SERUM LITHIUM, SODIUM AT{D POTASSIUMIN PATIENTSOF
BIPOLAR DISORDERS ON LITHIUM PROPHYI.AXIS
M. Amuba Singh*, K. Sohmat*,
Th. lbetombi Devi*, T. Rajen Singh*, W. Gyaneshwar Singh*
N. Heramani Singh**, Th. Bhimo Singft*r* and N. Biplag***
* Depailnent of Biochemlsbjrt, kychiahy** and Medlclne***
Regional Institute of Medical Sclences, Imphal - Zgg OO4
Abctract
Forty two patientsof bipolar disordersreceivinglithium prophylaxisin RegionalInstituteof Medical
Sciences,lmphal werestudiedto determinethe serumlithium concenhationand its conelationto the
prognosisof ihe disease.Serum levelsof sodium and potassiumwere also determinedto find a
possiblecorrelationwith the disease.The studywascanied out duringthe periodfrom January.1999
to December.2OO2.lt was observedthat the range of serum lithium level varied from 0.4 to
0.8 mmoVl with oral doseof lithiumcarbonatein the rangeof 600-1200mg/day.Moit of the patients
showed consistentclinical improvementachievingan early remissionbetween60 and 90 days of
prophylaxis.althoughsome patientsneeded150 da9n.With the increasein lithium levels,there was
correspondingincreasein potassiumlevel but within physiologicallimits- On the contrary. while
there was increasein lithium levels,therewas a correspondingdecreasein sodium levels.
Introduction
Lithium is presentin all tissuesand fluids of the
body, albeit in very low concenhation.Human
blood hasbeen reportedto contain0.006 mg of
lithium per millilihe. Lithium is distributedmore
evenlybetweenthe exhacellularand intacellular
spacesthan are sodium and potas5lurn(l).
Lithium is now establishedas a useful drug in
the prophylaxisof bipolar disorders.Severalwell
controlleddouble-blindstudieshaveadequately
shown that lithium carbonateis effectivein the
prevention of recurrent affectiveepisodesin
bipolar disorders(2.:r.4.5).
Contraryto Whatwas
originallybelieved,adequateprophylaxiscanbe
achievedwith plasmalevelsof lithium as low as
0.4 - 0.6 mmoVL.lt wasalsorecommended
that
prophylacticlithium levelof 0.5 - 0.8 mmoVl was
appropriate for most bipolar disorders(s).
However,higher{ithium levelsmore than 0.8
mmoVl may be maintainedin patienb who do
not respondat the recommended
lithiumlevel(6).
Since there has been no study so far about the
correlation between serum levels of lithium.
sodium and potassiumin bipolar disorders,the
present work is an attempt to find out the
correlationof serumlevelsof lithium,sodiumand
potassiumin patientsof bipolar disorders.
Methods
Forty two patienb of bipolar disorders formed
the subjecb for the study. Their age range was
17-58 year. The patienb who attended in the
deparbnentof Rychiatry as outpatienband also
thosewho were admittedin the ward during the
period from January 1999 to December,2ffi2
were included in the study. Screening
investigationsincludingblood and urine routine
examination;serumlevelsof sodium,potassium;
estimationof blood sugar,urea, creatinine,
cholesterol,liver function test and recordingof
ECG prior to therapywere done.
Lithium tableb were administeredat 600-1200
mg/day in two or three divided doses. The
preparationsused were lithosun (Sun) and
22
Intalith(lntas).After7 days of commencement
of lithium treatment,blood sampleswere drawn
twelve hours after the last oral dose of lithium.
The serumlithium,sodiumand potassiumlevel
were estimatedby flame photometryasdescribed
by Murray and Wooton respectively(7'st.
Estimation of serum lithium, sodium and
potassium were repeatedtwo times at weekly
intervalsand the dosagewas adjustedsuitably
to keep the serum lithium levelsin the accepted
pr o p h yla ctic range of 0.5 - 0.8 mmo l/ L .
Thereafterfor the first five months,the patients
were reviewedonce in 4-5 week. Duringeach
review:serum lithium, sodium and potassium
levels were estimated.Serum sodium and
potassiumlevelsat differentperiodsof treatment
were compared with the initial pre-treatment
le ve ls an d the statisticalsignific a n c eo f
observationswas analysed,usingstudent's"t"
test. The correlationbetweensemm levelsof
lithium,sodiumand potassiumwasalsoanalysed
usingthe sametest.
Results
Fortytwo patientsof bipolardisorderscomprised
the studypopulation.Therewere30 malesand
12 females.
It may be gatheredfrom Table-lthat mean oral
lithium (mg/day)and meansenrmlithium level
(mmol/L)were found to be 951.063and 0.643
respectively.
The oral lithium variedfrom 600 mg
to 1200mg while the serumlithiumlevelranged
from 0.4 mmol/L to 0.8 mmoVL.
Tablell dealswith meanand S.D.of serumlevels
of sodium over the days of therapy with test
results.Here,testwasconductedbetweenmean
of pre-treatmentand mean of other days of
therapy.Allthe testswerefound to be very highly
significantas the calculatedt-valuesweregreater
than the correspondingtable valuesof t even at
0.01% level of significance.The mean pretreatment value of serum sodium from all the
patienbwas 141.928+ 1.385mmoULand was
within the acceptednormal range of 136-145
mmoVl. Thus one can conCludethat meanpreheatnent s€rumsodium levelswas higher than
that of the other days of therapy.Furtherit may
be concluded that mean level was decreasing
accordingto the increaseof days of therapy.
Similarly, the same test i.e. studenb t-test was
carried out for serum potassium levels too in
order to test mean variation between preheabnentand other days of therapy.The mean
pre-heatnentvalue of serumpotassiumfrom all
thepatientswas4.090!0.162 mmoVLand was
within the accepted normal range of 3.5 to
5.0 mmoVL.It was found that all the testswere
very highly significantexcept at 120 days and
150 days of therapy.The former was highly
significantand the latterjust significant.In short.
pre-treatnentpotassiumlevelwaslowerthanthat
of other days of therapy.One more interesting
finding here was that the mean level was
increasingfor pre-treatmentupto 90 days of
therapy and thereafterthe hend was found to
decreaseto someextent(Table-lll).
TablelV showsthe meanand standarddeviation
valuesof serumlithium levels(mmol/L)forseven
stagesof days of therapy. It was observedthat
the level was raisingfrom 7 days of therapy to
30 daysof therapythen taperingdown upto 90
days of therapy then again sudden rise at 120
daysof therapyand then decreased.Statistically,
therewasnon-linearhendof meanlithiumlevels
with days of therapy.
TableV depicb the correlationshipbetweenthe
semmlevelswith statisticaltestand results.There
wasa positiveconelationbetweenserumlithium
and potassiumlevelswhile negativeconelation
existsbetween lithium and sodium as well as
betweenpotassiumand sodium.It interprebthat
while increasinglithium levels there was
conespondingincreasein potassiumlevel also
but within physiologicallimib. On the contrary,
while the potassiumlevel was increasedthe
serum sodium levels decreased. These
correlationswere not much significantas
evidencedby the valuesof P for allthe patients.
Serum Lithium,Sodium ond Potassium
in Potientsol Bipolar D'sorderson Lithium Prophyloxis
Discussion
In this study,the maximumdoseof lithiumwas
1200 mg/daywith a mean of 951 mg/day.The
maximumserumlithium levelwas 0.8 mmol/L
and the minimumwas0.4 mmoVl with a mean
of 0.64 mmoyl. Patientswere compliantwith
lithium heatment.And most patientsshowed
consistentclinicalimprovements,achievingan
earlyremissionanytimebetween60 and 90 days
of medication.The prophylacticrange of 0.4
mmol/L to 0.8 mmoVl is within the acceptable
adequaterange suggestedby most researchers
t3'e).
In thestudyof O'Connellet al(10),
themean
lithiumdosewas 1158mg/dayand only 86% of
t h e se r u m lithium levels were within t h e
prophylacticrange(0.5 - 1.2mEq/L).
The plasmalevelsof sodiumand potassiumare
maintainedconstantwithinnanowphysiological
limits through an active hansport of potassium
into cell,involvingNa*, K+ ATPaseregulationof
renal secretionand loss of potassiumby
aldosteroneand acid-basestatusof the body.
Lithium, as it entersthe cells disturbsthe
electrochemical
equilibriumacrossthe cell
m em br a n e and increase potassi u mconductance.
This resultsin a lossof potassium
into the extracellulartluid and consequently
hyperkalemia.Intracellularly,lithium replaces
sodium. which is fixed to the intracellular
e n zym e - siteof Na+. K +-A TP asedur in g
phosphorylationof the enzyme(11).
Cellular
mo d e lso f ch angesin membraneNa+, K +
activated ATPaseand proposalsof disordered
signalhansductionmechanisms
involvingeither
thephosphoinositolsystemor guaninenucleotide
b i nd in g pr o teins have receivedthe mo s t
attention. Lithium rirducesthe supply of |ree
inositol used to maintain the lipid precursors
involvedin intracellularsignalingand blocks
stimulation-induced
increasein GTP binding
23
capacity.Reductionof GTP and downstream
effectson proteinkinaseC arebeinginvestigated
as possibleexplanationsfor the therapeutic
effectsof the drug(l2).
(an
In a smallnumberof patients,spironolactone
aldosteroneantagonist)was shown to have a
beneficialeffectwhich may not be surprisingin
view of the opposing action of lithium and
aldosterone
on adenylcycla5s(1s't+).
Thishasled
theseworkersto suggestan aetiologicalrole for
aldosteronein bipolar disorders.
In this study,thereis a positivecorrelation(r =
+ 0.250)betweenserumlithium and potassium
levelswhilea negativecorrelation(r : - 0.334)
existsbetweenlithium and sodium as well as
between potassiumand sodium level too
(r = - 0.136).It interpretsthat while there is
increasein lithium levelsthereis corresponding
increasein potassiumlevels also, but within
physiologicallimits. On the contrary,there is
corresponding
decreasein sodiumlevelwiththe
increasein lithium level. While the potassium
level is increasedthe serum sodium also
decreases
within physiologicallimits.
In conclusion,the resultsof our study support
the fact that the regularuse of lithium modifies
the symptomatologyand thus justifying the
usefulness
of lithium prophylaxisin patientswith
bipolar disorders.It is also an interestingarea
for future researchbecausethe mechanismsof
a c t io n s o f lit h iu m f o r t h e ra p e u t ic a n d
prophylacticusesin patientsof bipolardisorders
are unclearthough it is a known fact that 80%
of these patients g.eteven complete cure by
lithium therapy. Further,this study identifiesa
relationshipbetween lithium, sodium and
potassiumlevelsin serumwhich can be a clue
for better understandingthe mechanismsof
a c t io n s o f lit h iu m a n d t o u n c o v e r n e w
informationswhich will help to fight mental
sufferingin humans.
lnd. J Med. Biochem.Vol.8, No. 1, 2004
24
Table : I :
Response to lithium
treatment
in study p0pulation
Range
(n = 421
Mean + S.D.
Oral Lithium
(mg/day)
600- 1200
951.063+ 145.769
Serumlithium
(mmoVL)
0.4- 0.8
0.643+ 0.020
Table : Il : Serum sodium level in bipolar disorder patients
Daysof therapy
Serumsodium
(mmol/L)
d.f.
t-value
P-value
Remarks
Mean+ S.D.
Pre-heatment
+ I3frc (42)
747.928
.7
740.825+ 1.465(40)
80
3.535
0,001
VHS
t4
140.405+ 1.461(37)
77
4.804
0.001
VHS
30
L40.277+ 1.596(36)
76
4.972
0.001
VHS
60
140.060+ 1.504(31)
77
7.948
0.001.
VHS
90
139.772+ 1.477(21]r
61
9.414
0.001
VHS
r20
139.714+ I.52L (27)
61
9.427
0.001
VHS
150
139.578+ I.574(79\
59
8.020
0.001
VHS
Figuresin the parenthesisindicatenumber of patients
Serum Lithium.Sodium qnd Potossiumin futientsof Bipolar Disorderson Lithium Prophyloxis
Table : lll :
Serum potassium
dicorder patlents
levels in bipoiar
Days of therapy
Serum Potassium
(mmoVL)
Mean + S.D.
Pre-heatment
4 090 + 0.762(42)
25
d.f.
t-value
P-value
Remarks
4.260+ 0.161(.40)
80
4.857
0.001
V HS
L4
4.508+ 0.LM(37)
77
14.928
0.001
V HS
30
4 566 + 0.126(36)
76
9.916
0.001
V HS
60
4.s96+ 0.119(31)
77
9.730
0.001
VHS
90
4.623+ 0.148(21)
61
7.301
0.001
V HS
L20
4.300+ 0.154(21)
67
2.837
0.01
HS
150
4.375+ 0.863(19)
9
2.O9s
0.05
S
1
Figuresin parenthesisindicatenumberof patients
Thble: lV : Serum Lithium levels in bipolar disorder patientc
Days of therapy
No. of patients
Serumlithiummmol/L
Mean + S.D.
7
40
0.592+ 0.085
t4
37
0.627+ 0.069
30
36
0.690+ 0.293
60
31
0.658+ 0.076
90
21
0.647+ 0.074
t20
27
0.661+ 0.080
150
19
0.652+ O.O77
lnd.J. Med.Biochem.
Vol.8. No.1,2004
26
Table : V: Correlation coefficients between serum Lithium (mmoVl), serum potassium
(mmoVl-) and serum sodium (mmoVl)
Between
r-value
Lithium and Potassium
+ 0.250
5
Lithuim and Sodium
- 0.334
Potassiumand Sodium
- 0.136
S.D.
d.f.
VHS
HS
5
IS
2
3
4
5
6
7
8
t-value
P value
Remarks
0.577
0.05
IS
5
0.792
0.05
IS
5
0.309
0.05
IS
Standarddeviation
Degreeof freedom
Very highlysignificant
Highly significant
Significant
Insignificant
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