Controlled trials of inositol in psychiatry

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Abstract

Inositol is a simple polyol precursor in a second messenger system important in the brain. Cerebrospinal fluid inositol has been reported as decreased in depression. A double-blind controlled trial of 12 g daily of inositol in 28 depressed patients for four weeks was performed. Significant overall benefit for inositol compared to placebo was found at week 4 on the Hamilton Depression Scale. No changes were noted in hematology, kidney or liver function. Since many antidepressants are effective in panic disorder, twenty-one patients with panic disorder with or without agoraphobia completed a double-blind, placebo-controlled, four week, random-assignment crossover treatment trial of inositol 12 g per day. Frequency and severity of panic attacks and severity of agoraphobia declined significantly with inositol compared to placebo. Side-effects were minimal. Since serotonin re-uptake inhibitors benefit obsessive compulsive disorder (OCD) and inositol is reported to reverse desensitization of serotonin receptors, thirteen patients with OCD completed a double-blind controlled crossover trial of 18 g inositol or placebo for six weeks each. Inositol significantly reduced scores of OCD symptoms compared with placebo. A controlled double-blind crossover trial of 12 g daily of inositol for a month in twelve anergic schizophrenic patients, did not show any beneficial effects. A double-blind controlled crossover trial of 6 g of inositol daily vs. glucose for one month each was carried out in eleven Alzheimer patients, with no clearly significant therapeutic effects. Antidepressant drugs have been reported to improve attention deficit disorder (ADDH) with hyperactivity symptomatology. We studied oral inositol in children with ADDH in a double-blind, crossover, placebo-controlled manner. Eleven children, mean age 8.9±3.6 years were enrolled in an eight week trial of inositol or placebo at a dose of 200 mg/kg body weight. Results show a trend for aggravation of the syndrome with myo-inositol as compared to placebo. Recent studies suggest that serotonin re-uptake inhibitors are helpful in at least some symptoms of autism. However a controlled double-blind crossover trial of inositol 200 mg/kg per day showed no benefit in nine children with autism. Cholinergic agonists have been reported to ameliorate electroconvulsive therapy (ECT)-induced memory impairment. Inositol metabolism is involved in the second messenger system for several muscarinic cholinergic receptors. Inositol 6 g daily was given in a crossover–double-blind manner for five days before the fifth or sixth ECT to a series of twelve patients, without effect. These results suggest that inositol has therapeutic effects in the spectrum of illness responsive to serotonin selective re-uptake inhibitors, including depression, panic and OCD, and is not beneficial in schizophrenia, Alzheimer's, ADDH, autism or ECT-induced cognitive impairment.

Introduction

This paper reviews, extends and compares the results of eight controlled studies of inositol treatment in different psychiatric disorders (Levine et al., 1995, Benjamin et al., 1995, Fux et al., 1996, Levine et al., 1994, Barak et al., 1996, Levine et al., 1996a, Levine et al., 1996bLevine et al., in press). Inositol is a simple isomer of glucose that is a key metabolic precursor in the phosphatidylinositol (PI) cycle. Unlike l-DOPA and tryptophan, which are amino acid precursors of monoamine neurotransmitters and which have been reported to have antidepressant properties, inositol is a precursor of an intracellular second messenger system. The PI cycle is a second messenger system for numerous neurotransmitters (Baraban et al., 1989).

Barkai et al. (1978)reported that depressed patients, both unipolar and bipolar, had markedly reduced levels of inositol in cerebrospinal fluid (CSF). In an open study (Levine et al., 1993a) of eleven depressed patients who had been resistant to previous antidepressant treatment, inositol treatment led to a decline in mean Hamilton Depression Scale (HDS) from 31.7±6 to 16.2±9. Levine et al. (1993b)showed that 12 g daily of inositol raised CSF inositol levels by 70%. We studied 12 g daily inositol in depression in a double-blind controlled trial (Levine et al., 1995).

Section snippets

Depression study

Diagnostic entry criteria for the study were Diagnostic statistics manual-III-revised version (DSM-III-R) major depressive disorder or bipolar affective disorder depressed. In fact, patients who were referred to the study and gave informed consent were all antidepressant treatment failures, or side effect dropouts, or in the case of the bipolar depressed patients were lithium prophylaxis patients who had few past problems with mania but intolerable continuation of depression. All medications

Panic study

Since some antidepressants are also effective against panic disorder we decided on a trial of inositol treatment for panic disorder. Patients had a DSM-III-R diagnosis of panic disorder or panic disorder with agoraphobia (Benjamin et al., 1995). Patients previously on medications withdrew from them at least one week before commencing a formal washout period; only two patients actually withdrew from medications this close to the study. Patients were prepared to go off conventional treatments in

Obsessive–compulsive disorder study

The role of serotonin in obsessive compulsive disorder (OCD) is supported by the specific effectiveness of serotonin re-uptake inhibition in this illness and the ability of serotonin agonists to exacerbate the syndrome. Rahman and Neuman (1993)reported that desensitization of serotonin receptors is reversed by addition of exogenous inositol. We therefore planned a trial of inositol in OCD. Since anti-OCD doses of serotonin selective re-uptake inhibitors (SSRI) are usually higher than

Schizophrenia study

Levine et al. (1993a)found no benefit of inositol treatment in unselected schizophrenic patients using 6 g inositol daily. Since many antidepressant compounds are useful in negative signs schizophrenia, we decided to repeat a study of inositol in schizophrenia using only patients with severe negative signs. Moreover, Levine et al. (1993a)studied inositol effects in schizophrenic patients taking high doses of neuroleptics, which could mask possible benefit of inositol on negative signs of

Alzheimer's disease study

Since antidepressant drugs may have beneficial effects in the demented elderly we considered a trial of inositol in Alzheimer's Disease. A dose of 6 g was chosen despite the safety of 12 g in younger patients, for geriatric pharmacokinetic considerations. Twelve female patients mean age of 81.6 years participated in the study (Barak et al., 1996). All patients were hospitalized at the Abarbanel Mental Health Center, psychogeriatric ward. All agreed to participate and informed consent was

ADDH

Antidepressants (Biederman et al., 1989) have been reported as having beneficial effects on ADDH children. Therefore, we examined the effect of 200 mg/kg inositol in ADDH (Levine et al., 1996a). Patients were offered inositol therapy in the out-patient children and adolescent clinic. Inclusion criteria for this study were:

  • 1.

    Age older than 4 years, no known physical illnesses.

  • 2.

    DSM-III-R diagnosis of ADDH by two senior psychiatrists.

  • 3.

    No history of mental retardation and IQ above 85.

  • 4.

    Written informed

Autism study

Recent studies of SSRI with positive benefit in autism have given renewed impetus to the search for effective treatments of autism. Rahman and Neuman (1993)showed that exogenous inositol enhances serotonin function in a rat brain electrophysiological model. We therefore performed a study of inositol in autism (Levine et al., in press).

The study was approved by the Helsinki Committee and informed consent signed by all the participants' legal guardians. Ten children entered the study after

ECT-induced cognitive impairment study

ECT-induced memory impairment may be pharmacologically reversible. We studied naloxone in ECT-induced memory impairment with negative results (Levine et al., 1990) and physostigmine with positive results (Levine et al., 1987). Some theories of ECT-induced memory deficits postulate a cholinergic deficit reversible with physostigmine (Levine et al., 1987), and several muscarinic cholinergic receptors are linked to PI as a second messenger. Therefore we hypothesized that exogenous inositol might

Discussion

Inositol is a precursor in the PI second messenger cycle linked to norepinephrine α-1, 5-Hydroxytriptamine-2 (5-HT-2) (serotonin) and other receptors thought to be involved in affective and anxiety disorders. This review demonstrates superiority over placebo of a second messenger precursor strategy in the treatment of depression as well as in the treatment of panic disorder and OCD. However, one should remember these are relatively small studies of a pilot nature.

Various catecholamine and 5-HT

Acknowledgements

The author would like to thank all his clinical collaborators in inositol studies: Yoram Barak, Mirtha Gonzalves, Henry Szor, Avner Elizur, Jonathan Benjamin, Alex Aviv, Mendel Fux, Daniel Levy, Aliza Ring, Ada Aviram, Agnes Holan, A. Glasman, T. Pomerantz and S. Stier. The author is especially grateful to Professor R.H. Belmaker, who conceived the possible utility of inositol as a therapeutic strategy in psychiatry

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