Lithium was discovered as a therapeutic remedy for psychiatric conditions in the mid-19th century and was reintroduced one century later [1] and it is still the most widely used medication for long-term management of bipolar disorder, where it is administered as a salt in the form of lithium carbonate/cirate/chloride/or sulfate. Bipolar disorder (BD) is a serious life-long disorder, characterized by recurrent episodes of depression and mania [2]. BD is classified, based on the presence of depressive along with manic or hypomanic episodes, into bipolar type I and type II disorder [3]. In bipolar II disorder, depression predominates, and the manic episodes are milder and briefer. This milder and less prolonged form of mania is referred to as hypomania. A person with bipolar I disorder, however, will experience a full manic episode and may or may not experience a major depressive episode [3]. BD affects 2.4% of the world population and is a leading cause of disability worldwide [4]. In its more severe forms, BD is associated with significant impairment of personal and social functioning and high risk of death through suicide as well as poor physical health. Lithium, having the strongest evidence of long-term relapse prevention, is the first-line treatment for both acute and maintenance treatment of BD. Furthermore, lithium is also prescribed for major depressive disorder as an adjunct therapy, as well as a treatment of vascular headaches and neutropenia [5,6]. In addition to its mood-stabilizing properties, remarkable neuroprotective and antiviral properties have also been attributed to lithium, with the use of lithium recently proposed as a potential treatment for Covid-19 [7]. Altogether, it is estimated that up to one million people worldwide take lithium on a daily basis [8].

Despite its global therapeutic use, the benefits of lithium are restricted by its narrow therapeutic index and the incidence of adverse effects [9]. The narrow margin between the safe and potentially toxic doses of lithium has resulted in self-administration of toxic doses accounting for 20–27% of hospitalized poisoning [9], and mortality rates of 9 to 25% reported from lithium toxicity [10]. The therapeutic effect of lithium salts is directly associated with its level in blood serum and there exist differences in individual pharmacokinetic and risk of intoxication [11]. Based on the differences in the excretion rates between individuals, the daily lithium dosage can vary between 10 and 80 mmol, which results in plasma concentrations of 0.4–1.2 mmol/L for effective treatment [12]. Lithium plasma levels greater than 1.2 mmol/L are potentially toxic and can be fatal. Therefore, avoidance of lithium intoxication has been, and continues to be, an important component in lithium treatment, and lithium serum levels must be monitored constantly to ensure its effectiveness and prevent adverse effects [9]. Lithium toxicity is associated with neurotoxic events, hyperthyroidism, hypercalcemia, and other serious conditions [10]. Considering the potential consequences of lithium toxicity, vigilant monitoring should be central in the treatment of BD patients. In the majority of cases, lithium toxicity is preventable with regular monitoring which can significantly reduce the number of toxic episodes in lithium-treated patients [9].

Additionally, treatment non-adherence is a persistent problem in psychiatry, with about 54% of patients not adhering to their prescription [10]. Despite lithium’s proven benefits regarding the prevention of severe affective episodes and suicide, discontinuation of lithium treatment is common amongst bipolar patients with about half of all individuals on lithium medication stopping their treatment at some point, which results in high levels of relapse. Along with psychiatric and physical reasons interfering with lithium treatment, lithium discontinuation has been suggested to be mainly due to its adverse effects which substantially impair the quality of life. Common adverse effects leading to lithium discontinuation are diarrhea, tremor, polyuria/polydipsia/diabetes insipidus, creatinine increase, and weight gain [13]. Therefore, side effects, toxicity burden associated with lithium medication, and the need for regular monitoring via vein puncture are the main reasons for lithium discontinuation and treatment non-adherence [9]. Consequently, the toxicity and treatment non-adherence burden associated with lithium medication has resulted in the widening of the mortality gap between BD patients and the general population. It is hence crucial to develop strategies to improve adherence and prevent unnecessary termination of lithium treatment [13].

Reaching and sustaining the right therapeutic level to avoid toxicity, dose-related adverse effects, and consequently, treatment non-adherence, requires regular therapeutic monitoring of lithium concentrations. In general, peak lithium concentrations in plasma occur two to four hours after an oral dose, with complete absorption occurring at around eight hours. Therefore, it is crucial to monitor lithium levels in serum twelve hours after the last dose [12]. Currently, lithium determination is performed by withdrawing blood samples from the patient by trained personnel, which is invasive and often painful, especially in patients with difficult venous access. The sample is then transported to the central laboratory where blood cells are removed before measurement, a procedure that can take up to 45 min. The quantification of lithium in clinical laboratories is performed by atomic absorption spectrometry (AAS), flame emission photometry (FEP), or conventional ion-selective electrodes (ISEs) [9,14]. These techniques are costly and require highly qualified personnel and elaborate laboratory methods that cannot be translated into point-of-care devices for personal monitoring. Moreover, with the current techniques, the whole analytical process of adjusting the dose after the first administration may have a variable lag time, usually from a few days to weeks [15]. The delay between sample extraction and the analysis of the results restricts the possibility of early detection, correction of problems, and prevention of potential adverse effects.

It is vital for BD patients to have comprehensive information about their pharmacological treatment at the appropriate time as it can substantially improve treatment adherence [13]. Patients’ perception of side effects or apprehension of lithium intoxication, as opposed to the actual presence of side effects, may further contribute to treatment non-adherence [9]. Therefore, there is a crucial need to have quicker and simpler ways to determine lithium levels. Development of a minimally invasive lithium-monitoring method will be a major advance in lithium therapeutic monitoring as it allows patients and non-medically-trained personnel to measure lithium levels and ensure patients are receiving the optimum dose [16]. Moreover, monitoring of drugs with narrow therapeutic range at home using wearable sensors can help reduce the burden on patients and health professionals associated with attendance of clinical settings and facilitate improved therapeutic monitoring [17]. Improved rates of lithium treatment monitoring will majorly enhance the quality of life of bipolar patients and will allow bipolar patients to monitor the drug during their treatment rather than taking single measurements weekly or monthly, which will greatly reduce the risk of adverse effects during the course of their treatment. The pivotal need for the development of low-cost and easy-to-use sensors for decentralized monitoring of lithium has resulted in a great interest in investigating novel lithium-monitoring techniques. Efforts have been made to develop minimally invasive point-of-care lithium-monitoring devices utilizing matrices such as blood, urine, sweat, saliva, and interstitial fluid (ISF). The current paper reviews the literature on investigated technologies for non-invasive monitoring of lithium medication in the treatment of BD.