Academic Editor: Rafael Franco
Currently, in psychiatry, lithium is a drug of choice as a mood stabilizer in the maintenance treatment of bipolar disorder for the prevention of manic and depressive recurrences. The second most important psychiatric use of lithium is probably increasing the efficacy of antidepressants in treatment-resistant depression. In addition to its mood-stabilizing properties, lithium exerts antisuicidal, antiviral, immunomodulatory, and neuroprotective effects. The goal of the review is to describe the experimental and clinical studies on the last three properties of lithium. Antiviral effects of lithium pertain mostly to DNA viruses, especially herpes viruses. The therapeutic effects of lithium in systemic and topical administration on labial and genital herpes were demonstrated in clinical studies. There is also some evidence, mostly in experimental studies, that lithium possesses antiviral activity against RNA viruses, including coronaviruses. The immunomodulatory effect of lithium can mitigate “low-grade inflammatory” conditions in bipolar illness. The neuroprotective properties of lithium make this ion a plausible candidate for the prevention and treatment of neurodegenerative disorders. A favorable effect of lithium was shown in experimental models of neurodegenerative disorders. On the clinical level, some preventive action against dementia and moderately therapeutic activity in Alzheimer’s disease, and mild cognitive impairment were observed. Despite promising results of lithium obtained in animal models of Huntington’s disease and amyotrophic lateral sclerosis, they have not been confirmed in clinical studies. A suggestion for common mechanisms of antiviral, immunomodulatory, and neuroprotective effects of lithium is advanced.
Medical use of lithium started in 1859 when an English physician, Alfred Baring Garrod (1819–1907), applied lithium carbonate in the treatment of gout . Exactly one and half-century ago (in 1871), an American neurologist, William Alexander Hammond (1828–1900), used lithium bromide in the treatment of mania . Fifteen years later, a Danish physician and scientist, Carl Lange (1834–1900), based on the “uric acid diathesis” theory of depression, reported on lithium carbonate in the treatment and prophylaxis of periodic depression . The introduction of lithium in contemporary psychiatry is credited to an Australian psychiatrist, John Cade (1912–1980), who described the efficacy of lithium carbonate in mania in 1949 . Samuel Gershon, who is now the only living witness of Cade’s activity in Australia, after he came to the USA, greatly contributed to the development of lithium therapy in this country . The first publications on lithium prophylactic effect in mood disorders took place in the early 1960s [6, 7]. Thirty years ago, lithium was shown to augment the efficacy of antidepressants .
Presently, the long-term lithium administration for the prevention of manic and depressive recurrences makes the most important recommendation for the use of this drug. Three meta-analyses of the 21st century have fully confirmed the prophylactic effectiveness of lithium in bipolar disorder, slightly better against manic than against depressive recurrences [9, 10, 11]. The studies also supported lithium prophylactic efficacy in recurrent depression . Lithium augmentation of antidepressants in treatment-resistant depression can be regarded as the second therapeutic indication for lithium. A review on this subject demonstrated that lithium is effective in both bipolar and unipolar depressed patients, and a successful outcome may be expected in at least 50% of them .
In addition to mood-stabilizing properties, lithium exerts antisuicidal, antiviral, immunomodulatory, and neuroprotective action. The evidence for the antisuicidal effect of lithium in bipolar disorder and recurrent depression has been accumulating since the early 1990s  and it has been confirmed by meta-analyses performed in the 21st century [15, 16]. While being on lithium prevents suicide, its discontinuation significantly increases this risk. The antisuicidal effect is not correlated with mood stabilization, which may seem counter-intuitive, however, it points to a specific and very important aspect of lithium activity . In the recent decade, in many countries, a negative correlation between suicides and lithium concentration in drinking water has also been demonstrated .
The main biochemical mechanisms of lithium action are connected with the
inhibition of the glycogen synthase kinase-3beta (GSK-3
In the present review, the experimental and clinical studies pertaining to antiviral, immunomodulatory, and neuroprotective properties of lithium are described. The mechanisms and clinical implications of these effects are discussed. Furthermore, a suggestion for a common mechanism for the antiviral, immunomodulatory, and neuroprotective effects of lithium is advanced.
Experimental evidence for the antiviral effect of lithium was initially provided in 1980 when the researchers from the University of Birmingham showed that lithium in a concentration of 5–30 mmol/L inhibits replication of the herpes simplex virus (HSV) in hamster kidney cells . Several years later, the in vitro antiviral activity of lithium on HSV in rabbit cells was observed . In 1988, Romanian virologists demonstrated a reduction in virus yield in human embryo fibroblasts cultures infected with HSV when pre-treated with lithium chloride at concentrations of 1–10 mmol/L . Birmingham’s researchers suggested that lithium may directly inhibit HSV replication as well as impair the viral DNA synthesis by the displacement of potassium and magnesium ions in biochemical reactions .
Labial herpes is caused by an infection of herpes simplex virus type 1 (HSV-1), occurring in approximately 1/3 of the population. Its course is characterized by frequent recurrences. At the time of Skinner and collaborators’  findings, the case reports of labial herpes remissions while using lithium appeared [31, 32]. A further case report on suppression by lithium of recurrent herpes labialis came out in 1999 .
Retrospective research of labial herpes in patients receiving lithium for prophylactic purposes was carried out within a collaborative study of the Department of Adult Psychiatry, Poznan University of Medical Sciences, and the Department of Psychiatry of the University of Pennsylvania. The studied Polish population consisted of 69 patients (24 male, 45 female) receiving lithium for 8 years. Among them, 28 persons had recurrent labial herpes. During lithium therapy, the full cessation of recurrence of herpes occurred in 13 patients, among 7 the frequency of recurrences decreased, among 6 it remained at the same level and in 2 it increased. The general decrease in recurrence frequency was 64%. The best effect was observed in patients in whom lithium concentration in the serum was higher than 0.65 mmol/L, and intracellular (erythrocyte) lithium concentration exceeded 0.35 mmol/L. The American population consisted of two groups of 52 people, matched by gender (21 males and 31 females in each group), age (on average 45 years), and length of systematic drug treatment (on average 5 years). In the first group, including patients with bipolar disorder treated with lithium, the frequency of labial herpes recurrences in comparison with the 5-year period preceding the treatment decreased by 73%. In the second group, including patients with recurrent depression receiving antidepressant drugs, no significant difference was observed .
The therapeutic efficacy of lithium succinate ointment in the treatment of focal herpes lesions has also been demonstrated. A preparation called Efalith, produced by Nova Scotia, containing 8% of lithium succinate and 0.05% of zinc sulfate was used. The study included 42 patients (4 male, 38 female) with recurrent herpes. In most of them, recurrences were very frequent (every 1–6 months). Application of the ointment commenced 1–3 days after the appearance of lesions and continued 3–7 times a day for the first 3 days and then 1–2 times a day. All patients were completely cured after 2–7 (on average 4) days of treatment. In 6 patients, herpes lesions showed signs of bacterial infection—the lesions subsided when lithium succinate was used, without the need for antibacterial treatment. In a period of one-year follow-up, herpes lesions reappeared in 6 patients, but never in the area where the ointment was previously applied . Thus, the antiviral effect of lithium on HSV-1 infection was confirmed with both systemic and topical treatment. However, in the case of the latter, a possible therapeutic contribution of zinc cannot be excluded.
Genital herpes, which may also be a recurring affliction, is caused by an infection of herpes simplex virus type 2 (HSV-2). In this condition, the first use of lithium was that of topical application of 8% lithium succinate ointment in a controlled study by Skinner , including 73 patients with recurring genital (HSV2) herpes. The ointment was applied 4 times a day for 7 days, and a quantitative measure of HSV2 was performed. The median duration of pain/discomfort was reduced in lithium-treated patients compared with the placebo group from 7 to 4 days. HSV2 excretion at day 4 or 5 was present in 11/20 (55%) placebo-treated compared with 5/37 (14%) lithium-treated patients. Virus concentration in the lithium group was reduced by 30-fold as compared to patients receiving a placebo.
The research on oral lithium carbonate as a prophylactic treatment of genital
herpes recurrences was performed in two placebo-controlled studies by Amsterdam
and collaborators [37, 38]. In the first one, 10 women with recurrent genital
HSV-2 infection were given oral lithium for 12 months and followed for 18 months.
During the active treatment phase, average daily lithium doses were 587
The antiviral effect of lithium on the DNA viruses has also been demonstrated for the Parvoviridae family. Chen and collaborators  observed the inhibition of porcine parvovirus (PPV) replication in swine testis cells by lithium chloride at a lithium concentration of 5 mmol/L, and, as in other DNA viruses, the effect occurred in the early phase of PPV replication. It was also shown that lithium suppressed the synthesis of viral DNA and proteins of canine parvovirus and inhibited viral entry into feline kidney cell cultures . Parvoviruses are the pathogens in a few diseases in humans (e.g., erythema infectiosum caused by parvovirus B19). However, no trials of lithium in these conditions have been conducted so far.
Experimental studies performed in the last three decades demonstrated the antiviral effect of lithium on some RNA viruses. In the murine acquired immune deficiency syndrome induced by the murine leukemia retrovirus, the animals receiving lithium, 1 mmol/L, demonstrated a marked reduction in the development of lymphadenopathy and splenomegaly . Lithium chloride also inhibited the replication of the foot-and-mouth disease virus , feline calicivirus , and mammalian orthoreovirus .
On the clinical side, the studies of lithium effect on the RNA viruses pertained mostly to those responsible for respiratory infections. Amsterdam and collaborators , in a retrospective study including 236 patients with mood disorders, among those 177 taking lithium carbonate and 59 receiving antidepressants on a chronic basis, showed a statistically significant reduction in mean yearly rates of flu-like infections in lithium- but not antidepressant-treated patients. Recently, Landen and collaborators  demonstrated a 28% decrease in respiratory infections, part of which most likely due to the RNA viruses, during chronic lithium administration. To rule out the possibility that this could be due to lithium’s effect on psychiatric symptoms, the effect of another mood-stabilizer valproate was studied, which turned out to increase such infections by 35%. However, the comparison of the efficacy in preventing mood recurrences between these two mood stabilizers was not performed.
Given the Covid-19 (Coronavirus Disease 2019) pandemics, experimental studies on lithium effect on the representatives of Coronaviridae family performed in the last two decades are of interest. The study of lithium chloride effect on the replication of avian coronavirus infectious bronchitis virus (IBV) in Vero cells (an African Green monkey kidney-derived epithelial cell line), and DF-1 cells, (an immortalized chicken embryo fibroblast cell line) showed that with lithium chloride concentrations, 5–50 mmol/L, the RNA and protein levels of IBV, as well as viral progeny production were reduced dose-dependently in both cell types . Also, lithium chloride limited in vitro both early and late stages of infection and inhibited apoptosis in porcine coronavirus causing transmissible gastroenteritis . In type II porcine reproductive and respiratory syndrome virus, lithium chloride reduced RNA production and protein transduction . In Vero cells, lithium chloride showed effectiveness in suppressing infection of the porcine epidemic diarrhea virus by inhibiting the virus entry, replication, and apoptosis . Furthermore, lithium chloride at concentrations of 10–60 mmol/L inhibited viral replication of porcine delta coronavirus (PDCoV) in porcine kidney cells (LLC-PK1). These effects occurred at the early stage of PDCoV replication and were associated with the inhibition of the PDCoV induced apoptosis .
It should be noted that in most experimental papers, lithium concentration exceeds several times the concentration needed for clinical lithium use (i.e., 0.5–1.0 mmol/L). Therefore, the extrapolation from experimental studies to the clinic should be done with caution.
Shortly after the outbreak of the Covid-19 pandemics, Nowak and Walkowiak 
presented the above experimental data on the possible effect of lithium on
coronaviruses in experimental studies. They postulate that lithium could be
clinically useful in this condition given that it inhibits GSK-3
The first mention of the immunomodulatory effect of lithium can be traced back to 1950 when Radomski and collaborators  reported an increase of leukocytes during lithium treatment. This effect was subsequently confirmed in many clinical reports [58, 59] and its mechanisms have been extensively studied. It has been found that lithium induces marrow granulopoiesis, influencing hematopoietic stem cells (HSC). Lithium influences SC directly, by stimulating pluripotent stem cell (PSC) proliferation, and indirectly, by increasing the production of granulocyte colony-stimulating factor (G-CSF) and other growth factors. Hammond and Dale  demonstrated that administration of lithium to dogs with cyclic neutropenia eliminated abnormalities in neutrophils, as well as in platelets, reticulocytes, and monocytes, indicating the effect of lithium on the HSC level. Levitt and Quesenberry  found that lithium primarily stimulates pluripotential SC and the progenitor cells for granulocytes and monocytes (GMP). Lithium also stimulates the production of hematopoietic growth factors. In healthy persons, lithium administration results in an increased release of G-CSF and increased bone marrow neutrophil production in vitro . Elevated G-CSF levels in the urine and enhanced production of G-CSF by peripheral blood mononuclear cells (PBMCs) were observed [63, 64].
The use of the aforementioned effect in psychiatry is for the prevention and
treatment of neutropenia that may occur during clozapine treatment . This
applies primarily to schizophrenic patients, but also to bipolar affective
disorder, for which clozapine has been increasingly employed. Lithium should be
introduced at leukocyte values of 3.5
Immuno-inflammatory processes are thought to play an important role in the pathogenesis of mood disorders. For many years, bipolar illness has been perceived as a condition characterized by a “low-grade inflammation”. Furthermore, in these inflammatory processes occurring in the central nervous system (neuroinflammation), the most important cells are microglia [68, 69]. Probably, the main immunomodulatory effect of lithium is a mitigation of the immune-endocrine component of bipolar disorder. In a review paper in 2000 by the author of this article, it was mentioned that lithium attenuates the acute-phase reaction, production of pro-inflammatory cytokines, and excessive activation of the hypothalamic-pituitary-adrenal axis . A subsequent review of the anti-inflammatory effect of lithium was published in 2014 .
For lithium’s immunomodulatory activity, its inhibition of the GSK-3
In a clinical study, decreased levels of inflammatory markers in serum in rapid
cycling bipolar patients after 30 days of lithium treatment were observed .
Boufidou and collaborators  presented a study comparing the cytokine levels
(IL-2, IL-6, IL-10, and IFN-
We conducted a study assessing the influence of long-term lithium treatment on VSELs (very small embryonic-like stem cells) and expression of mRNAs of neuronal and glial markers in peripheral blood of bipolar disorder patients with a long lasting disease. Patients not treated with lithium were characterized by a significantly higher number of VSEL cells, proportional to the duration of the disease, and higher expression of markers in comparison to healthy individuals matched in terms of sex and age. This may indicate that the excessive mobilization of VSELs and higher expression of mRNA of neuronal and glial markers cause an exaggeration of regenerative and inflammatory processes during the course of the bipolar disorder. On the other hand, in patients treated with lithium, the number of VSEL cells did not differ from the values found in healthy individuals and showed a negative correlation with the duration of treatment with lithium and serum concentrations of lithium. Also, the expression of neuronal and glial markers was, in many cases, similar to that of healthy individuals. The results indicate that long-term treatment with lithium of bipolar affective disorder may inhibit excessive regenerative and inflammatory processes in this disease . This may be in contrast with the stimulating effect of lithium on hematopoietic stem cells , which is also clinically beneficial.
The neuroprotective effect of lithium may be reflected by the lithium-induced increase in cerebral grey matter volume both in healthy subjects and in patients with bipolar disorders. This was first suggested in 2000  and confirmed in several reports reviewed by Hajek and Weiner . The brain structures influenced by either short-term or long-term lithium administration included the prefrontal cortex, anterior cingulate, and hippocampus. The most frequent reports demonstrated larger grey matter volumes in patients treated with lithium compared to those not receiving lithium. The association between lithium treatment and larger grey matter volume was not dependent on mood state and diagnostic subtype. In our own study, bipolar patients receiving lithium had larger hippocampal volumes than those not receiving lithium, and the volumes of lithium-treated subjects were similar to those of healthy controls . In two studies, the effects of lithium were compared with anticonvulsants and antipsychotics, possessing mood-stabilizing properties. The use of lithium increased grey matter volume of the subgenual anterior cingulate, the hippocampus-amygdala complex and the insula, which was associated with better clinical effect. Such an outcome was not found by using any other mood stabilizer [87, 88]. In experimental studies, it was found that lithium accumulates in neurogenic regions that may be relevant to the effects described above .
Many experimental studies have shown protective effects of lithium either after ischaemic insults or ionizing radiation, both protection from acute injury [90, 91] as well as regenerative effects even long after the injury [92, 93] were evidenced. In a mouse model, lithium may alleviate the spatial cognitive impairment induced by repeated cerebral ischemia-reperfusion by the inhibition of excessive autophagy through mTOR signaling activation . Also, the neuroprotective effect of lithium makes this ion a plausible candidate for the prevention and treatment of neurodegenerative disorders.
An inhibition by lithium of GSK-3
In the fly Drosophila adult-onset model of AD, lithium may ameliorate
amyloid-beta pathology through inhibition of GSK-3
It has also been proposed that lithium protects against dementia. Population studies have shown an association between lithium treatment and a reduction of dementia risk . Employing the Danish nationwide register of lithium prescriptions, it was found that in patients taking lithium for a long time, the rate of dementia decreased to the same level as the rate for the general population while in persons treated with anticonvulsant drugs, the risk of dementia increased with the duration of treatment . Long-term treatment with lithium was also associated with a reduced rate of dementia in patients with bipolar disorder, in contrast to such treatment with anticonvulsants, antidepressants, and antipsychotics . A possible effect of trace doses of lithium has been recently proposed in a Danish study of Kessing and collaborators  showing a negative association between the incidence of dementia and lithium concentration in drinking water. Concurring with this, an American study demonstrated that changes in AD mortality were negatively correlated with trace lithium in drinking water .
The first single-blind, randomized, placebo-controlled multicenter trial
investigating the effects of lithium treatment on CSF dementia biomarkers and
cognitive performance included 71 patients with early AD treated with a lithium
level of 0.5–0.8 mmol/L over 10 weeks. No significant changes in CSF biomarkers
or cognitive parameters were found . However, secondary data analysis showed
associations of lithium treatment with increased concentration of BDNF and a
further subgroup analysis demonstrated that patients showing higher BDNF
concentrations also had cognitive improvement . Two years later, Forlenza
et al.  investigated the effects of a low dose lithium treatment
(0.25–0.5 mmol/L) on cognitive parameters and CSF biomarkers of dementia in 45
patients with amnestic mild cognitive impairment (aMCI). After 12 months,
lithium-treated patients who did not convert to AD showed a significantly reduced
concentration of hyperphosphorylated tau protein. In the lithium group, the
conversion rate to AD was similar to that of non-lithium-treated patients,
although converters showed less cognitive decline. Nunes et al. 
studied the effects of a lithium microdose of 300
Two meta-analyses suggested possible procognitive effects of lithium in patients with MCI and AD. The first, including three clinical trials with a total of 232 patients, demonstrated a significant slowing of cognitive decline associated with lithium treatment . The second included five randomized controlled trials investigating the effects of lithium and tideglusib, an inhibitor of GSK-3, on cognition in patients with MCI and AD. In the subgroup of lithium-treated patients, some beneficial effects on cognitive parameters were observed, which correlated with treatment duration .
The attempts to use lithium in another neurodegenerative disorder, Huntington’s
disease (HD) started in the 1970s. The rationale for such use at that time was
associated with the therapeutic effects of lithium regarding movement disorders
such as tardive dyskinesia. However, the results of three controlled trials of
lithium in HD involving small numbers of patients were negative [115, 116, 117]. In
recent years, a rationale for using lithium in HD was based on animal studies. In
a rat excitotoxic model of HD disease in which quinolinic acid was unilaterally
infused into the striatum, lithium suppressed striatal lesions and promoted
neuronal survival and proliferation in this brain structure . HD is caused
by a polyglutamine expansion mutation in the huntingtin protein, which can be
cleared by macroautophagy. A potential therapeutic mechanism of lithium in HD has
also been attributed to its property of augmenting macroautophagy by inhibiting
inositol monophosphatase and GSK-3
The most recent review regarding the possible use of lithium in HD was performed in 2014, in which the authors compared lithium with another mood stabilizer, valproic acid (VPA). In clinical studies, lithium treatment improved mood, and VPA treatment both stabilized mood and moderately reduced chorea. However, the main features of HD were unaffected by treatment with either drug. In experimental studies, both lithium and valproic acid (VPA) have shown multiple beneficial effects, including behavioral and motor improvement, enhanced neuroprotection, and lifespan extension. In transgenic HD mice, combined lithium/VPA treatment was more effective than treatment with either drug alone. The authors postulate a clinical trial using lithium/VPA combination in HD patients . However, in recent years such a trial has not been performed.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that usually leads to death with 3–5 years from diagnosis. There is no effective treatment of ALS and all attempts are at an experimental stage. A part of ALS cases is due to mutations of the gene coding for the enzyme copper-zinc superoxide dismutase (SOD1), and a mouse model of ALS (transgenic mice overexpressing the human mutant SOD1) was created. In this model, administering lithium concurrently with an antioxidant, Neu2000, resulted in an improvement of motor neuron survival, motor function, and reduced mortality . Fornari et al.  using the ALS mouse showed a marked neuroprotective action of lithium, with a delay of disease onset and increase in life span. However, such a beneficial effect of lithium was not confirmed in two subsequent studies that used this model [124, 125]. In a clinical study, Italian investigators were the first to suggest that giving lithium in doses leading to plasma levels 0.4–0.8 mmol/L may delay the progression of ALS . However, another Italian group was not able to confirm lithium effects either in therapeutic (0.4–0.8 mmol/L) or sub-therapeutic (0.2–0.4 mmol/L) doses . Also, American researchers found no evidence that lithium in combination with riluzole, the drug used in ALS, slows the progression of the disease more than riluzole alone . More recently, Van Eijk et al.  performed a meta-analysis to assess whether genetic subgroups in ALS trials differently responded to treatment with lithium. It was found that the effect of lithium was dependent on the UNC13A gene and the 12-month survival probability for UNC13A carriers treated with lithium improved from 40% to 70%. Therefore, the possibility of using lithium in some patients with ALS remains an open issue.
The summary of the antiviral, immunomodulatory, and neuroprotective effects of lithium is presented in Table 1 (Ref. [27, 28, 29, 30, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 45, 46, 47, 48, 49, 50, 51, 53, 54, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 72, 73, 74, 75, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 95, 96, 97, 98, 100, 101, 102, 104, 105, 106, 107, 109, 110, 111, 112, 113, 114, 118, 119, 120, 122, 123, 128, 129]).
|Effect||Experimental studies||Clinical studies||Mechanisms|
|Antiviral||Inhibiting HSV replication [27, 28, 29]||Suppression of labial herpes (HSV-1) and genital herpes (HSV-2) recurrences by systematic and topical administration [34, 35, 36, 37, 38]||Impairing the viral DNA synthesis by the displacement of potassium and magnesium |
|Inhibiting replication of parvoviruses [39, 40]||Beneficial effect on respiratory infections [45, 46]||Inhibition of GSK-3|
|Inhibiting replication of RNA viruses, including coronaviruses [41, 42, 43, 47, 48, 49, 50, 51]|
|Immuno-modulatory||Increase of leukocytes [60, 61]||Increase of leukocytes [57, 58, 59]||Increased G-CSF production [62, 63, 64]|
|Decrease of microglial activation [73, 74, 75]||Therapeutic effect in drug-induced neutropenia [65, 66, 67]||Inhibition of GSK-3|
|Mitigating the “low-grade inflammation” in bipolar disorder [77, 78, 79, 80, 81, 82, 83, 84, 85]||Decrease of VSELs|
|Inhibiting excessive regenerative processes||Reduction of mRNA of neural and glial markers |
|Neuroprotective||Protective effect after ischemic insults and irradiation [90, 91, 92, 93]||Increase in cerebral grey matter [84, 85, 86, 87, 88, 89]||Inhibition of GSK-3|
||Reduction of dementia risk [104, 105, 106, 107]||Stimulation of BDNF [109, 120, 129]|
|Beneficial effects in experimental models of HD and ALS [118, 119, 122, 123]||Beneficial effects in AD, MCI [109, 110, 111, 112, 113, 114] and UNC13A carriers of ALS ||Effect on autophagy through mTOR signaling |
|HSV, herpes simplex virus; GSK-3|
The main indication for lithium in psychiatry is for the prevention and treatment of affective episodes, as a mood stabilizer. The antiviral, immunomodulatory, and neuro-protective effects of this ion contribute to its therapeutic effects in mood disorders. However, these properties of lithium can be also useful in other clinical conditions. For example, in subsection 3.1, it has been shown that the lithium property of increasing leukocyte count can be used both in psychiatry and elsewhere.
The antiviral effect of lithium against herpes infections can be applied clinically for the suppression of recurrences of labial and genital infections both in patients with a mood disorder and in other populations. In patients with bipolar disorder, it may also be important for lithium’s pro-cognitive action. American researchers found that infection with HSV-1 was an independent predictor of decreased cognitive functioning (mostly immediate verbal memory) in bipolar patients . In our study, we demonstrated that in a cohort of bipolar patients receiving lithium for an average of 13 years, excellent lithium responders presented cognitive functions at the level of healthy subjects without bipolar disorder. We may hypothesize that it could be partly due to the effect of lithium on herpes viruses. Furthermore, in such patients, serum BDNF concentrations were also similar to those of healthy subjects, which may point to lithium’s neuroprotective effect . It may also suggest that mood stabilization by itself can be naturally beneficial for cognitive function regardless of anti-HSV effect and BDNF levels. The effect against herpes infection can be also connected with lithium’s activity, both prophylactic and therapeutic, in dementia. Recently, Izhaki  presented convincing evidence for a major role for HSV-1 in AD, and a possible anti-HSV-1 mechanism of lithium in its anti-dementia activity was proposed .
The immunomodulatory effect of lithium in bipolar disorder plays an important role in mitigating the condition of the “low-grade inflammation” in this illness. In bipolar disorder, this process is present both in the central nervous system and in the peripheral blood including excessive production of proinflammatory cytokines by microglia and in the periphery as well as an excess of regenerative processes involving some stem cells (VSEL) . De-Paula and collaborators  demonstrated that lithium, both in therapeutic and subtherapeutic concentrations inhibited the secretion of proinflammatory and enhanced that of antiinflammatory cytokines in co-cultures of neurons and glial cells. Because the role of proinflammatory cytokines released from microglia was also evidenced in Alzheimer’s disease , this effect of lithium can also contribute to its therapeutic activity in some neurodegenerative disorders.
The neuroprotective effect of lithium in bipolar disorder may be important for improving neuroplasticity, which is deficient in this illness . This discovery gave rise to attempts of repurposing lithium for neurodegenerative disorders. However, in these disorders, there has been a conspicuous discrepancy between the results of experimental and clinical studies. Despite promising findings with lithium treatment obtained in animal models, an immediate reflection of these in clinical studies of HD and ALS has been weak. The only positive results would be a possibility of decreasing the risk of AD with long-term lithium use as well as some therapeutic effects obtained in AD and MCI, as described in subsection 4.3. Therefore, it seems that the issue of clinical application of lithium in neurological disorders should be a subject of further well-designed clinical studies in the future.
Although the antiviral, immunomodulatory, and neuroprotective effects of lithium
can be perceived as distinct, there may be overlapping biological mechanisms. The
most important is probably the inhibition by lithium of the GSK-3
There has also been evidence for the contribution of the phosphatidylinositol and BDNF systems in both immunomodulatory and neuroprotective activity, involving the phosphatidyl-inositol-3-kinase/Akt (protein kinase B)/CREB/BDNF pathway . Another mechanism can be the inhibition of excessive autophagy through mTOR signaling activation .
In conclusion, the antiviral, immunomodulatory, and neuroprotective effects of lithium constitute an important part of its biological properties. These mechanisms may add to the therapy of mood disorders and also repurpose lithium for other therapeutic indications.
AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; BDNF, brain-derived
neurotrophic factor; cAMP, cyclic ademosine monophosphate; CREB, cAMP response
binding protein; G-CSF, granulocyte-colony stimulating factor; GSK-3
This research received no external funding.
The author declares no conflict of interest.