Pharmrev 120 000007

1521-0081/76/3/323–357$35.00 dx.doi.org/10.1124/pharmrev.120.
000007
PHARMACOLOGICAL REVIEWS Pharmacol Rev 76:323–357, May 2024
U.S. Government work not protected by U.S. copyright
ASSOCIATE EDITOR: ROBERT DANTZER
New Advances in the Pharmacology and Toxicology of

Lithium: A Neurobiologically Oriented Overview
Analia Bortolozzi,1 Giovanna Fico,1 Michael Berk, Marco Solmi, Michele Fornaro, Joao Quevedo, Carlos A. Zarate, Jr.,
Lars V. Kessing, Eduard Vieta,2 and Andre F. Carvalho2
Institut d’Investigacions Biomediques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain (A.B.); Institut
d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain (A.B., G.F., E.V.); Centro de Investigacion Biomedica en Red de
Salud Mental (CIBERSAM), ISCIII, Madrid, Spain (A.B., G.F., E.V.); Hospital Clinic, Institute of Neuroscience, University of Barcelona,
Barcelona, Spain (G.F., E.V.); IMPACT- The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin
University, Geelong, Victoria, Australia (M.B., A.F.C.); Department of Psychiatry, University of Ottawa, Ontario, Canada (M.S.); The
Champlain First Episode Psychosis Program, Department of Mental Health, The Ottawa Hospital, Ontario, Canada (M.S.); Department of
Child and Adolescent Psychiatry, Charite Universit€ atsmedizin, Berlin, Germany (M.S.); Section of Psychiatry, Department of Neuroscience,
Reproductive Science and Odontostomatology, Federico II University of Naples, Naples, Italy (M.F.); Center of Excellence on Mood Disorders,
Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at
Houston (UT Health), Houston, Texas (J.Q.); Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health,
National Institutes of Health, Bethesda, Maryland (C.A.Z.); Copenhagen Affective Disorders Research Centre (CADIC), Psychiatric Center
Copenhagen, Rigshospitalet, Denmark (L.V.K.); and Department of Clinical Medicine, University of Copenhagen, Denmark (L.V.K.)
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
Significance Statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
II. Clinical Use in Mood Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
A. Acute Mania . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
B. Acute Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
C. Maintenance and Prophylaxis of Mood Episodes in Bipolar Disorder . . . . . . . . . . . . . . . . . . . . 326
D. Antisuicidal Effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
E. Neuroprotective and Neurotrophic Effects of Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
III. Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
A. Inositol Monophosphatase, Posphoglucomutase, and Glycogen Synthase Kinase-3
Inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
B. Protein Kinase C and Myristoylated Alanine-Rich C Kinase Substrate Inhibition . . . . . . . . 331
C. Enhancement of Trophic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
D. Factors Affecting Apoptotic Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
E. Intracellular Signaling Cascades . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
1. PI3K/Akt Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
2. MEK/ERK Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
3. Wnt/b-Catenin Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
4. Calcium/Calmodulin-Dependent Protein Kinase II/CREB Pathway and Calcium Channels . 334
F. Oxidative Stress Pathways and Mitochondrial Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
G. Protein Quality Control Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
Address correspondence to: Dr. Andre F. Carvalho, Deakin University, P.O. Box 281, Geelong, Victoria, Australia 3220. E-mail:
[email protected]
This work was supported by Grant PID2019-105136RB-100 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making
Europe” (to A.B.). M.B. is supported by a NHMRC Senior Principal Research Fellowship and Leadership 3 Investigator Grant (1156072 and
2017131). G.F.’s work is supported by a fellowship from “La Caixa” Foundation (ID 100010434 - fellowship code LCF/BQ/DR21/11880019).
E.V. has received grants and served as consultant, advisor, or CME speaker for the following entities: AB-Biotics, AbbVie, Angelini, Biogen,
Biohaven, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research,
Glaxo-Smith Kline, Idorsia, Janssen, Lundbeck, Medincell, Novartis, Orion Corporation, Organon, Otsuka, Rovi, Sage, Sanofi-Aventis, Sunovion,
Takeda, and Viatris outside the submitted work. G.F. has received CME-related honoraria or consulting fees from Angelini, Janssen-Cilag, and
Lundbeck, Abbot. A.B. has received grants and served as a consultant for miCure Therapeutics. The other authors do not have an actual or
perceived conflict of interest with the contents of this article.
1
A.B. and G.F. contributed equally to this work as first authors.
2
E.V. and A.F.C. contributed equally to this work as senior authors.
dx.doi.org/10.1124/pharmrev.120.000007.
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324 Bortolozzi et al.
1. Ubiquitin-Proteasome System and Autophagy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336

2. Endoplasmic Reticulum Stress and Unfolded Protein Response Pathway . . . . . . . . . . . . . . . . . 336
H. Immunomodulatory Role of Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
IV. Ketamine, Lithium, and the Targeting of Homeostatic Synaptic Plasticity . . . . . . . . . . . . . . . . . . . 337
V. Biology of Lithium’s Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
VI. Lithium-Modified microRNA Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
VII. Repurposing Lithium for Brain Disorders Beyond Bipolar Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . 342
A. Parkinson Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
B. Huntington Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
C. Alzheimer Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
D. Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
E. Traumatic Brain Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
F. Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
VIII. Limitations for Lithium Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
A. Renal Funcion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
B. Thyroid and Parathyroyd Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
C. Lithium and Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
D. Metabolic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
E. Skin and Hair Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
F. Cognitive Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
G. Toxicity in Overdose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
IX. Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
Abstract——Over the last six decades, lithium has able insights into how lithium-induced modifications at
been considered the gold standard treatment for the the homeostatic synaptic plasticity level may play a piv-
long-term management of bipolar disorder due to its effi- otal role in its clinical effectiveness. We focused on find-
cacy in preventing both manic and depressive episodes ings from translational studies suggesting that lithium
as well as suicidal behaviors. Nevertheless, despite nu- may interface with microRNA expression. Finally, we are
merous observed effects on various cellular pathways exploring the repurposing potential of lithium beyond bi-
and biologic systems, the precise mechanism through polar disorder. These recent findings on the therapeutic
which lithium stabilizes mood remains elusive. Further- mechanisms of lithium have provided important clues to-
more, there is recent support for the therapeutic poten- ward developing predictive models of response to lithium
tial of lithium in other brain diseases. This review offers treatment and identifying new biologic targets.
a comprehensive examination of contemporary under-
standing and predominant theories concerning the Significance Statement——Lithium is the drug of
diverse mechanisms underlying lithium’s effects. These choice for the treatment of bipolar disorder, but its mech-
findings are based on investigations utilizing cellular anism of action in stabilizing mood remains elusive. This
and animal models of neurodegenerative and psychiatric review presents the latest evidence on lithium’s various
disorders. Recent studies have provided additional sup- mechanisms of action. Recent evidence has strengthened
port for the significance of glycogen synthase kinase-3 glycogen synthase kinase-3 (GSK3) inhibition, changes at
(GSK3) inhibition as a crucial mechanism. Furthermore, the level of homeostatic synaptic plasticity, and regula-
research has shed more light on the interconnections tion of microRNA expression as key mechanisms, provid-
between GSK3-mediated neuroprotective, antioxidant, ing an intriguing perspective that may help bridge the
and neuroplasticity processes. Moreover, recent advance- mechanistic gap between molecular functions and its
ments in animal and human models have provided valu- clinical efficacy as a mood stabilizer.
ABBREVIATIONS: AD, Alzheimer disease; Akt, serine/threonine kinase; ALS, amyotrophic lateral sclerosis; AMPAR, a-amino-3-hydroxy-
5-methyl-4-isoxazolepropionic acid receptor; Ab, b-amyloid; Bcl-2, B-cell lymphoma 2; BD, bipolar disorder; BDNF, brain-derived neurotrophic
factor; CaMKII, calcium/calmodulin-dependent protein kinase II; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element
binding protein; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; FDA, Food and Drug Administration; GDNF, glial
cell line–derived neurotrophic factor; GSK3, glycogen synthase kinase-3; GWAS, genome-wide association studies; HD, Huntington disease;
I-2, protein phosphatase-1/inhibitor-2 complex; IGF, insulin-like growth factor; IL, interleukin; IMPase, inositol monophosphatase;
IP3, inositol 1, 45-triphosphate; ISPC, induced pluripotent stem cell; MDD, major depressive disorder; miRNA, microRNA; mTOR,
mammalian target of rapamycin; NCS-1, neuronal calcium sensor protein 1; NF-jB, nuclear factor j-light-chain-enhancer of activated
B cells; NMDAR, N-methyl-D-aspartate receptor; PD, Parkinson disease; PGM, posphoglucomutase; PI3K, phosphatidylinositol
3-kinase; PKC, protein kinase C; PP1, protein phosphatase 1; PRS, polygenic risk score; SNP, single nucleotide polymorphism; STAT,
signal transducer and activator of transcription; TBI, traumatic brain injury; TLR4, Toll-like receptor 4; TrkB, tropomyosin receptor kinase B;
UPR, unfolded protein response.
Potential Therapeutic Effects of Lithium 325
I. Introduction of lithium can be investigated across various levels,
encompassing cellular and intracellular neuronal alter-
Lithium is an element of the alkali-metal group with ations, neural networks, and neurocognition. As a
an atomic weight of 6.94 (de Laeter et al., 2003). Lithium result, the clinical response to this treatment may
salts, which include lithium cation, lithium citrate, vary, leading to a heterogeneous outcome (Ikonomov
lithium carbonate, and lithium sulfate, possess mood- and Manji, 1999; Pasquali et al., 2010; Freland and
stabilizing properties and have been used for the treat- Beaulieu, 2012; Forlenza et al., 2014; Akkouh et al.,
ment of manic-depressive illness ever since John Cade’s 2020; Puglisi-Allegra et al., 2021). The etiology of BD
discovery in the mid-20th century (Shorter, 2009). remains incompletely understood, thought to arise from
Lithium was officially approved to treat acute manic an intricate interplay of elements that involve abnormal-
episodes by the US Food and Drug Administration ities in neuroanatomical structure and function, dis-
(FDA) in 1970 and affective recurrences in 1974 af- rupted signaling pathways and gene expression,
ter more than 30 years of recollected clinical evidence impaired synaptic plasticity, and decreased brain cell
on its efficacy (Cade, 1949; Gershon, 1970; Davis and density (Carvalho et al., 2020). Additionally, lithium’s
Fann, 1971). However, its pharmaceutical promotion was neurotrophic effects have been suggested to potentially
initially discouraged due to its low price and unpatent- mitigate some of these impairments (Puglisi-Allegra
ability, along with the potential for serious adverse effects et al., 2021). Recent advances in genetics and bioinfor-
(McKnight et al., 2012; Rybakowski et al., 2022) that lim- matics illuminate lithium’s pharmacology and have
ited lithium’s commercial appeal and uptake. Despite its renewed the interest in its mechanism (Hou et al., 2016;
demonstrated clinical efficacy, lithium’s use has witnessed Cearns et al., 2022), together with a rediscovery of lith-
a considerable decline in recent years (Rhee et al., 2020; ium in clinical practice (Anmella et al., 2021).
Carvalho et al., 2021; Bauer, 2022), concurrently with the This review will delve into the contemporary under-
discovery and marketing of second-generation anti- standing and recent advancements concerning lith-
psychotics for the treatment of bipolar disorder (BD) ium’s biologic functions and its roles in various brain
(Yatham, 2005), that proved equal efficacy in the disorders. To be precise, we start with a perspective
management of acute manic episodes (Segal et al., on the clinical use of lithium in mood disorders. Next,
1998; Berk et al., 1999). we discuss its molecular mechanisms and physiologic
The FDA-labeled indications of lithium are limited to roles in cellular processes, broadening the perspective
the maintenance treatment of BD as well as the treat- on new potential biologic underpinnings related to dif-
ment of acute manic episodes in BD; however, its use is ferent clinical uses of lithium. Moreover, we present
not limited to these conditions. Lithium is mainly used limitations to the use of lithium through the explica-
for the prophylaxis of recurrence and in the acute treat- tion of mechanisms implied in its toxicity, and we con-
ment of manic, hypomanic, and depressive episodes in clude our review with new perspectives and future
patients with BD (Carvalho et al., 2014; Malhi et al., directions in lithium treatment and research.
2015; Fountoulakis et al., 2017; Verdolini et al., 2021;
Nestsiarovich et al., 2022), although its efficacy may be
II. Clinical Use in Mood Disorders
greater preventing mania than depression when consider-
ing its polarity index (Popovic et al., 2012; Carvalho et al., BD is a severe psychiatric disorder characterized by
2014; Vieta et al., 2018). Lithium is additionally employed recurring mood episodes of depression alternating with
as an adjunctive treatment, augmenting the effect of anti- episodes of euphoria (called manic/hypomanic episodes),
depressants in individuals diagnosed with major depressive affecting approximately 2% of the general population
disorder (MDD) (Undurraga et al., 2019). Evidence from (Vieta et al., 2018). Despite the pharmacological guide-
many observational studies and randomized controlled tri- lines for treatment being well established, most indi-
als also supports the antisuicidal effect of lithium (Cipriani viduals still experience high rates of mood recurrences
et al., 2013). Because of its narrow therapeutic index (ap- or significant residual symptoms while on medication
proximately 2), regular plasma monitoring of lithium (Perlis et al., 2006). Lithium is considered a gold stan-
concentration is essential. It should be administered dard in treating all phases of BD, and it is recommended
to reach a concentration of 0.5–1 mEq/L 10–14 hours in all different international treatment guidelines
after the last administration (Malhi et al., 2020). Many (Fountoulakis et al., 2017; Malhi et al., 2020; Yatham
patients with BD show an excellent response to lith- et al., 2018). The targeted lithium level, also known as
ium; however, the response may vary among patients the therapeutic range, is the desired concentration of
(Kessing et al., 2011; Fornaro et al., 2016a; Hui lithium in the blood to achieve optimal treatment out-
et al., 2019; Lin et al., 2021; Stone et al., 2021). comes in individuals with BD. The specific targeted lith-
Even though lithium is commonly employed in clini- ium levels can vary among countries and guidelines.
cal practice and is acknowledged for its effectiveness in For example, the American Psychiatric Association
treating BD, the mechanism through which it produces (Hirschfeld et al., 2003) or the Canadian Network for
its effects remains largely unclear. The intricate impacts Mood and Anxiety Treatments and International
Society for Bipolar Disorders guidelines (Yatham (Chengappa et al., 2004; de Bartolomeis and Perugi, 2012;
et al., 2018) recommend a range of 0.8–1.2 mEq/L for Grande and Vieta, 2015, Kishi et al., 2022). Response
acute mania and 0.6–1.0 mEq/L for maintenance treat- to lithium appears to be better in patients with classic
ment. Similarly, the National Institute for Health and (euphoric) mania, whereas response rates are relatively
Care Excellence [National Collaborating Centre for worse in mixed states (Swann et al., 1997; Sportiche
Mental Health (UK), 2014] in the United Kingdom et al., 2017; Grunze et al., 2018) or rapid cycling
suggests a range of 0.8–1.0 mEq/L for acute mania and (Calabrese et al., 2005). Lithium is primarily used in
0.4–1.0 mEq/L for maintenance treatment. Monitoring concentrations in the range of 0.8–1.2 mmol/L during
lithium levels and adhering to the recommended acute mania (Yatham et al., 2018).
ranges are essential to ensure the effectiveness of
treatment and minimize the risk of side effects. Sev- B. Acute Depression
eral guidelines also recommend the use of lithium for Despite the high rates of patients with BD experienc-
treating patients with MDD or individuals with a ing multiple depressive episodes during their life, with
high risk of suicidality (Kennedy et al., 2016). In ad- a significant impact on global functioning (Manning,
dition to its effectiveness in managing and preventing 2005; Undurraga et al., 2012), few pharmacological op-
mood disorder symptoms, there is a belief that lith- tions exist to treat acute depressive episodes (Nivoli
ium has the potential to induce neurotrophic and
et al., 2011; Vieta and Valenti, 2013; Correia-Melo et al.,
neuroprotective effects across a diverse array of cellular
2017). Lithium is not approved for treating depressive
pathways. Moreover, it may impact brain circuits associ-
episodes for bipolar type I or type II patients since evi-
ated with behavioral, cognitive, and motor-related func-
dence of its efficacy on acute depressive episodes in
tions (Puglisi-Allegra et al., 2021). Indeed, it has been
recently reported that lithium might exert neuroprotec- monotherapy is less robust than that in acute manic
tion in stroke (Chen et al., 2022b), neurodegenerative episodes (Manchia et al., 2019; Rakofsky et al., 2022).
diseases such as dementia (Forlenza et al., 2014; Morris Indeed, a recent meta-analysis showed no statistically
and Berk, 2016; Velosa et al., 2020), spinal cord injury significant differences between lithium versus antide-
(Yang et al., 2012), and other diseases involving the ner- pressants or placebo in patients with bipolar depression
vous system, including BD (Bauer et al., 2003). Indeed, (Rakofsky et al., 2022). It should be noted that lithium
the number of lifetime affective episodes in BD might might be the most studied drug in BD. Still, its effect on
result in biologic insult, ultimately worsening the acute bipolar depression remains underexplored, with
course of the illness, which is conceptualized as most studies having several methodological limitations
“neuroprogression.” For these reasons, lithium’s clinical (Fountoulakis et al., 2022). Nevertheless, the use of lithium
use and neuroprotective effect should be seen as inter- for the treatment of acute bipolar depressive episodes is
twined entities since lithium might prevent neuroprog- every day and is also supported by clinical guidelines for
ression, and advanced neuroprogression might impact its antisuicidal properties and prophylactic effect against
lithium’s clinical response in BD (Bauer et al., 2017). affective recurrences, especially in combination with other
agents (Malhi et al., 2020).
A. Acute Mania
Despite not being the first-line option, lithium is
A manic episode is marked by elevated or irritable also prescribed to treat acute depression in patients
mood, increased energy levels, reduced need for sleep, with MDD, often as adjunctive treatment to conven-
and diminished attention span, among other symptoms tional antidepressants (Undurraga et al., 2019). Lithium
that may include aggressive behavior and impulsiveness. monotherapy did not show superiority over citalopram
Lithium is one of the indicated first-line treatments for in unipolar depressed patients (Bschor et al., 2013) and
acute mania. It has proven to be more effective than is not an established treatment of acute major depres-
placebo and equal to other mood stabilizers or antipsy- sion. Two studies showed that lithium is superior to
chotics in several studies (Cipriani et al., 2011; Hayes antidepressants (Bauer et al., 2000) or electroconvul-
et al., 2016; Bohlken et al., 2021). In addition, a recent sive therapy (Lambrichts et al., 2021) in preventing
meta-analysis including 36 randomized controlled trials relapses in MDD, but these results should be replicated
showed that lithium was more effective than placebo at in larger samples. Lithium’s role as an augmentation of
inducing response (odds ratio, 2.13; 95% CI, 1.73–2.63) antidepressants in treatment-resistant major depressive
or remission (odds ratio, 2.16; 95% CI, 1.73–2.69) in episodes is well clinically established and proven in sev-
acute mania (McKnight et al., 2019). However, it is often zquez et al., 2021).
eral clinical trials (Dold et al., 2018; Va
administered as a combination therapy with atypical
antipsychotics, (e.g., olanzapine, aripiprazole, cariprazine, C. Maintenance and Prophylaxis of Mood Episodes in
and asenapine, among others) (Conus et al., 2015; Bipolar Disorder
Kishi et al., 2022) to treat concomitant acute agita- The maintenance treatment of BD represents a major
tion or aggressive behavior during manic states clinical challenge since the lifetime recurrence rate of
affective episodes of both polarities is 95%, with a major trial reported no significant difference between lithium
impact on long-term disability and quality of life (Perlis and placebo in preventing suicide among veterans
et al., 2006; Vazquez et al., 2015; Etain et al., 2021). (Katz et al., 2022). However, this study reported off-
Noteworthy, people with BD experience depression therapeutic ranges of lithium levels (between 0.54 and
more frequently than they experience mania or hypo- 0.46 mmol/L) and had other critical methodological limi-
mania (Kupka et al., 2007). This may encourage the tations (Manchia et al., 2022). Contrasting results about
use of lithium in real-world clinical practice beyond the antisuicidal effect of lithium have been reported re-
the sole FDA approval, also aiming at reducing the cently (Nabi et al., 2022), but the reasons for the discrep-
odds of polypharmacy in BD (Fornaro et al., 2016b). ancy between these findings and previous meta-analyses
Lithium continues to be the preferred choice for may depend on the seemingly arbitrary inclusion and
maintenance treatment in both types I and II of BD exclusion of randomized controlled trials and an un-
(Hayes et al., 2016; Kessing, 2019). A network meta- satisfactory reinterpretation of data compared with the
analysis comparing the efficacy and tolerability of original publications (Bschor et al. 2022). The putative
various pharmacological treatments for bipolar dis- mechanism by which lithium exerts its antisuicidal ef-
order maintenance therapy demonstrated that lith- fect is mainly attributed to the mood-stabilizing proprie-
ium was more effective than a placebo in preventing ties in patients with mood disorders but also to some of
mood relapses (Kishi et al., 2021). Furthermore, in a its intrinsic characteristics in reducing impulsive or
multicenter, randomized, open-label trial involving aggressive behavior (M€ uller-Oerlinghausen and Lew-
individuals with BD type I, it was found that both itzka, 2010).
combination therapy with lithium and valproate, as
well as lithium monotherapy, were more effective at E. Neuroprotective and Neurotrophic Effects of Lithium
preventing relapses compared with valproate mono- Extensive evidence shows that lithium exerts a neu-
therapy (Geddes et al., 2010). In general, combina- roprotective effect through several biologic mechanisms.
tion therapy with lithium proved superior to mood- These include the reduction of oxidative stress and
stabilizer monotherapy in preventing recurrence of inflammation, up-regulation of mitochondrial function,
any type for up to 12 months (Kishi et al., 2021). and activation of neurotrophic response (Diniz, et al.,
Among other mood stabilizers, lithium also demon- 2013; Rybakowski et al., 2018). BD is a chronic disease
strated a higher preventive effect for manic episodes characterized by recurrent affective episodes associ-
compared with depressive episodes (Nestsiarovich et al., ated with related structural, functional, and the afore-
2022). In the long-term treatment of BD, target serum mentioned neurochemical brain changes in an illness-
levels should generally be around 0.6–1 mmol/L to reach related process conceptualized as “neuroprogression”
optimal clinical efficacy. There has been a recent proposal (Berk, 2009). The biologic underpinnings of BD neuro-
suggesting a dose-response relationship in which higher progression are thought to include different pathways,
serum lithium levels are associated with a reduced risk encompassing regulation of neurogenesis and apopto-
of recurrence (Hsu et al., 2022). sis to inflammation and redox stress-related pathways
and epigenetic modifications (Berk, 2009). The changes
D. Antisuicidal Effect affecting brain structure and function differ from those
Lithium has been associated with reduced suicide risk observed at the onset of the disease and become more
in individuals with BD or MDD as well as in the general evident with illness’ chronicity, which is linked to a
population in diverse observational and randomized clin- high number of depressive or manic episodes. Indeed,
ical trials (Cipriani et al., 2013). The reduction of suicide the neuroprogression construct suggests that each
risk is up to 60% after long-term lithium treatment. A mood episode might cause a biologic insult and conse-
rebound effect with increased rates of suicide with lith- quent neural damage, therefore increasing brain vulner-
ium discontinuation or in patients with poor treatment ability to developing future illness episodes (Berk, 2009).
adherence has also been reported (Gonzalez-Pinto et al., Neuroprogression influences the prognosis of BD,
2006). Lithium concentrations in drinking water might linked to a poorer response to treatment, including
also influence suicide risk, although the evidence is con- lithium (Fico et al., 2021), atypical antipsychotics (Berk
troversial (Del Matto et al., 2020; Rybakowski, 2022). In et al., 2011) and psychotherapy, cognitive and functional
the Systematic Treatment Enhancement Program for decline, and a higher tendency to relapse (Bauer et al.,
Bipolar Disorder study, the presence of suicidal ideation 2017). However, neuroprogression is probably only evi-
was found to be similar among patients with BD receiv- dent in a subgroup of patients with BD (Martino et al.,
ing lithium treatment and those not receiving it 2017). Because of the progressive nature of BD, it is
(Goldberg and Chengappa, 2009). Moreover, the study essential to commence disease-modifying treatments
revealed no significant relationship between lithium as early as possible. Lithium has been shown to prevent
use and suicide attempts or completions as well as structural and cognitive change after the first episode of
for other mood-stabilizing medications (Marangell mania (Berk et al., 2017; Daglas et al., 2017). Indeed,
et al., 2008). Interestingly, one recent randomized clinical good lithium responders also seem to show lower levels
of deterioration during follow-up (Bergh€ ofer et al., 2013). mechanisms (Malhi et al., 2013; Malhi and Outhred,
Thus, lithium’s unique neuroprotective proprieties might 2016; Won and Kim, 2017). Lithium is pleiotropic, and it
be key in targeting neurobiological alterations during neu- regulates a variety of proteins/cellular regulatory path-
roprogression in BD (Rybakowski and Suwalska, 2010; ways impacting different structural and functional levels
Squassina et al., 2017; Vecchio et al., 2020) as well as in of the brain, from molecular and cellular elements to
other neurodegenerative diseases (Forlenza et al., 2014). synaptic plasticity, neurotransmission, and brain circuits.
Lithium’s neuroprotective effect may be reflected in in- Hence, it is unclear if the agent has a single mechanism
creased cerebral gray matter in healthy subjects and pa- of action or works through a combination of synergistic
tients with BD (Moore et al., 2000; Berk et al., 2017; Hozer mechanisms (Fig. 1) (Alda, 2015; Anand et al., 2020;
et al., 2021). Also, lithium might ameliorate cellular signal Kavalali and Monteggia, 2020, Haggarty et al., 2021;
transduction pathways, mood regulation, and neurocogni- Ochoa, 2022).
tive function in BD (Puglisi-Allegra et al., 2021). Whether Earlier studies have highlighted the primary criteria
the proposed preventive effects of lithium are exerted for confirming the direct molecular targets of lithium,
on the systems mentioned above to prevent changes which include 1) the inhibition of the target protein’s
and, thus, cognitive decline in BD is unknown to date. activity at lithium concentrations that are therapeuti-
A better understanding of lithium’s impact on neu- cally significant (0.62–1.2 mM) both in vitro and in vivo
roprogression and its underlying biologic pathways procedures, 2) comparable outcomes by employing inhib-
affecting mood regulation and neurocognitive func- itors of the suggested target that are chemically distinct
tions might help to disentangle the etiology of BD. from lithium, 3) that the mimicking of lithium’s effect is
achieved by impairing the function of the proposed tar-
III. Mechanism of action get gene, and 4) restoring of target function or a down-
stream effector that revers the effect of lithium (Phiel
A. Inositol Monophosphatase, Posphoglucomutase, and Klein, 2001; O’Brien et al., 2011).
and Glycogen Synthase Kinase-3 Inhibition Specific lithium targets have been identified, including
The therapeutic and mood-stabilizing effects of lithium enzymes such as inositol monophosphatase (IMPase) and
are thought to involve neurotrophic and neuroprotective magnesium-dependent phosphomonoesterases, which are
Fig. 1. Lithium (Li1) modulates a number

of cellular pathways in the brain involved
in neuroplasticity and neuroprotection. In-
hibition of GSK3 is clearly central to its
therapeutic mechanisms. Recent research
has elucidated the direct and indirect effects
of lithium on neurotrophic response, ER
stress, UPR, autophagy, oxidative stress,
inflammation, and mitochondrial function,
mechanisms modulated by lithium that
facilitate cell viability. Lithium elicits ho-
meostatic synaptic plasticity that is de-
pendent on AMPAR expression on the cell
surface and requires BDNF/TrkB signal-
ing. Structural imaging studies indicate
that lithium may lead to neuroprotection
by increasing gray matter volumes in the
amygdala, hippocampus, and prefrontal
cortex. Conversely, findings from neuro-
psychological and functional magnetic
resonance imaging studies suggest that
the overall influence of lithium on cogni-
tion leans toward potential cognitive im-
pairment. Different biologic pathways
might be targeted during affective epi-
sodes: neurotransmitter modulation, in-
hibition of GSK-3 and dopamine regulation
in mania, enhancement of neuroplasticity
and neurotransmitter modulation in depres-
sion and cAMP signaling, and glutamate
and GABA regulation during maintenance
phases. MARCKS, myristoylated alanine-
rich C kinase substrate.
structurally related (Hallcher and Sherman, 1980). Several mechanisms are involved in the control of GSK3
These enzymes, which encompass inositol polyphos- actions, including phosphorylation, protein complex for-
phate 1-phosphatase (IPPase), fructose 1,6-bisphos- mation, and subcellular distribution. In addition, GSK3
phatase (FBPase), and bisphosphate 30 -nucleotidases has many unique properties, such as constitutive activity
(BPntase), possess a shared metal ion-binding consen- in cells and inhibition by extracellular stimuli, unlike
sus sequence. Additionally, phosphoglucomutase (PGM), other kinases, that are usually activated by extracellu-
responsible for converting glucose-1-phosphate (G1P) to lar stimuli. Phosphorylation on a serine residue of N-
glucose-6-phosphate (G6P), requires magnesium and is terminal GSK3 (serine 21 in GSK3a and serine 9 in
directly inhibited by lithium (York et al., 1995, 2001; GSK3b) leads to activity inhibition of GSK3. There are
Phiel and Klein, 2001). Additionally, lithium directly several protein kinases, including serine/threonine
inhibits glycogen synthase kinase-3 (GSK3), a crucial kinase (Akt; previously known as protein kinase B),
enzyme in glycogen metabolism that is now known to protein kinase A, and protein kinase C (PKC), known to
regulate various cell functions (Klein and Melton, 1996; phosphorylate GSK3 to inhibit its function (Fang et al.,
Cohen and Frame, 2001; Beurel et al., 2015). 2000). GSK3 activity is also negatively regulated through
Despite their structural differences, all three classes growth factor stimulation of mitogen-activated protein
of lithium targets—IMPase, PGM, and GSK3—rely on kinases (MAPKs) and mammalian target of rapamycin
magnesium for their function. In each instance, lithium (mTOR) (Doble and Woodgett, 2003; Kirshenboim et al.,
competes to occupy a magnesium-binding site (Snitow 2004).
et al., 2021). It is noteworthy that the identified primary GSK3 maintains cellular homeostasis by interact-
targets of lithium are intricately linked to the regulation ing with numerous substrates, such as transcription
of glucose metabolism or the control of phosphoglucose factors, glycolytic enzymes, pro- and antiapoptotic
levels. Specifically, PGM catalyzes the isomerization of factors, mitochondrial channels, membrane receptors,
G6P to G1P, IMPase plays a crucial role in gluconeogene- and cytoskeleton-associated proteins (Duda et al., 2018).
sis, and GSK3 acts to inhibit the incorporation of glucose The dysregulation of GSK3 is associated with numerous
into glycogen. prevalent and frequently comorbid diseases, such as
Indeed, the risk of type 2 diabetes is up to 3 times diabetes and/or insulin resistance, Alzheimer disease
higher in patients with BD than in healthy controls of (AD), Parkinson disease (PD), schizophrenia, MDD and
similar age and sex. Over half of BD patients have im- BD, among others (Jope and Johnson, 2004; Beurel
paired glucose metabolism, including insulin resistance, et al., 2015). Studies in human post mortem brain and
impaired glucose tolerance, or type 2 diabetes (Calkin peripheral cells have identified correlations between
et al., 2015; Vancampfort et al., 2016; Gim enez-Palomo alterations in GSK3 function and mood regulation,
et al., 2022). Interestingly, improvement in insulin resis- suggesting that depression may be associated with
tance with metformin is associated with improved symp- impaired inhibitory control of GSK3, and mania with
toms of BD (Calkin et al., 2022). Furthermore, lithium GSK3 hyperactivity (Karege et al., 2007; Diniz et al.,
treatment also affects downstream effectors, including 2011; Jope, 2011; Iwahashi et al., 2014).
adenylate cyclase, the phosphoinositol cascade, and the Consequently, a decline in serine phosphorylation of
metabolism of arachidonic acid. (Gould et al., 2004; GSK3 was observed in peripheral blood mononuclear
Quiroz et al., 2004; Rao and Rapoport, 2009; Chiu et al., cells during the disease state, and its levels were found
2013). Since lithium affects other magnesium-dependent to rise following lithium therapy (Li et al., 2010). Addi-
proteins, it has been estimated that there are >3000 tionally, recent evidence indicates that BD exhibits a bi-
human proteins whose function may be modified by modal pattern of energy, with enhanced energy levels
lithium treatment (Davies et al., 2000, Piovesan et al., during manic episodes and decreased energy levels dur-
2012; Puglisi-Allegra et al., 2021). Lithium’s capacity to ing depressive episodes. Notably, individuals experienc-
interact with a wide range of molecules grants it signifi- ing mania demonstrate heightened mitochondrial
cant potency as a pharmacological tool and makes it a respiration and ATP production as opposed to individu-
valuable asset in both clinical and preclinical research als during euthymia or depression, who display dimin-
(Fig. 2). ished mitochondrial function (Morris et al., 2017).
GSK3 is a serine/threonine protein kinase (PK) with The notion that GSK3 represents the therapeutic
two isoforms, GSK3a and GSK3b. Although both iso- target of lithium is reinforced by preclinical research
forms are expressed at comparable levels in the mouse involving genetic modifications of GSK3 or its down-
brain (Yao et al., 2002), in the human brain, the b iso- stream components. Downregulation of GSK3b mimics
zyme predominates (Lau et al., 1999), highlighting its the effects of lithium on behavior in mice, whereas
critical role in the functioning of the human central ner- GSK3b overexpression reverts the lithium-induced
vous system. Furthermore, GSK3 plays a pivotal role in neurobehavioral effects in mice (O’Brien et al., 2004,
numerous cellular processes and diseases (Harwood, 2011), indicating that GSK3 is a critical target of lith-
2001; Jope and Johnson, 2004; Beurel et al., 2015). ium in mammalian behaviors. Moreover, in b-arrestin
Fig. 2. Representative scheme of the main molecular and cellular targets modulated directly and indirectly by lithium (Li1). Lithium inhibits IMPase
(A), including inositol polyphosphate 1-phosphatase (IPPase), fructose 1,6-bisphosphatase (FBPase), and bisphosphate nucleotidases (BPntase). These enzymes
are part of the phosphatidylinositol 4,5-bisphosphate (PIP2) cycle, one of the signaling pathways underlying many cellular functions, such as G-coupled neuro-
transmitter receptors (GPCR) signaling, cytokinesis, endocytosis, and apoptosis. Phospholipase C (PLC) mediates the hydrolysis of PIP2 to the secondary mes-
sengers diacylglycerol (DAG) and IP3, which, in turn, activate downstream signaling pathways, including PKC and IP3 receptor (IP3R)/ER stress/ UPR.
Therefore, lithium inhibits ER stress (ERS), altered UPR signaling, and increased intracellular Ca21 levels through depletion of free inositol (B) and subsequent
lower IP3 levels and IP3R activation (C). ERS and abnormal UPR result in the buildup of misfolded or unfolded proteins, faulty autophagy, and cell death via
apoptosis. Lithium acts to counter these effects through the IP3/IP3R mechanism (C). Lithium directly inhibits GSK3 and facilitates the phosphorylation of
GSK3 at the N-terminal serine (D). Lithium also acts by inhibiting PKC (D) through an intricate myristoylated alanine-rich C kinase substrate (MARCKS)
pathway initiated by its inhibition of GSK3 (D). Inhibition of PKC and GSK3 by lithium prevents the potentially harmful effects of downstream activation of these
pathways. These include 1) oxidative stress pathway (E) due to accumulation of reactive oxygen species (ROS) scavenged from damaged mitochondria and downre-
gulation of the transcriptional nuclear factor (erythroid-derived 2)-like 2 (Nrf2); 2) impaired transcription of neurotrophic, neuroprotective, and antioxidant genes
(F), such as BDNF, vascular endothelial growth neurotrophic (VEGF), IGF, Bcl-2, and Nrf2, which is reversed by lithium through inhibition of GSK3 (D) and acti-
vation of the CREB transcription factor placed downstream of GPCRs (F); 3) activation of the inflammasome, production of proinflammatory cytokines underlying
activation of the STAT/interferon-c (INFc)/NF-kB pathway (G); and 4) accumulation of hyperphosphorylated s, which is concurrent to cytoskeletal altera-
tions and autophagy impairment (H). The anti-inflammatory effects of lithium are also produced by suppressing TLR4 signaling (G). Lithium also modi-
fies the expression of miRNAs and their targeted mRNA, suggesting that they could play a role in modulating lithium’s clinical efficacy (I). Modified from
Puglisi-Allegra et al. (2021). eIF2a, eukaryotic translation initiation factor 2a.
2 knockout mice, lithium administration fails to impact and cellular effects in rats (Georgievska et al., 2013).
Akt/GSK3 signaling but still induces behavioral changes Additionally, GSK3b inhibition alone did not increase
associated with GSK3 inhibition, resembling the effects brain-derived neurotrophic factor (BDNF) levels. In
observed in wild-type mice. Correspondingly, specific contrast, lithium administration did (Caberlotto et al.,
GSK3 inhibitory peptides reproduce the behavioral 2013), indicating that other mechanisms/pathways may
outcomes of lithium in mice (Gould et al., 2004; be involved in the therapeutic responses to lithium
Kaidanovich-Beilin et al., 2004; Beaulieu et al., (Fig. 2).
2004, 2008). Thus, lithium inhibits GSK3 signaling by However, the mechanisms underlying GSK3 lithium-
binding directly to the magnesium-sensitive site of the induced inhibition and how it contributes to both anti-
enzyme and indirectly by increasing the phosphoryla- manic and antidepressant effects remain uncertain.
tion of this kinase at specific serine21/9 residues. Recent research suggests that mood stabilizers work
Valproate, in addition to antidepressants (including by blocking GSK3, which, in turn, makes cells more
the rapid-acting antidepressant ketamine) and antipsy- responsive to natural extracellular signals, like neuro-
chotics, indirectly suppresses GSK3 activity through trophins and neurotransmitters. These signals typically
the phosphorylation of serine21/9. This suggests a com- activate Akt, leading to the phosphorylation and deacti-
mon mechanism involving GSK3 across these treat- vation of GSK3 inactivation (Puglisi-Allegra et al., 2021;
ments (Beurel et al., 2011; Zarate and Machado-Vieira, Snitow et al., 2021) (Fig. 3). However, GSK3 opposes its
2016; Snitow et al., 2021). Nevertheless, a recent study phosphorylation through two mechanisms: one involving
using selective GSK3b inhibitors, such as AZ1080 and the inhibition of Akt through a b-arrestin complex and
compound A, showed that GSK3b inhibition alone the other involving the activation of protein phosphatase
does not replicate the lithium-induced behavioral 1 (PP1) by GSK3, which is inhibited by protein
[see Kleandrova and Speck-Planche (2020), Vignaux

et al. (2020), Zhu et al. (2020), and Reilley et al.
(2021) for more details].
B. Protein Kinase C and Myristoylated Alanine-Rich
C Kinase Substrate Inhibition
PKC is a family of enzymes involved in mood regu-
lation, relying on calcium and phospholipids for acti-
vation. The conventional PKC isoforms (a, bI, bII, c)
necessitate both calcium and diacylglycerol for activa-
Fig. 3. Positive feedback mechanisms regulating GSK3. (A) GSK3 is phos- tion, whereas the newer PKC isoforms (d, e, g, h, l)
phorylated and inhibited by AKT in response to upstream signals. PP1 de-
phosphorylates and activates GSK3. GSK-3 inhibits AKT and activates PP1, can be activated solely by diacylglycerol (Zarate and
thereby potentiating its activity. (B) Lithium, directly and indirectly, inhibits Manji, 2009). The conventional PKC isoforms are the
GSK3 and disrupts both feedback loops. Disruption of these feedback loops
by lithium may leave an increased response of endogenous ligands (e.g., neu- prevailing variants and are prominently present in mul-
rotransmitters such as glutamate, dopamine, and serotonin) that signal tiple brain regions, with a notable presence at presyn-
through AKT and whose synaptic levels are affected in BD. Modified from aptic terminals, including those in the prefrontal cortex,
Snitow et al. (2021).
amygdala, and hippocampus (Naik et al., 2000; Zarate
and Manji, 2009). PKC signaling is involved in several
intracellular pathways regulating neuronal excitability,
phosphatase-1/inhibitor-2 complex (I-2). Deactivation of
neurotransmitter release, glutamate signaling, and neu-
Akt hinders the phosphorylation and suppression of
roplasticity (Zarate et al., 2003, 2006a; Chu et al., 2014;
GSK3. Lithium and other GSK3 inhibitors interfere
Pahl et al., 2014) and underlies many of the patho-
with this process by disrupting the complex, enabling
logic mechanisms, including neuroinflammation and
Akt to stay active and continue phosphorylating GSK3
mitochondrial dysfunction related to oxidative stress
(Beaulieu et al., 2004; O’Brien et al., 2011). The phos-
and apoptosis (Jun et al., 2014; Nam et al., 2015).
phorylation of GSK3 at I-2 prompts its detachment
Accumulating evidence from both human and animal
from PP1, which subsequently leads to the dephosphor-
studies strongly supports the substantial role played by
ylation of GSK-3 and the restoration of its activity. Lith-
this enzyme group in BD. Inhibiting PKC has been
ium and other GSK3 inhibitors block the process by
shown to effectively reduce manic-like behaviors and
which PP1 dephosphorylates GSK3 in an I-2–dependent mitigate hippocampal cell degeneration in rat models of
manner (Zhang et al., 2003; Freland and Beaulieu, 2012; mania induced by sleep deprivation (Abrial et al., 2013).
Snitow et al., 2021). Individuals with BD show increased PKC activity in
As a result, when GSK3 is pharmacologically inhib- both central (cortical) and peripheral (platelet) regions
ited, it lowers the threshold for endogenous signals to when compared with healthy controls (Wang and Fried-
deactivate cellular GSK3 clusters. This means that man 1996; Wang et al., 1999). Finally, a meta-analysis
even relatively weak signals can generate a consistent involving 8700 patients with unipolar and bipolar de-
response due to the increased inhibition of GSK3. This pression has identified a significant correlation between
mechanism may explain how lithium sensitizes cells to PKCe genetic locus and suicidality (Saxena et al., 2017).
endogenous neurotransmitters or other signals that may Furthermore, genomic investigations have established
be diminished in BD, and it may account for the effec- correlations between specific loci and lithium respon-
tiveness of lithium treatment as an adjunct to antide- siveness, indicating a potential shared genetic predis-
pressants in treatment-resistant depression (Snitow position for both the disease and the response to
et al., 2021). treatment (Turecki et al., 2001; Khayachi et al., 2021).
Lithium shows efficacy in treating both manic and de- In this context, research has shown that long-term
pressive episodes in BD and is a potential drug for neu- lithium treatment leads to a reduction in PKC levels
rodegenerative diseases. Unfortunately, lithium suffers in the platelets of individuals with BD (Soares et al.,
from significant drawbacks, mainly a narrow therapeutic 2000). Additionally, both lithium and valproic acid have
window and renal toxicity (Davis et al., 2018). Undoubtedly, shown the ability to inhibit PKC activity in vitro and
among the many molecular targets of lithium, GSK3b in vivo (Chen et al., 1994, 2000a; Zarate and Manji
may be in part responsible for its therapeutic effects, 2009), which has led to the study of PKC as a potential
so the development of selective inhibitors of this kinase therapeutic drug target.
could influence the side effects of lithium. Although Remarkably, the prolonged use of quercetin, which is
beyond the scope of this review, in recent years, the a nonspecific PKC inhibitor, has been observed to block
application of machine learning is accelerating the methylphenidate-induced hyperlocomotion and lipid per-
discovery of potential drugs with GSK3b inhibitory oxidation in mice (Kanazawa et al., 2017). Furthermore,
activity that can be repurposed as therapeutics for tamoxifen, another potent PKC inhibitor, has shown effi-
mood disorders and/or neurodegenerative disorders cacy in the treatment of acute manic or mixed episodes
in BD (Yildiz et al., 2008, 2016; Amrollahi et al., 2011; The potential mechanisms for how lithium increases
Kulkarni et al., 2014; Talaei et al., 2016). It is worth BDNF levels are complex. Lithium affects adenyl cy-
noting that despite its promising antimanic proper- clase enzymes, increasing and stabilizing the production
ties (Talaei et al., 2016; Palacios et al., 2019; Novick of cyclic adenosine monophosphate (cAMP) (Manji and
et al., 2020), the FDA has not granted its approval Lenox, 2000). Increased cAMP levels increase protein ki-
for the treatment of manic episodes. However, a new nase A activity, an enzyme that phosphorylates and acti-
PKC inhibitor called endoxifen has received approval vates numerous other molecules and enzymes, including
in India (Ahmad et al., 2021). the transcription factor cAMP response element binding
protein (CREB). When activated through phosphoryla-
C. Enhancement of Trophic Factors tion, CREB increases BDNF transcription and produc-
Putative mechanisms for the therapeutic effects of tion (Zheng et al., 2011). Promoter exons are regions of a
lithium also include the upregulation of trophic factors gene that promote its transcription to produce more of a
and activation of their receptors (Hashimoto et al., targeted protein. The BDNF gene has several promoter
2004, Seelan et al., 2008; Gideons et al., 2017; Haupt exons, and studies in animal models suggest that lith-
et al., 2021). In addition to being the first choice in the ium upregulates the function of promoter exon IV.
treatment of BD, recent reports point to lithium having When exposed to therapeutic concentrations of lithium,
beneficial effects on Alzheimer disease (Nelson et al., cultured rat cortical neurons exhibited elevated levels
2014; Damri et al., 2020), and there are suggestions that of BDNF mRNA containing exon IV and an enhanced
lithium may help individuals with PD (Guttuso et al., activity of BDNF promoter IV (Yasuda et al., 2009;
2019). At least part of the reason that lithium has bene- Dwivedi and Zhang, 2015). Through increased BDNF
fits in these pathologic conditions is probably due to its production, lithium may enhance neurogenesis, nerve
effects on BDNF levels. cell growth and survival, and neural plasticity. These
BDNF, acting via the tropomyosin receptor kinase effects explain at least part of the therapeutic effects
B (TrkB) receptor to promote cortical development, syn- seen with its use. More recently, Gideons et al. (2017)
aptic plasticity, neurogenesis, and neuronal viability, is have highlighted the necessity of BDNF-TrkB signaling
recognized for its significant contribution to BD and in the lithium-induced antimanic-like response, whereas
other psychiatric disorders (Fernandes et al., 2011; Autry this mechanism does not appear to be involved in the
and Monteggia, 2012; Malhi et al., 2013; Scola and An- antidepressant-like effects of lithium. Furthermore, they
dreazza, 2015; Rowland et al., 2018). Six separate meta- have identified a direct impact of lithium treatment on
analyses consistently demonstrated that in BD, BDNF the trafficking of a-amino-3-hydroxy-5-methyl-4-isoxazole
plasma levels were significantly lower than those in propionic acid receptors (AMPARs), wherein there is a
healthy controls, schizophrenia, or unipolar depression decrease in the cell surface expression of AMPARs due
(Molendijk et al., 2014; Fernandes et al., 2015; Rowland to a sustained increase in dynamin-mediated AMPAR
et al., 2018). Moreover, BDNF levels are reduced in ma- endocytosis. This process is reliant on the proper func-
nia or depression but not during euthymia (Tunca et al., tioning of BDNF-TrkB, offering valuable mechanistic in-
2014; Fernandes et al., 2015; Rowland et al., 2018). Fur- sights into the actions of lithium that may underpin its
thermore, in individuals with BD, BDNF mRNA levels therapeutic efficacy in the treatment of BD. Further-
in white blood cells are also lower in individuals with BD more, alterations in BDNF levels induced by lithium
compared with unaffected individuals (D’Addario et al., alone can effectively inhibit the activity of GSK3b (Ma-
2012). Post mortem analysis of hippocampal tissue has chado-Vieira et al., 2009). It’s worth noting that BDNF
also revealed reduced BDNF protein levels in patients not only acts as a mediator for gene expression linked
with BD (Knable et al., 2004). Manic (Frey et al., 2006; to synaptic plasticity through PKC signaling (Arevalo
Jornada et al., 2010; Fries et al., 2015) and depressive- and Wu, 2006) but also plays a role as a regulator of
like behavioral animal models (Tsankova et al., 2006; PKC itself, influencing BDNF and other neurotrophins’
Bj€orkholm and Monteggia, 2016; Koo et al., 2019) have expression (Xu et al., 2013, 2015b). The intricate inter-
also shown a decrease in both BDNF mRNA and protein play between these pathways underscores the complex
levels in the hippocampus. Conversely, lithium treatment role that neurotrophins play in regulating a wide range
has been associated with increased BDNF protein levels of neuronal signaling mechanisms, rendering them sig-
(Cunha et al., 2006; Tramontina et al., 2009; de Sousa nificant molecular targets of lithium.
et al., 2011) and increased BDNF mRNA and protein Other trophic factors have been identified as molecu-
expression in the hippocampus, cortex, and amygdala lar targets of lithium, such as glial cell line–derived neu-
in rodent models and in cultured cortical neurons rotrophic factor (GDNF), vascular endothelial growth
(Fukumoto et al., 2001; Yasuda et al., 2009; Jornada factor, and insulin-like growth factor (IGF). However,
et al., 2010). Lithium treatment also increases TrkB the mechanisms involved are less understood than those
activity in neuronal cultures and enhances BDNF- of BDNF (Scola and Andreazza, 2015). GDNF levels in-
TrkB signaling (Hashimoto et al., 2002). crease with lithium treatment in astrocyte cultures
(Emamghoreishi et al., 2015). Hence, it is plausible When cells face harmful insults, lithium plays a protective
that the neuroprotective benefits of lithium may not be role by preserving mitochondrial function, by reducing re-
restricted solely to neurons but could also encompass as- active oxygen species, thus preventing cell apoptosis (Hou
trocytes. Several findings on the effects of GDNF in BD et al., 2015).
reveal that different stages of the disorder and pharmaco- Consistent with these findings, recent research
logical treatment with lithium may alter GDNF expres- affirms (confirms) that lithium protects the hippocam-
sion in BD. However, there is some controversy about the pus from apoptosis by engaging neuroprotective and
possibility of considering GDNF as a nonspecific periph- anti-inflammatory pathways (Liechti et al., 2014; Dwivedi
eral factor marker that may respond to lithium treatment and Zhang, 2015). Indeed, lithium decreased the expres-
(Scola and Andreazza, 2015). Lithium may increase vas- sion of proapoptotic genes Bad, Bax, and caspase 3. Inter-
cular endothelial growth factor expression through phos- estingly, a clinical study showed that BD patients who
phatidylinositol 3-kinase (PI3K)/GSK3b–dependent and - respond to lithium showed an increased ratio of anti- to
independent pathways in brain endothelium and astro- proapoptotic genes in blood cells. In contrast, patients
cytes, contributing to lithium’s ability to promote neuro- who do not respond to lithium had no significant effect
vascular remodeling after stroke (Guo et al., 2009). (Lowthert et al., 2012). Thus, effects on pro- and antia-
Furthermore, genetic investigations have indicated poptotic genes might underpin lithium action in clinical
the involvement of IGF in BD as its gene is situated in response to BD. There are several possibilities whereby
the chromosomal region 12q23.2, a region associated lithium modulates the transcription of pro- and antiapop-
with BD pathophysiology (Curtis et al., 2003; Pereira totic genes. One could be that BDNF-induced activation
et al., 2011). Interestingly, the mRNA expression of IGF- of extracellular signal-regulated kinase (ERK) signal-
binding protein-2, a protein with high affinity for IGF-1 ing may lead to increased expression of these genes. For
or IGF-2, used to transport these factors to other tissues example, the Bcl-2 gene contains binding sites for CREB,
or organs, was found to be reduced in the prefrontal cor- a transcription factor activated by ERK1/2.
tex of individuals with BD (Bezchlibnyk et al., 2007). Interestingly, lithium has earlier been shown to upre-
Moreover, patients with BD exhibited lower blood lev- gulate ERK expression in cultured cells and rats’ frontal
els of IGF-1 compared with those with schizophrenia cortex and hippocampus (Chen and Manji, 2006). Fur-
(Palomino et al., 2013). Intriguingly, IGF-1 was observed thermore, lithium also upregulates the expression of
to be upregulated in lymphoblastoid cells derived from BAG-1, a gene that binds to and increases the activity
lithium-responsive BD patients (Squassina et al., 2013), of Bcl-2 (Zhou et al., 2005). Thus, the effect of lithium on
suggesting that one potential mechanism of lithium’s Bcl-2 could be associated with increased expression of
action might involve the regulation of IGF-1 secretion, BAG-1 (Dwivedi and Zhang, 2015).
a known cell survival factor that prevents apoptosis
(Fidaleo et al., 2017). E. Intracellular Signaling Cascades
1. PI3K/Akt Pathway. As stated above, BDNF in-
D. Factors Affecting Apoptotic Signaling duction is an early and essential step in the neuro-
Apoptosis, the process of programmed cell death driven plasticity and neuroprotection activity of lithium as
by signal transduction, has been a subject of extensive demonstrated using different animal models of trau-
research. Seminal studies have revealed that lithium has matic brain injury (TBI) (Ciftci et al., 2020), cerebral
several remarkable effects: 1) it elevates the expression ischemia (Fan et al., 2015; Ates et al., 2022), and
of the B-cell lymphoma (Bcl-2) protein, a key regulator of many others (Dou et al., 2005; Nowicki et al., 2008). It
programmed cell death; 2) it reduces the expression of has been suggested that neuroprotection may originate
proapoptotic proteins such as p53 and Bax; and 3) it from activating the PI3K/Akt signal transduction path-
hinders the release of cytochrome c from mitochondria way (Kilic et al., 2017). Additionally, the trophic influ-
induced by glutamate in cultured neurons (Chen and ence of BDNF is intricately connected to the activation
Chuang, 1999). In addition to its impact on neurons, induced by lithium in cell survival pathways, specifi-
chronic lithium administration also increases Bcl-2 cally the PI3K/Akt and MEK/ERK (also known as the
protein levels in astrocytes, which are crucial for neu- Ras-Raf-MEK-ERK) pathways (Chiu et al., 2013).
ronal survival (Keshavarz et al., 2013). It is noteworthy Akt, a serine/threonine kinase regulated by PI3K,
that differences in Bcl-2 gene expression may serve as a experiences activation through phosphorylation at
distinguishing factor between lithium responders and Thr308 and Ser473 residues (Jacinto et al., 2006).
nonresponders (Beech et al., 2014), suggesting that the Notably, lithium has been shown to induce the phosphor-
effectiveness of lithium treatment might be linked to the ylation of Akt at Ser473 (Tian et al., 2014; Fan et al.,
preservation of neurons and their supporting cellular 2015). Early studies conducted with cultured rat cerebel-
structures. Furthermore, valproate also exhibits antia- lar granule cells revealed that lithium rapidly counter-
poptotic properties, hinting at a potential shared mech- acted Akt-glutamate–induced inactivation by stimulating
anism where mood stabilization coincides with the PI3K, leading to increased phosphorylation of Akt at its
reduction of apoptotic pathways (Gupta et al., 2012). Ser473 residue. This Akt activation triggers alterations
in Bcl-2–associated death promoter, CREB, members in the mammalian brain. Furthermore, lithium contrib-
of the forkhead family, and procaspase-9, which are utes to learning and memory processes. Recent neuroim-
antiapoptotic targets (Chiu et al., 2013). Similarly, in cul- aging research underscores the significance of the
tured human neuroblastoma cells, lithium treatment hippocampus as a key target for the effects of lithium.
demonstrated an inhibitory effect on caspase-3 activation Studies in mice and humans show an accumulation of
induced by neurotoxins mimicking the neurochemical lithium in the hippocampal regions of the brain after re-
changes associated with PD. This inhibition occurred in peated oral administration (Zanni et al., 2017; Stout
a manner dependent on PI3K (King et al., 2001). More et al., 2020; Palmos et al., 2021). In addition, large mega-
recently, Ates et al. (2022) reported that, in a mouse analyses from the ENIGMA neuroimaging consortium
model of brain ischemia, the phosphorylation of Akt at suggest that smaller hippocampal volumes are a common
Thr308 was significantly higher than that at the Ser473 feature among psychiatric disorder patients (Hibar et al.,
residue following the administration of a therapeutic 2016; van Erp et al., 2016; Logue et al., 2018). Neverthe-
dose of 2 mmol/kg lithium. This finding suggests that less, individuals with bipolar disorder who are on long-
the PI3K/Akt pathway plays a major role in lithium’s term lithium treatment display larger hippocampal
neuroprotective activity. volumes compared with their nonmedicated counter-
2. MEK/ERK Pathway. Genetic studies of BD and parts within the BD patient group (Hajek et al., 2012).
molecular studies of lithium’s mechanism have previ- This indicates that lithium therapy could potentially
ously pointed to MEK/ERK pathways. Reduced phos- mitigate the reductions in hippocampal volume typically
phorylation of ERK1/2 has been observed in post mortem observed in individuals with psychiatric disorders, either
samples collected from the prefrontal cortex of patients through the preservation of existing neurons or the stim-
with BD (Yuan et al., 2010) and in both the prefrontal ulation of neurogenesis.
cortex and hippocampus of individuals who died by sui- These data align with preclinical research indicating
cide (Dwivedi et al., 2009). Preclinical studies showed that mice treated with lithium experience increased
that lithium might engage ERK to alter the expression
neurogenesis, which is associated with the activation
of PER2 by activating the transcription factor egr-1 (Kim
of Wnt signaling. This activation is evident through
et al., 2013). Furthermore, U0126, both a K252a and the
enhanced nuclear b-catenin staining in newly formed
MEK inhibitor, inhibits the antidepressant-like effects
neurons (Fiorentini et al., 2010; Valvezan and Klein,
induced by BDNF (Shirayama et al., 2002), supporting
2012). The inhibition of GSK3 by Wnt canonical signal-
the notion of TrkB’s involvement in activating the
ing allows the translocation of b-catenin to the nucleus
MEK/ERK pathway. ERK, in turn, regulates several
and facilitates activation of b-catenin/TCF-LEF target
downstream effector systems, including the transcrip-
genes critical for synapse plasticity and neurogenesis
tion factor nuclear factor j-light-chain-enhancer of acti-
(Valvezan and Klein, 2012). Moreover, lithium’s impact
vated B cells (NF-kB) and ribosomal S6 kinase (RSK).
Additionally, ERK inhibits GSK3b and activates CREB extends to suppressing astrogliogenesis through non–
(Steelman et al., 2004). CREB functions as a shared down- GSK3-mediated mechanisms. Consequently, lithium
stream effector for both the PI3K/Akt and MEK/ERK appears to enhance the neuronal differentiation of neural
signaling pathways. When it is activated through phos- stem cells through a dual mechanism, promoting neuro-
phorylation, it assumes a pivotal role in bolstering cell genesis while curtailing astrogliogenesis (Zhu et al.,
survival by upregulating the expression of cell-protective 2011; Kerr et al., 2018). However, recent in vitro findings
proteins, like BDNF and Bcl-2 (Finkbeiner, 2000). Inter- have suggested that high-dose lithium treatment at
estingly, treatment with lithium enhances ERK phos- 2.25-mM levels can increase the generation of neuro-
phorylation; however, the lithium-induced enhancements blasts, neurons, and glial cells in human hippocampal
in BrdU-positive cells and cognitive function were hin- progenitors. This treatment also influences the expres-
dered by the administration of U0126 (Yan et al., 2007a). sion of genes responsible for regulating the molecular
In addition, more recently ERK was identified as a regu- layer’s volume in the dentate gyrus (Palmos et al., 2021).
lator of lithium’s effect on circadian rhythm amplitude in These findings support the idea that adult hippocampal
fibroblasts from BD patients and demonstrated that neurogenesis and gliogenesis are mechanisms that could
p-ERK1/2 is decreased in BD cells (McCarthy et al., help explain the therapeutic effects of lithium.
2013; 2016). 4. Calcium/Calmodulin-Dependent Protein Kinase II/
3. Wnt/b-Catenin Pathway. Lithium serves multi- CREB Pathway and Calcium Channels. Lithium treat-
ple essential functions in maintaining the proper func- ment not only exerts a neuroprotective action through
tioning of the nervous system, including its role in Akt activation but also through calcium/calmodulin-
enhancing neurogenesis, synaptic plasticity, and cell sur- dependent protein kinase II (CaMKII) activation and
vival (Chen et al., 2000b; Schloesser et al., 2008; Kim calcium mobilization, respectively, leaving an inhibi-
and Thayer, 2009). Neurogenesis, a critical process for tion of apoptosis signaling (Kang et al., 2003). Indeed,
hippocampal plasticity, continues throughout adulthood activation of these kinases leaves a lithium-induced
neuroprotective function in a rat model of ischemia- F. Oxidative Stress Pathways and Mitochondrial
induced brain injury (Sasaki et al., 2006). Dysfunction
CaMKII plays a critical role in neurotransmission, A growing body of evidence points to disrupted mito-
synaptic plasticity, learning, and memory. In post chondrial function in psychiatric conditions, including
mortem brain samples from patients with BD, lower BD, as well as in neurodegenerative diseases that mani-
levels of CaMKII mRNA expression were reported in fest psychiatric symptoms. In fact, various mitochondrial
different laminae of Brodmann’s area nine and area abnormalities have been documented in psychiatric dis-
46 compared with control subjects (Xing et al., 2002). orders, encompassing reduced expression of peroxisome
These early observations suggested that decreased proliferator-activated receptor c (PPARc), diminished
CaMKII expression/function in patients with BD seems mitochondrial respiration, imbalances in proinflamma-
to be associated with some of the affective and cognitive tory and apoptotic responses, and impaired mitochon-
alterations reported in BD. Preclinical studies in rats drial motility (Pei and Wallace, 2018, Preston et al.,
confirmed that CAMKII-CREB signaling pathway acti- 2018; Galts et al., 2019; Kolar et al., 2021; van Rensburg
vation in the hippocampus and prefrontal cortex are im- et al., 2022). BD is hypothesized as being a biphasic dys-
plicated in memory consolidation of inhibitory avoidance regulation of mitochondrial biogenesis, decreased in
learning (Ghasemzadeh and Rezayof 2016; Amiri et al., depression and increased in mania (Morris et al., 2017).
2020). Furthermore, Amiri et al. (2020) also reported Although exploring signaling pathways and mechanisms
that glutamate NMDA receptors are involved in the related to mitochondrial dysfunction exceeds the scope
interactive effects of lithium and olanzapine on mem- of this review, we will briefly report evidence indicating
ory consolidation through the CAMKII-CREB signal- the involvement of oxidative stress pathways in several
ing pathway. central nervous system disorders as well as their regula-
Recent findings also focus on the role of calcium, tion by lithium.
calcium channels, and neuronal calcium sensor pro- Research involving individuals with bipolar disorder
tein 1 (NCS-1) in the etiology of BD (D’Onofrio et al., has indicated that lithium reduces levels of lipid peroxi-
2017; Garcia-Rill et al., 2019). In the manic or mixed dation and enhances mitochondrial function, effectively
state, patients with BD display reduced auditory elec- countering the impacts of oxidative stress (Khairova
troencephalogram synchronization in the b/c band et al., 2012; De Sousa et al., 2014, 2015). Using different
animal models of cerebral ischemia or neurotoxicity
during a click train paradigm (O’Donnell et al., 2004).
induced by 3-nitro propionic acid or kainic acid, lith-
c band oscillations are essential to information proc-
ium was found to prevent neuronal sensitivity to oxi-
essing during states of arousal, such as sensory percep-
dative damage (Rojo et al., 2008; Castro et al., 2009;
tion and motor behavior, and are thought to be involved Khan et al., 2015; Chen et al., 2016). The protective
in memory formation (Kann et al., 2014, Mably and effects of lithium against oxidative damage are evident
Colgin, 2018). Therefore, a decrease in high-frequency through several indicators, including reduced levels of
c band activity may underlie many of the symptoms of lipid peroxidation, as measured by thiobarbituric acid
BD, such as sleep disturbances, emotional dysregula- reactive substances (TBARS) or 4-hydroxynonenal
tion, attention and memory deficits, and impairments (4-HNE), decreased protein carbonylation, and a decrease
in fine motor skills (Goldberg and Chengappa, 2009). in the production of reactive oxygen species (Shao et al.,
Importantly, the reticular activating system, especially 2005; Rojo et al., 2008; Castro et al., 2009). Further-
the pedunculopontine nucleus, generates c oscillations more, lithium treatment has been shown to boost the
via calcium channels, pointing to roles for the reticular expression of antioxidant enzymes such as catalase
activating system and calcium in the disease progression (Khan et al., 2015), heme-oxygenase-1 (HO-1) (Khan
(D’Onofrio et al., 2017; Byrum et al., 2019). Human post et al., 2015; Chen et al., 2016), and NAD(P)H quinone
mortem studies reported increased expression of NCS-1 oxidoreductase-1 (NQ01) (Chen et al., 2016) as well as
in the brains of patients with BD and schizophrenia restoring levels of glutathione and glutathione-trans-
ferases (GstD1, GstD2), crucial mediators of neuronal
(Koh et al., 2003). Lithium appears to act by inhib-
defense against oxidative damage (Kerr et al., 2017).
iting the interaction between NCS-1 and inositol
Moreover, the inhibition of GSK3 mirrors many of
1,4,5-triphosphate (IP3) receptor (Schlecker et al., 2006),
these antioxidant properties of lithium. This has been
preventing the action of excess NCS-1 and restoring in- shown in studies utilizing GSK3 antisense oligonucleoti-
tracellular pathways that mediate normal c oscillations. des, short-interfering RNAs, and specific GSK3 inhibi-
Although low levels of NCS-1 allow high-threshold cal- tors (e.g., SB216763, TDZD-8) in rat models of cerebral
cium channels to mediate intrinsic membrane oscillations, ischemia and in the SAMP8 mouse model, which simu-
high levels of NCS-1 inhibit the oscillations. Therefore, lates aging-associated AD (Rojo et al., 2008; Chen et al.,
optimal concentrations of lithium reduce the effects of 2016). In this context, the transcription factor nuclear
NCS-1 overexpression by normalizing c band activity. factor (erythroid-derived 2)-like 2 (Nrf2) has emerged
as a pivotal molecular mediator responsible for trans- induced schizophrenia-like behavior (Yuan et al., 2015;
mitting lithium’s antioxidant effects following GSK3 Jevtic et al., 2016). Interestingly, although the search for
activation. Nrf2 operates by upregulating the expression studies linking autophagy to BD yields very few direct re-
of a variety of genes containing antioxidant response sults, evidence points to mitochondrial dysfunction in BD
elements, thus effectively mitigating oxidative dam- because of impaired autophagy and, especially, to the role
age (Kerr et al., 2018). of mood stabilizers in its prevention (Toker and Agam
2015; Scaini et al., 2016; Bar-Yosef et al., 2019). Con-
G. Protein Quality Control Mechanisms
sidering the robust therapeutic effects of lithium on
1. Ubiquitin-Proteasome System and Autophagy. Pro- mood disorders, autophagy may occupy a central place in
tein homeostasis is the equilibrium between the synthe- its antimanic and antidepressant action. It is worth not-
sis and breakdown of proteins. For neurons, where the ing that the mood-stabilizing effects observed with cer-
removal of impaired components cannot be accomplished tain drugs that induce autophagy, like valproate and
via cellular division, qualitative adjustments to the prote- rapamycin, are not unexpected. These medications are
ome and the prompt removal of damaged and misfolded originally prescribed for different therapeutic purposes
proteins are crucial processes (Douglas and Dillin, 2010; but have shown additional mood-stabilizing properties
Balchin et al., 2016; Kerr et al., 2018). Intriguingly, (Puglisi-Allegra et al., 2021).
lithium influences proteostasis by diminishing protein 2. Endoplasmic Reticulum Stress and Unfolded Protein
synthesis and augmenting protein degradation, thus Response Pathway. The endoplasmic reticulum (ER)
regulating proteasomal activity and autophagy. These serves as the main site for protein synthesis, folding,
effects may hold promise for addressing a range of neu- and trafficking within cells. Additionally, it functions as
rodegenerative diseases, such as AD, PD, and various an intracellular calcium store and is extremely suscepti-
forms of dementia. This potential benefit can be attrib- ble to disruptions in its internal environment, leading
uted to its ability to either enhance the clearance of ab-
to ER stress. To ensure cell survival, the unfolded protein
normal protein aggregates, a common hallmark of these
response (UPR) is activated as an adaptive reaction to
disorders, or maintain protein homeostasis for the proper
ER stress. Both ER stress and abnormal UPR have sig-
function of neuronal cells. Furthermore, lithium pro-
nificant implications in the development of various neu-
motes the breakdown of proteins prone to forming ag-
ropsychiatric and neurodegenerative disorders, playing
gregates, including mutated huntingtin, phosphorylated
a central role in their pathogenesis. (Bengesser et al.,
s, and a-synuclein (Motoi et al., 2014).
2016; Limanaqi et al., 2019). Numerous investigations
Although rapamycin is the most widely used phar-
have proposed that the UPR pathway might be in-
macological agent to induce autophagy through inhibi-
volved in the pathophysiology of BD. Additionally, it
tion of the mTOR pathway, the mechanism by which
has been suggested that mood stabilizers could poten-
lithium acts as an autophagy enhancer appears to be
independent of the mTOR pathway. Several studies tially exert their therapeutic effects by triggering the
have identified the ability of lithium to deplete free activation of the UPR (Chen et al., 2000a; Kakiuchi
inositol and subsequently lower IP3 levels, through in- et al., 2003; Shao et al., 2006; Kim et al., 2009; Pfaffen-
hibition of IMPase and inositol transporters, as an seller et al., 2014; Bengesser et al., 2016).
mTOR-independent pathway to induce autophagy Evidence for altered UPR in BD comes from studies
(Sarkar and Rubinsztein, 2006; Chiu et al., 2013). The reporting an abnormal response to ER stress inducers.
lithium-caused “inositol depletion” has a positive feed- When stimulated with thapsigargin and tunicamycin,
back mechanism, in which the incremental effect of lith- individuals with BD displayed either an unresponsive
ium is greater the higher the concentration of the IMP- or reduced expression of UPR markers, including eIF2a,
IMPase complex (Harwood, 2005; Yu and Greenberg, GRP78 (Bip), GRP94, XBP1, and CHOP (Hayashi et al.,
2016). This evidence led to the hypothesis that lithium 2009; Pfaffenseller et al., 2014). Remarkably, altera-
may exert its therapeutic effect through inositol deple- tions in these markers appear to have predictive value
tion, which mediates the autophagy effect. Lithium’s for lithium responsiveness in BD (Breen et al., 2016).
ability to induce autophagy has mainly been showcased Lithium increases the expression of UPR chaperones
through animal models of neurodegenerative disorders (i.e., GRP78, GRP94, and calreticulin) in rats in both
characterized by the accumulation of misfolded pro- brain tissue and cultured cells (Shao et al., 2006). How-
teins (Cuervo et al., 2004; Levine and Kroemer, 2008; ever, it is worth noting that some studies have reported
Rubinsztein et al., 2012). More recent studies indicate that mood stabilizers have no significant impact on the
the possible involvement of aberrant autophagy in UPR pathway. For instance, valproate led to increased
schizophrenia as altered autophagy markers, e.g., beclin1 GRP78 protein levels in HEK293 cells, but neither val-
and microtubule-associated protein one light chain 3 proate nor lithium had a substantial effect GRP78
(LC39), among others, have been identified in post expression in Neuro-2a cells (Kakiuchi et al., 2003,
mortem brain samples from patients with schizophrenia 2009). Additionally, valproate and lithium did not in-
as well as in perinatal animal models of phencyclidine- duce changes in XBP1SH-SY5Y and lymphoblastoid
cells. (Kakiuchi et al., 2003). Despite these discrepan- mediators such as interleukin (IL)-1b, interferon-c, IL-6,
cies, a substantial body of research in mammals strongly and MCP1, which are associated with M1 macrophages.
supports an induced activation of UPR by mood stabil- Conversely, it increases the production of anti-inflamma-
izers. Several mechanisms have been proposed as poten- tory cytokines (Martin et al., 2005).
tial contributors to potentially underlie the activation of Another potential downstream target of GSK3 is a sig-
the UPR by these mood stabilizers. These mechanisms nal transducer and activator of the transcription (STAT)
include histone deacetylases inhibition, upregulation of family. There are seven members of the STAT protein
the wolframin gene (WFS1), and myoinositol depletion family in mammals. Among them, STAT3 was discovered
(Shi et al., 2007; Kakiuchi et al., 2009; Jadhav et al., as a component of the IL-6–activated acute phase
2016), although these mechanisms have been de- response factor (APRF) complex, which has a crucial role
scribed primarily for valproate (Sulliman et al., in stimulating the expression of innate immune media-
2021). tors (Hillmer et a., 2016). Furthermore, GSK3 phosphor-
ylates and activates STAT3 by facilitating its interaction
H. Immunomodulatory Role of Lithium with the proinflammatory interferon-c receptor as dem-
New evidence indicates a correlation between an onstrated in primary astrocytes from mice. Treatments
increased susceptibility to mood disorders and the with lithium or GSK3 inhibitor TDZD-8 treatment blocks
inflammatory responses of the immune system, along- these effects (Beurel and Jope, 2009; Rowse et al., 2012).
side alterations in the phenotype of macrophages trig- In addition, molecular mediators of the anti-inflam-
gered by the activation of microglia. Changes in the matory effects of lithium also correlate with Toll-like
activation of microglia and the presence of inflamma- receptor 4 (TLR4) pathways (Kerr et al., 2018). TLR4
tory factors are also an early characteristic seen in serves as a pattern-recognition receptor responsible for
individuals with dementia (Calsolaro and Edison, detecting specific pathogen-associated molecular pat-
2016; Sakrajda and Szczepankiewicz, 2021). There is terns, such as lipopolysaccharide, along with cytokines.
also evidence revealing that mitochondrial dysfunc- After binding to its ligand, TLR4 recruits signaling
tion plays a crucial role in the development of neuro- adaptors and initiates a series of signaling cascades
degenerative diseases, including AD, PD, Huntington that result in the activation of NF-jB and the release
disease (HD), amyotrophic lateral sclerosis (ALS), or of inflammatory cytokines (Lien et al., 2000; Cheong
multiple sclerosis, by increasing innate and adaptive et al., 2011). The anti-inflammatory effects of lithium
immune responses that result in neuroinflammation via suppression of microglial activation and attenuation
(Garabadu et al., 2019; Zang et al., 2022). In addition, of overexpression of proinflammatory cytokines and che-
mitochondrial dysfunction and impaired energy me- mokines are thought to be dependent on TLR4 signaling.
tabolism are also involved in the pathophysiology of Indeed, lithium inhibited lipopolysaccharide-induced
mood disorders (Kato, 2006; Cikankova et al., 2017; TLR4 expression and microglial activation through
Allen et al., 2018; Culmsee et al., 2019). The mito- the PI3K/Akt/FoxO1 signaling pathway (Dong et al.,
chondrial hypothesis proposes a reciprocal relationship 2014). Furthermore, changes in the levels of TLR4
between changes in cell energy metabolism and in- expression and its associated transcription factor
flammation. It suggests that disturbances in energy NF-jB were found to be associated with lithium’s
metabolism can activate the inflammasome, leading to ability to alleviate memory deficits in elderly rats.
elevated cytokine production and eventual apoptotic This improvement in memory was connected to reduc-
cell death. Conversely, inflammation can also impact the tions in the levels of TNF-a and IL-1b in the hippocam-
generation of energy within the cell (Ghosh et al., 2018; pus (Lu et al., 2015, Cheng et al., 2016). Taken together,
Kerr et al., 2018; Sakrajda and Szczepankiewicz, 2021; these data suggest that lithium’s anti-inflammatory and
Tang et al., 2021). In this review, we will emphasize the neuroprotective effects may be mediated independently
pharmacological role of lithium as an immunomodula- of GSK3 inhibition through modulation of TLR4, NF-jB,
tory agent. and STAT3 signaling.
Previous research has indicated that lithium can re-
duce the levels of proinflammatory cytokines, both in IV. Ketamine, Lithium, and the Targeting of
peripheral tissues and within the central nervous sys- Homeostatic Synaptic Plasticity
tem, and these changes have been linked to its efficacy
(Boufidou et al., 2004; Beurel and Jope, 2014). Lithium’s Recent studies indicate that ketamine and lithium
most well known mechanism of action is the inhibition target the same synaptic process, i.e., elicit functional
of GSK3, which can impact various transcription fac- synaptic plasticity (Kavalali and Monteggia, 2020; Price
tors, including NF-jB. NF-jB plays a critical role in the et al., 2021), albeit their targets are widely divergent,
innate immune response and regulates the production and their mechanisms are different. Therefore, com-
of cytokines (Jope et al., 2007). The reduction in NF-jB’s bined lithium and ketamine treatment may enhance
transcriptional activity, induced by lithium’s inhibition of antidepressant responses by promoting molecular sig-
GSK3b, results in decreased production of proinflammatory naling cascades and bioenergetic pathways essential to
enable synaptic processes. Over the last 10 years, clini- 2018). Certainly, some of the most consistently observed
cal research has shown that administering a low dose findings in this context involve the inhibition of GSK3,
of ketamine intravenously leads to a swift and effective the upregulation of neurotrophins, and shifts in AMPAR
antidepressant response in individuals with depression, expression (Hashimoto et al., 2002; Pisanu et al., 2016;
including those with treatment-resistant depression and Kavalali and Monteggia, 2020; Price et al., 2021). Recent
bipolar depression (Berman et al., 2000; Zarate et al., investigations into the synaptic mechanisms influ-
2006b; Price et al., 2009; Daly et al., 2018; Wilkowska enced by lithium have unveiled a significant reduction
et al., 2020). Ketamine is recognized as a noncompetitive in AMPAR-mediated miniature excitatory postsynaptic
antagonist of the glutamatergic N-methyl-D-aspartate current amplitudes. This reduction is contingent on
receptor (NMDAR), and several initial targets for its ac- BDNF and its TrkB receptor (Gideons et al., 2017).
tions have been proposed in the literature. These targets Such an effect on glutamatergic neurotransmission
include NMDARs on GABA interneurons (Homayoun may play a role in counterbalancing the heightened
and Moghaddam 2007; Quirk et al., 2009) and NMDAR glutamatergic signaling observed in individuals with BD
and AMPAR on pyramidal neurons (Zanos et al., 2016; during manic episodes (Ong€ ur et al., 2008; Lan et al.,
Artigas et al., 2018). Similar to other rapid-acting anti- 2009). Furthermore, these findings align with additional
depressant treatments (Duman et al., 2016; Jimenez- evidence gathered from post mortem brain tissue of indi-
Sanchez et al., 2016), ketamine’s mechanism of action viduals with BD (Hashimoto et al., 2007; Eastwood and
involves the activation of AMPARs. This effect may Harrison, 2010). Electrophysiological recordings in hu-
result from the blockade of NMDARs in specific sub- man neurons derived from induced pluripotent stem
sets of GABA neurons or direct activation of AMPARs. cells of patients with BD have also indicated molecular
Studies utilizing [1H]-magnetic resonance spectroscopy and functional alterations associated with increased
have revealed that ketamine increases the levels of glutamatergic neurotransmission (Mertens et al., 2015).
glutamine, which serves as a marker for glutamatergic Notably, the decrease in cell surface AMPAR expression
transmission, in the anterior cingulate cortex of healthy is contingent on BDNF/TrkB signaling (Gideons et al.,
individuals (Rowland et al., 2005). Similarly, research 2017). Consequently, although lithium elevates BDNF
employing [13C]-NMR in rats has shown that ketamine expression and diminishes AMPAR function, ketamine
increases cortical labeling of glutamate, glutamine, and also increases BDNF levels, leading to enhanced AMPAR
GABA (Chowdhury et al., 2012). These findings align responses. Further research is essential to unravel the
with previous observations of increased glutamate efflux intricate mechanisms through which BDNF/TrkB sig-
using microdialysis procedures (Adams and Moghaddam, naling, influenced by either ketamine or lithium, can
2001). Nevertheless, the antidepressant effects of keta- evoke such diverse effects at both synaptic and behav-
mine can be blocked by opioid receptor antagonists ioral levels.
(Williams et al., 2018). These observations indicate that Downstream of these mechanisms, both lithium and
ketamine, at least in part, enhances presynaptic gluta- ketamine initiate neurotrophic cascades through activa-
matergic neurotransmission, leading to rapid upregulation of MEK/ERK and CREB pathways, which provide
tion of AMPAR and BDNF/TrkB activation to promote bioenergetics stimuli for neuronal and synaptic plasticity,
neurotrophic signaling through mTOR activation and play a critical role in antidepressant responses (Kim
(Li et al., 2010) and GSK3b inhibition (Beurel et al., et al., 2013; McCarthy et al., 2016; Reus et al., 2016).
2011). These molecular cascades, in turn, have been Consequently, lithium is a promising candidate for
shown to functionally promote the development of new adjunctive treatment to ketamine and has shown po-
synaptic connections to enhance connectivity between tential as a boosting agent for other antidepressant
mood-related brain regions (Duman and Aghajanian, approaches for treatment-resistant depression and
2012; Costemale-Lacoste et al., 2016; Gerhard et al., bipolar depression (Nelson et al., 2014; Costi et al.,
2016; Zarate and Machado-Vieira, 2016; Fullana 2019; Caldiroli et al., 2021). For example, in a rodent
et al., 2022). model of treatment-resistant depression, augmentation
Lithium activates neurotrophic and neuroprotective of imipramine with lithium was shown to promote cen-
cellular cascades (Quiroz et al., 2004, 2010; Sinha et al., tral and peripheral insulin signaling, which directly cor-
2005; Dwivedi and Zhang, 2015; Costemale-Lacoste related with the antidepressant behavioral response
et al., 2016), including the stimulation of neurotrophic (Walker et al., 2019). In addition, lithium has been
molecular pathways (i.e., BDNF/TrkB and mTOR acti- shown to potentiate the synaptogenic and antidepres-
vation, GSK3 inhibition) (Machado-Vieira et al., 2009; sant effects of subthreshold doses of ketamine in naıve
Gideons et al., 2017), direct modulation of bioenergetic rats (Liu et al., 2013). Similarly, lithium was found to
factors (i.e., increased IGF expression) (Fidaleo et al., enhance the antidepressant response to ketamine in
2017; Price et al., 2021), and protection of mitochondrial antidepressant-unresponsive animals, along with pe-
health, cellular energy metabolism, and antioxidant de- ripheral insulin efflux and region-specific prefrontal cor-
fense (Rojo et al., 2008; Castro et al., 2009; Kerr et al., tex insulin signaling (Price et al., 2021). However, Xu
et al. (2015a) reported that therapeutic doses of lithium support the importance of the glutamatergic system in
(0.79 ± 0.15 mEq/L in serum) did not correlate with an lithium response (McCarthy et al., 2010).
improvement in antidepressant efficacy of ketamine at a Despite GWAS providing insights into the genetics of
dose of 0.5 mg/kg in treatment-resistant bipolar depres- lithium response, they face several limitations. These in-
sion. Some considerations should be taken into account clude small sample sizes, challenges in replicating re-
for a plausible explanation of the differences obtained be- sults across diverse ancestries or populations, and the
tween preclinical and clinical studies on the lithium ef- use of heterogeneous definitions for clinical response to
fects as an enhancer of the antidepressant ketamine lithium. To overcome these limitations, the ConLiGen
action (Liu et al., 2013; Xu et al., 2015a). These include collaboratory consortium was established in 2008 to facil-
1) the difference in the experimental design of the itate high-quality, well powered analysis of lithium treat-
studies; 2) the small number of patients included (n 5 ment response data (Schulze et al., 2010).
23 subjects), not sufficient for statistical power; 3) the In a GWAS from the ConLiGen consortium on 2563
use of subtherapeutic doses of lithium and ketamine in patients with BD, a single locus for four linked SNPs on
the animal model, whereas patients received stable chromosome 21 was associated with lithium response
therapeutic levels of lithium for 4 weeks prior to keta- (Hou et al., 2016).
mine infusion; and 4) treatment-refractory patients Individuals carrying these alleles linked to treat-
versus an untreated rat model as well as other varia- ment response exhibited a reduced relapse rate in an
bles directly related to differential metabolism between independent prospective study involving 73 patients
humans and rodents. In any case, further studies receiving lithium monotherapy. The identified region en-
are needed to determine the appropriate timing of compasses two long noncoding RNA genes (AL157359.3
administration of lithium or selective GSK-3 inhibi- and AL157359.4), implying their potential role as regula-
tors to enhance the synaptic and antidepressant ef- tors of gene expression in the central nervous system
fects of ketamine. Based on the broad pharmacology (Hou et al., 2016).
of ketamine and lithium, these data support that es- GWAS, despite their limitations, can nowadays be
sential synaptic plasticity may provide new insights and used to calculate the polygenic risk score (PRS), which is
targets for advancing the treatment of mood disorders. a numerical score that quantifies an individual’s genetic
risk for a particular trait (as for example lithium
V. Biology of Lithium’s Response response) or disease based on the cumulative effect of
multiple genetic variants, typically SNPs scattered
Clinical response to lithium when used as a mood- across the genome. Although GWAS on lithium response
stabilizer agent varies considerably, with half of the pa- failed to generate good estimates to calculate the lithium
tients showing an incomplete response. Family studies response-PRS due to lack of statistical powers, PRSs of
showed a pattern of heritability of response to lithium other phenotypes have been used to predict lithium re-
among generations (Grof et al., 2002). Both heterogene- sponse in BD. Indeed, higher schizophrenia and major
ity and familiar transmission of the response could be depression PRSs were associated with poorer response to
explained on genetic bases. Candidate-gene studies lithium, whereas BD-PRS showed no such association
were able to identify a large number of genes coding (Schubert et al., 2021). In a multiethnic study, individu-
for GSK3b, BDNF, and the serotonin transporter as- als with higher PRS for major depressive disorder were
sociated with lithium response (Pisanu et al., 2018). less likely to respond to lithium treatment compared
However, the mild effect of these variants suggested with those with lower scores in the multiethnic sample
the hypothesis of a polygenic nature of lithium re- and in the European sample, though no significant asso-
sponse. Genome-wide association studies (GWAS) are ciation was observed in the Asian sample (Amare et al.,
ideal to study complex traits or diseases since they 2021). In another sample, a higher PRS for attention-
test the association between millions of common ge- deficit/hyperactivity disorder or major depression was
netic variants distributed across the human genome associated with a poorer response to lithium (Coombes
with a specific phenotype on large populations (Tam et al., 2021). As for GWAS, the effect size estimate for
et al., 2019). Results of GWAS studies on lithium re- PRS is modest as well as the generalizability of the re-
sponse are, to date, contrasting, with several studies sults. Nevertheless, PRS with clinical variables and using
failing to find genome-wide associations replicating machine-learning models might significantly improve the
previous results (Perlis et al., 2009, Squassina et al., prediction of lithium response (Cearns et al., 2022).
2011). A study that used a formal definition of clinical In a flow-cytometric study, the expression levels of
response to lithium (i.e., using the Alda Scale) (Manchia 28 intracellular proteins in CD41 lymphocytes and
et al., 2013) identifies two significant single nucleo- monocytes were analyzed before and after 16 weeks
tide polymorphisms (SNPs) located in the glutamate- of lithium treatment in patients with BD, divided accord-
decarboxylase-like protein 1 (GADL1) associated with ing to lithium response. Results showed that lithium in-
lithium response (Chen et al., 2014). These results might duced divergent changes in protein expression depending
on an individual’s response to treatment (Gao et al., involvement extends across nearly all biologic pro-
2023). cesses, encompassing cell proliferation, development,
Furthermore, a network-based integrative analysis of differentiation, and programmed cell death. The identi-
transcriptomic and genomic data revealed 41 differen- fication of over 1500 miRNA genes highlights their piv-
tially expressed genes in lithium responders versus non- otal role, with each miRNA having the potential to
responders, and post-GWAS gene prioritization identified target multiple mRNAs. Highlighted by their multiface-
1119 candidate genes. Functional enrichment highlighted ted role, miRNAs hold considerable importance in shap-
focal adhesion and the extracellular matrix (ECM) as the ing cellular states and outcomes (Lin and Gregory, 2015)
most significant functions, emphasizing the importance given their ability to either inhibit the translation of tar-
of dysregulation in these pathways in understanding get mRNA or expedite its degradation. Moreover, they
lithium response and underlying BD mechanisms can serve as enhancers of translation or even impact
(Niemsiri et al., 2023). transcription by binding to gene promoters. Considering
Induced pluripotent stem cells (iPSCs) have emerged
the intricate nature of the nervous system at both the
as a valuable tool in BD research in disease modeling,
cellular and transcriptional levels, it is not surprising
drug screening, and personalized medicine. iPSCs are
that approximately 75% of annotated miRNAs find ex-
somatic adult cells that have been reprogrammed to
pression within the brain (Kosik, 2006, Artigas et al.,
exhibit pluripotent characteristics, meaning they can
2018; Bortolozzi et al., 2021). Intriguingly, miRNAs can
differentiate into any cell type in the human body,
including neurons. In a recent study, an iPSC model be released from the brain and enter circulatory bio-flu-
for BD was created, identifying mitochondrial abnormal- ids, where they remain remarkably stable (Cheng et al.,
_
2014; Zurawek and Turecki, 2021; Clausen et al., 2022).
ities and hyperactive action-potential firing in young
neurons derived from patients with BD. The hyperexcit- Alterations in the miRNA levels have been reported in
ability phenotype was selectively reversed by lithium brain tissue as well as in blood from patients with mood
treatment in neurons from responsive patients, suggest- disorders, including BD (Forstner et al., 2015; Maffioletti
ing that iPSC models may aid in the development of tar- et al., 2016; Fries et al., 2018; Clausen et al., 2022).
geted therapies for BD (Mertens et al., 2015). Indeed, Interestingly, several studies have shown that lithium
circadian rhythms in neuronal precursor cells (NPCs) modifies the expression of miRNAs and their targeted
and reprogrammed glutamatergic neurons were dis- mRNA (Chen et al., 2009; Hunsberger et al., 2015;
rupted to a greater extent in samples obtained from Reinbold et al., 2018; Pisanu et al., 2019; Marie-Claire
lithium nonresponders as compared with lithium res- et al., 2021), suggesting that they could play a role in
ponders (Mishra et al., 2021). Furthermore, in iPSC modulating lithium’s clinical efficacy.
models, lithium increases mitochondrial respiration Here, we summarize translational studies showing the
capacity only in lithium responders, suggesting involve- involvement of miRNAs in lithium’s actions (Table 1).
ment of mitochondrial functions in the mechanisms of Previous studies have identified several miRNAs and
mood stabilizers (Osete et al., 2021). iPSC-derived brain their predicted mRNA effectors in the rat hippocampus
organoids have also been studied to model BD. One as targets for the action of mood stabilizers (Zhou et al.,
study explored the effects of long-term lithium treatment 2009). Some of these miRNAs, such as miR-221 and
on iPSC-derived human cortical spheroids from healthy miR-34a, have been shown to be influenced by lithium
controls and patients with BD (Osete et al., 2023). BD treatment in lymphoblastoid cell lines derived from
human cortical spheroids displayed altered neuronal patients with BD (Chen et al., 2009). Although certain
characteristics compared with controls, and lithium miRNAs, like miRNA-134, have been linked to treat-
treatment exerted opposite effects on neuronal excit- ment response in bipolar mania, (Rong et al., 2011), the
ability between BD and controls. Also, 132 lithium-
majority of available data suggests that lithium’s impact
associated differentially expressed genes related to so-
on miRNA levels is largely independent of its clinical ef-
dium ion homeostasis and kidney-related pathways were
ficacy. A recent study compared miRNA and targeted
identified in the same study, highlighting the potential of
mRNA expression profiling of lymphoblastoid cell lines
iPSC-derived three-dimensional brain models for preci-
sion medicine in psychiatry (Osete et al., 2023). Although before and after in vitro lithium treatment to identify
these studies are intriguing, their connection with the networks of miRNAs and their targets involved in lith-
individual genomic load of each patient concerning ium response (Hunsberger et al., 2015). The lympho-
lithium response has yet to be established. blastoid cell lines used in the study were obtained from
both lithium-responsive and nonresponsive BD patients.
The results indicated that in vitro lithium treatment
VI. Lithium-Modified microRNA Pathways
led to the downregulation of the Let-7 family of miRNAs
MicroRNAs (miRNAs) have arisen as regulators of in both groups. Furthermore, a genome-wide analysis of
gene expression post-transcriptionally, albeit they are miRNAs in 2563 patients, categorized by their response
not classified as part of the epigenetic machinery. Their to lithium, identified 15 miRNAs significantly associated
TABLE 1
Studies reporting the effects of lithium on miRNA expression
miRNAs Samples Method Target Genes Lithium Effects Reference
miR-221, miR-152, miR-15a, Lymphoblastoid RT-qPCR miRNA-targets were predicted Day 4: Increased miR-221, Chen et al., 2009
miR-494, miR-155, cell lines; BD (n 5 20); LiCl by miRanda or TargetScan. miR-152, miR-15a, and
miR-181c, miR-34a, treatment at 1 mM for 4 and Five genes (AP2A1, AP2S1, miR-155 and decreased
miR-605, miR-17-3p, 16 days CD2AP, EIF1, and VCL) were miR-494 levels
miR148a, miR-200C, significantly enriched and Day 16: Lithium increased
miR-181b, miR-513 linked to biologic processes, miR-221, miR-152,
i.e., complex macromolecular miR-155 and miR-34a levels
assembly, protein
complex assembly, and
cellular component assembly
Let-7b, let-7c, miR-105, Kyoto Wistar rats; Microarray and RT- Predicted miRNA-targets: Reduced levels of let-7b, Zhou et al., 2009
miR-128a, miR-24, hippocampus samples; qPCR PTEN, axonal guidance, ERK, let-7c, miR-128a, miR-24a,
miR-30c, miR34a, Li2CO3 1.2 g/kg for 1 week Wnt/b-catenin, and miR-30c, miR-34a, and
miR-221, miR-144, b-adrenergic signaling miR-221, and increased
mR-136 pathways miR-144 levels
miR-134 Human plasma, drug-free BD RT-qPCR Not reported Increased miR-134 after Rong et al., 2011
patients (n 5 21) 4 weeks of combined
treatment with antipsychotics
and mood stabilizers (lithium
and valproate)
miR-34a, miR-147, miR-182, Rat cerebellar Affymetrix GeneChip, Predicted miRNA-targets: Increased miR-182, miR-147, Hunsberger et al., 2013
miR-222, miR-495, and granule cells; LiCl 3 mM for RT-qPCR TGF-b signaling, KEGG and miR-222 following the
miR-690 6 days pathway, and other pathways combination treatment with
including axonal guidance, lithium 1 valproate. miR-34a
focal adhesion, actin and miR-495 were both shown
cytoskeletal regulation, and to be downregulated following
long-term potentiation combination treatment.
Let-7 miRNA In vitro study comparing GRANITE Predicted miRNA-targets: Let-7 family is consistently Hunsberger et al., 2015
vehicle versus chronic lithium Let-7 miRNA family has been downregulated by lithium in
treatment in patient-derived implicated in both groups, where this
lymphoblastoid cells from neurodegeneration, cell miRNA family has been
Potential Therapeutic Effects of Lithium
either responders or non- survival, and synaptic implicated in

responders (n 5 8) development neurodegeneration, cell
survival, and synaptic
development
miR-124 Mouse model of focal cerebral RT-qPCR miR-124 target: RE1-silencing Lithium increased miR- Doeppner et al., 2017
ischemia; LiCl 1 mg/kg bolus transcription factor (REST, 124 expression
then 2 mg/kg/day for 7 day also known as NRSF)
1.692 miRNAs were tested BD (n 5 2.563) ConLiGen GWAS Not reported Fifteen miRNAs associated Reinbold et al., 2018
dataset with lithium response, among
them miR-499a showed a
robust association with
lithium response
miR-320a miR-155-3p, and Lymphoblastoid cell lines from Microarray and RT- Validated miRNA-targets: Thirty-one miRNAs were Pisanu et al., 2019
their target genes were BD patients ER (n 5 12) and qPCR calpain small subunit 1 differentially expressed in ER
validated NR (n 5 12) to lithium (CAPNS1), regulator of G versus NR and inversely
protein signaling 16 (RGS16), correlated with 418 genes
transcription factor SP4 (Sp4) differentially expressed
disorders (miR-320a and SP4) between the two groups.
Squassina et al., 2020
(continued)
341
with two lithium response phenotypes (Reinbold et al.,
ER, excellent responder to lithium; GRANITE, Genetic Regulatory Analysis of Networks Investigational Tool Environment; KEGG, Kyoto Encyclopedia of Genes and Genomes; LCL, lymphoblastoid cell line; LR, low risk of sui-
2018).
Furthermore, Pisanu et al. (2019) reported differential
Reference
expression levels of 31 miRNAs in lymphoblastoid cell

lines from individuals who exhibited excellent responses
to lithium compared with nonresponders. Notably,
changes in miRNA levels showed an inverse correla-
tion with 418 differentially expressed genes in the two
groups. Overall, these data provided new insights into
between SC and LR. miR-4286
was increased in SC compared
three in-cell lines treated with
lithium-treated LCLs from SC

miR-186–5p was decreased in
with LR at baseline, whereas
compared with HC. Mir-4286

LiCl (miR-4286, miR-186–5p,
(miR-4286, miR-337–3p) and
was also increased in the the molecular processes involved in lithium effects
Two miRNAs at baseline
differentially expressed
lithium-treated LCLs
that may help us fill the gap between molecular func-
miR-423–5p) were
tions and the clinical efficacy of mood stabilizers.

Lithium Effects
VII. Repurposing Lithium for Brain Disorders

Beyond Bipolar Disorder
In addition to effectively treating BD, lithium is cur-
rently under active investigation for a broad array of
neuropsychiatric (i.e., treatment-resistant depression,
suicidal behavior, post-traumatic stress disorder, schizo-
miR-4286 targets part of the
insulin resistance pathway
phrenia, and autism spectrum disorder) and neurologic

and neurodegenerative (i.e., PD, HD, AD and frontotem-
Target Genes
poral dementia, ALS, TBI, and stroke) disorders as well

as gastrointestinal disease, cardiovascular disease,
and neoplasia, among other conditions. In addition,
TABLE 1—Continued
as of July 2022, the US National Institutes of Health

lists 191 planned, recruiting, or active clinical trials
cide; NR, non-responder to lithium; RT-qPCR, quantitative reverse-transcription polymerase chain reaction; SC, suicidal.
for lithium effects on several disorders (http://www.

clinicaltrials.gov). In this section, we will present a sum-
mary of promising translational research and provide a
concise overview of the current knowledge regarding the
nCounter miRNA
expression Assay
(Nanostring and
mechanism responsible for lithium-induced neuroplas-

RT-qPCR
Method
ticity and neuroprotection in neurologic and neurode-

generative disorders.
A. Parkinson Disease
Several studies have provided evidence of lithium’s
neuroprotective properties in cellular and animal models
n 5 7) and with a low risk of
LCLs from patients with BD
(1 mM) of LiCl or drug-free

Therapeutic concentrations
of PD (Kim et al., 2011; Lieu et al., 2014; Hou et al.,

who died by suicide (SC,
suicide (LR, n 5 11).
2015; Lazzara and Kim, 2015; Guttuso et al., 2019, Zhao

were evaluated.
et al., 2019; Vallee et al., 2021). Accumulation and ag-

Samples
gregation of the a-synuclein protein, one of the main

histopathological features of PD, may lead to dysfunc-
tional autophagy and lysosomal processes (Cuervo
et al., 2004). Lithium treatment reduces a-synuclein
aggregation by targeting autophagy through the Akt/
mTOR pathway (Motoi et al., 2014). Furthermore, mito-
chondrial complex I inhibitors like 1-methyl-4-phenyl-
miR–186–5p, miR–423–5p
1,2,3,6-tetrahydropyridine (MPTP) and rotenone are

commonly used neurotoxins to induce PD-like symptoms
miR-4286, miR-337–3p
in animal models (Cannon et al., 2009). Notably, lithium

treatment has been found to alleviate rotenone-induced
toxicity in human neuroblastoma SH-SY5Y cells. This
protective effect is characterized by reduced nuclear frag-
mentation and apoptosis, accompanied by an increase
miRNAs
in autophagy markers (Xiong et al., 2011). Further-

more, in an MPTP mouse model treated with lithium,
researchers observed a decline in mitochondrial mem- Currently, there are no ongoing clinical trials for
brane potential, decreased generation of reactive oxygen lithium and HD. The latest one (clinicaltrials.gov
species, and an enhanced presence of lysosomes and au- identifier: NCT00095355) was designed to examine
tophagy vacuolar organelles (Li et al., 2013). Likewise, whether lithium, given alone or with divalproex, in-
lithium administration protects against oxidative stress creases BDNF levels in the cerebrospinal fluid of HD
in a transgenic mouse model with overexpression of patients.
mutant A53T a-synuclein (Kim et al., 2011). Other pre-
clinical studies reported that transplantation of stem C. Alzheimer Disease
cells preincubated with lithium in rodents with PD im- Lithium has been proposed as a potential therapy
proves cognitive functions and motor coordination in for dementia as positive effects have been described in
these animals through the regulation of the Wnt/b- cellular and animal models of dementia (Tsaltas et al.,
catenin signaling pathway (Qi et al., 2017). Currently, 2009; Forlenza et al., 2012; Hampel et al., 2019). There
an active phase 1 clinical trial (clinicaltrials.gov identi- is evidence for its neuroprotective effects from experi-
fier: NCT04273932) is investigating lithium therapy as mental research and clinical studies using brain im-
a potential disease-modifying therapy in PD (McFarthing aging (Kessing et al., 2010; Puglisi-Allegra et al.,
et al., 2022). 2021; Chen et al., 2022b). Two meta-analyses (Matsu-
naga et al., 2015; Velosa et al., 2020) and a subsequent
B. Huntington Disease randomized controlled trial (Forlenza et al., 2019) have
Previous preclinical studies reported that lithium suggested that lithium has beneficial effects on cogni-
treatment induces considerable protection against neu- tion in mild cognitive impairment and AD. Lithium
rodegeneration in an HD-like fly model by inhibiting has the capacity to intervene at various points in the
IMPase and reducing inositol and IP3 levels (Sarkar biochemical processes associated with the onset and
et al., 2008). In addition, other studies showed that progression of AD. This includes enhancing autophagy,
1–10 mM lithium enhances the autophagy of trans- exerting antiapoptotic effects, and initiating neurotro-
fected mutant huntingtin in COS-7, SKNSH, PC12, and phic cascades. For example, several preclinical studies
mouse embryonic fibroblast cells. Lithium has mixed ef- showed that therapeutic doses of lithium leave a de-
fects on autophagy, improving it by downregulating crease in sprotein hyperphosphorylation through inhibi-
GSK-3b, inositol species, and cytoplasmic transcription tion of GSK3b, resulting in a reduction of cognitive
factor p53 or, at higher lithium doses, reducing autoph- impairment in rodents (Phiel et al., 2003; Nakashima
agy by activating mTOR through GSK-3b inhibition et al., 2005; Engel et al., 2006; Sudduth et al., 2012).
(Chiu et al., 2011; Lauterbach, 2013). In addition, early Accumulation of autophagy vacuoles has been demon-
studies on lithium reported its neuroprotective effects strated in post mortem brain tissue from AD patients,
against apoptotic processes at clinically relevant concen- possibly due to altered autophagy vacuole clearance, but
trations using various striatal cell culture models of HD, it may also reflect a flawed process of downstream lyso-
i.e., striatal medium spiny neurons from YAC128 trans- somal degradation (Boland et al., 2008; Barnett and
genic mice, striatal cells exposed to mutant huntingtin, Brewer, 2011). Once more, it is worth noting that lith-
or excitotoxic quinoline (Senatorov et al., 2004). Simi- ium-induced autophagy might act in opposition to the
larly, lithium exhibits neuroprotective properties in the anticipated autophagy suppression observed in AD. This
quinoline injection model, not solely by inhibiting apo- suppression is attributed to the gradual rise in mTOR
ptosis but also by promoting the proliferation of neuro- activity throughout the progression of the disease
nal and astroglial progenitors within the striatum or (Tramutola et al., 2015; Damri et al., 2020).
facilitating their migration from the subventricular zone In addition, lithium favors synthesizing and releasing
(Senatorov et al., 2004). Low-dose lithium (20–40 mg/kg neurotrophic factors such as BDNF, whose increased
per day per rectal mucosal absorption) reversed BDNF availability promotes cell survival, stimulates hippocam-
deficits in the YAC128 HD transgenic mouse (Pouladi pal neurogenesis, and increases synaptic plasticity (Kerr
et al., 2012). Decades ago, lithium’s clinical application et al., 2018; Forlenza et al., 2019). Indeed, accumulation
in patients with HD was investigated before its neu- of b-amyloid (Ab) in the brain is associated with memory
roprotective properties were recognized. Remarkably, decline in healthy individuals as a prelude to AD.
lithium demonstrated a significant reduction in cho- BDNF polymorphisms have been identified as potential
rea and remarkable improvement in voluntary move- moderators of Ab-related cognitive decline in preclinical
ments and motor function in patients with HD. AD (Lim et al., 2015). Moreover, BDNF has been shown
Individuals in the initial phases of the disease ap- to reduce Ab production within the brain (Nigam et al.,
peared to derive greater benefit from lithium treatment, 2017). However, BDNF therapeutic potential is hindered
experiencing advantageous mood and temperament sta- by its short half-life and its inability to penetrate the
bilization (Chiu et al., 2013). Conversely, other clinical blood-brain barrier (Wurzelmann et al., 2017). Lithium
studies showed that lithium did not yield any favorable can effectively activate the molecular pathway that in-
effects in individuals with HD (Chiu et al., 2013). creases BDNF synthesis. Recently, a new microdose
formulation of lithium, NP03, has been reported to be effects, postpones the onset and duration of the disease,
effective in amyloid pathology after the onset of Ab and extends the lifespan in G93A SOD-1 mice—muta-
plaques by increasing BDNF levels and reducing tions in copper-zinc superoxide dismutase 1 (SOD1) are
markers of neuroinflammation and cellular oxidative a known genetic cause of ALS, and the SOD1 G93A
stress (Wilson et al., 2020; Kok et al., 2022). Addition- mouse has been used extensively to investigate molecular
ally, although the precise molecular mechanisms respon- mechanisms in ALS (Kreilaus et al., 2020)—by triggering
sible for lithium’s anti-inflammatory effects in dementia autophagy, promoting the generation of mitochondria,
models remain unclear, there is correlational evidence and inhibiting reactive astrogliosis (Fornai et al., 2008).
implicating the involvement of GSK3, STAT, and NFkB In recent studies, it has been discovered that lithium
pathways in playing a causative role (Jope et al., 2017; exerts neuroprotective effects by suppressing the upre-
Kerr et al., 2018). Lastly, there is epidemiology evidence gulation of Notch signaling and postsynaptic protein
that levels of lithium in drinking water are associated Homer1b/c in the spinal cord of G93A SOD-1 mice. This
with the risk for dementia (McGrath and Berk, 2017). mechanism leads to an increase in the Bcl-2/Bax ratio,
Taken together, these preclinical data support that lith- contributing to the neuroprotective properties of lithium
ium has a crucial role in AD, encouraging clinical stud- in this context (Wang et al., 2015; Jiang et al., 2016).
ies in patients to evaluate the efficacy of lithium in Moreover, a clinical study showed significant benefits
contrasting Ab and s pathology (Velosa et al., 2020). Sev- in ALS patients who received riluzole plus lithium for 15
eral clinical trials are currently in progress focusing on months compared with those who received riluzole alone.
the effect of lithium as a treatment to prevent impair- Lithium delayed disease progression in ALS patients as
ment of cognition in elders (clinicaltrials.gov identifier: assessed by quantitative measures of muscle strength
NCT03185208) as well as in the treatment of psycho- and preservation of lung function (Fornai et al., 2008).
sis and agitation in AD (clinicaltrials.gov identifier: Similarly, the combined administration of lithium and
NCT02129348). valproate significantly extended the survival of ALS
patients and provided neuroprotection by elevating the
D. Amyotrophic Lateral Sclerosis levels of antioxidant defense markers. These changes
The pathogenesis of ALS involves interconnected were assessed at baseline, 5 months, and 9 months
processes, including altered proteostasis, ER stress, ab- through the analysis of plasma samples. However, the
normal UPR signaling, mitochondrial dysfunction, and clinical trial was prematurely terminated at 21 months
impaired autophagy. Interestingly, lithium treatment owing to the occurrence of treatment-related adverse
has demonstrated efficacy in ALS patients who possess events (Boll et al., 2014). Findings derived from three
genetic variations in the UNC13 presynaptic protein. randomized trials revealed that although lithium did
These genetic variations are linked not only to ALS not improve the overall 12-month survival rate in the
spectrum disorders but also to psychiatric conditions general ALS population, it significantly raised the
(Lipstein et al., 2017; Nakamura et al., 2018; Limanaqi 12-month survival probability from 40.1% to 69.7%
et al., 2019). Lithium’s neuroprotective and neurotro- among individuals carrying the UNC13A variant (van
phic effects on motor function are achieved by targeting Eijk et al., 2017). Further investigations delving into the
processes associated with UPR signaling, excitotoxicity, molecular mechanisms by which lithium operates with
and autophagy dysfunction, whether at synapses or in respect to ER stress, UPR, and autophagy may unveil
cell bodies. potential neurobiological processes at play in the early
Markers of ER stress and UPR are increased in the stages of ALS, potentially leading to the identification of
blood and the spinal cord in both ALS patients and preventive or therapeutic targets.
ALS-like mouse models. Notably, the activation of XBP1
represents an early pathologic event in motor neuron E. Traumatic Brain Injury
disease (Ilieva et al., 2007; Hetz et al., 2009; Ito et al., TBI consists of an initial primary injury that causes
2009; Montibeller and de Belleroche, 2018; Vats et al., mechanical damage to neurons, glia, and blood ves-
2018). Studies conducted in vitro suggest that lithium sels. This primary injury is frequently succeeded by a
can alleviate ER stress by inhibiting GSK3b (Song sequence of secondary injuries that commence hours
et al., 2002; Takadera et al., 2007) and modulatin gene or even days following the initial trauma and that can
transcription via the PKC-GSK3b (Chen et al., 2000a; lead to neurodegeneration as well as cognitive and mo-
Hiroi et al., 2005). Lithium also has the potential to mit- tor impairments. TBI is also recognized as a potential
igate ER stress and aberrant UPR signaling by stimu- contributor to the onset of neurodegenerative conditions
lating autophagy. In fact, the administration of lithium such as AD. In fact, tauopathy and Ab plaques are
resulted in reduced levels of ER stress-related proteins, known to be the key pathologic markers of TBI, which
including GRP78, ATF-6, and CHOP, while simulta- contribute to the progressive deterioration associated
neously enhancing the autophagy process to safeguard with chronic traumatic encephalopathy and AD (Leeds
motor neurons in the spinal cord (He et al., 2017; Tong et al., 2014; Shim and Stutzmann, 2016). Its pathophysi-
et al., 2018). Similarly, lithium provides neuroprotective ology requires pharmacologic agents that act coordinated
to increase cell survival and decrease cell death path- treating cerebral ischemia represents a viable strat-
ways. In this context, there is growing evidence to sup- egy. In this context, previous studies using rodent
port the idea that lithium could potentially alleviate the models of stroke showed that lithium treatment in-
neurologic impairments resulting from TBI by acting as duces antiapoptotic mechanisms, leading to decreased
an inhibitor of GSK3-mediated signaling (Leeds et al., caspase-3 activity, reductions in activated protein one
2014; Welling et al., 2017). Using murine models of TBI, and proapoptotic p53 expression, and increases in anti-
lithium was reported to attenuate hippocampal neurode- apoptotic Bcl-2 and heat shock protein 70 (HSP70) lev-
generation, IL-1b expression, and brain edema. It also els (Xu et al., 2003; Bian et al., 2007). Furthermore,
inhibits microglia activation, matrix metallopeptidase-9 lithium enhanced hippocampal neurogenesis in a pre-
expression, and cyclooxygenase-2 induction (Reis et al., clinical model of global cerebral ischemia. The effects,
2015; Dell’Osso et al., 2016). In addition, low doses of as mentioned earlier, are not both dependent on the
combined lithium and valproate were more helpful in at- GSK3b pathway and involve other signaling pathways,
tenuating TBI than either agent used alone, leading to a
such as prosurvival MAPK/ERK1/2 (Yan et al., 2007a,b;
reduction in neurodegeneration and neuroinflammation
Sawe et al., 2008).
associated with improved behavioral outcomes (Yu et al.,
Further research endeavors were undertaken to
2013). Zhu et al. (2010) achieved comparable outcomes,
explore the therapeutic potential of administering lithium
demonstrating that the administration of lithium led to
following a stroke event. In a rat ischemia/reperfusion
a decrease in tissue damage while enhancing memory
performance and spatial learning abilities. In addition, model, poststroke lithium treatment demonstrated a no-
these data were associated with a decreased proinflam- table reduction in infarct volume and a corresponding de-
matory IL-1b expression (Zhu et al., 2010). Likewise, crease in neurologic deficits (Ren et al., 2003). Moreover,
lithium treatment was reported to reduce depressive- this neuroprotective effect was correlated with a decrease
like behavior in mice after cold-induced TBI (Ciftci in apoptosis levels and an elevation in HSP70 levels
et al., 2020). Although not strictly a traumatic brain (Ren et al., 2003). In addition, lithium administration
injury, lithium has been shown to be neuroprotective led to improved spatial learning and memory perfor-
in people with cancer receiving chemotherapy or radio- mance in mice subjected to ischemia-reperfusion (Fan
therapy (Khasraw et al., 2012). et al., 2015). Although the precise mechanisms govern-
These discoveries suggest the potential repurposing ing how lithium regulates inflammation, apoptosis, and
of mood stabilizers like lithium and valproate, whether neuroplasticity after a stroke are still largely shrouded
used individually or in combination, as viable pharma- in mystery, emerging evidence hints at the possibility
ceutical options for addressing neurologic disorders char- that lithium may exert its influence not only within the
acterized by excitotoxic components, the best example of brain parenchyma but also directly on the endothelium
which is TBI. Currently, a phase 3 study (clinicaltrials. itself (Bosche et al., 2016). Consistent with this observa-
gov identifier: NCT05126238) examines the hypothesis tion, Haupt et al., (2020) reported that lithium-induced
that preoperative lithium administration may reduce impact on endothelium cells could reverse early blood-
brain damage during carotid artery surgery. brain barrier breakdown after stroke, resulting in a con-
F. Stroke trolled modulation of leukocyte infiltration into the brain
parenchyma. In addition to preclinical investigations,
Ischemic stroke is a severe life-threatening disease there is data from two clinical trials. One assessed retro-
that causes degeneration and death of neurons, leading spective risk in patients treated with lithium (Lan et al.,
to the loss of motor function and frequent occurrence of
2015), and the other examined the prospective motor re-
cognitive impairment and depression (Pendlebury and
covery of stroke patients undergoing lithium treatment
Rothwell, 2009; Brown et al., 2012; Makin et al., 2013).
(Mohammadianinejad et al., 2014). Thus, a randomized
The intricate pathophysiology of this condition encom-
clinical trial on the effects of lithium in stroke patients
passes an initial acute stage, during which neuronal loss
is induced by a combination of hypoxia and nutrient demonstrated enhanced motor recovery after early
deprivation. These factors set in motion mechanisms treatment with low-dose lithium (Mohammadianinejad
that ultimately give rise to neuroinflammation and et al., 2014). More recently, however, evidence-based
apoptosis. The subsequent phase, marked by delayed guidelines from the European Academy of Neurology
brain injury, is further compounded by the subse- and the European Federation of Neurorehabilitation So-
quent restoration of blood vessel perfusion. Improv- cieties do not recommend lithium intervention for early
ing neurologic outcomes after an ischemic stroke is a motor rehabilitation after acute ischemic stroke due to
major clinical priority. However, most neuroprotec- safety and tolerability concerns (Beghi et al., 2021). Cur-
tants for stroke effective in rodent research have not rently, some clinical trials (e.g., clinicaltrials.gov identifier:
been efficacious in clinical practice (Haupt et al., 2021; NCT05126238) aim to examine a lithium-based medi-
Chen et al., 2022a). Therefore, repurposing market- cation to improve neurologic outcomes after carotid ar-
approved neuroprotective drugs, such as lithium, for tery surgery.
VIII. Limitations for Lithium Treatment caused by the effect of lithium on protein conformation
and subsequent iodotyrosine coupling defects (Lazarus,
Despite its widely proven efficacy, lithium use is some- 1998). These molecular alterations result in clinical
times limited due to its narrow therapeutic index requiring manifestations such as hypothyroidism, goitre, or
routine monitoring of serum concentrations, possible nega- hyperthyroidism (Perez-Castro et al., 2021). The risk
tive effects on endocrine and renal function, or teratogenic- of developing hypothyroidism and subclinical hypothy-
ity (McKnight et al., 2012). roidism in long-term treated patients is 6 times higher
A. Renal Funcion than in the general population (McKnight et al., 2012).
Lithium-induced hyperthyroidism is less frequent and is
Nephrogenic diabetes insipidus is the most common characterized by transient and painless thyroiditis. The
renal side effect of lithium therapy, characterized by risk of developing primary hyperparathyroidism during
loss of the ability of the kidney to concentrate urine lithium treatment is relatively high, and it is probably
due to resistance to vasopressin (Garofeanu et al., caused by the inactivation of the calcium-sensing recep-
2005). Rarely, when nephrogenic diabetes insipidus is tor and interference with intracellular second messenger
uncontrolled, it may result in distal renal tubular aci- signaling, with a subsequent increase in parathyroid
dosis (Weiner et al., 2014). Polyuria may rapidly occur hormone and blood calcium levels (Szalat et al., 2009).
during lithium treatment but is usually resolved once Therefore, both thyroid and parathyroid function should
lithium is interrupted (Garofeanu et al., 2005). Long- be monitored in clinical practice by baseline blood tests
term lithium treatment occasionally causes nephrotoxi- of thyroid-stimulating hormone and calcium and regular
city, characterized by kidney dysfunction and interstitial yearly follow-ups (Malhi et al., 2017).
nephritis with microcyst formation and, occasionally,
focal segmental glomerulosclerosis (Gr€unfeld and Rossier, C. Lithium and Pregnancy
2009). In a longitudinal recent study on a large popula- Clinical concerns have been raised regarding the risk
tion of patients treated with lithium or valproate, results of lithium during pregnancy. A recent meta-analysis
showed that lithium was meaningfully associated with showed that lithium-exposed women had higher odds
adverse kidney outcomes, but the absolute risks did not of any congenital anomaly or cardiac malformations
significantly differ from those observed with valproate compared with nonexposed ones (Fornaro et al., 2020).
therapy (Bosi et al., 2023). However, the risk of chronic However, the risk of congenital malformations at any
kidney disease increased with lithium levels >1 mmol/L time during pregnancy was globally low, being higher
(Bosi et al., 2023). In line with this evidence, another for the first trimester or with higher lithium doses.
study showed that long-term lithium therapy was not Also, there are no significant differences in obstetric out-
linked to nephrotoxicity in the absence of acute intoxi- comes in women with BD that take lithium during preg-
cation episodes (Clos et al., 2015) nor to increased nancy compared with those not treated with lithium except
rates of chronic kidney disease (Kessing et al., 2015). for an impact on newborn Apgar scores (Sague-Vilavella
Although the biologic underpinnings of nephrotoxicity et al., 2022). However, although lithium treatment in the
are complex and poorly understood, several molecular peripartum period is considered safe, attention should be
mechanisms might be implicated, including the suppres- paid during the first trimester in particular, always priori-
sion of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) tizing the lowest effective dose (Clark et al., 2022).
signaling, inhibition of GSK3a, competition with magne-
sium ions, and overactivity of cyclooxygenase-2 (Gong D. Metabolic Effects
et al., 2016). Weight gain is a distressing adverse effect that has
been previously associated with lithium treatment
B. Thyroid and Parathyroyd Function
(Gitlin, 2016). Lithium might have an insulin-like effect
Thyroid (Kibirige et al., 2013) and parathyroid on increasing glucose uptake and glycogen production in
(Meehan et al., 2018) abnormalities affect up to 25% animal models (de Groot et al., 2017; Jung et al., 2021).
of patients receiving lithium treatment. Lithium is In humans, the administration of lithium induces insulin-
highly concentrated in the thyroid glands and inhibits like hypoglycemia (Shah et al., 1986). Likewise, lithium
iodine uptake, iodothyrosine coupling, and thyroxine induces the suppression of GSK3, a key regulator of glyco-
secretion and modifies thyroglobulin structure (Perez- gen metabolism cell proliferation on differentiation
Castro et al., 2021). Lithium competes for the iodide (Snitow et al., 2021). However, a recent meta-analysis
transport in thyroid glands, ultimately leading to did not show a significant increase in weight in pa-
reduced iodine reuptake (Shopsin et al., 1973). Lithium tients taking lithium compared with the ones without
may also increase the thyroid-stimulating hormone se- lithium or against placebo (Gomes-da-Costa et al.,
cretion in response to the inhibitory effect on thyroxine 2022). Indeed, patients with BD have a higher risk
(T4) availability, which leads to the inhibition of cAMP compared with the general population of developing
and alteration of tubulin polymerization (Lazarus, 1998). weight-related conditions, including metabolic syndrome,
The alteration of thyroglobulin structure might be diabetes, or obesity, independently of lithium treatment
(Prillo et al., 2021). A combination treatment with lith- twitching), renal (renal failure), cardiovascular (T wave
ium antipsychotics is often used both in the acute and inversion, conduction disturbances, arrhythmias, atrio-
maintenance phases of BD. Antipsychotics, in particular ventricular node dissociations, cardiovascular collapse),
olanzapine and clozapine, induce more pronounced and hematologic (leukocytosis) systems. Indeed, clinical
metabolic side effects compared with lithium, includ- guidelines suggest monitoring serum lithium concentra-
ing weight gain (Pillinger et al., 2020). Aripriprazole tions regularly to avoid lithium overdose (Malhi et al.,
showed no significant differences in the long-term use 2017).
compared with lithium in terms of metabolic parame- Lithium’s adverse effect and toxicity profile might
ters in patients with BD type I (McIntyre et al., be one of the causes of its decreased clinical usage
2011). When used in combination with antipsychotics, during the last decade. The majority of side effects
lithium showed to improve manic symptoms but also under lithium treatment are not life-threatening and
increase the risk of metabolic syndrome (K€ ohler-Fors- can be easily managed.
berg et al., 2023).
E. Skin and Hair Disorders IX. Conclusions and Future Directions
There is conflicting evidence on the risk of skin and In this review, we focused on the multiple functions
hair disorders with lithium treatment. Mechanisms of lithium that demonstrate its exceptional pharmacol-
involved in lithium-related skin disorders might involve ogy and therapeutic effects to highlight common mecha-
cAMP cascade or the inhibition of the synthesis of pros- nisms of action in different brain disorders. As the
taglandins, which ultimately stimulates neutrophil func- complex therapeutic mechanisms of lithium are unrav-
tion (Jafferany, 2008). Although recent meta-analyses do eled, valuable information is provided to better under-
not point to an increased rate of adverse skin reactions, stand the pathophysiology of the diseases in which it is
clinicians should not overlook cutaneous symptoms dur- implicated and point to possible new therapeutic devel-
ing lithium treatment (Pinna et al., 2017). opments. Converging evidence from preclinical and clin-
ical models firmly supports the concept that lithium
F. Cognitive Effects exerts regulatory effects on diverse cellular pathways
Concerns regarding cognitive impairment in patients within the brain that are crucial for neuroplasticity and
treated with lithium have been raised (Wingo et al., neuroprotection. These include neurotrophic response,
2009). Accumulating evidence is somewhat contrasting, ER stress, UPR, autophagy, oxidative stress, mitochon-
suggesting that the cognitive effects of lithium are nu- drial function, and inflammation. This wide range of in-
anced or showing a positive effect of lithium on cognitive tracellular responses may be secondary to two key
performance. Some studies have indicated that lithium effects: inhibition of GSK3 and IMPase by lithium, in
treatment may not only preserve but potentially improve which dysregulation has been implicated in diverse
certain aspects of neurocognitive function in individuals neuropathological conditions. Therefore, a more pro-
with BD (Burdick et al., 2020). Notably, cognitive domains found and precise understanding of the specific thera-
such as verbal learning, memory recall, and executive peutic mechanisms of lithium will aid us in establishing
functions (Rybakowski et al., 2009) have been found to a better understanding of the complex mechanisms
exhibit positive responses to lithium therapy. However, underlying the pathophysiology of BD.
individual responses may vary, and some patients may Although the promotion of autophagy is widely recog-
report subjective experiences of cognitive numbness nized as the primary molecular mechanism explaining
(Grandjean and Aubry, 2009). Despite these reports, lithium’s protective effects in neurodegenerative diseases,
lithium’s overall cognitive effects seem to lean toward there is still a lack of understanding regarding how lith-
benefiting neurocognitive functioning in patients with ium’s ability to enhance autophagy might contribute to
BD, further supporting its continued use as a valuable therapeutic benefits for patients with neuropsychiatric
treatment option with careful monitoring and manage- disorders, including BD. An inability to effectively clear
ment of side effects. misfolded proteins through autophagy can result in the
accumulation of these substrates within cells. Conse-
G. Toxicity in Overdose quently, a shared pathogenic factor implicated in neu-
Lithium is dangerous in overdose, and clinical signs rodegenerative disorders is the inhibition of autophagy,
of toxicity might be seen at lithium serum concentra- often stemming from mTOR activation. However, the
tions equal to or more than 1.5 mEq/L (Oruch et al., signaling pathway of lithium as an autophagy enhancer
2014). Symptoms and signs of lithium toxicity may might be an mTOR-independent pathway involving IP3
involve different systems, such as the gastrointestinal signaling. Indeed, although the pathophysiology of neu-
(nausea, vomiting, diarrhea), neurologic (confusion, leth- rodegenerative diseases is clearly different from mood
argy, seizures, and coma, named syndrome of irrevers- disorders, cognitive impairment and functional decline
ible Lithium-Effected Neurotoxicity and attributed to are present in many bipolar patients, and neuroimaging
cerebellar dysfunction), musculoskeletal (tremor or muscle findings confirm decreased neuroplasticity and its anatomic
correlates, particularly concerning gray matter loss (Vieta Akkouh IA, Skrede S, Holmgren A, Ersland KM, Hansson L, Bahrami S,
Andreassen OA, Steen VM, Djurovic S, and Hughes T (2020) Exploring lithium’s
et al., 2018). transcriptional mechanisms of action in bipolar disorder: a multi-step study.
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Amare AT, Schubert KO, Hou L, Clark SR, Papiol S, Cearns M, Heilbronner U,
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Authorship Contributions
Bengesser SA, Fuchs R, Lackner N, Birner A, Reininghaus B, Meier-Allard N,
Wrote or contributed to the writing of the manuscript: Bortolozzi, Stracke A, Kapfhammer HP, Reininghaus EZ, and Wallner-Liebmann S (2016)
Fico, Berk, Solmi, Fornaro, Quevedo, Zarate, Kessing, Vieta, Carvalho. Endoplasmic Reticulum Stress and Bipolar Disorder - Almost Forgotten Therapeutic
Drug Targets in the Unfolded Protein Response Pathway Revisited. CNS Neurol
Disord Drug Targets 15:403–413.
Bergh€ofer A, Alda M, Adli M, Baethge C, Bauer M, Bschor T, Grof P, M€ uller-
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1521-0081/76/3/323–357$35.00 dx.doi.org/10.1124/pharmrev.120.

ASSOCIATE EDITOR: ROBERT DANTZER

New Advances in the Pharmacology and Toxicology of

1. Ubiquitin-Proteasome System and Autophagy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336

Fig. 1. Lithium (Li1) modulates a number

[see Kleandrova and Speck-Planche (2020), Vignaux

either responders or non- survival, and synaptic implicated in

with two lithium response phenotypes (Reinbold et al.,

expression levels of 31 miRNAs in lymphoblastoid cell

lithium-treated LCLs from SC

compared with HC. Mir-4286

tions and the clinical efficacy of mood stabilizers.

VII. Repurposing Lithium for Brain Disorders

phrenia, and autism spectrum disorder) and neurologic

poral dementia, ALS, TBI, and stroke) disorders as well

as of July 2022, the US National Institutes of Health

for lithium effects on several disorders (http://www.

mechanism responsible for lithium-induced neuroplas-

ticity and neuroprotection in neurologic and neurode-

(1 mM) of LiCl or drug-free

of PD (Kim et al., 2011; Lieu et al., 2014; Hou et al.,

suicide (LR, n 5 11).

2015; Lazzara and Kim, 2015; Guttuso et al., 2019, Zhao

et al., 2019; Vallee et al., 2021). Accumulation and ag-

gregation of the a-synuclein protein, one of the main

1,2,3,6-tetrahydropyridine (MPTP) and rotenone are

in animal models (Cannon et al., 2009). Notably, lithium

in autophagy markers (Xiong et al., 2011). Further-

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