a review of the possible relevance of inositol and the phosphatidylinositol second messenger system...
TRANSCRIPT
human psychopharmacology
Hum Psychopharmacol Clin Exp 2005; 20: 309–326.
Published online 6 May 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hup.693
REVIEW ARTICLE
A review of the possible relevance of inositol and thephosphatidylinositol second messenger system (PI-cycle)to psychiatric disorders—focus on magnetic resonancespectroscopy (MRS) studies
Hyeonjin Kim1, Brent M. McGrath2 and Peter H. Silverstone2*
1Department of Biomedical Engineering, University of Alberta, Edmonton, Alberta, Canada2Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada
Myo-inositol is an important part of the phosphatidylinositol second messenger system (PI-cycle). Abnormalities in nervecell myo-inositol levels and/or PI-cycle regulation has been suggested as being involved in the pathophysiology and/or treat-ment of many psychiatric disorders including bipolar disorder, major depressive disorder, panic disorder, obsessive-compul-sive disorder, eating disorders and schizophrenia. This review examines the metabolism and biochemical importance ofmyo-inositol and the PI-cycle. It relates this to the current in vivo evidence for myo-inositol and PI-cycle involvement inthese psychiatric disorders, particularly focusing upon the magnetic resonance spectroscopy (MRS) findings in patient stu-dies to date. From this review it is concluded that while the evidence suggests probable relevance to the pathophysiologyand/or treatment of bipolar disorder, there is much less support for a significant role for the PI-cycle or myo-inositol in anyother psychiatric disorder. More definitive investigation is required before PI-cycle dysfunction can be considered specific tobipolar disorder. Copyright # 2005 John Wiley & Sons, Ltd.
key words— myo-inositol; magnetic resonance spectroscopy; bipolar disorder; major depressive disorder; panic disorder;anxiety; obsessive-compulsive disorder; anorexia nervosa; bulimia nervosa; schizophrenia
INTRODUCTION
Understanding the neurochemical underpinnings ofpsychiatric disorders remains a goal not yet clearlyattained for any psychiatric disorder, although currentprogress often involves psychopharmacologically dri-ven hypotheses (Rudnick, 2002). Given the complex-ity of neuronal functioning, it is not surprising thatnumerous abnormalities in neurotransmitter systemshave been reported for most psychiatric disorders.
However, signal transduction pathways (or secondmessenger systems) may be of particular relevancesince they are in a pivotal position in the central ner-vous system (CNS); forming complex signaling net-works that allow neurons to receive, process andrespond to information (Bhalla and Iyengar, 1999).In this way, signal transduction pathways are able toaffect the functional balance between multiple neuro-transmitter systems, thus playing an integral role inmediating neuronal signaling and downstream cellularresponse (Manji and Lenox, 2000).
Among the signal transduction pathways currentlywell understood, the phosphatidylinositol secondmessenger system (PI-cycle) has been reported to bealtered in several psychiatric disorders. The purposeof this review is to examine the evidence thatalterations in the chemistry, the regulation and thesynthesis of PI-cycle constituents—most notably
Received 8 October 2004
Copyright # 2005 John Wiley & Sons, Ltd. Accepted 22 March 2005
* Correspondence to: Professor P. H. Silverstone, Departments ofPsychiatry and Neuroscience, University of Alberta, 1E1.07Mackenzie Center, 8440-112 Street, Edmonton, AB, Canada, T6G2B7. Tel: þ1-(780) 407-6576. Fax: þ1-(780) 407-6672.E-mail: [email protected]
Contract/grant sponsors: Canadian Institutes of Health Research;Alberta Heritage Foundation for Medical Research.
myo-inositol—are involved in the pathophysiologyand/or treatment of specific psychiatric disorders,including mood disorders, anxiety disorders and schi-zophrenia. Suggested involvement of the PI-cycle inthese disorders comes from animal studies (Einatand Belmaker, 2001) as well as human volunteerand patient studies (Colodny and Hoffman, 1998).The best method for measuring the activity of thePI-cycle in vivo is by using magnetic resonance spec-troscopy (MRS). This is because myo-inositol can bemeasured directly with 1H-MRS (Figure 3) and inosi-tol monophosphates can be measured indirectly with31P-MRS where it is contained within the phosphomo-noester (PME) peak (Figure 4). In several conditionsMRS evidence is available and when present this isreviewed in detail.
MYO-INOSITOL AND THE PI-CYCLE
A growing body of evidence suggests that alterationsin brain myo-inositol may be associated with psychia-tric disorders such as bipolar disorder (Gould et al.,2004) and schizophrenia (Sharma et al., 1992), andto a lesser extent with neurological diseases such asAlzheimer’s disease (Birchall and Chappell, 1988)and hepatic encephalopathy (Tarasow et al., 2003).In order to understand how abnormalities in brainmyo-inositol could be involved in such conditions, itis important to have some understanding of its rolein the CNS.
Inositol, a simple isomer of glucose, is an importantdietary and cellular constituent (Colodny and Hoffman,1998). First isolated from muscle (Cantarow andSchepartz, 1962; Doisy, 1967), this ubiquitous, cycliccarbohydrate has a 6-carbon ring structure and can befound in any one of nine isomeric compositions, ofwhich myo-inositol is the most abundant biologicallyactive stereoisomer in the CNS (Ross, 1991; Freyet al., 1998). Myo-inositol is unique among the inosi-tol isomers, in that it has a single axial hydroxyl groupat carbon 2 (Figure 1) (Vandal, 1997), is an importantgrowth factor for human cells (Holub, 1982; Ross,1991), is an important non-nitrogenous CNS osmolyte(Thurston et al., 1989), and is a precursor in the PI-cycle second messenger system (Berridge and Irvine,1989; Berridge et al., 1989).
In mammalian cells, a sustained supply of myo-inositol is required for the synthesis of membranephospholipids, continuation of PI-cycle activity andthe maintenance of intracellular free myo-inositollevels. It is synthesized in brain de novo from glu-cose-6-phosphate (G-6-P) (Holub, 1982), first intoinositol-1-monophosphate (IP1) by IP1 synthase, and
subsequently into myo-inositol by inositol monopho-sphatase (IMPase) (Figure 2). The highest concentra-tions are found in brain, stomach, kidney, intestine andliver (Cantarow and Shepartz, 1962; Horub, 1982;Sherman et al., 1985; Greil et al., 1991). Some ofthe total unbound myo-inositol in brain is synthesizedfrom glucose and the rest is transported from blood.Although the transfer rate is relatively low due tothe blood–brain barrier (Cantarow and Shepartz,1962; Holub, 1982; Berridge and Irvine, 1989; Isaackset al., 1994), the concentration of free myo-inositol inmammalian brain and cerebrospinal fluid (CSF) ishigher than in plasma (Holub, 1982; Greil et al.,1991). Nonetheless, in neurons the primary sourceof myo-inositol is from the recycling of PI-cycle con-stituents (Figure 2), with only about 3% of brain myo-inositol derived from plasma (Spector, 1998).
In neurons, the PI-cycle is activated followingligand binding with guanine nucleotide-binding(Gq)-protein coupled receptors, including adrenergic(�1A and �1B), serotonergic (5-HT1C and 5-HT2),dopaminergic (D1), glutaminergic (mGlu1 and mGlu5)and cholinergic (M1 and M3) receptor subtypes(Fisher et al., 1992) among others (Colodny andHoffman, 1998) (Figure 2). More specifically, ligandbinding to Gq-protein coupled receptors stimulatesphospholipase C (PLC)-mediated hydrolysis of phos-phatidylinositol 4,5-bisphosphate (PIP2) into the sec-ond messengers 1,2-diacylglycerol (DAG) andinositol 1,4,5-trisphosphate (IP3) (Atack, 2000).DAG and IP3 each, in turn, initiate separate cascadesof cellular events, including the activation of proteinkinase C (PKC) and mobilization of intracellular cal-cium (Ca2þ), respectively, each of which have multi-ple downstream cellular effects (Berridge and Irvine,1989; Berridge, 1997; Bootman et al., 2002). The sub-sequent metabolism of IP3 proceeds via two separatepathways; however, both converge on a single,
Figure 1. The molecular structure of myo-inositol. It has asymmetric ring structure with six carbons numbered sequentially
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common step—the dephosphorylation of the inositolmonophosphates (IP1) by IMPase to produce myo-ino-sitol (Figure 2). Myo-inositol is then utilized in theresynthesis of PI.
With respect to brain distribution, myo-inositol wasinitially found only in astrocytes and was not observedin the neuronal cells of rat brain when measured byproton- (1H-) and carbon- (13C-) magnetic resonancespectroscopy (MRS), suggesting that myo-inositolmay be a useful glial marker (Brand et al., 1993). Inthis study, less than 0.5 mM was observed in neuronalcells in comparison with �6 mM of total myo-inositolin brain. It has been suggested that myo-inositol maybe stored in glial cells before its consumption in thePI-cycle of neurons (Frey et al., 1998), and that astro-cytes may regulate extracellular myo-inositol concen-
trations (Wolfson et al., 2000). Regionally, nodifferences in myo-inositol concentrations werereported between grey and white matter (Petroffet al., 1989). Other studies have suggested that myo-inositol concentrations are highest in the hypothala-mus and lowest in the cortex (Lubrich et al., 1997).In a post-mortem study, cerebral myo-inositol levelswere found not to be affected by age or sex, or tochange across brain regions (Shimon et al., 1997).
Given the diversity of the receptors coupled tothe PI-cycle, combined with fact that the humanbrain obtains most of it’s myo-inositol supply fromresynthesis through the PI-cycle (Berridge et al.,1982; Sherman et al., 1985), alterations in myo-inosi-tol concentration and any resultant perturbation inPI-cycle functioning (Vaden et al., 2001) may affect
Figure 2. The PI second messenger system works as follows. An agonist (A) binds to a receptor complex, made up of a receptor (R),Gq-protein, and phospholipase C (PLC). Agonist binding leads to the PLC-catalysed breakdown of phosphatidylinositol 4,5-bisphosphate(PIP2) into inositol-1,4,5-trisphosphase (Ins[1,4,5]P3) and 1,2-diacylglycerol (DAG). Ins[1,4,5]P3 subsequently binds to specific receptorson the endoplasmic reticulum (ER) causing the release of stored intracellular calcium (Ca2þ). IP3 is sequentially broken down into inositolbisphosphates (IP2), inositol monophosphates (IP1) and finally, into myo-inositol. Myo-inositol can also be synthesized de novo fromglucose-6-phosphate (G-6-P), through an IP1 intermediate. The metabolism from IP1 to myo-inositol is catalysed by the enzyme inositolmonophosphatase (IMPase), which is uncompetitively inhibited by lithium (Liþ). Reduced levels of myo-inositol prevent the efficientresynthesis of PI from myo-inositol and cytidine monophosphorylphosphatidate (CMP-PA). The large dark circles show the location of eachphosphate molecule within each respective metabolic intermediate
pi cycle in psychiatric disorders 311
Copyright # 2005 John Wiley & Sons, Ltd. Hum Psychopharmacol Clin Exp 2005; 20: 309–326.
specific neuronal ganglia. As a result, these alterationsin myo-inositol metabolism could have widespreadeffects and therefore it is conceivable that changesin PI-cycle activity may underlie many psychiatricconditions. Supportive of these suggestions have been
animal findings that lithium, valproate and carbama-zepine can all alter PI-cycle functioning (O’Donnellet al., 2000; Williams et al., 2002). While lithiumhas been shown to inhibit the IMPase-driven break-down of IP1 to myo-inositol, it is not clear how othermood stabilizers influence inositol levels or alter PI-cycle functioning. One possibility points to the invol-vement of the high affinity myo-inositol transport sys-tem. In particular, it has been shown that lithium,valproate and carbamazepine all inhibit the uptakeof inositol in cultured astrocytes at therapeuticallyrelevant concentrations and with a time course applic-able to their clinical action (Lubrich and van Calker,1999). However, it is not clear how this relates to ino-sitol’s involvement in psychiatric illness, as the inhibi-tion is non-selective, occurring across several brainregions, including cortex, hippocampus, tegmentumand cerebellum.
EFFECTS OF INOSITOL ADMINISTRATION
The potential importance of PI-cycle functioning inpsychiatric disorders is evident when one considersthe number of receptor types/subtypes that interactwith this signal transduction pathway. As inositol isthe common precursor to all other PI-cycle constitu-ents (Figure 2), maintaining a stable intracellular con-centration may be important for symptom preventionand treatment in psychiatric disorders. As a result,several studies have investigated the effects of inositoladministration on brain inositol levels and on changesin psychiatric symptoms in several disorders. Inositoladministration has been reported to increase braininositol concentrations in both rats (Patishi et al.,1996; Kofman et al., 1998; Pettegrew et al., 2001),and humans (Moore et al., 1999); however, acutechanges may reverse with chronic administration(Moore et al., 1999; Pettegrew et al., 2001).
In animals, inositol administration has been shownto increase activity levels and reduce immobility timein animal models of depression (Einat et al., 2002,2001, 1999b), as well as reducing anxiety-like beha-viours in most (Cohen et al., 1997; Bersudsky et al.,1999; Kofman et al., 2000; Einat and Belmaker, 2001;Einat et al., 1998) but not all (Cohen et al., 1996)animal models of anxiety. Similar anxiolytic effectshave been reported following administration of epi-inositol, a non-naturally occurring stereoisomer ofmyo-inositol (Einat et al., 1998; Bersudsky et al.,1999). In humans, inositol administration has beenreported to improve depressive symptoms (assessedwith the Hamilton Depression Scale) after 4 weekscompared with placebo (Levine et al., 1995; Levine,
Figure 3. A 1H-MRS spectrum of the human brain at 3.0 T. Fordata acquisition, a stimulated echo sequence was used with thevoxel size of 2.5 cm3 localized in the occipital cortex. (1: creatine(methylene)þ phosphocreatine, 2: glutamateþ glutamine, 3: myo-inositolþ glycine, 4: taurine, 5: total choline compounds, 6:creatine (methyl)þ phosphocreatine, 7: N-acetylaspartate)
Figure 4. A 31P-MRS spectrum of the human brain at 3.0 T. Fordata acquisition, a 90�-pulse-acquire sequence was used incombination with 1D-image selected in vivo spectroscopy (ISIS)for a 20 cm slice selected from temporal lobe. (1: phosphomo-noesters, 2: inorganic phosphate, 3: phosphodiesters, 4: phospho-creatine, 5: �-ATP, 6: �-ATP, 7: �-ATP)
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1997). Similar improvements have been reported forpatients with panic disorder (Benjamin et al., 1995;Levine, 1997) and obsessive-compulsive disorder(Fux et al., 1996; Levine, 1997). Inositol administra-tion was shown not to effect cerebral spinal fluid(CSF) inositol monophosphatase activity in patientswith schizophrenia (Atack et al., 1998); moreover,apomorphine-induced stereotypy was not reversedfollowing acute inositol administration (Einat andBelmaker, 2001). Levine (1997) found no sympto-matic improvement following inositol treatment inpatients with schizophrenia and attention deficithyperactivity disorder. Furthermore, no improvementfollowing inositol treatment was observed in patientswith post-traumatic stress disorder (Kaplan et al.,1996).
It has been noted that this spectrum of the clinicalutility of inositol parallels that of the selective seroto-nin reuptake inhibitors (Levine, 1997; Einat andBelmaker, 2001); however, the evidence that this classof drugs acts via effects on PI-cycle functioningremains weak, even though 5-HT2 receptors are linkedto the PI-cycle signal transduction pathway (Levineet al., 1999). Moreover, inositol administration hasbeen reported not to alter brain monoamine concentra-tions (Einat et al., 1999a), suggesting that monoamineregulation per se is not its mode of action. Rather, ino-sitol may act through regulation of receptor density ormodulation of downstream cellular events, includinggene expression. Given the reported effects of inositoltreatment in animal models of psychiatric disordersand in patients themselves, the following sections willreview findings from studies that have assessed theeffect of treatment on inositol levels in several psy-chiatric disorders, particularly focusing on the in vivofindings from magnetic resonance spectroscopy(MRS) studies.
BIPOLAR DISORDER
Bipolar disorder (BPD) is characterized by periods ofdepression interspersed with (usually shorter) periodsof mania or hypomania (Thomas, 2004). Much of thework investigating the role of myo-inositol in psychia-tric disorders has focused on BPD. This followed ear-lier findings suggesting that lithium may be clinicallyeffective via its attenuation of myo-inositol produc-tion. This may follow its effect as an uncompetitiveinhibitor of IMPase (Allison et al., 1976; Allisonand Stewart, 1971; Berridge et al., 1982), the enzymeresponsible for breaking down inositol monopho-sphates into myo-inositol (Figure 2). This uncompeti-tive inhibition implies the involvement of an
overactive PI-cycle turnover in bipolar symptomatol-ogy, detectable by increased levels of PI-cycle consti-tuents, including myo-inositol. Table 1 summarizesthe MRS findings for inositol in bipolar disorder todate. For a more detailed review of the findings inbipolar disorder the reader is referred to Silverstoneet al. (2005).
Bipolar depressed patients
In a study of unmedicated BPD bipolar and unipolarpatients, Frey and associates (1998) reported reducedmyo-inositol concentrations in the frontal lobes ofpatients compared with healthy controls, although thisfinding was significant only when the groups werepaired by age.
In a well-conducted study by Moore and colleagues(1999) in which absolute metabolite concentrationswere measured, a reduction of myo-inositol concen-trations were reported in the frontal lobe of medicateddepressed BPD patients, but not in the occipital, par-ietal or temporal regions, following both acute (5–7days) and chronic (3–4 weeks) lithium treatment. Ina separate study, no difference in myo-inositol concen-trations were reported for the anterior cingulate cortexbetween depressed BPD patients and healthy controls(Moore et al., 2000) and in the dorsolateral prefrontalcortex of healthy controls following lithium treatment(Brambilla et al., 2004). Recent studies failed to findany differences between regional white matter myo-inositol concentrations between drug-free depressedand mixed-mood BPD patients and healthy controls(Dager et al., 2004), and in grey matter amonglithium-treated BPD patients, but not valproate-trea-ted BPD patients (Friedman et al., 2004), relative tohealthy controls. In a series of studies Kato andassociates (1992) also reported higher PME concen-trations in the frontal lobe of lithium-treateddepressed BPD patients compared with both euthymicpatients and healthy controls (Kato et al., 1992,1994b, 1995).
The findings from most of these studies would beconsistent with a reduction in myo-inositol concentra-tions and an increase in inositol monophosphatesconcentrations.
Manic or hypomanic patients
In a study examining patients before and after lithiumtreatment, there was a trend at baseline towards highermyo-inositol concentrations in the anterior cingulatecortex of manic BPD children compared with healthycontrols (Davanzo et al., 2001). Following 7 days
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—"a
nte
rior
cingula
teco
rtex
mI
inm
anic
or
mix
edB
PD
Ipat
ients
com
par
edw
ith
hea
lthy
contr
ols
Dru
gfr
eech
ildre
n—
$an
teri
or
cingula
ted
cort
exm
Ibet
wee
nm
anic
or
mix
edB
PD
Ipat
ients
and
hea
lthy
contr
ols
Chan
get
al.
,2003
3T
1H
-MR
SP
RE
SS
15
—$
DL
PF
Cm
Ibet
wee
nfa
mil
ial
euth
ym
icB
PD
Ipat
ients
and
hea
lthy
contr
ols
Chil
dre
nvar
ious
med
icat
ions
Fri
edm
anet
al.
,2004
1.5
T1H
-MR
SP
EP
SI
21
—"g
rey
mat
ter
mI
inli
thiu
m-t
reat
ed
BP
Dpat
ients
com
par
edw
ith
hea
lthy
contr
ols
Post
-lit
hiu
mor
—$
gre
ym
atte
rm
Ibet
wee
nli
thiu
man
dval
pro
ate-
trea
ted
BP
Dpat
ients
val
pro
ate
—$
gre
ym
atte
rm
Ibet
wee
nval
pro
ate-
trea
ted
BP
Dpat
ients
and
hea
lthy
contr
ols
Bra
mbil
laet
al.
,2004
1.5
T1H
-MR
SS
TE
AM
12
—$
left
and
right
DL
PF
Cm
Iin
hea
lthy
volu
nte
ers
foll
ow
ing
4w
eeks
of
lith
ium
trea
tmen
tP
ost
-lit
hiu
mD
ager
etal.
,2004
1.5
T1H
-MR
SP
EP
SI
32
—$
regio
nal
mI
bet
wee
ndep
ress
edor
mix
ed-m
ood
BP
DI
and
BP
DII
pat
ients
and
hea
lthy
contr
ols
Dru
gfr
ee—
$w
hit
em
atte
rm
Ibet
wee
ndep
ress
edor
mix
ed-m
ood
BP
DI
and
BP
DII
pat
ients
and
hea
lthy
contr
ols
Ham
akaw
aet
al.
,2004
1.5
T3
1P
-MR
SD
RE
SS
13
—$
bas
algan
gli
aP
ME
and
PD
Ebet
wee
neu
thym
icB
PD
pat
ients
and
hea
lthy
contr
ols
Var
ious
med
icat
ions
aT
he
sam
ple
size
rep
rese
nts
the
nu
mb
ero
fp
atie
nts
inea
chst
ud
y.m
I,m
yo
-in
osi
tol;
PM
E,
ph
osp
ho
mon
oes
ters
;P
DE
,p
ho
sph
odie
ster
s;D
LP
FC
,d
ors
ola
tera
lp
refr
on
tal
cort
ex;
ISIS
,im
age-
sele
cted
invivo
spec
trosc
opy;
L-C
OS
Y,
two-d
imen
sional
loca
lize
dch
emic
alsh
ift
corr
elat
edsp
ectr
osc
opy;
PE
PS
I,photo
nec
ho-p
lanar
spec
trosc
opic
imag
ing;
PR
ES
S,poin
t-re
solv
edsp
ectr
osc
opy;
ST
EA
M,st
imu
late
dec
ho
acqu
isit
ion
mod
e.
314 h. kim ET AL.
Copyright # 2005 John Wiley & Sons, Ltd. Hum Psychopharmacol Clin Exp 2005; 20: 309–326.
lithium treatment, myo-inositol concentrations in theanterior cingulate cortex were significantly reducedin the manic children compared with the healthy con-trols. In a follow-up study the same group reportedincreased myo-inositol concentrations in the anteriorcingulate cortex of manic BPD children comparedwith healthy controls, thus confirming the trendobserved in their early study (Davanzo et al., 2003).
Reduced myo-inositol was observed in the basalganglia of four lithium-treated manic BPD patients,while no difference was observed for occipital cortexwhen compared with healthy controls (Sharma et al.,1992). In three studies one group found higher PMEconcentrations in the frontal lobe of lithium-treatedmanic and hypomanic BPD patients compared witheuthymic bipolar patients and healthy controls (Katoet al., 1991, 1993, 1994b). However, this findingwas not supported in a subsequent study carried outby the same group (Kato et al., 1995). A study ofmanic and mixed BPD patients, most of who werereceiving sodium valproate in addition to other medi-cations found no differences in frontal lobe myo-ino-sitol concentrations when compared with healthycontrols (Cecil et al., 2002).
These findings overall may suggest that there maybe both raised myo-inositol and inositol monopho-sphates concentrations in manic and hypomanicpatients, possibly normalizing with treatment. How-ever, not all studies have been consistent with thissuggestion.
Euthymic patients
Most studies have suggested that euthymic patients,whether treated or not, appear to have normal myo-inositol and inositol monophosphates concentrations,although some studies have found these reduced.Thus, using 1H-MRS, no differences in frontal lobemyo-inositol concentrations were observed betweenunmedicated euthymic BPD patients (n¼ 20) andhealthy controls (Winsberg et al., 2000). Anotherstudy found no difference in PME concentrations inthe frontal lobe of unmedicated euthymic BPDpatients when compared with healthy controls (Katoet al., 1998). In contrast, however, two 31P-MRS stu-dies reported significantly lower PME concentrationsin the frontal (Deicken et al., 1995a) and temporal(Deicken et al., 1995b) lobes of unmedicated, euthy-mic BPD patients compared with healthy controls.
Among medicated euthymic BPD patients, two 1H-MRS studies reported no changes in myo-inositol con-centrations in treated bipolar patients (Bruhn et al.,1993; Chang et al., 2003). Several studies utilizing
31P MRS suggest that euthymic BPD patients on treat-ment have PME concentrations that are not signifi-cantly different from healthy controls (Kato et al.,1994b, 1995; Murashita et al., 2000; Silverstoneet al., 2002; Hamakawa et al., 2004), although otherstudies did find reduced concentrations (Kato et al.,1993, 1994a).
MAJOR DEPRESSIVE DISORDER
It is conceivable that the PI-cycle may be involved insome aspects of major depressive disorder (MDD),since platelets from MDD patients have increasedIP3 binding sites (Dwivedi et al., 1998) as well asincreased IP1 (Mikuni et al., 1991; Pandey et al.,2001) and IP3 (Alvarez et al., 1999) concentrations.Moreover, treatment with antidepressants appears tonormalize increased IP3 concentrations in respondersonly (Alvarez et al., 1999). While not as extensivelystudied as bipolar disorder, several MRS studies haveinvestigated inositol, and these are summarized inTable 2. In a study of unmedicated MDD patients,Kumar and associates (2002) reported increasedmyo-inositol concentrations in frontal white matter.Wyckoff and colleagues (2003) also reportedincreased myo-inositol concentrations in the left dor-solateral white matter of unmedicated late-life MDDpatients. Moreover, a recent study correlated theincrease in left dorsolateral prefrontal cortex myo-inositol with increased cognitive function in healthyvolunteers by not in late-life MDD patients (Elderkin-Thompson et al., 2004). In contrast, in a similarstudies, no differences in frontal lobe myo-inositolconcentrations were found between unmedicatedMDD patients and healthy controls (Gruber et al.,2003a; Binesh et al., 2004). In another 1H-MRS study,(Coupland et al., in press) reduced dorsomedial pre-frontal cortex myo-inositol was found in 13 unmedi-cated MDD patients, with similar findings reportedin the anterior cingulate cortex as well (Rosenberget al., 2004).
In medicated MDD patients, no differences in fron-tal lobe myo-inositol concentrations were found whencompared with healthy controls (Frey et al., 1998);however, among MDD patients on antidepressanttreatment, reduced myo-inositol levels were reportedfor the right frontal lobe (Frey et al., 1998). In a sepa-rate study, no differences in myo-inositol concentra-tions were reported for the anterior cingulate gyrusand parietal white matter between MDD patientsand healthy controls (Auer et al., 2000). Studiesexamining changes in PME concentrations in the fron-tal lobe of medicated MDD patients have also been
pi cycle in psychiatric disorders 315
Copyright # 2005 John Wiley & Sons, Ltd. Hum Psychopharmacol Clin Exp 2005; 20: 309–326.
Tab
le2
.M
RS
fin
din
gs
tod
ate
inm
ajo
rd
epre
ssiv
ed
iso
rder
Stu
dy
Tec
hn
iqu
eN
aF
ind
ing
sN
ote
s
Kat
oet
al.
,1
99
21
.5T
31P
-MR
SD
RE
SS
12
—"f
ron
tal
lob
eP
ME
ind
epre
ssed
MD
Dp
atie
nts
com
par
edw
ith
euth
ym
icB
PD
pat
ien
tsV
ario
us
—$
fron
tal
lob
eP
ME
and
PD
Eb
etw
een
dep
ress
edM
DD
pat
ien
tsan
deu
thy
mic
MD
Dp
atie
nts
and
hea
lth
yco
ntr
ols
med
icat
ions
Mo
ore
etal.
,1
99
71
.5T
31P
-MR
SIS
IS3
5—
$b
asal
gan
gli
aP
ME
and
PD
Eb
etw
een
dep
ress
edM
DD
pat
ien
tsan
dh
ealt
hy
con
tro
lsD
rug
free
Fre
yet
al.
,1
99
81
.5T
1H
-MR
SS
TE
AM
22
—#r
igh
tfr
on
tal
lobe
mI
ind
epre
ssed
MD
Dp
atie
nts
com
par
edw
ith
hea
lth
yco
ntr
ols
Var
iou
s—
$le
ftfr
on
tal
lobe
mI
bet
wee
nd
epre
ssed
MD
Dp
atie
nts
and
hea
lth
yco
ntr
ols
med
icat
ions
Vo
lzet
al.
,1
99
81
.5T
31P
-MR
SIS
IS1
4—
"fro
nta
llo
be
PM
Ein
dep
ress
edM
DD
pat
ien
tsco
mp
ared
wit
hh
ealt
hy
con
tro
lsIn
-pat
ien
tsvar
iou
s—
Per
centa
ge
of
fronta
llo
be
PM
Ein
dep
ress
edM
DD
pat
ients
was
neg
ativ
ely
corr
elat
edw
ith
deg
ree
of
dep
ress
ion
med
icat
ions
Au
eret
al.
,2
00
01
.5T
1H
-MR
SP
RE
SS
19
—$
ante
rior
cingula
teco
rtex
mI
bet
wee
ndep
ress
edM
DD
pat
ients
and
hea
lthy
contr
ols
Var
ious
med
icat
ions
—$
par
ieta
llo
be
wh
ite
mat
ter
mI
bet
wee
nd
epre
ssed
MD
Dp
atie
nts
and
hea
lth
yco
ntr
ols
Ku
mar
etal.
,2
00
21
.5T
1H
-MR
SP
RE
SS
20
—"l
eft
DL
PF
Cw
hit
em
atte
rm
Iin
dep
ress
edM
DD
pat
ien
tsco
mp
ared
wit
hh
ealt
hy
con
tro
lsE
lder
lyd
rug
free
—$
ante
rio
rci
ngu
late
gre
ym
atte
rm
Ib
etw
een
dep
ress
edM
DD
pat
ien
tsan
dh
ealt
hy
con
tro
lsW
yck
offet
al.
,2
00
31
.5T
1H
-MR
SP
RE
SS
8—
"lef
tD
LP
FC
wh
ite
mat
ter
mI
corr
elat
edw
ith
dec
reas
edm
agn
etiz
atio
ntr
ansf
erra
tio
sin
dep
ress
edM
DD
pat
ien
tsbu
tn
ot
inh
ealt
hy
con
tro
lsE
lder
lyd
rug
free
—N
osu
chas
soci
atio
ns
wer
efo
un
din
ante
rio
rci
ng
ula
teg
rey
mat
ter
Gru
ber
etal.
,2
00
3a
3T
1H
-MR
SS
TE
AM
17
—#p
refr
on
tal
cort
exw
hit
em
atte
rm
Iin
dep
ress
edM
DD
pat
ien
tsco
mp
ared
wit
hh
ealt
hy
con
trols
Dru
gfr
ee
Ro
sen
ber
get
al.
,2
00
41
.5T
1H
-MR
SP
RE
SS
14
—$
ante
rio
rci
ngu
late
cort
exm
Ib
etw
een
MD
Dp
atie
nts
and
OC
Dp
atie
nts
and
hea
lth
yco
ntr
ols
Dru
gn
aı̈ve
Bin
eshet
al.
,2
00
41
.5T
1H
-MR
SL
-CO
SY
15
—$
pre
fro
nta
lco
rtex
wh
ite
mat
ter
mI
bet
wee
nd
epre
ssed
MD
Dp
atie
nts
and
hea
lth
yco
ntr
ols
Eld
erly
dru
gfr
eeE
lder
kin
-T
ho
mpso
net
al.
,2
00
4
1.5
T1H
-MR
SL
-CO
SY
14
—"l
eft
DL
PF
Cm
Ico
rrel
ated
wit
hin
crea
sed
cog
nit
ive
fun
ctio
nin
hea
lth
yco
ntr
ols
bu
tn
ot
ind
epre
ssed
MD
Dp
atie
nts
Eld
erly
dru
gfr
ee
—C
han
ge
inle
ftD
LP
FC
mI
did
no
tre
late
wit
hch
ang
esin
lear
nin
g,
reca
ll,
reco
gn
itio
n,
exec
uti
ve
fun
ctio
n,
hy
po
thes
isg
ener
atio
n,
or
pro
cess
ing
spee
dC
ou
pla
ndet
al.
,in
pre
ss3
T1H
-MR
SS
TE
AM
13
—#d
ors
alm
edia
lp
refr
on
tal
cort
exm
Iin
MD
Dp
atie
nts
com
par
edw
ith
hea
lth
yco
ntr
ols
Dru
gfr
ee
aT
he
sam
ple
size
repre
sents
the
num
ber
of
pat
ients
inea
chst
udy.
mI,
myo
-in
osi
tol;
PM
E,
ph
osp
ho
mon
oes
ters
;P
DE
,p
ho
sph
odie
ster
s;D
LP
FC
,d
ors
ola
tera
lp
refr
on
tal
cort
ex;
DR
ES
S,d
epth
-res
olv
edsu
rfac
esp
ectr
osc
opy;
L-C
OS
Y,tw
o-d
imen
sional
loca
lize
dch
emic
alsh
ift
corr
elat
edsp
ectr
osc
opy;
PR
ES
S,
poin
t-re
solv
edsp
ectr
osc
opy;
ST
EA
M,
stim
ula
ted
echo
acquis
itio
nm
ode.
316 h. kim ET AL.
Copyright # 2005 John Wiley & Sons, Ltd. Hum Psychopharmacol Clin Exp 2005; 20: 309–326.
mixed, with two studies showing no changes (Katoet al., 1992; Moore et al., 1997) while one studyreported an increase in PME concentrations (Volzet al., 1998) between patients and healthy controls.
Treatment studies with inositol have also beenmixed. While one double-blind placebo-controlledstudy in 28 MDD patients showed that 4 weeks of ino-sitol (12 g/day) could increase mood compared withplacebo (Levine et al., 1995), addition of inositol toexisting treatment does not appear to increase efficacy(Levine et al., 1999; Nemets et al., 1999). In a relateddisorder, pre-menstrual dysphoric disorder, inositolhas no beneficial effects (Nemets et al., 2002). Takentogether these findings do not suggest consistentchanges in PI-cycle activity in MDD patients, on oroff medications. Moreover, the possible role of inosi-tol in the treatment of MDD must remain experimen-tal at present.
ANXIETY
Anxiety disorders are one of the most prevalent psy-chiatric disorders, afflicting upwards of one-fourthof the general population over their lifetime (Kessleret al., 1994). Human anxiety is often characterizedwithin two broad forms, acute and chronic. Acuteanxiety, or panic, is characterized by its out-of-the-blue onset, while chronic anxiety often involvesapprehensiveness, excessive worry and physicalsymptoms, including the development of stomachulcers (Battaglia and Ogliari, 2005). While the preciseaetiology is unknown, Table 3 reviews the MRS find-ings for involvement of myo-inositol.
Panic and phobia
Panic disorder (PD) is a chronic, disabling condition(Doyle and Pollack, 2004), often associated with thefalse belief that symptoms of normal physiologicalarousal, such as increased heart rate, sweating or diz-ziness are signs of impending heart attacks or of losingcontrol (Clark et al., 1997). To date there have been nopublished 1H-MRS studies examining myo-inositol inPD patients. However, one study has examinedpatients with chronic back pain and found that myo-inositol concentrations in those with higher anxietylevels were no different from those with lower anxietylevels (Grachev et al., 2002a). The same group exam-ined a patient who developed anxiety following abrain hematoma and reported reduced myo-inositolconcentrations in the left orbital-frontal cortex(Grachev et al., 2002b). In a group of social phobiapatients, myo-inositol concentrations were reported
to be increased in both cortical and subcortical greymatter (Tupler et al., 1997), but no such differenceswere found in a similar group in the anterior cingulateand occipital regions (Phan et al., 2005). In anotherstudy, utilizing 31P-MRS, no differences in frontallobe PME concentrations were found between medi-cated PD patients and healthy controls (Shioiri et al.,1996).
Healthy volunteers
In healthy volunteers, two studies by the same groupfound an association between increased orbital-frontalmyo-inositol concentrations and higher anxiety levels(Grachev and Apkarian, 2000), most notably in oldermale volunteers (Grachev and Apkarian, 2000). In aseparate volunteer study, acute administration of theanti-anxiety benzodiazepine, lorazepam, showed noeffect on left dorsolateral prefrontal myo-inositol con-centrations (Brambilla et al., 2002). While adminis-tration of inositol does not protect against meta-chlorophenylpiperazine (m-CPP)-induced panicattacks in volunteers (Benjamin et al., 1997), it hasshown efficacy in two small double-blind cross-overstudies in PD patients (Benjamin et al., 1995; Palatniket al., 2001). Taken together, the in vivo evidence todate is insufficient to draw any conclusions regardingPI-cycle involvement in PD or its treatment. Nonethe-less, the two small clinical studies of inositol treat-ment do warrant further examination in largerpopulations, by other research groups.
Obsessive-compulsive disorder
Obsessive–compulsive disorder (OCD) can be anincapacitating psychiatric disorder (Antony et al.,1998; Skoog and Skoog, 1999) and is characterizedby repetitive intrusive thoughts and compulsivetime-consuming behaviors (Aouizerate et al., 2004).
The MRS investigations of myo-inositol in OCDthat have been published, have consistently shownno differences between patients and controls, eitherwith treatment or in drug free states (Bartha et al.,1998; Rosenberg et al., 2000; Benazon et al., 2003;Rosenberg et al., 2004). Treatment studies havereported that inositol administration has little effecton stereotopic behaviors in guinea-pigs, while alsofailing to attenuate dextro-amphetamine inducedmotor changes (Harvey et al., 2001). Interestingly,this study did find that inositol administration doesincrease striatal dopamine (D2) receptor density. In areview of the neuromolecular aspects of OCD, theseauthors proposed that any clinical effects of inositol
pi cycle in psychiatric disorders 317
Copyright # 2005 John Wiley & Sons, Ltd. Hum Psychopharmacol Clin Exp 2005; 20: 309–326.
Tab
le3
.M
RS
fin
din
gs
tod
ate
inan
xie
ty
Stu
dy
Tec
hn
iqu
eN
aF
ind
ing
sN
ote
s
Panic
andphobia
Sh
ioir
iet
al.
,1
99
61
.5T
31P
-MR
SD
RE
SS
18
—$
fronta
llo
be
PM
Ean
dP
DE
bet
wee
np
anic
dis
ord
erpat
ients
and
hea
lthy
contr
ols
Var
ious
med
icat
ions
Tu
ple
ret
al.
,1
99
71
.5T
1H
-MR
SS
TE
AM
19
—"c
ort
ical
and
sub
cort
ical
gre
ym
atte
rm
Iin
soci
alp
ho
bia
pat
ien
tsco
mp
ared
wit
hh
ealt
hy
con
tro
lsD
rug
free
Gra
chev
etal.
,2
00
2b
1.5
T1H
-MR
SS
TE
AM
1—
#lef
to
rbit
alfr
on
tal
cort
exm
Iin
aan
xio
us
pat
ien
tw
ith
ale
ftp
ost
erio
rte
mpora
l-par
ieta
llo
be
hem
atom
aco
mpar
edw
ith
hea
lthy
contr
ols
Cas
est
ud
y
—$
rig
ht
orb
ital
fro
nta
lco
rtex
,D
LP
FC
,se
nso
rim
oto
rco
rtex
,th
alam
us,
insu
laan
dci
ngula
teco
rtex
mI
inan
anxio
us
pat
ient
wit
ha
left
post
erio
rte
mpora
l-par
ieta
llo
be
hem
ato
ma
com
par
edw
ith
hea
lth
yco
ntr
ols
Gra
chev
etal.
,2
00
2a
1.5
T1H
-MR
SS
TE
AM
12
—N
oas
soci
atio
nb
etw
een
DL
PF
C,
orb
ito
fro
nta
lco
rtex
,ci
ngu
late
cort
exan
dth
alam
us
mI
and
anx
iety
level
sin
chro
nic
low
erb
ack
pai
np
atie
nts
Var
ious
med
icat
ions
Ph
anet
al.
,2
00
54
T1H
-MR
SS
TE
AM
10
—$
ante
rio
rci
ng
ula
tean
do
ccip
ital
cort
exm
Ib
etw
een
gen
eral
ized
soci
alan
xie
typ
atie
nts
and
hea
lth
yco
ntr
ols
Dru
gn
aı̈ve
Healthyvolunteers
Gra
chev
and
Ap
kar
ian,
20
00
1.5
T1H
-MR
SS
TE
AM
16
—"l
eft
orb
ital
fron
tal
cort
exm
Iis
asso
ciat
edw
ith
hig
her
anx
iety
sco
res
on
the
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mb
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E,
ph
osp
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ters
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DE
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ho
sph
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PF
C,
do
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late
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nta
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;D
RE
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epth
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M,
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ula
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ech
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isit
ion
mo
de.
318 h. kim ET AL.
Copyright # 2005 John Wiley & Sons, Ltd. Hum Psychopharmacol Clin Exp 2005; 20: 309–326.
on obsessive-compulsive symptoms may be viaeffects on serotonin receptors linked to the PI-cycle(Harvey et al., 2002).
In a placebo-controlled crossover study of 13patients with OCD, findings suggested that inositolin doses up to 18 g/day could reduce symptoms (Fuxet al., 1996). Interestingly, a recent single photonemission computed tomography study correlatedreduced brain perfusion in the prefrontal cortex,temporal lobe and parietal cortex with clinicalresponse (Yale-Brown Obsessive-Compulsive Scalescore� 50% of baseline score) to 12 weeks of inositoltreatment (Carey et al., 2004). However, two otherstudies reported little overall improvement in sympto-matology when inositol was added to existing treat-ment (Fux et al., 1999; Seedat and Stein, 1999).From the data available to date, evidence does notsupport an in vivo neurochemical myo-inositol altera-tion, but may point to a neuromodulatory role for myo-inositol in the treatment of OCD. That said, theregions assessed with MRS in vivo, have not includedthe orbital frontal cortex, a region long consideredimportant in OCD (Baxter et al., 1988; Rauch et al.,1994; Breiter et al., 1996), and wherein inositol treat-ment may act to alleviate symptoms.
EATING DISORDERS
Both anorexia nervosa (AN) and bulimia nervosa(BN) are medical conditions complicated by multipleneuroendocrine dysfunctions, nutritional deficienciesand psychiatric diagnoses (Patrick, 2002). The patho-physiology underlying both AN and BN have yet to befully characterized (Roser et al., 1999), making
focused preventative and treatment actions difficult.Table 4 summarizes the MRS findings for inositolinvolvement in AN and BN.
A recent 1H-MRS study of 11 unmedicated femaleAN patients reported reduced dorsolateral prefrontalcortex myo-inositol relative to healthy controls, inver-sely correlating this reduction with duration of illness(Ohrmann et al., 2004). In an earlier 1H-MRS study of20 patients with AN or BN, reduced frontal white mat-ter myo-inositol concentrations were found in patientscompared with healthy controls, with those patientswith the lowest body mass index having the greatestreductions (Roser et al., 1999). Interestingly, no dif-ferences in myo-inositol concentrations were foundin the occipital grey matter, while increased myo-ino-sitol concentrations were reported for the cerebellum(Roser et al., 1999). No differences in parieto-occipi-tal myo-inositol concentrations were reported in aseparate study between AN patients and healthy con-trols (Hentschel et al., 1999). The reduced frontalwhite matter myo-inositol level may be the result ofhyponatremia (Videen et al., 1995; Alvin et al.,1993); however, the regional variations cannot beexplained in this manner. Moreover, it has been sug-gested that cerebral metabolic changes observed inpatients with AN can be reversed with treatment(Mockel et al., 1999). In this way, myo-inositol’s roleas a CNS osmolyte may be more important in the con-text of AN and BN than any primary pathophysiologi-cal role in the PI-cycle. In addition, a small double-blind crossover trial of inositol (18 g) versus placeboin 12 patients with BN, reported that inositol treat-ment is as effective in BN patients as it is in patientswith MDD, PD or OCD (Gelber et al., 2001). These
Table 4. MRS findings to date in eating disorders
Study Technique Na Findings Notes
Videen et al.,1995
1.5T 1H-MRSSTEAM
12 — # occipito-parietal grey matter mI in hyponatremiapatients compared with healthy controls
Elderly
Hentschel et al.,1999
15 — $ thalamus and occipito-parietal white matter mIbetween anorexia nervosa patients and healthy controls
Mockel et al.,1999
22 — $ thalamus and occipito-parietal lobe mI betweenanorexia nervosa patients and healthy controls
Pre/posttherapy
Roser et al.,1999
1.5T 1H-MRSSTEAM
20 — # frontal lobe white matter mI in anorexia and bulimianervosa patients compared with healthy controls
Females
— $ occipital grey matter and cerebellum mI betweenanorexia and bulimia nervosa patients and healthy controls
Ohrmann et al.,2004
1.5T 1H-MRSSTEAM
11 — # left DLPFC mI in anorexia nervosa patients comparedwith healthy controls
Femalesdrug free
— $ left anterior cingulate cortex mI between anorexianervosa patients and healthy controls
aThe sample size represents the number of patients in each study.mI, myo-inositol; DLPFC, dorsolateral prefrontal cortex; STEAM, stimulated echo acquisition mode.
pi cycle in psychiatric disorders 319
Copyright # 2005 John Wiley & Sons, Ltd. Hum Psychopharmacol Clin Exp 2005; 20: 309–326.
are interesting findings; however, more investigationand replication are required before definitive hypoth-eses can be formulated.
SCHIZOPHRENIA
Schizophrenia is a severe and incapacitating psychia-tric disorder. The disease usually presents itself inearly adulthood, and is characterized by a heteroge-neous group of symptoms, including positive (halluci-nations and delusions) and negative (flattened affectand apathy) symptoms, as well as cognitive andaffective deficits. Among psychiatric disorders, schi-zophrenia is the most disabling, requiring a dis-proportionate share of mental health resources(Mueser and McGurk, 2004). The in vivo MRS find-ings for inositol in schizophrenia are summarized inTable 5.
It has been suggested that antipsychotic medica-tions may be clinically effective via a dampeningaction on an overactive PI-cycle (Jope et al., 1998).Using 1H-MRS, increased concentrations of parietalmatter myo-inositol were reported in one study ofmedicated patients with schizophrenia (Auer et al.,2001), while no significant changes in myo-inositolconcentrations were observed in the prefrontal cortex,frontal lobe, hippocampus and thalamus in three sepa-rate studies (Block et al., 2000; Delamillieure et al.,2000, 2002). While the possible effects of medicationcannot be excluded in these studies, a study of bothmedicated and unmedicated patients with schizophre-nia reported no changes in parietal cortex myo-inositolconcentrations, irrespective of medication status(Bluml et al., 1999). Furthermore, inositol treatmenthas been shown to lack effectiveness in schizophrenia(Levine et al., 1993). A post-mortem study of patientswith chronic schizophrenia found a reduction in myo-inositol concentrations in the frontal and occipital cor-tex, as well as in the cerebellum; however, the activityof inositol monophosphatase did not differ from thatof healthy controls (Shimon et al., 1998).
In contrast to the 1H-MRS studies, a decreasein prefrontal cortex PME concentrations werereported in both unmedicated (Pettegrew et al., 1989,1991) and medicated patients with schizophrenia(Williamson et al., 1991), although no changes inPME concentrations were observed in the same brainregions of medicated patients (Volz et al., 1997,1998). Interestingly, an increase in basal gangliaPME concentrations were reported in medicatedpatients with schizophrenia (Fujimoto et al., 1992),as well as in the parietal cortex of both medicatedand unmedicated patients (Bluml et al., 1999). Similar
inconsistencies have also been reported in PDE con-centrations in patient studies. An increase in PDEconcentrations was observed in the prefrontal cortexof unmedicated and medicated patients (Pettegrewet al., 1989, 1991; Deicken et al., 1994), and in thetemporal region of medicated patients (Fujimotoet al., 1992). In contrast, no alteration in the concentra-tion of PDE was reported in the parietal cortex of bothmedicated (Williamson et al., 1991; Bluml et al.,1999) and unmedicated patients with schizophrenia(Bluml et al., 1999), while a decrease in PDE concen-trations were reported in the prefrontal region of medi-cated patients (Volz et al., 1997, 1998). Taken together,MRS studies in patients with schizophrenia have beeninconclusive and, overall, are not suggestive of alteredPI-cycle activity in the regions evaluated.
CONCLUSIONS
The findings from this review suggest that the PI-cycleis likely to be significantly involved in bipolar patho-physiology, but evidence to date is much less suppor-tive for the PI-cycle being involved in either theetiology or treatment of any other psychiatric disorder.At this stage, it is impossible to know whether thedegree of support for PI-cycle involvement in bipolardisorder versus the other psychiatric disordersreviewed is disorder specific, or whether bipolar disor-der has received a disproportionate amount of atten-tion in this regard, possibly as a result of historicaldevelopments surrounding lithium’s action on PI-cycle activity. This issue is compounded by the factthat several investigations have indeed reported posi-tive changes in depressive and anxious symptoms inanimals and humans treated with inositol, indicatingthat inositol and the PI-cycle may play a physiologicalrole in related disorders. Moreover, many of the clin-ical MRS studies conducted in psychiatry to date haveinvestigated similar brain regions across disorders, notout of pathophysiological relevance, but more com-monly because of the current limitations surroundingMRS methodology, which makes biochemical analy-sis of finer cortical and subcortical structures difficult.
Refinement of MRS methodology and advance-ment in available technology are beginning to allowfor higher-resolution single- or multi-voxel spectro-scopic imaging, which provides greater differentiationbetween neuro-anatomical structures, while still pos-sessing superior signal-to-noise ratios and acceptableacquisition times (Gruber et al., 2003; Di Costanzoet al., 2003; Li et al., 2001). These advancementswill provide the means through which disorder-specific, a priori pathophysiological hypotheses can
320 h. kim ET AL.
Copyright # 2005 John Wiley & Sons, Ltd. Hum Psychopharmacol Clin Exp 2005; 20: 309–326.
Tab
le5
.M
RS
fin
din
gs
tod
ate
insc
hiz
op
hre
nia
Stu
dy
Tec
hn
iqu
eN
aF
ind
ing
sN
ote
s
Pet
teg
rew
etal.
,1
99
11
.5T
31P
-MR
S1
1—
#do
rsal
pre
fron
tal
cort
exP
ME
insc
hiz
op
hre
nia
pat
ien
tsco
mp
ared
wit
hh
ealt
hy
con
tro
lsF
irst
epis
od
e—
"do
rsal
pre
fron
tal
cort
exP
DE
insc
hiz
op
hre
nia
pat
ien
tsco
mp
ared
wit
hh
ealt
hy
con
tro
lsd
rug
naı̈
ve
Wil
liam
sonet
al.
,1
99
12
T31P
-MR
SF
RO
GS
10
—#l
eft
dors
alpre
fronta
lco
rtex
PM
Ein
schiz
ophre
nia
pat
ients
com
par
edw
ith
hea
lthy
contr
ols
Var
ious
med
icat
ions
—$
left
do
rsal
pre
fro
nta
lco
rtex
PD
Ein
sch
izo
ph
ren
iap
atie
nts
com
par
edw
ith
hea
lth
yco
ntr
ols
Fu
jim
oto
etal.
,1
99
22
T31P
-MR
S1
6—
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tte
mpora
llo
be
PD
Ein
schiz
ophre
nia
pat
ients
com
par
edw
ith
hea
lthy
contr
ols
Var
ious
med
icat
ions
—#b
asal
gan
gli
aP
DE
insc
hiz
op
hre
nia
pat
ien
tsco
mp
ared
wit
hh
ealt
hy
con
tro
ls—
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alg
ang
lia
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ph
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ith
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ols
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par
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llo
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DE
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hy
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tro
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42
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llo
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izop
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nia
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ols
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arie
tal
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71
.5T
31P
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SIS
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3—
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PF
CP
DE
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nia
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mp
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hh
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hy
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tro
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tsvar
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sm
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ns
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bet
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olz
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81
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CP
DE
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ophre
nia
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ith
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lthy
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ious
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icat
ions
—$
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PF
CP
ME
bet
wee
nsc
hiz
op
hre
nia
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ien
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dh
ealt
hy
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tro
ls—
No
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tionsh
ipb
etw
een
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dP
ME
and
dose
or
type
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psy
choti
cB
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let
al.
,1
99
91
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1H
,31P
-MR
SS
TE
AM
,P
RE
SS
13
—$
par
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rtex
mI
bet
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nia
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and
hea
lthy
contr
ols
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ious
med
icat
ions
—"p
arie
tal
cort
exP
ME
insc
hiz
op
hre
nia
pat
ien
tsco
mp
ared
wit
hh
ealt
hy
con
tro
ls—
$p
arie
tal
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DE
bet
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nsc
hiz
op
hre
nia
pat
ien
tsan
dh
ealt
hy
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trols
Del
amil
lieu
reet
al.
,2
00
01
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1H
-MR
SS
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AM
27
—$
thal
amu
sm
Ib
etw
een
sch
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ph
ren
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nts
and
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lth
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ntr
ols
—N
ore
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onsh
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etw
een
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and
age
of
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onse
tor
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of
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ess
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00
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1H
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RE
SS
25
—$
left
fron
tal
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ean
db
asal
gan
gli
am
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ilia
lsc
hiz
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hre
nia
pat
ien
ts,
un
affe
cted
fam
ily
mem
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so
fsc
hiz
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nia
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hy
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tro
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us
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-MR
SP
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—$
left
thal
amu
san
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ftp
arie
tal
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ite
mat
ter
mI
bet
wee
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hre
nia
pat
ien
tsan
dh
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hy
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tro
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ario
us
med
icat
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Del
amil
lieu
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1H
-MR
SS
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AM
17
—$
med
ial
pre
fron
tal
cort
ex,
thal
amu
s,an
dh
ipp
oca
mp
us
mI
bet
wee
nsc
hiz
op
hre
nia
pat
ien
tsan
dh
ealt
hy
con
trols
Var
ious
med
icat
ions
—N
ore
lati
onsh
ipb
etw
een
mI
and
dura
tion
of
illn
ess
or
dose
of
anti
psy
choti
cK
esh
avan
etal.
,2
00
31
.5T
31P
-MR
SS
pin
echo
16
—#p
refr
on
tal
cort
exP
ME
inin
div
idu
als
ath
igh
risk
for
sch
izop
hre
nia
com
par
edw
ith
no
n-h
igh
risk
hea
lth
yco
ntr
ols
Hig
hri
skd
rug
free
—$
pre
fron
tal
cort
exP
DE
bet
wee
nin
div
idu
als
ath
igh
risk
for
sch
izo
ph
ren
iaco
mp
ard
wit
hn
on
-hig
hri
skh
ealt
hy
con
tro
ls
aT
he
sam
ple
size
repre
sen
tsth
en
um
ber
of
pat
ien
tsin
each
stud
y.m
I,m
yo
-in
osi
tol;
PM
E,
ph
osp
ho
mon
oes
ters
;P
DE
,p
ho
sph
odie
ster
s;D
LP
FC
,d
ors
ola
tera
lp
refr
on
tal
cort
ex;
FR
OG
S,
fast
rota
tin
gg
rad
ien
tsp
ectr
osc
opy;
ISIS
,im
age-
sele
cted
invivo
spec
trosc
opy;
L-C
OS
Y,
two-d
imen
sional
loca
lize
dch
emic
alsh
ift
corr
elat
edsp
ectr
osc
opy;
PE
PS
I,photo
nec
ho-p
lanar
spec
trosc
opic
imag
ing;
PR
ES
S,
poin
t-re
solv
edsp
ectr
osc
opy;
ST
EA
M,
stim
ula
ted
ech
oac
qu
isit
ion
mo
de.
pi cycle in psychiatric disorders 321
Copyright # 2005 John Wiley & Sons, Ltd. Hum Psychopharmacol Clin Exp 2005; 20: 309–326.
be developed, tested and refined. While the majorityof MRS investigations into the physiological role ofmyo-inositol and the PI-cycle in psychiatry havefocused on patients with bipolar disorder, consideringthe above information, little can be concluded regard-ing the degree of specificity of these findings to bipo-lar disorder. Greater in vivo characterization of thebiochemistry of discrete brain structures and theirinnervations, across distinct disorders, will help betterestablish the level of importance myo-inositol and thePI-cycle play in other common psychiatric disorders.
ACKNOWLEDGEMENTS
This work was supported in part by peer-reviewedgrants from the Canadian Institutes of HealthResearch (CIHR) and the Alberta Heritage Founda-tion for Medical Research (AHFMR).
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