Fwd: [SSRI-Research] Inosito (Niacin) ­ Clinical Applications for Exogenous Use

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[sSRI-Research] Inosito (Niacin) & shy; Clinical Applications for

Exogenous Use

 

Inositol & shy; Clinical Applications for Exogenous Use

 

Lisa Colodny, Pharm D. and Ronald L. Hoffman, M.D

 

http://www.thorne.com/altmedrev/fulltext/inositol3-6.html

 

Abstract

 

Recent advances in nutritional and biochemical research have documented inositol

as an important dietary and cellular constituent. The processes involved in

inositol metabolism and its derivatives in the tissues of mammals have been

characterized in vivo as well as at the enzymatic level. Biochemical functions

defined for phosphatidylinositol in biological membranes include the regulation

of cellular responses to external stimuli and/or nerve transmission as well as

the mediation of enzyme activity through interactions with various specific

proteins. Altered production of inositol has been documented in patients with

diabetes mellitus, chronic renal failure, galactosemia, and multiple sclerosis.

Inositol has been reported to be effective in treating central nervous system

disorders such as depression, Alzheimer's disease, panic disorder, and

obsessive-compulsive disorder. It has documented benefit for use in pediatric

respiratory depression syndrome. In addition, recent studies have

evaluated its usefulness as an analgesic. Inositol has been studied extensively

as potential treatment to alleviate some negative effects associated with

lithium therapy. The use of inositol in pregnant women remains controversial.

Although its benefit in preventing neural tube defects in embryonic mice is

documented, the risk of inducing uterine contractions limits its usefulness in

pregnancy. (Altern Med Rev 1998;3(6):432-447)

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Introduction

 

Inositol has been identified as an important dietary and cellular constituent.

Biochemical functions of phosphoinositol (PI) in cell membranes include

regulation of cellular responses to external stimuli as well as mediation of

enzyme activity.

 

In mammals, inositol exists as phosphorylated derivatives, various

phosphoinositides, and in its free form. These membranous bound

phosphatidylinositols are cleaved by phospholipase C to form diacylglycerol

(DAG) and the inositol phosphates. Subsequent enzymatic processes produce a

variety of mono-, bi-, tri-, and tetraphosphate inositols depending on specific

substrate and the enzyme as described in the diagram that follows. For example,

the Ins-1,4,5-P3 kinase is stimulated by calcium. Therefore, the conversion of

Ins-1,4,5-P3 to the Ins-1,3,4,5-P4 is facilitated when cytosolic concentrations

are increased due to any agonistic action at the cell membrane site. Likewise,

the action of the enzyme, polyphosphate 1-phosphomonoesterase is inhibited by

lithium and also by calcium in the physiologic range (Figure 1).1

 

The end product of each pathway eventually is inositol, which is recycled back

as a component of the original PI precursor. In addition, this parent compound,

phosphatidylinositol, can moderate the activity of numerous membrane enzymes.

 

Glycosyl-phosphatidylinositol (GPI) structures covalently anchor several enzymes

(acetylcholinesterase, alkaline phosphatase, membrane dipeptidase, and

5-nucleotidase) to the outer surface of the plasma membrane.2 In addition, these

GPI anchors may provide the protein with other properties, such as phospholipase

cleavage susceptibility and the ability to cluster in detergent insoluble

domains. These anchors can also act as signalers both intracellularly and

transmembranously to regulate metabolic processes of the cells. This allows for

enzymes to be activated when agonist activity is high, thereby decreasing

further mobilization of calcium. Inactive enzymes remain attached to the

membrane and allow agonist stimulation when calcium demand is decreased.

 

The inositols are ubiquitous, cyclic carbohydrates with a basic 6-carbon ring

structure. There are actually nine isomers of inositol, of which myo-inositol is

the most abundant isomer in the central nervous system of mammals (Figure 2).

Myo-inositol is unique in that it has a single axial hydroxyl group at the

number 2 carbon.1

 

 

 

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Physiology

 

Because amines, polypeptides, and glycoproteins cannot penetrate the lipid layer

of target cell membranes, an alternative activator is required. It is known that

most hormones act as a " second messenger " by binding to these cell membrane

receptors and beginning a cascade of reactions that produces a " messenger " to

actually potentiate the intended action.3

 

This " second messenger " concept is not unique to hormones. The original " second

messenger " to be discovered was cyclic adenosine monophosphate (cAMP). For this

reason, cAMP is also the best understood. For example, the hormonal effects of

epinephrine and norepinephrine are regulated by cAMP. The neurotransmitters

released at nerve endings are also regulated by cAMP.

 

When the agonist binds to the cell membrane receptor, ATP is converted to cAMP

which in turn activates a kinase enzyme. The kinase becomes the " second

messenger " as it continues in the cycle to promote the original agonistic effect

(Figure 3).

 

Phosphoinositide composition of the central nervous system cell membranes are

fatty-acid enriched and consist primarily of phosphatidylinositol (PI),

phospha-tidylinositol-4-phosphate (PIP), and

phosphatidylinositol-4,5-biphosphate (PIP2). Once the membrane is stimulated,

phospholipase C is activated and consequently inositol triphosphate along with

diacylglycerol is produced. PI is used as a precursor for

phosphatidylinositol-3-phosphate [PI(3)P] and 3,4,5-triphosphate (Figure 4).1

 

Cytoplasmic calcium concentration is kept very low by active transport carriers,

calcium pumps in the cell membrane itself, and in the endoplasmic reticulum.

Usually the calcium concentration inside the cytoplasm is 5,000-10,000 times

less than the concentration in the extracellular fluid.

 

This endoplasmic store of calcium can be accessed upon stimulation by inositol.

Inositol triphosphate is released from the cell membrane and travels through the

cytoplasm until it reaches the endoplasmic reticulum. This inositol then

releases the sequestered calcium, which can go on to mediate the release of

neurotransmitters in response to depolarization (Figure 5).4

 

In addition to releasing endoplasmic reticulum calcium, myo-inositol functions

as the major central nervous system non-nitro-genous osmoregulator. Modulation

of this inositol pool is regulated in response to states of high or low

osmolalities. The inositol pool is supplied via a sodium/inositol transporter, a

sodium dependent active transport system, and a passive low affinity

transporter.

 

Hypo- or hyperfunctioning occurs in different areas of the brain depending on

the concentration of a specific myo-inositol pool.1 Regulation of the brain

inositol system is maintained exclusively by the production of intrinsic

myo-inositol. Levels of intrinsic myo-inositol must be closely regulated, as an

increase or decrease in the concentration can directly affect cellular

signaling. IMPase, a magnesium dependent enzyme that hydrolyzes myo-inositol

monophosphate into intracellular myo-inositol, accomplishes this regulation.5

 

Using rats as models, Kitamura et al proposed modulation of osmolality by

inositol occurs in the renal medulla, especially the ascending limb of Henle.6

During this study, acute renal failure was induced by injection of MMI (2-0, C

methylene-myo-inositol), a sodium transport inhibitor, producing a significant

increase in serum creatinine and urea nitrogen 12 hours after the dose was

administered. The subsequent administration of myo-inositol prevented acute

renal failure and improved tubular injury after MMI injection.6 This may suggest

a future role for inositol supplementation to improve renal function in

compromised patient populations.

 

The specificity of the IP3 receptors as well as the identification of other

inositol receptors may play an important role in the development of newer

inositol agents that can be directed to a specific receptor or enzyme. Recently,

the work of Monkawa et al identified three different types of

inositol-1,4,5-triphosphate receptors in the rat kidney.7 Type 1 inositol

triphosphate receptors were most commonly located in the glomerular mesangial

cells and in vascular smooth muscle cells. Receptors of type 2 specificity were

located in the collecting ducts from the cortex to the inner medulla. Type 3

inositol triphosphate receptors can be found at all sites.6

 

Although receptor differences in the human model are not as clearly understood,

calcium may have the potential to inhibit IP3 binding to types 1 and 3

triphosphate receptors. Calcium binding to type 3 receptors may be stimulated at

intermediate concentrations of calcium. As a result of these differences, type 3

receptors are more sensitive to IP3 than type 1 receptors when the cytosolic

calcium concentration is within normal range.8 However, as the cytosolic calcium

concentrations increase, type 1 receptors become more sensitive to IP3 compared

to type 3 receptors.

 

In addition to the IP3 receptors, numerous non-inositol receptors have been

identified in the central nervous system that can potentially interact with the

inositol signaling system. The receptors listed in Table 1 are linked to the G

proteins and produce DAG and inositol-1,4,5-triphosphate as second messengers.1

The receptors listed can be found in nearly every human organ system. The

potential interactions between these receptors and their agonists are

responsible for regulation of the body on a day-to-day basis. In view of the

intricacy of these systems and their actions, a perfect balance is required for

regulation of the signaling systems.

 

Theoretically, an imbalance of inositol concentration could potentially affect

the development and function of one or all of these receptors. Therefore, any

organ system that houses these receptors could also be potentially affected.

Cholinergic receptors are located in the liver, heart, stomach, and lungs.

Serotonin and glutamine receptors are found mostly in the CNS tissues.

Adrenergic receptors are present in various tissues including CNS, vascular

tissues, and heart. Histaminergic receptors are predominantly found in the lungs

and stomach. Given the omnipresence of inositol or inositol related entities,

maintaining a state of euinositolism may be a promising objective for regulation

of functions required for development and/or maintenance of organ systems.

 

Under normal conditions the average dietary intake of inositol is only about one

gram per day. Fortunately, oral intake of inositol accounts for only one of

three pathways for inositol production. Inositol monophosphate can be produced

as a result of a receptor mediated salvage system and from glucose-6-phosphate.

Inositol from either of these two pathways is metabolized by a lithium sensitive

enzyme, polyphosphate-1-phospho-monoesterase. These two pathways account for the

majority of inositol produced (Figure 6). Inositol accumulation from the third

pathway, attained as a result of dietary uptake, is considered a minor pathway.

 

 

 

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Potential Clinical Applications

 

A change in CNS availability of inositol may produce altered brain signaling and

eventually lead to the development of neurological disorders. Studies evaluating

the effectiveness of inositol indicate it may be effective in the treatment of

depression, Alzheimer's disease, panic disorder, obsessive compulsive disorder,

autism, post-traumatic stress disorder, and pain control.

 

Depression: The prevalence of depression in the United States is not

definitively known. Depressive symptoms occur in 13-20 percent of the U.S.

population. Depression is twice as likely to occur in females, average age of

onset being 35-45; whereas it is 55 years of age for men.

 

The biological etiology for depression is believed to be linked to a deficiency

of neurotransmitters at post-synaptic receptor sites. In the catechol-amine

theory the deficiency is norepinephrine; in the indolamine theory the deficiency

is serotonin. Receptors linked to the inositol signaling system include

serotonin (5HT2a and 5HT2b) and norepinephrine (alpha 1a, 1b, and 1d).

Therefore, inositol may be an important participant in this neurological arena.

 

Presently, serotonin reuptake inhibitors (SSRIs) are the primary class of agents

utilized for depressed patients. Kavoussi et al reported bupropion (a

semi-serotonin agent) and sertraline (an SSRI) equally effective for the

treatment of depression.9 However, orgasm dysfunction, nausea, vomiting,

somnolence, and sweating were frequently reported side-effects in the sertraline

group.10 Lydiard et al reported amitriptyline not superior to placebo for

several subjective assessments of depression.11 Van Houdenhave et al reported 23

percent of study patients experienced mild to moderate gastrointestinal effects

for sertraline treated patients and a withdrawal rate of eight percent.12

Venlafaxine was evaluated by Dunner et al and a dropout rate of 11.5 percent due

to side-effects associated with therapy was reported.13 Presently, the SSRIs as

a class are probably the best tolerated antidepressants currently available for

use in patients with depression. They are commonly selected over the

anticholinergic agents due to their effectiveness and lack of anticholinergic

side-effects.

 

Anticholinergic effects of antidepressants include dry mouth, blurred vision,

constipation, and urinary hesitancy. Autonomic effects include sweating,

impotence and ejaculation dysfunction. At normal doses cardiac adverse effects

include tachycardia and EKG changes. Other effects include: orthostatic

hypotension, sedation, restlessness, insomnia, weight gain, anorexia, nausea,

vomiting, tremor, and confusion.

 

In 1978, Barkai et al demonstrated depressed patients had significantly

decreased CSF levels of inositol as compared to healthy patients.14 In 1993 this

theory was expanded to conclude that administration of high-dose inositol could

increase CSF levels by as much as 70 percent.15 This led to the study of

inositol for treatment of depression.16,17

 

In 1995 Levine et al completed a, double-blind study for treatment of depression

using inositol at a dose of 12 grams daily compared to placebo.18 Patients

receiving inositol showed significant improvement in depression as ranked by the

Hamilton Depression Rating Scale (33.4 +/- 6 versups 21.6 +/- 10). Side-effects

experienced by the inositol group were nausea and flatus. There were no

hematological abnormalities in laboratory parameters. A few patients experienced

mild elevations in fasting serum glucose concentrations. The researchers

concluded that twelve grams daily was well tolerated. Another important

observation was the absence of manic episodes in the bipolar patients treated

with inositol. This lack of manic episodes may suggest that when the signaling

system is not overactive, addition of inositol will not increase the signaling

system's activity.18

 

Another study reported in 1995 by Levine et al evaluated the potential for

relapse of depression once inositol therapy was discontinued. In this study,

patients treated with 12 grams inositol daily experienced significant

antidepressant effects. Half of the patients who responded to therapy relapsed

rapidly on discontinuation of inositol.19

 

It can be concluded that inositol at a dose of 12 grams daily may be effective

in treating the clinical manifestations of depression and should be considered a

treatment alternative. In addition to the possible clinical responses relative

to symptom resolution, therapy with inositol may be advantageous since potential

side-effects of the more conventional therapy can be avoided.

 

Panic Disorder: Panic disorder begins as an acute or spontaneous attack of

anxiety that involves an intense, terrifying fear. The attack seems to peak in

about ten minutes and lasts approximately 20-30 minutes. The disorder is usually

progressive and patients may develop anticipatory anxiety as a result. Most

patients will eventually develop symptoms of avoidance behavior or agoraphobia.

 

Several drugs for the treatment of panic disorders are available, although

response is often unpredictable. Conventional therapy includes SSRIs, the

serotonergic agent clomipramine, tricyclic antidepressants such as imipramine or

desipramine, MAOIs (especially phenelzine), alprazolam, and clonazepam. However,

treatment with these medications continues to produce a significant number of

adverse reactions.

 

Papp et al concluded clomipramine at therapeutic doses produced a significant

number of adverse drug reactions and a high drop rate.20 Paroxetine for panic

disorder was evaluated by Ballenger et al who reported adverse drug reactions

consistent with those most commonly reported for the class as a whole.21 The

most compelling adverse drug reaction information was reported by Cowly et al,

who found 27 percent of the clinical trials reporting intolerable side-effects

as the most common reason for treatment failures, especially with tricyclic

antidepressants.22 Rosenbaum et al concluded clonazepam in higher doses was more

likely to cause somnolence and ataxia, while normal maintenance doses were more

likely to be associated with depression, dizziness, fatigue, and irritability.23

 

Benjamin et al expanded the clinical use of inositol by evaluating its

effectiveness in panic disorder.24 This was an eight week double-blind,

crossover study whereby patients were treated with 12 grams inositol daily for

four weeks and then crossed over to the other study arm. Improvement was

assessed using patient diaries, the Marks-Matthews Phobia Scale, the Hamilton

Anxiety Rating Scale, and the Hamilton Depression Scale. The frequency and

severity of panic attacks and the severity of agoraphobia declined significantly

more after inositol than after placebo (a decrease from 10 attacks per week to 3

per week in the treated group compared to a decrease from 10 to 6 in the placebo

group.) The authors conclude inositol's efficacy and safety, and the fact that

inositol is a natural component of the human diet make it a potentially

attractive therapeutic agent for panic disorder.

 

Obsessive Compulsive Disorder (OCD): OCD is the fourth most common psychiatric

disorder. It is estimated 2.5 percent of adults and one percent of children meet

the DSM-IV classification for OCD. It usually first appears late in adolescence

or early adulthood. OCD incidence is higher in females than in males. The age of

onset is usually earlier in males than in females, 6-15 years compared to 20-29

years, respectively.25

 

Although OCD can occur following a brain injury, there is usually no

neurological precipitant. Most compelling for the evidence suggesting a

biological cause is the successful treatment using SSRIs. Currently the

medication of choice for treating OCD is the benzodiazepine agent, clomipramine.

Flament et al reported a 26-percent discontinuation rate for OCD treated with

clomipramine and 11 percent for those treated with the serotonin agent,

sertraline. In addition, there is poor tolerance for long-term use of

clomipramine.26 Nausea, vomiting, and decreased sleep were the most commonly

reported side-effects in a study of citalopram for OCD.27 Patients also reported

decreased sexual desire and orgasmic dysfunction.

 

Since the phosphatidylinositol cycle as a second messenger is known to affect

several neurotransmitters, including serotonin receptors, inositol at 18 grams

daily was studied for treatment in OCD in a double-blind, placebo controlled,

crossover trial. Thirteen patients were treated for six weeks. There was a

significant improvement at week six during the inositol period when compared to

placebo period. There were no side-effects reported during the study period.28

The improvement noted with inositol in this study was comparable to that

reported for fluvoxamine and fluoxetine.28 Longer periods of inositol therapy

may produce even more significant results.

 

Alzheimer's Disease: Alzheimer's Disease (AD) is a degenerative brain disorder

that affects approximately four million people in the United States.29 This

number is anticipated to increase to nearly nine million by the year 2040. It is

estimated that currently more than 10 percent of the U.S. population aged 65 or

older and 48 percent of those aged 85 or older have AD.30

 

Annually, the national cost of AD is estimated at 110 billion dollars. This

includes the direct costs of medical care and social services, informal costs,

and costs due to lost productivity. First characterized in 1907 by Alois

Alzheimer, AD is a dementia of insidious onset, with deterioration of

intellectual ability occurring gradually. Clinically, it is a progressive brain

failure that results from neuronal dysfunction and ultimately cell death.

Multiple neuronal pathways are destroyed in AD. This destruction is believed to

be caused by accumulation of neuritic plaques and neurofibrillary tangles (NFT).

 

NFTs are located intracellularly within the cytoplasm of neurons. The neuritic

plaques are extracellularly located (brain and cerebral vasculature). Both the

plaques and NFTs significantly interfere with neuronal transmission.

 

Although the role of aluminum in AD is still speculative at best, the presence

of aluminosilicates at the core of senile plaques in diseased neurons is a

consistent feature found in the CNS of AD patients during autopsy.31 It is known

that aluminum inhibits the incorporation of inositol into phospholipids and the

hydrolysis of the phosphoinositides by binding to one of two specific phosphate

groups. This copulation of phosphate and aluminum affects the calcium releasing

effects of the cell. The resulting profound disturbance of the

phosphatidylinositol second messenger system may account for neuronal

malfunction and eventual cell death.31

 

Currently all medications for AD are palliative. Even with newer agents like

tacrine, the prognosis for AD is not improved. The newer agents do not affect

the underlying disease processes, although progression of the disease may be

retarded. Table 2 lists the currently approved agents and those currently being

studied for Alzheimer's disease.30,32-39

 

Since the potential role of aluminum as a causative agent for cell death may be

affected by the deregulation of calcium concentration, possibly due to inositol

depletion, supplementation with inositol may produce positive CNS effects.

Recent data suggests the loss of PI second messenger system target sites and IP3

receptors may add to cognitive impairment and the failure of conventional

therapies in AD. Therefore, supplementation of inositol to replenish the

diminished PI system may be beneficial in the treatment of AD.

 

In 1996 Barak et al completed a double-blind, controlled, crossover study of six

grams inositol daily compared to placebo for 30 days in 11 Alzheimer's

patients.40 Patients in the study were diagnosed with dementia of the AD type as

classified by DSM - IIIR and aged 65 years or older. The Cambridge Mental

Disorder of the Elderly Examination (CAMDEX) was used as the basic assessment

parameter and was administered upon admission into the study. Included in CAMDEX

is part A: patient's present physical and mental state, part B: Cognitive

Subscale of CAMDEX (CAMCOG), part C: interviewers observations, and part D:

physical examination. CAMCOG was repeated at two, four, six, and eight weeks.

Participants scored 80 or less on the CAMCOG examination and their symptoms of

depression were not severe.

 

Patients were excluded from the study if they had a history of psychiatric,

alcohol, and/or drug addiction disorders, or abnormalities in baseline

laboratory values (blood count, electrolytes, liver or kidney functions, VDRL,

or CT scan) not consistent with AD. Patients with additional neurologic,

metabolic, endocrinologic disorders, or presence of internal disease that

grossly impaired brain functioning were also excluded.

 

Subjects were given either three grams inositol or placebo in the morning and

again in the evening. After four weeks patients were crossed over into the other

arm (inositol or placebo) for an additional four weeks. Only benzodiazepines

were allowed during the study period (15 mg of oxazepam or equivalent), provided

the patient was receiving it on study entry.

 

Analysis of the improvement scores of all patients who completed the study

showed inositol increased the total CAMCOG score from a baseline of 31.36 +/-

20.90 to 40.09 +/- 24.54, while the placebo group increased from baseline of

35.9 +/- 25.96 to 39.27 +/- 25.10. The authors concluded only two of the eight

subscales (language and orientation) showed significant improvement with

inositol. Adverse effects of the inositol treated group were considered mild and

transient (insomnia and flatus).

 

Further studies targeting orientation and/or improvement in language skills are

warranted. The relatively small number of patients enrolled in the study may

have lacked the statistical power to identify other significant differences that

may have existed. It is also questionable why the researchers decided to use

inositol at a dose of six grams when it is known relatively larger doses (12

grams or more) are generally required. Thirdly, the length of time inositol was

administered may have been too short since studies in which patients were

treated for three to five months produced more favorable results.

 

Recent advances in AD neurobiology have provided evidence for development of

more effective and less toxic strategies for disease management. Of most

significance is the realization that muscarinic receptors (M1) post-synaptically

are relatively preserved in AD patients, whereas the number of pre-synaptic

receptors (M2) are reduced (Figure 7).41 Therefore, stimulation of intact

post-synaptic membranes by M1 receptor agonists may theoretically be more

efficacious in treatment of AD than treatment with conventional therapies like

acetylcholinesterase inhibitors that predominantly act on dysfunctional

pre-synaptic membrane receptors.

 

Inositol's proposed mechanism of action in the CNS does not include direct

manipulation with either pre- or post-receptors. However, it may indirectly

affect the relationship between receptor and agonist. By mediating the

physiochemical characteristics of the M1 pre-synaptic receptor (solubility,

osmolality, etc.), inositol may alter the binding site and influence the

signaling that occurs as a result.

 

The development of a diagnostic test to confirm the existence of an " Alzheimer's

protein " may also provide beneficial early therapy for patients predisposed to

AD. In December 1997 the discovery of a protein called AD7c-NTP in nerve cells

that may cause Alzheimer-like changes, including cell death, was announced.42

This might enable physicians to identify patients with the AD protein and begin

appropriate therapy, which can include inositol given its benign adverse

reaction profile. Presently, the debilitating neurological signs on presentation

are often the initial prognosticators of AD. By this time, however, the damage

that has occurred is usually severe and untreatable. Physicians may opt to

include inositol in addition to one of the other agents for AD before

neurological deterioration is severe.

 

Post Traumatic Stress Disorder (PTSD): PTSD is a pathological reaction to a

psychologically traumatic experience. Symptoms may be acute or delayed, and are

characterized by nightmares and flashbacks where the event is re-experienced.

 

Resistance to drug therapy may best be explained by Adamac who reported the

traumatic event may actually produce a " photograph " of the occurrence in the

CNS. This permanent emotional memory may be triggered exogenously and the event

is relived continually upon exposure to agonists.43

 

Only about 50 percent of PSTD patients reported significant improvement in

depressive symptoms at one month when compliant with medications. SSRIs produced

better outcomes than norepinephrine inhibitors.

 

In 1996 the effects of inositol in patients suffering from PSTD were evaluated

by Kaplan et al. Patients were given 12 grams daily or placebo for four weeks,

then crossed over into the other study group for an additional four weeks. There

were no significant differences in improvement between the treated group as

compared to the placebo group.44

 

Autism: The use of inositol at 200 mg/kg was evaluated in nine children for the

treatment of autism.45 The investigators concluded there was benefit for its use

in this patient population. Studies on a larger population seem warranted.

 

Respiratory Distress Syndrome Disorder (RDSD): One of the oldest documented uses

of inositol is for use in neonatal RDSD.46 It is known that inositol

administration to immature animals increases pulmonary surfactant levels.

Administration of inositol at 80 mg/kg parenterally to premature infants may

decrease the likelihood of respiratory distress syndrome. Hallman et al

concluded parenteral inositol therapy during the early neonatal period may also

decrease the incidence of severe, chronic injury of the retina.47

 

Analgesia: Given the success of inositol for some central nervous system

disorders, its use for pain control was recently evaluated. Tarnow et al

reported an analgesic effect for inositol-1,2,6-triphosphate in a double-blind,

randomized study of 24 patients undergoing cholecystectomy.48 Opioid analgesia

requirements were significantly reduced when patients received a bolus inositol

dose of 240 mg followed by 90 mg/hr for 24 hours. There were no side-effects

reported with the bolus or maintenance infusions.

 

The analgesic relationship between inositol and pain was also investigated by

Raffa et al who reported the phosphoinositide pathway may play an important role

in opioid efficacy and in the development of morphine tolerance.49

 

The recent work of Ferrara et al proposed an anti-edematous action of

alpha-trinositol when used to treat canine scald injuries, reportedly through a

decrease of the transmembrane flux.50

 

Lithium-Induced Adverse Reactions: It is believed lithium inhibits inositol

monophosphatase which in turn depletes brain stores of inositol. In fact, this

may be the mechanism for lithium's effectiveness in treating manic-depressive

disorder.

 

Concern is therefore warranted over the concept of treating lithium induced

side-effects with inositol, since administration of inositol may cause the

concentration of inositol to rise and subsequently reintroduce manic or

depressive episodes. However, the exogenous administration of inositol does not

appear to alter the manic-depressive control at all.

 

It is theorized inositol derived from inositol phosphate breakdown is recycled

for use in membranous phosphatidylinositol. Hyperactivated systems would be

affected by lithium's depletion of the recyclable inositol pool, whereas

isosystems would not be affected.51 A similar finding was reported by Berridge

et al who concluded lithium inhibits phosphoinositide derived second messengers

of activated systems only.52

 

Johnson et al concluded inositol depletion induced by lithium can be bypassed by

introduction of exogenous inositol.53 They administered inositol at 1500 mg

daily (500 mg three times daily) to 11 patients who experienced

polyuria-polydipsia as a result of lithium treatment. Forty-five percent of the

patients experienced dramatic improvement in polyuria-polydipsia complaints;

another 36 percent reported mild improvement. This improvement may be more

related to the osmoregulatory effect of inositol than its function as a second

messenger. Improvement was also noted in lithium-induced psoriasis.

 

 

 

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Possible Clinical Contraindications for Inositol Supplementation

 

Attention Deficit Hyperactivity Disorder (ADHD): ADHD is a disorder of early

childhood which can be symptomatic well into adulthood. These patients are

inattentive, impulsive, quick-tempered, unable to tolerate stress, and are

restless since childhood. ADHD is most commonly treated with methylphenidate,

but propranolol and tricyclic antidepressants are also alternatives.

 

Evaluation of inositol in 11 children with attention deficit hyperactivity

disorder was reported in 1995 by Levine et al in a double-blind, crossover

study.54 There were no therapeutic advantages observed in the inositol group. In

fact, there was a trend toward the worsening of the disorder in the inositol

treated group. Therefore, inositol appears to have no clinical advantages for

the treatment of ADHD and may even antagonize the condition.

 

Schizophrenia: Schizophrenia accounts for 7-20 percent of all psychiatric

hospital admissions. It is estimated that 0.5-1.0 percent of the worldwide

population will experience a schizophrenic episode at some point in life.

Schizophrenia usually begins in adolescence and early childhood, only rarely

beginning before adolescence or after the age of 40. It affects the sexes

equally and usually becomes more pronounced at approximately age 20. Males tend

to have an earlier onset than females (15-24 years versus 25-34 years,

respectively).

 

The most accepted and well-supported biochemical etiology for the development of

schizophrenia involves the neurotransmitter, dopamine. It is believed excessive

concentrations of dopamine may induce psychotic/schizophrenic episodes.

 

Although anti-psychotics drugs are effective in treating the disorder, the

adverse reactions associated with them can be severe. The side-effects can range

from Parkinsonian-like symptoms to anticholinergic effects (dry mouth,

constipation, urinary retention, drowsiness, etc) depending on the

pharmacological class of the agent. Therefore, noncompliance with anti-psychotic

medications is a pivotal problem for patients and caregivers.

 

In 1993, Levine et al performed the first study utilizing inositol as an agent

for schizophrenia. This study found no significant benefit of inositol

supplementation.55,56 However, the authors concluded the dose of six grams daily

was probably not sufficient to produce a significant clinical effect. Large

exogenous doses are usually required since inositol absorption from the

periphery into the CNS is poor. In addition, losses of seven to eight grams

daily can result from degradation by renal enzymes.57

 

Another theory for the lack of efficacy of inositol may be explained by the

recent work of Jope et al who reported schizophrenia may be associated with an

increased, rather than decreased, activity of the phosphoinositol signaling

system.58 Therefore, it may be contra-indicated in schizophrenia.

 

Pregnancy: Inositol may stimulate uterine contractions. Oxytocin is a potent

uterine stimulator whose clinical use in labor and delivery is well documented.

Phaneuf et al reported oxytocin's clinical effectiveness is due to the

activation of phospholipase C to produce inositol-1,4,5-triphosphate which

releases calcium from intracellular stores and stimulates uterine

contractions.59 The activation of the phosphatidylinositol signaling system by

calcium agonists is also supported by the work of Chien et al who noted

dose-related myometrial contractions when laboratory mice were injected with a

calcium agonist.60

 

Reece et al reported inositol supplementation of 0.08 mg/kg/day significantly

decreased embryonic neural tube defects from 20.4 percent to 9.5 percent in

diabetic rats. They concluded the incidence of diabetic embryopathy and

congenital malformations may be reduced by supplementation with inositol.61

Similarly, Greene et al stated about 30 percent of all neural tube defects are

resistant to supplementation with folic acid alone. However, addition of

inositol significantly decreased the incidence of spinal neural tube defects in

mice by increasing protein kinase activity and delaying the closure of the

neuropore. They concluded that combination therapy of folic acid and inositol

may prevent neural tube defects like spina bifida in humans.62 Therefore, while

inositol may prevent neural tube defects, its use during pregnancy may be

contraindicated due to the potential for uterine stimulation.

 

 

 

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Conclusion

 

Propelled by incredible advances in the understanding of the pathological

etiologies and characteristics of psychiatric disorders, prospects for treatment

have brightened considerably in the last 10 years. It is known that a change in

the CNS concentration of inositol may lead to modified brain cell signaling

pathways, and possibly to the development of a psychiatric disorder. Recent

evidence indicates inositol has psychoactive effects by interacting with the

second messenger system and ulti-mately regulating the cytosolic concentration

of calcium.

 

The signaling by calcium is known to mediate an array of cellular functions

(secretion, contraction, and conduction). Due to the role calcium plays, its

regulation intracellularly is known to be a complex phenomenon involving a

number of active and passive transport systems. Inositol is now established as a

significant mediator of calcium mobilization in the endoplasmic reticulum.

Modifying this mobilization of calcium may be effective in treating some CNS

disorders like Alzheimer's disease, depression, panic disorder, obsessive

compulsive disorder, and as an analgesic for pain control. Likewise, its use to

alleviate lithium-induced adverse reactions is also promising.

 

The benefit of inositol therapy in post traumatic stress disorder and autism has

yet to be established. To date most studies have been characteristically small

in number. In addition, studies have not consistently approached rea-listic

doses of inositol for therapeutic effect to be evaluated. There is a need for

additional studies to be performed utilizing large numbers of patients and

increased supplemental doses of inositol.

 

At this time inositol supplementation for the treatment of schizophrenia and

attention deficit hyperactivity disorder is not believed to be effective. In

fact, it may be contraindicated as it might exacerbate these conditions. The

risk of premature labor induction versus benefit for prevention of embryonic

defects should be considered thoroughly before initiation of inositol therapy

during pregnancy.

 

As new clinical studies involving inositol are concluded and the research is

evaluated, the understanding of inositol's role in intracellular and

extracellular signaling may provide even better insight into the therapeutic

applications of inositol and inositol-based products.

 

 

 

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