 28 days on 28 depressed patients using a large dose (12 grams per day) of inositol. The Hamilton Depression (HAMD) Scale was used to evaluate patients after the 28-day trial period, and a significant overall benefit was confirmed in the inositol group compared to the placebo group (Table 1). No changes were noted in liver, kidney, or hematological function as a result of the high-dose inositol supplementation.
Bipolar Depression
Statistically nonsignificant differences favored inositol in 22 subjects treated for 6 weeks for bipolar depression. (11) This study noted the appeal of minimal side effects and the agent’s ‘natural substance’ aspect.
Obsessive-Compulsive Disorder
Levine (3) completed a review of research studies using inositol on psychiatric patients. The review highlighted some interesting findings with OCD patients. Serotonin plays a definitive role in obsessive-compulsive disorder as confirmed by the effectiveness of SSRIs in OCD patients and the fact that serotonin agonists exacerbate the syndrome. Rahman and Neuman (12) effectively reduced serotonin receptor desensitization via the administration of myo-inositol.
These research findings, coupled with the knowledge that SSRIs have proven beneficial in the treatment of OCD, (13) influenced Fux et al. (9) to complete a double-blind, placebo-controlled, random, crossover treatment trial of inositol on OCD. Thirteen patients, all of whom met DSM-III-R criteria for OCD, completed the trial. Six patients began the trial on placebo and seven began the trial on inositol (18 grams per day) for a total of six weeks for the first phase and six weeks for the crossover phase. The researchers administered 18 grams of inositol rather than 12 grams (typical dose for depressive patients) because OCD patients generally respond to higher relative doses of SSRIs than is needed to effect change in most depressives. The OCD patients were free of drug and alcohol abuse and had no evidence of diabetes or GI disorder. OCD was assessed using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and depression and anxiety were assessed using the Hamilton Depression Scale (HDS) and Hamilton Anxiety Scale (HAS). The mean improvement in OCD symptoms from baseline to six weeks was 5.9[+ or -]5.0 for inositol versus 3.5[+ or -]2.8 for placebo (p=0.04; t-test). This indicates a measurable positive response of OCD patients to inositol. Table 2 further details the results of this study with respect to inositol’s effect on subscale obsession, subscale compulsion, anxiety, and depression, all of which showed marked improvement with the administration of inositol versus the placebo.
Panic Disorder
Panic attacks are recurring attacks of severe anxiety without an apparent cause. Agoraphobia (irrational fear and avoidance of crowds, travel, and multiple situations), depression, alcohol abuse, and suicide are common symptoms and may be exacerbated by post-traumatic stress. Current treatments usually consist of antidepressant drugs and cognitive-behavioral therapy. (8)
Antidepressant medications affecting serotonin metabolism are effective about 70% of the time for dramatic, short-term improvement of anxiety symptoms. However, chronic residual symptoms often persist in the long term. 25-75% of patients with panic disorder discontinue drug treatment because of side effects, and these patients quickly relapse. (8) This has led researchers to study the effects of inositol on patients suffering from this condition.
In one study, (5) twenty-one patients diagnosed with panic disorder with or without agoraphobia were given 12 grams of inositol per day or placebo. In the treatment group, the severity and frequency of panic attacks declined significantly with minimal associated side effects. The average number of panic attacks per week in patients treated with inositol fell from 10 to 3.5 per week. The researchers concluded that these results were “clinically meaningful” in the management of panic attacks.
More recently, inositol was compared with the antidepressant fluvoxamine in the treatment of panic disorder. (8) This study represents a more stringent test of the effects of inositol in treating panic disorder because it is the first to compare inositol with an established antidepressant drug. In this study of 20 patients with panic disorder, inositol was found to be slightly but significantly more effective than fluvoxamine in reducing the number of panic attacks (p<0.049). Otherwise, it was comparable to fluvoxamine on all other measures (HAS, phobia, and Clinical Global Impression (CGI) Scale). Since inositol appears to be as effective as fluvoxamine, patients may prefer it and continue to take it for the long term because side effects are extremely rare and mild.
Bulimia nervosa and Binge Eating
Gelber et al. (7) conducted a double-blind crossover trial comparing 18 g inositol to placebo in 12 patients with bulimia nervosa and binge eating. They took each test substance for 6 weeks. Inositol was significantly better than placebo on the Global Clinical Impression, the Visual Analogue Scale, and the Eating Disorders Inventory. The study concluded, “Inositol is as therapeutic in patients with bulimia nervosa and binge eating as it is in patients with depression and panic and obsessive-compulsive disorders.”
Insomnia
Extreme situational stress can have a major impact on sleep rhythm and dreaming. (14) As of yet, there are no clinically valid controlled studies confirming the use of inositol in stimulating sleep in insomniacs. However, based on what is known about the role of inositol in regulating serotonin levels, researchers have speculated that inositol may assist people suffering with insomnia. Because it has no known side effects and is present in healthy whole foods, a diet rich in inositol may improve disrupted sleep patterns.
Retinopathy of Prematurity
In a completely different vein, Friedman et al. (15) demonstrated that infants receiving high inositol formula supplements and with higher serum inositol concentrations at birth and after 30 days had a significantly lower incidence of severe retinopathy of prematurity than those receiving the lower inositol formula and with lower serum concentrations. The p value was <.05), and the odds ratio was 4.7.
Not for Use During Pregnancy
Researchers have documented the preventive effect of inositol in folate-resistant neural tube defects in rats and mice, (16,17) as well as its positive effect in treating hyperglycemia-induced embryopathy. (18) However, inositol may cause dose-related uterine contractions because it has an intimate relationship with oxytocin, a key uterine stimulator. Oxytocin activates phospholipase C to produce inositol-1,4,5-triphosphate, which causes the release of calcium from intracellular stores and stimulates uterine contractions. (19,20) Thus, it is possible that inositol in high doses may stimulate uterine contractions via its role in the oxytocin stimulatory pathway, making it potentially dangerous for pregnant women.
Inositol in Food
Inositol in the form of phytic acid has been proposed as a possible agent in the cancer-fighting potential of whole grains. (21) The compound is heat- and acid-stable and is found in high concentration in many food items, including cereal grains, nuts, and seeds. Phytic acid is a metal chelator that can suppress damaging metal-catalyzed redox reactions, making it a natural antioxidant. Indeed, a high concentration of phytic acid in fruits and vegetables prevents oxidative browning and putrefaction by inhibiting polyphenol oxidase. (22)
The foods in which phytic acid is found are typically high in numerous other antioxidants, including quercetin and flavonoids. Phytic acid is also a major source of dietary phosphorus. (23) It is unclear if physiologically effective doses of inositol for treating mood can be achieved through diet alone.
In the Lab
Carey (24) has recently demonstrated in 14 patients with OCD that improvement during inositol treatment parallels specific single photon emission computed tomography (SPECT) changes in certain areas of the brain. These findings suggest inositol’s clinical effects are mediated through neuronal circuitry that is different from those involved with the SSRIs, implying an “overlapping but distinct mechanism of action.”
Brink et al., (25) exploring the mechanism of action of mI in depression and related anxiety disorders, found both similarities and differences in the effects of myo-inositol (mI), fluoxetine and imipramine on serotonin 5HT2A and muscarinic acetylcholine receptors in human neuroblastoma cells. These findings may help to explain why mI seems to be effective exclusively in selective serotonin reuptake inhibitor-sensitive disorders.
Conclusion
Inositol’s clinical efficacy coupled with the absence of significant side effects suggests that this nutrient may be an attractive addition to treatment plans for patients suffering from panic disorder, clinical depression, and/or obsessive-compulsive disorder. While inositol has shown benefit in some SSRI responsive conditions, it is not indicated as a replacement for SSRIs or as a treatment for all SSRI responsive conditions. Further research is necessary to elucidate the full potential of this natural compound in the treatment of mental illnesses and other conditions.
Indications for Use
* Mild to moderate depression (4)
* Obsessive-compulsive disorder (OCD) (9)
* Panic attacks (5,8)
Potential Indications for Use
* Diabetes (26)
* Insomnia (anecdotal)
* Alzheimer’s Disease (27)
* Liver Disorders (anecdotal)
* Bipolar depression (11)
* Retinopathy of prematurity (15)
* Bulimia nervosa and binge eating (7)
No Proven Benefit to Date
* Depression not responsive to SSRIs (28)
* Premenstrual dysphoric disorder (29)
* Synergy with SSRIs (10)
* Anergic schizophrenia, attention deficit-hyperactivity disorder and autism (3)
Drug/Nutrient Interactions: Inositol works synergistically with methyl donors.
Dosage Recommendations: 12-18 grams per day, depending on application (See reports of clinical trials summarized herein).
Table 1. Inositol vs. placebo (Hamilton Depression Scale) for the
treatment of depression in 28 depressed patients. (4)
Placebo Inositol
Baseline 32.87[+ or -]5.4 33.38[+ or -]6.1
After 2 weeks 29.27[+ or -]7.2 27.31[+ or -]8.0
After 4 weeks 28.93[+ or -]10.4 21.61[+ or -]9.7
Total Change ~3.94 ~11.7
([F.sub.1,26] = 4.48, p = 0.04)
Table 2. The effect of inositol on OCD patients: Placebo vs. inositol on
Y-BOCS scores. (9)
Patient Total change in Baseline Placebo
Y-BOCS score (6 wks)
1 -10 22 17
2 -5 17 15
3 -7 27 24
4 -8 30 27
5 -11 14 13
6 -15 28 20
7 -11 16 8
8 -3 21 17
9 -4 18 11
10 +1 24 23
11 +1 24 23
12 0 34 35
13 -2 26 23
HAS[+ or -]S.D. N/A 15.00[+ or -]9.7 13.50[+ or -]9.5
HDS[+ or -]S.D. N/A 14.83[+ or -]8.6 13.75[+ or -]9.6
Patient Inositol
(6 wks)
1 11
2 12
3 20
4 22
5 3
6 13
7 5
8 18
9 14
10 25
11 23
12 34
13 24
HAS[+ or -]S.D. 12.33[+ or -]10.3
HDS[+ or -]S.D. 11.0[+ or -]9.1
References
1. Belmaker, R. H. et al. 1995. Manipulation of inositol-linked second messenger systems as a therapeutic strategy in psychiatry. Adv Biochem Psychopharmacol 49: 67-84.
2. Hooper, N. 1997. Glycosyl-phosphatidylinositol anchored membrane enzymes. Clin Chim Acta 266(1): 3-12.
3. Levine, J. 1997. Controlled trials of inositol in psychiatry. Eur Neuropsychopharmacol 7(2): 147-155.
4. Levine, J. et al. 1995. Double-blind, controlled trial of inositol treatment of depression. Am J Psychiatry 152(5): 792-794.
5. Benjamin, J. et al. 1995a. Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder. Am J Psychiatry 152(7): 1084-1086.
6. Benjamin, J. et al. 1995b. Inositol treatment in psychiatry. Psychopharmacol Bull 31(1): 167-175.
7. Gelber et al. 2001. Effect of inositol on bulimia nervosa and binge eating. Int J Eat Disord. 29(3):345-8.
8. Palatnik, A. et al., 2001. Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. J Clin Psychopharmacol 21(3): 335-339.
9. Fux, M. et al. 1996. Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry 153(9): 1219-1221.
10. Levine, J. et al. 1999. Combination of inositol and serotonin reuptake inhibitors in the treatment of depression. Biol Psychiatry 45(3): 270-273.
11. Chengappa et al. 2000. Inositol as an add-on treatment for bipolar depression. Bipolar Disord. 2(1):47-55.
12. Rahman, S. and R. S. Neuman. 1993. Myo-inositol reduces serotonin (5-HT2) receptor induced homologous and heterologous desensitization. Brain Res 631(2): 349-351.
13. Greist, J. H. et al. 1995. Efficacy and tolerability of serotonin transport inhibitors in obsessive-compulsive disorder. A meta-analysis. Arch Gen Psychiatry 52(1): 53-60.
14. Hefez, A. et al. 1987. Long-term effects of extreme situational stress on sleep and dreaming. Am J Psychiatry 144(3): 344-347.
15. Friedman CA, et al. 2000. Relationship between serum inositol concentration and development of retinopathy of prematurity: a prospective study. J Pediatr Ophthalmol Strabismus Mar-Apr;37(2): 79-86.
16. Greene, N. D. and A. J. Copp. 1997. Inositol prevents folate-resistant neural tube defects in the mouse. Nat Med 3(1): 60-66.
17. Reece, E. A. et al. 1997. Dietary intake of myo-inositol and neural tube defects in offspring of diabetic rats. Am J Obstet Gynecol 176(3): 536-539.
18. Khandelwal, M. et al. 1998. Dietary myo-inositol therapy in hyperglycemia-induced embryopathy. Teratology 57(2): 79-84.
19. Colodny, L. and R. L. Hoffman. 1998. Inositol–clinical applications for exogenous use. Altern Med Rev 3(6): 432-447.
20. Gill, D. L. et al. 1989. Calcium signalling mechanisms in endoplasmic reticulum activated by inositol 1,4,5-trisphosphate and GTP. Cell Calcium 10(5):363-374.
21. Graf, E. and J. W. Eaton. 1993. Suppression of colonic cancer by dietary phytic acid. Nutr Cancer 19(1): 11-19.
22. Graf, E. et al. 1987. Phytic acid. A natural antioxidant. J Biol Chem 262(24): 11647-1150.
23. Zhou, J. R. and J. W. Erdman. 1995. Phytic acid in health and disease. Crit Rev Food Sci Nutr 35(6): 495-508.
24. Carey et al. 2004. Single photon emission computed tomography (SPECT) in obsessive-compulsive disorder before and after treatment with inositol. Metab Brain Dis. 19(1-2):125-34.
25. Brink CB et al. 2004. Effects of myo-inositol versus fluoxetine and imipramine pretreatments on serotonin 5HT2A and muscarinic acetylcholine receptors in human neuroblastoma cells. Metab Brain Dis. 19(1-2):51-70.
26. Cai, F. et al. 1990. Preliminary report of efficacy of diabetic polyneuropathy treated with large dose inositol. Hua Xi Yi Ke Da Xue Xue Bao 21(2): 201-203.
27. Barak, Y. et al. 1996. Inositol treatment of Alzheimer’s disease: A double blind, crossover placebo controlled trial. Prog Neuropsychopharmacol Biol Psychiatry 20(4): 729-735.
28. Nemets et al. 1999. Inositol addition does not improve depression in SSRI treatment failures. J Neural Transm. 106(7-8):795-8.
29. Nemets et al. 2002. Myo-inositol has no beneficial effect on premenstrual dysphoric disorder. World J Biol Psychiatry. 3(3):147-9.
by Gina L. Nick, PhD, ND
Chief Scientific Officer at Longevity Through Prevention, Inc.
Phone: 866-587-4622X702 * Fax: 866-587-4622 * E-mail: drgina@LTPonline.com
P.O. Box 6936 * Laguna Niguel, California 92677 USA
www.LTPonline.com
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