1. Renal Side Effects

1.1. Polyuria

Lithium reduces renal concentrating ability, resulting in excessive urination (polyuria) with concomitant polydipsia. This effect can appear in the first weeks of lithium therapy, whereas a reduction in urinary specific gravity can in some patients last over years of lithium treatment. In its most extreme manifestation, the polyuria may have a form of diabetes insipidus. The mechanism is due to lithium’s effect on the collecting tubules which generate cyclic adenosine monophosphate in response to antidiuretic hormone. A molecular-genetic analysis revealed an association of polyuria with glycogen synthase kinase-3beta (GSK-3β) gene polymorphism [7]^[1], which corresponds to the role of this enzyme in the regulation of urinary concentrating ability [8]^[2]. Polyuria is usually alleviated when the dose of lithium is reduced. If the effects of lithium are very good, a trial of amiloride could be also recommended. In the case of diabetes insipidus, a decision of lithium discontinuation can be made, and following this, the polyuria usually disappears ^[3].

1.2. Nephropathy

The most serious concern in patients on long-term lithium therapy is the possibility of nephropathy in the course of interstitial nephritis. In such conditions, the main changes in laboratory results are increased creatinine concentration and decreased glomerular filtration rate (GFR). The biopsy findings reveal interstitial fibrosis of the cortex and medulla, interstitial changes with benign lymphatic invasion, glomerular fibrosis, and focal nephron atrophy [9]^[4]. The renal sonography discloses the presence of microcysts and macrocysts, punctate echogenic foci, and hyperechoic cortex, where the presence of macrocysts is associated with impaired renal function [10]^[5]. A recent pharmacogenetic study suggests an association of decreasing GFR during long-term lithium treatment with a polymorphism of the Acid Sensing Ion Channel Neuronal-1 (ACNN1) gene [11]^[6]. The International Group for The Study of Lithium Treated Patients (IGSLI) evaluated lithium’s impact on kidneys in patients treated with lithium for 8–48 years (mean 18 years). It was concluded that long-term lithium treatment was associated with a gradual decline of renal functioning by about 30% more than that that due to aging alone. The GFR declined by 0.7%/year of age and 0.9%/year of treatment, both by 19% more among women than men [12]^[7]. Recently Rej et al. [13]^[8] demonstrated that lithium was associated with a greater risk for impairment of renal function compared to valproate in the population of older adults (mean age 71 years), and the effect was more evident with higher lithium concentrations (>0.7 mmol/L). Swedish investigators studying the cohorts of the LISIE and MONICA projects (more than two thousand patients) concluded that lithium was the commonest cause of moderate-to-severe chronic kidney disease, although comorbidities also played a role. The decline was significantly greater in patients being on more than 10 years of lithium than in all other groups [14]^[9]. A meta-analysis by Schoretsanitis et al. [15]^[10] showed that one-fourth of patients receiving long-term lithium may develop impaired kidney function, which is two-fold higher compared with the non-lithium population. However, it is thought that generally, the long-term renal outcome of lithium administration in contemporary studies may be better compared with those before the 21st century which may be due to the recommendations for lower prophylactic lithium concentrations [16]^[11]. In summary, the risk factors for long-term lithium-induced kidney impairment include older age, concomitant comorbidities, higher serum lithium concentrations, and longer duration of lithium treatment [12]^[7]. Hayes et al. [17]^[12], using a 5-year kidney failure risk equation in a group of over 1600 patients, found predictive factors of high risk of chronic kidney diseases such as younger age at the commencement of lithium, female sex, and lower baseline GFR. The authors point out that individuals at high risk of poor GFR trajectory may be identified before starting lithium treatment. In patients in which progressive kidney damage occurs, a decision may be considered to discontinue lithium and replace it with another mood-stabilizing drug. However, such an option should be taken with great caution because other mood-stabilizing drugs, especially in excellent lithium responders, may not be effective, and the further course of the disease may be drug-resistant ^[3]. In Poznań, a five-year observation of four patients exhibiting very good lithium prophylactic effects was conducted. In three males and one female aged 67–69, with an average lithium treatment duration of 27 ± 9 years, the GFR was less than 50 mL/min/1.73 m². During the follow-up period, in three patients (two males and one female) with an initial GFR of 47–48 mL/min/1.73 m², renal parameters such as GFR, creatinine concentration, and urinary specific gravity did not show any significant changes. Therefore, these patients were advised to continue taking lithium at the current doses and to have an annual check-up of renal condition. In a patient with GFR of 32 mL/min/1.73 s m² whose GFR decreased by 14% and creatinine concentration increased by 10%, the lithium dose was reduced by half, and a periodic consultation with a nephrologist was recommended [18]^[13]. Two cases were reported on reintroducing lithium treatment in bipolar patients after renal transplantation due to end-stage renal disease [19,20]^[14][15]. The second case describes the 65-year-old woman, an excellent lithium responder, who after lithium discontinuation was hospitalized more than 40 times within two years and after re-starting lithium therapy was able to achieve remission of symptoms once again [20]^[15]. The recommendations for monitoring renal status in patients treated longitudinally (ten years or more) with lithium suggest that serum lithium levels measurement as well as those of urea, electrolytes, and creatinine should be performed every 3 to 6 months. A referral to nephrologist’s evaluation should be considered if GFR is <30 mL/min/1.73 m² and a progressive decline in GFR is observed, particularly if the decrease is more than 4/mL/min/1.73 m² [21]^[16]. Other cautions should include avoiding combining lithium with medications that can increase nephrotoxic potential (e.g., nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, some antibiotics as well as cytostatic and immunosuppressive drugs). Acute episodes of renal toxicity should be warded off, and, if possible, lithium should be administered in one daily dose. In the case of exacerbation of chronic kidney disease, the lithium dose must be reduced. Sometimes, even very low lithium doses providing a concentration of 0.2–0.3 mmol/L may be sufficient and a decision to discontinue lithium may not be necessary [21]^[16].

2. Gastrointestinal Side Effects

Gastrointestinal side effects present most commonly as nausea and diarrhea. Nausea occurs in 10–20% of lithium-treated patients being more frequent at the initiation of lithium treatment. The symptom is usually rather tolerated by the patients and gradually subsides during long-term therapy. Nausea may correlate with lithium levels, especially peak levels. Therefore, if it causes a major inconvenience, the patient can be advised to take lithium after meals, to use a multiple daily dose regimen or, if possible, to switch to sustained release preparations. Vomiting is rare in the beginning period of lithium treatment if the lithium level is kept at the therapeutic range. If it occurs, the lithium dose should be reduced. In the first months of treatment, diarrhea may occur in up to 10% of lithium-treated patients. Higher serum lithium levels (e.g., 0.8 mmol/L) may be connected with a predisposition to this symptom and lowering the dose may be recommended. Perhaps in some patients, diarrhea may be associated with sustained-release lithium preparations due to more distal absorption of the drug. In such cases, switching to regular lithium formulation may be helpful. Both vomiting and diarrhea develop in the situation of lithium poisoning [21]^[16].

3. Neurological Side Effects

3.1. Tremor

The most common of lithium side effects is tremor, mainly of the hands, reported in about 20–25% of the patients, perhaps more often in men. Usually, it appears in the first few weeks after starting lithium therapy, especially in patients with other predisposing factors such as older age and combined therapy with antipsychotics, antidepressants, and antiepileptic drugs. Some research indicated that hand tremor is related more to brain lithium concentration than serum lithium levels. The tremor is fine, similar to essential tremor, different than Parkinson-type tremor, and most apparent when taking planned actions such as lifting the cup or other precise hand movements. The recommended action to alleviate symptoms of tremors is the reduction of lithium dose. If such treatment is not efficient, the administration of propranolol at doses of 20–80 mg/day is a potentially effective strategy [22]^[17].

3.2. Other

The extrapyramidal symptoms, such as parkinsonism, tardive dyskinesia, or akathisia can also occur during lithium treatment, especially in older age and with combined therapy with neuroleptics. There are also reports on cerebellar symptoms such as nystagmus and gait disturbances, sometimes occurring even with the therapeutic level of lithium. In such cases, if they do not disappear after major reduction of lithium dose, discontinuation of the drug should be considered [22]^[17].

3.3. Lithium Intoxication

The symptoms of neurotoxicity always appear during lithium poisoning. This can be caused by overdosing, both intentional and accidental, dehydration, infection with fever, and the addition of other drugs. Symptoms appear when lithium concentration reaches 1.2 mmol/L and above. Mild poisoning manifests as weakness, severe hand tremor, mild ataxia, concentration disorders, and diarrhea. Severe poisoning presents with vomiting and neurological disturbances, mainly cerebellar symptoms (tremor, nystagmus, dysarthria, dizziness, ataxia), less often parkinsonian symptoms, choreoathetoid movements, or epileptic seizures. The disturbance of consciousness develops, which is mostly manifested as a stupor. Treatment of lithium poisoning includes intensive somatic care with forced lithium elimination by the infusion of physiological saline. For severe poisoning and high lithium concentration (>2 mmol/L), hemodialysis is very effective for a rapid decrease in lithium concentration [23]^[18]. In some patients, cognitive disorders and neurological deficits, mostly as symptoms of cerebellar damage (ataxia), may be a sequel of lithium poisoning. For defining such cases, the acronym SILENT (syndrome of irreversible lithium-effectuated neurotoxicity) was coined [24]^[19]. Lithium intoxication may also predispose to further kidney damage [9]^[4].

4. Thyroid Side Effects

Adverse lithium effects on the thyroid were observed as early as in the 1960s [25]^[20]. Lithium accumulates in the thyroid gland at three- to four-fold higher concentrations than in plasma. Administration of the drug causes a reduced production and release inhibition of thyroid hormones. The most common thyroid side effects associated with long-term lithium treatment are hypothyroidism and goiter. The prevalence of goiter is estimated at 30–59% of lithium-treated patients. The mechanisms of lithium-induced goiter can include the inhibition of thyroid hormone release resulting in an increase in TSH that leads to the increment of the thyroid volume. Additionally, the activation by lithium of tyrosine kinase and the influence on intracellular signaling by cyclic AMP and Wnt/beta-catenin induces the proliferation of thyrocytes [27]^[21]. In our study mentioned above, the thyroid volume was significantly higher in the lithium-treated group than in the lithium-naïve group as were more numerous focal changes >1 cm. The percentage of goiter was significantly higher in the lithium-treated group (40%) than in the lithium-naïve group (18%). In lithium-treated patients, the incidence of goiter was similar in male and female patients (37% vs. 41%). Importantly, the structural changes were not related to the concentrations of thyroid hormones [26]^[22]. Additionally, although lithium is supposed to interfere with thyroid immunity, no difference in thyroid autoantibodies was found between the two groups [28]^[23]. After starting lithium, it is recommended to monitor thyroid functions every 6 months. The presence of elevated TSH, hypothyroidism, and/or goiter during successful lithium therapy makes by no means evidence to discontinue the drug. All such conditions constitute indications for the thyroxine treatment; the dose can be consulted with an endocrinologist. Whereas, in very rare cases of hyperthyroidism, an endocrinologist’s intervention is a necessity, and possible lithium discontinuation may be considered [23]^[18].

5. Metabolic Side Effects

5.1. Weight Gain

Weight gain is an inconvenient side effect in lithium-treated patients, and in rare cases, may lead to clinical obesity. In some subjects, especially women, it can significantly impair compliance. The mechanisms of action may include the consumption of high-calorie drinks, insulin-like actions of lithium on carbohydrate and fat metabolism, as well as sodium retention. Bopp et al. [29]^[24] showed that in lithium augmentation of antidepressants, weight gain could be associated with leptin gene polymorphism. Whereas, in a recent meta-analysis, it was shown that weight gain on lithium cannot be remarkable and lower than on some active comparators (e.g., valproate) [30]^[25]. The main preventive and therapeutic strategies include diet, physical activity, and monitoring of thyroid function. Combined therapy with drugs of low weight-gain potential (lamotrigine, aripiprazole) or the addition of topiramate may be considered. Some case reports describe the use of metformin with good results [31]^[26].

5.2. Calcium and Bone Metabolism

Lithium can increase calcium reabsorption in the kidneys, stimulate parathormone (PTH) secretion, and cause a calcium-phosphate imbalance in the form of primary lithium-induced hyperparathyroidism. A meta-analysis has found that patients undergoing lithium therapy have on average higher concentrations of calcium and PTH [32]^[27]. In Poznan, in the study of 90 patients (30 males and 60 females) aged 60 ± 10, and treated with lithium for 16 ± 10 years, hypercalcemia was found in 10% of them (7% males and 12% females). Among the nine patients with hypercalcemia, three were found to have hyperparathyroidism [33]^[28]. Lithium-induced hyperparathyroidism can be due to lithium’s action on the calcium-sensing receptor and GSK-3, revealed by unmasking hyperparathyroidism in patients with a subclinical parathyroid adenoma or possibly by initiating multiglandular hyperparathyroidism [34]^[29]. Therefore, in people treated with lithium for a long time, it is advisable to monitor serum calcium levels, and in a situation of their increase, also PTH levels. In the case of lithium-induced hyperparathyroidism with significant clinical symptoms, treatment is similar to that of primary hyperparathyroidism. In contrast to possible disturbances in calcium metabolism, there are some data on the positive effect of lithium on bone mineral density [35]^[30]. A recent retrospective cohort study performed in Denmark showed that while bipolar disorder was associated with an increased risk of osteoporosis, the treatment with lithium resulted in a decrease in such risk [36]^[31].

6. Cognitive Side-Effects

Moderate cognitive impairment is perceived by clinicians as associated with lithium treatment. Contrary to that, the results of animal research in various models point to lithium exerting a favorable effect on cognitive functions. Additionally, patients with bipolar disorder (BD) have cognitive problems of various intensity, worsening during manic or depressive episodes, and sometimes also persisting during euthymia. Therefore, this should be adjusted when assessing the lithium effect. It seems that lithium treatment may not negatively affect previously impaired cognitive functions in bipolar patients [37]^[32]. Italian authors have carried out neuropsychological tests on lithium-treated bipolar I patients in the state of euthymia, gender- and age-matched patients with the illness receiving other mood-stabilizing drugs, and healthy individuals. It was found that bipolar patients showed deficits in visual memory and executive functions. However, after taking into account the method of treatment, it turned out that these deficits occurred only in patients using mood stabilizers other than lithium [38]^[33]. Additionally, in a more recent study, longitudinal monotherapy with lithium resulted in a significant improvement in the global cognitive index score [39]^[34]. The neurobiological processes connected with the favorable effect of lithium on cognitive functions may include an enhancement of the BDNF system and inhibition of GSK-3β. Interestingly, because of the pathogenic importance of herpes viruses in Alzheimer’s disease [42]^[35] and lithium’s antidementia activity (see later), the antiviral effect of lithium against herpes viruses may also be taken into account. It was found that infection with herpes simplex virus type 1 in BD was connected with a decrease in cognitive functioning [43]^[36], and the association between cognitive impairment and HSV-1 positivity both in BD and schizophrenia was recently confirmed [44]^[37].

7. Dermatological Side-Effects

Among the lithium-induced dermatological side-effects, exacerbated acne and psoriasis, as well as de novo occurrence of such conditions, should be mentioned. Psoriasis of moderate to severe intensity may be a contraindication for the introduction of lithium. Dermatological symptoms may be related to the concentration of lithium, and therefore an attempt at dose reduction may be made. If the effects of lithium are good, drugs recommended for these diseases can be used. Only in very severe cases, it may be necessary to replace lithium with another mood stabilizer. Recently, a case of a treatment-resistant female bipolar patient with psoriasis was presented, in whom, after the introduction of lithium, a remission of bipolar illness was achieved as well as a reduction of psoriatic changes. This could be explained by lithium’s immunomodulatory activity [45]^[38].

8. Cardiological Side-Effects

According to a recent review, the most important cardiological side effect of lithium is sinus bradycardia. In persons with genetic predisposition, a clinical presentation of Brugada syndrome may occur. Additionally, electrocardiographic changes (ECG) can appear, such as reversible T wave inversion, sinus node dysfunction, sinoatrial blocks, PR prolongation, QT prolongation/dispersion, and ventricular tachyarrhythmias. The rare cases of ST elevation, myocardial infarction, and heart blocks were also described. The ECG changes are generally dependent on both the duration of lithium treatment and the serum concentration of the drug [46]^[39]. Therefore, periodic ECG monitoring in patients during long-term prophylactic lithium treatment is recommended. In severe cases of arrhythmia, if lithium therapy is necessary, cardiological consultation should be considered.

9. Sexual Side Effects

Sexual side effects are rarely reported by lithium-treated patients, and they also are under-researched. The literature survey from 2015 indicates that lithium may reduce sexual thoughts and desire, worsen erectile function, and diminish sexual satisfaction, and an increased risk of such dysfunctions may appear with concomitant benzodiazepine use. The mechanism behind this should be a reduction by lithium of testosterone concentration and impairing nitric oxide-mediated relaxation of cavernosal tissue [48]^[40]. A report from 2014 suggests the prevalence of sexual dysfunction in the group of bipolar patients with mean duration of lithium treatment of 10 years one-third of them [49]^[41]. In a recent multicenter cross-sectional study, lithium in monotherapy or in combination with benzodiazepines was found to be related to worse total sexual functioning than anticonvulsants in monotherapy [50]^[42]. Although sexual dysfunction during lithium treatment appears associated with a lower level of overall functioning and may reduce compliance, limited treatment approaches were suggested. In one study, aspirin 240 daily, was reducing overall sexual dysfunction and improved erectile dysfunction [51]^[43]. However, it seems that, especially in diminished arousal, modern phosphodiesterase-5 inhibitors should be considered.