*Co esponding au ho : Debo shi Na h
Copy igh © 2025 Au ho (s) e ain he copy igh o his a icle. This a icle is published unde he e ms o he C ea i e Commons A ibu ion License 4.0.
B idging Biology and The apy: Ad ances in Managemen o Bipola Diso de
Va sha Velmu ugan, Debo shi Na h *, Vinee h Chandy and Visaga Pe umal
Depa men o Pha macology, T. John College o Pha macy.
Wo ld Jou nal o Biology Pha macy and Heal h Sciences, 2025, 24(01), 106-113
Publica ion his o y: Recei ed on 12 Augus 2025; e ised on 26 Sep embe 2025; accep ed on 29 Sep embe 2025
A icle DOI: h ps://doi.o g/10.30574/wjbphs.2025.24.1.0851
Abs ac
Bipola diso de is a complex psychia ic illness ha is cha ac e ized by al e na ing episodes o mania and dep ession
ha signi ican ly a ec he quali y o li e. I is a ch onic condi ion ha has mul i ac o ial pa hophysiological mechanisms
ha emain incomple ely unde s ood, and he apeu ic ou comes o en ail o achie e long- e m emission. This e iew
isi s he changing landscape o he de elopmen o bipola diso de , in pa icula , he con ibu ions o me abolic
dys unc ion and diabe es, which a e inc easingly acknowledged as impo an con ibu o s o disease onse ,
p og ession, and ea men esis ance. The e iew also explo es cu en ad ancemen s, bo h pha macological and non-
pha macological ad ancemen s o he managemen o he disease. By in eg a ing he insigh s om se e al biological
domains, he need o a b oade and pe sonalized ea men pa adigm ha goes beyond neu o ansmi e heo ies is
highligh ed o imp o ing pa ien ou comes.
Keywo ds: Bipola diso de ; Diabe es Melli us; Oxida i e s ess; Neu oin lama ion; T ea men
G aphical abs ac
Cu en ad ancemen s in he ea men o Bipola Diso de
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1. In oduc ion
Bipola diso de is a ch onic, ecu en psychia ic condi ion cha ac e ized by episodes o mania and hypomania
accompanied by dep ession, signi ican ly impac ing daily unc ioning (1). Acco ding o he DSM-5-TR, Bipola I diso de
is iden i ied by a leas one manic episode. In compa ison, Bipola II diso de in ol es a leas one hypomanic and one
majo dep essi e episode wi hou any his o y o ull mania (2). Globally, Bipola I Diso de a ec s app oxima ely 1.06%
o he adul popula ion. Meanwhile, Type II Bipola Diso de has an incidence o 1.57% wo ldwide, wi h a mode a ely
highe occu ence in he Uni ed S a es (3,4,5). F om being misunde s ood as pa ano mal beha iou o “madness,”
bipola diso de has e ol ed om a hea ily s igma ized condi ion o being o mally ecognized as a mood diso de
wi hin psychia ic amewo ks (6).
The symp oms o bipola diso de o en coincide wi h como bidi ies such as schizoph enia and dep ession, esul ing in
misdiagnosis. This o en delays he he apeu ic ou comes and wo sens mania, isk o suicide, and subs ance abuse
(7,8,9). A la es epo by Global Bu den o Disease (GBD) concludes ha he e was a hike in he popula ion a ec ed by
bipola diso de , wi h he numbe inc easing om 2 million in 1990 o a ound 4 million in 2019. Al hough he e is a
signi ican inc ease globally in he yea s li ed wi h disabili y (YLDs), while age-s anda dized incidence emains
cons an , his demons a es disabili y endu ance ega dless o he apeu ic ad ancemen s(10,11).
While he e is no cu e o bipola diso de , se e al he apies ha e p o en o manage acu e episodes and sus ain long-
e m emission, which include mood s abilize s such as li hium, some a ypical an i psycho ics, and an i-epilep ics (12).
The con en ional ea men s p oduce ex ensi e side e ec s while also o e looking he in e connec ed ole o gene ic
suscep ibili y, HPA axis dys unc ion, neu o ansmi e dys egula ion, and in lamma o y pa hways and impai men in
neu al ci cui y ha agg a a e he diso de (13,14,15). While hese ac o s ha e been s udied ex ensi ely o yea s,
hey’ e o en explo ed indi idually, ailing o cap u e he in e ac ions among mul iple physiological sys ems. The ole
o sys emic ac o s, such as me abolism o glucose and impai men in glucose me abolism, was highligh ed as a
p edisposing ac o in he p og ession o mood diso de s by ecen esea ch. (16). Dys unc ion in me abolism may
con ibu e o he gene a ion o eac i e oxygen species which ele a es he oxida i e s ess in neu onal cells. Oxida i e
s ess is highly associa ed wi h in lamma ion o neu ons and dys unc ion o mi ochond ia, which u he po en ia es
neu onal damage (17,18,19). The cascade o e en s con ibu es o mood ins abili y and may desc ibe he ela ionship
be ween me abolic diso de s like Diabe es melli us wi h bipola diso de . Ho monal imbalance is ano he key sys emic
con ibu o wi h ele a ed co isol le els, impai ed nega i e eedback, and glucoco icoid esis ance se ing as a
biological ma ke o bipola diso de (15,20,21).
This e iew aims o ocus on key indings ac oss h ee key a eas-me abolic dys egula ion ( ela ed o Diabe es melli us),
ho monal imbalance, and oxida i e s ess, wi h an emphasis on ecen ad ances in ea men app oaches o bipola
diso de .
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2. Pa hophysiology
2.1. Role o Me abolic Dys egula ion
Type 2 Diabe es Melli us is cha ac e ized by ch onic hype glycemia and insulin esis ance, which leads o impai ed
glucose up ake and sys emic me abolic dis u bance, ha no only dis up s pe iphe al me abolism bu also b ain
homeos asis (22). These changes in biochemis y impai s he PI3K/Ak pa hway and lowe he glucose anspo e
ac i i y (GLUT 3 and GLUT 4) in he neu ons and impai he neu onal ene gy me abolism hus con ibu ing o al e a ion
in insulin signalling and impai ed mi ochond ial unc ion (23,24).
Mi ochond ial dys unc ion ollowed by ine icien oxida i e phospho yla ion esul s in he o e p oduc ion o eac i e
oxygen species (ROS), including supe oxide and hyd ogen pe oxide, ha su passes he endogenous an ioxidan sys ems
like supe oxide dismu ase (SOD), glu a hione, and ca alase. This edox imbalance causes oxida i e s ess, lipid
pe oxida ion, p o ein oxida ion, and DNA agmen a ion, con ibu ing o neu onal inju y and educed synap ic plas ici y
and neu o ansmi e egula ion (25,26). Clinical s udies ha e consis en ly epo ed ele a ed le els o oxida i e
bioma ke s such as malondialdehyde (MDA) and 8-hyd oxy-2'-deoxyguanosine (8-OHdG), o en co ela ing wi h manic
and dep essi e se e i y (27,28). Fu he mo e, oxida i e s ess ac s as a cen al media o ha links me abolic
dys egula ion o neu oin lamma ion h ough pa hways such as NF-κB ac i a ion and mic oglial o e ac i a ion ha
con ibu e o p og essi e neu odegene a ion in bipola diso de (26,29). Epidemiological e idence shows pa ien s wi h
diabe es ha e an inc eased isk o de eloping bipola diso de , es ablishing a s ong pa hophysiological link be ween
he me abolic dys unc ion and mood dys egula ion (30).
2.2. Ho monal Imbalance
Ho mones play a i al ole in egula ing b ain unc ion and emo ional s abili y. Dis up ions in he body’s ho monal
sys ems- especially s ess ho mones, hy oid ho mones, and sex ho mones ha e been closely linked o mood and
beha io al changes due o al e a ions in neu o ansmi e signaling, synap ic plas ici y, and neu oendoc ine
homeos asis.
2.3. HPA axis and Co isol
Hypo halamic pi ui a y axis (HPA) con ols he body’s esponse o s ess and is closely is consis en ly associa ed wi h
mood diso de s such as bipola diso de . O e ac i a ion o HPA leads o pe sis en ly high co isol le els ha can impai
he hippocampal s uc u e, educe BDNF, and dis up he se o one gic and dopamine gic ansmission con ibu o s in
mood ins abili y in bipola diso de (15,20,31). Ch onic co isol ele a ion may also exace ba e oxida i e s ess and
neu oin lamma ion, wo sening mood dys egula ion (32).
2.4. Thy oid ho mones
Thy oid ho mones, especially iiodo hy onine (T3), a e essen ial o b ain me abolism and neu o ansmi e
egula ion. They modula e CNS unc ion h ough di ec e ec on se o onin, no epineph ine, and dopamine ecep o
sensi i i y (33,34). Thy oid imbalance, bo h hypo hy oidism and hype hy oidism, is associa ed wi h mood
dis u bances (35). S udies show ha educed hy oid unc ion is associa ed wi h dep essi e symp oms, while inc eased
le els may po en ia e manic ea u es (36).
2.5. Sex ho mones
Sex ho mones play a modula o y ole in he egula ion o emo ions and neu o ansmission. Es ogen enhances
se o one gic and dopamine gic signaling, p o iding a s abilizing e ec on mood in addi ion o i s neu op o ec i e
ac i i y (37,38). Fluc ua ions in es ogen, such as hose obse ed du ing he mens ual cycle, pos pa um, o
menopause, a e associa ed wi h inc eased ulne abili y o mood episodes (39). Simila ly, es os e one dys unc ion in
men may con ibu e o i i abili y, impulsi i y, o agg ession (40).
The dis u bances in hese ho mones can collec i ely in luence he syn hesis, elease, and ecep o sensi i i y o
neu o ansmi e s such as dopamine, se o onin, and no epineph ine. Ho monal imbalance can cause an ups eam
igge o p ecipi a e neu o ansmi e imbalance, which unde lies mood ins abili y in bipola diso de .
2.6. Cu en app oaches
The p ima y ea men app oach in ol es mood s abilize s like li hium, an ipsycho ics, and some imes an idep essan s
ailo ed o he pa ien ’s clinical phase and esponse (41,42). Combina ion he apy is o en needed o e icien
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managemen o he diso de . Psycho he apy, li es yle modi ica ion, and psychoeduca ion a e also c ucial in achie ing
long- e m s abili y. Main enance ca e wi h egula ollow-up is o en c ucial as i 's ch onic and p one o elapse e en
a e symp om emission (43,44).
3. Ad ancemen s in he managemen o bipola diso de
3.1. Pha macological ad ancemen s
3.1.1. Psychedelic-assis ed he apy
Psychedelics such as psilocybin, once used in non-medical o in o mal se ings, a e now gaining p ominence wi hin he
scope o pha macological ad ancemen s o mood diso de s (45). Psilocybin, h ough i s ac i e me aboli e psilocin, ac s
as a 5-HT 2A agonis ha is known o inc ease he unc ional b anching o b ain ne wo ks, he eby enhancing
communica ion and emo ional modula ion, e ec i ely es o ing dys egula ed neu al ci cui s implica ed in neu al
diso de s (46). A ecen open-label clinical ial demons a ed ha a single dose o syn he ic psilocybin combined wi h
psycho he apy led o apid and sus ained emission o dep essi e symp oms in indi iduals wi h bipola II diso de
wi hou any se ious ad e se e ec s (47).
3.1.2. Ke amine and glu ama e gic agen s
Ke amine is a no el, inno a i e ea men o bipola diso de . I p ima ily ac s by blocking NMDA ecep o s, esul ing
in glu ama e su ge and AMPA ac i a ion, which engages in key neu o ophic pa hways such as BDNF elease, GSK-3
be a inhibi ion, and MTORC1 ac i a ion, which con ibu e o synap ic plas ici y and enhanced neu onal connec i i y
comp omised by dep ession (48). IV ke amine in usions ha e demons a ed signi ican sho - e m bene i s by achie ing
an idep essan e ec s wi hin almos 40 minu es; howe e , i is s ill being s udied o long- e m e ec s, sa e y p o ile,
and dosing s a egies (49).
3.1.3. Epigene ic modula o s
Mood s abilize s such as li hium, alp oa e, que iapine, and olanzapine ha e shown impo an epigene ic e ec s ha
con ibu e o he s abiliza ion o mood in he long e m. These medica ions ac h ough DNA me hyl ans e ases
(DNMTs) and his one deace ylases (HDACs), which b ing abou ch oma in emodelling and egula e he exp ession o
genes. Li hium and alp oa e educe me hyla ion a he BDNF p omo e , inc easing he le el o mRNA o BDNF and
p o iding neu o ophic suppo (50). Valp oa e also inhibi s HDAC, enhancing his one ace yla ion and up egula ion o
BDNF and GDNF. O e all, hese epigene ic mechanisms imp o e neu oplas ici y o he b ain and egula e he
neu o ansmi e s o b ing abou s abiliza ion o mood (51).
3.2. Non-pha macological and al e na i e
3.2.1. Nu aceu icals and li es yle in e en ion
Nu aceu ical in e en ions ha e gained a en ion as adjunc s a egies in he managemen o bipola diso de , by
a ge ing in lamma ion, oxida i e s ess, and me abolic dys unc ion (52). Omega-3 polyunsa u a ed a y acids ha e
bene icial e ec s in p o ec ing neu ons and educing p o-in lamma o y media o s and cy okines, making hem
esponsible o an idep essan e ec s (53). N-ace ylcys eine (NAC) exhibi s an ioxidan and an i-in lamma o y ac ion
in addi ion o eplenishing glu a hione and modula ing dopamine gic and se o one gic ansmission, he eby desi able
o bipola dep ession (54). Die a y in e en ions like he ke ogenic die ha e demons a ed neu op o ec i e e ec s
and a e e ec i e o imp o ing mood and educing dep ession (55). This die is u he alida ed as a signi ican po ion
o pa ien s wi h bipola diso de also su e om ype 2 diabe es melli us, hus comba ing he como bidi ies e icien ly.
3.2.2. Ch ono he apy
T iple ch ono he apy (TCT), which is a combina ion o sleep dep i a ion, sleep phase ad ance, and sleep b igh ligh
he apy, has shown a apid and sus ained an idep essan e ec by ealigning ci cadian hy hm, ho monal iming, and
mood dys egula ion (56). TCT ese s dis up ed ci cadian hy hms by in luencing sleep dep i a ion o induce mood
ele a ion h ough inc eased neu o ansmi e ac i i y, while sleep phase ad ance and b igh ligh he apy s abilize
mela onin and suppo he es ablishmen o a heal hy ci cadian hy hm (57). Case epo s also p o e TCT o be
success ul in indi iduals wi h ECT- esis an bipola diso de , whe e a single cou se led o du able emission (58).
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3.2.3. T ansc anial Magne ic S imula ion (TMS)
High- equency epe i i e ansc anial magne ic s imula ion o e he le do sola e al p e on al co ex ( TMS) has
shown good esul s in ea men - esis an bipola dep ession, educing symp oms in 50% o indi iduals wi hou any
no able se ious side e ec s (59). I modula es he dopamine gic and se o one gic sys ems and inc eases exp ession o
BDNF, con ibu ing o enhanced neu oplas ici y and an idep essan e ec s. I also imp o es he connec i i y o he
dys unc ional on o-limbic sys em, a cha ac e is ic o bipola dep ession (60).
4. Conclusion
Bipola diso de emains an in ica e and mul i ac o ial men al illness ha has di e implica ions on he heal hca e
sys em, wi h signi ican disease bu den and a ec s he quali y o li ing o indi iduals. Al hough Con en ional esea ch
and ea men ocus on neu o ansmi e s and monoamine dys egula ion, he e is a g owing need o emphasize
al e na e and less explo ed pa hways, pa icula ly hose in ol ing me abolic dys unc ion, such as diabe es and
ho monal imbalance. While being c i ically ele an pa hways o he pa hophysiology o bipola diso de , hey also
ep esen aluable a ge s o in e en ion. Al hough ounda ional, he cu en pha macological egimen alls sho in
deli e ing long- e m emission and comba ing a wide spec um o symp oms, especially in ea men - esis an pa ien s.
This gap d aws a en ion o he u gency o de eloping he apeu ic op ions beyond adi ional d ug-based app oaches.
Eme ging non-pha macological in e en ions such as ch ono he apy and li es yle modi ica ions show a p omising
pe o mance as bo h adjunc s and s andalones. Howe e , he pa h o comple e eco e y is s ill a long way om being
co e ed. Exis ing ea men s mus inco po a e a mo e indi idualized and in eg a i e amewo k ha accoun s o an
a ay o biological pa hways by b idging he ields o neu oscience, psychia y, and endoc inology. Fu u e esea ch mus
ocus on op imizing and alida ing he no el and inno a i e s a egies in addi ion o e ining pha macological he apies.
This ou look would inc ease he possibili y o a aining inclusi e long- e m ou comes o indi iduals li ing wi h he
challenging condi ion.
Compliance wi h e hical s anda ds
Disclosu e o con lic o in e es
No con lic o in e es o be disclosed.
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