Lithium Therapeutic Monitoring in Bipolar Disorder: Comparison
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SLince the mid-20th century, lithium continues to be prescribethium was discovered as a first-line mood stabilizer for the management of bipolar disorder (BD). However, lithium has a very narrow therapeutic index, and it is crucial to carefully monitor lithium plasma levels as concentrations greater than 1.2 mmol/L are potentially toxic and can be fatal. The quantification of lithium in clinical laboratories is performed by atomic absorption spectrometry, flame emission photometry, or conventional ion-selective electrodes. All these techniques are cumbersome and require frequent blood tests with consequent discomfort which results in patients evading treatment. Furthermore, the current techniques for therapeutic remedy for psychiatric conditions in the mid-19th century and was reintroduced one century later 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 monitoring require highly qualified personnel and expensive equipment; hence, it is crucial to develop low-cost and easy-to-use devices for decentralized monitoring of lithiumcarbonate/cirate/chloride/or sulfate. Bipolar disorder (BD) is a serious life-long disorder, characterized by recurrent episodes of depression and mania.

  • lithium monitoring
  • lithium sensors
  • therapeutic drug monitoring

1. Introduction

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.

2. DLithium Therapeutiscussioc Monitoring in Bipolar Disorder

Employing optical techniques for monitoring lithium levels offers numerous advantages including high accuracy, specificity, and good biocompatibility. Nevertheless, development of optical lithium sensors is associated with some challenges. For example, the use of optical lithium ligands is limited by the intrinsic properties of lithium cation such as its small size and its high charge density which can result in poor coordination ability. Therefore, the right optical lithium ligand should be identified to allow selective and efficient sensing of lithium [16][17]. Furthermore, in the development of optical lithium ligands, the response time for signal detection should be considered. The response time of small ligands used for lithium detection has been reported to vary from a few seconds to 30 min, with most of the optical sensors displaying detection after 1–10 min, because of the time needed for Li+ cation to coordinate with ionophore, and the necessary duration for stabilizing the detection signal [18]. Therefore, the equilibration time for Li+ coordination must be considered which depends on the ligand that is employed in the membrane for preparation of the optical sensor. The reversibility of ligands for lithium detection is another crucial parameter to be considered. This is because after Li+ detection the lithium sensor is classically non-reusable and should only be reused in the condition of a total de-coordination of lithium cation from coordination sites and the recovery of initial optical properties [18]. Ultimately, the optical lithium detection/quantification must not or must only slightly affect the studied biological system. Lithium determination using FES, FAAS, and ISE methods has been evaluated [19]. It has been suggested that although the percentage of lithium recovery for FES and FAAS methods was high, ISE showed the most satisfactory results for recovery of lithium in pooled patient’s serum [19]. Nevertheless, it is suggested that FES remains the preferred method for lithium measurement in many laboratories. This is mainly due to the lack of standardization and validation of novel technologies which calls for a strong collaboration between academic, industrial, and medical partners. Moreover, it is demonstrated that a higher average lithium concentration for patients’ serum samples was measured by ISE and that ISE determination is easier and more precise. Nonetheless, the accuracy of ISEs may depend on other interfering factors [19]. For example, one of the main challenges associated with ISEs for lithium monitoring is the ongoing research on finding suitable ionophores with sufficiently high selectivity in respect to sodium [20][21]. In general, accurate measurement of lithium concentration by ISE requires either very high selectivity of the membrane for Li+ or an algorithm that will compensate for interference from sodium [20]. Furthermore, the electrochemical (EC) sensors giving a current response directly proportional to analyte concentration are preferred to potentiometric ISEs, which give a potential response that is proportional to the logarithm of analyte activity [22]. In general, ISEs have been mainly coupled with potentiometric and voltammetric detection methods which both suffer from limitations such as drifting of electrode-electrolyte interface impedance. Employment of electrical impedance spectroscopy is also an interesting but understudied approach for lithium detection. While tetrapolar electrical impedance spectroscopy offers a high degree of sensitivity to conductivity variations in samples, it lacks sensitivity towards lithium ion and must be combined with other techniques such as optical methods. Tripolar configurations, measuring the properties of functionalized electrodes, can also be investigated as they might offer a higher degree of selectivity for lithium determination. Solid-contact ion-selective electrodes (SC-ISEs) also have some limitations, including the need for calibration, limited selectivity, poor reliability, and potential drift [23][24]. Lastly, measuring compounds using capillary electrophoresis (CE) can also be challenging due to wall adsorption shifting performance, particularly over multiple runs. Therefore, different types of surface coatings have been investigated to reduce issues relating to adsorption effects [21]. Capillary electrophoresis microchips [25][26][27] also have several disadvantages, including complicated channel design and fabrication procedures and high-voltage manipulation using expensive instruments [28]. Moreover, band-broadening in CE is a general problem for samples containing a high concentration of ionic constituents as it can lead to poor resolution [26]. An important step in the development of a point-of-care (POC) device for therapeutic monitoring of lithium is matrix selection. Direct analysis of whole blood without any sample pretreatment remains one of the main challenges in blood monitoring. Therefore, combining sample treatment steps with the sensing methodologies on a single device can facilitate the development of a point-of-care device for lithium monitoring [21]. Blood-related matrices have some major limitations; namely, blood sampling is relatively invasive and may be impractical for certain patient populations. The costs associated with collecting, transporting, and processing blood samples are also significant [21]. As aforementioned, dried blood spot (DBS) and dried plasma spot (DPS) have been investigated for lithium analysis [29]. However, when using DBS and DPS to alleviate large-volume venous sampling, the influence of temperature, humidity, and sunlight exposure must be considered. Additionally, patients or caregivers must be well instructed to lower the chance of sample contamination. Several biological fluids such as sweat, saliva, and ISF have been investigated as alternative matrices to replace blood-based approaches. Nevertheless, the accumulated knowledge on drug concentration and therapeutic response dynamics needs to be established for different matrices to correlate drug levels with blood and plasma concentrations. Several studies have investigated saliva for lithium therapeutic monitoring. Although saliva can be collected easily even without patient stimulation, sensing in saliva is challenging as plaques and bacteria might attach on the sensor surface and compromise the efficacy of the system. Moreover, another limitation is the timing of saliva sampling since equilibrium of analyte transport between the blood and saliva must be present [30]. Lastly, the concentrations in saliva are strongly dependent on dietary intake. ISF, providing a medium between vasculature and cells and rich in molecules and metabolites targeted in TDM, has also been investigated for lithium monitoring. Nonetheless, one of the common challenges with ISF is the extraction of a reasonable amount of analytes for downstream analysis. Careful consideration must also be given to microneedles or under-the-skin excitation currents which are used to take out interstitial fluid, as these methods can cause irritation and discomfort in the dermis layer, especially during prolonged monitoring [31]. Sweat-based approaches for lithium TDM suffer from several issues as well. For example, the analyte concentration profiles may be location dependent as sweat glands are unevenly distributed, the sweat glands need to be stimulated by exercise or thermal heating to achieve analyte collection, and there can be high inter- and intra-individual variability. Other constraints regarding drug stability, concentration accuracy, sweat evaporation, and chance of contamination during the sampling process must also be considered. Finally, urine, which is investigated by several studies for lithium monitoring, requires sensitive analytical methods and is limited by the wide variation between and within patients.
 

References

  1. Shorter, E. The history of lithium therapy. Bipolar Disord. 2009, 11, 4–9.
  2. Craddock, N.; Sklar, P. Genetics of bipolar disorder. Lancet 2013, 381, 1654–1662.
  3. Harrison, P.J.; Geddes, J.R.; Tunbridge, E. The Emerging Neurobiology of Bipolar Disorder. Trends Neurosci. 2018, 41, 18–30.
  4. Merikangas, K.R.; Jin, R.; He, J.-P.; Kessler, R.C.; Lee, S.; Sampson, N.A.; Viana, M.C.; Andrade, L.H.; Hu, C.; Karam, E.G.; et al. Prevalence and Correlates of Bipolar Spectrum Disorder in the World Mental Health Survey Initiative. Arch. Gen. Psychiatry 2011, 68, 241–251.
  5. de Mendiola, X.P.; Hidalgo-Mazzei, D.; Vieta, E.; González-Pinto, A. Overview of lithium’s use: A nationwide survey. Int. J. Bipolar Disord. 2021, 9, 1–8.
  6. Matsuura, H.; Kimoto, S.; Harada, I.; Naemura, S.; Yamamuro, K.; Kishimoto, T. Lithium carbonate as a treatment for paliperidone extended-release-induced leukopenia and neutropenia in a patient with schizoaffective disorder; a case report. BMC Psychiatry 2016, 16, 161.
  7. Murru, A.; for the International Group for The Study of Lithium Treated Patients (IGSLi); Manchia, M.; Hajek, T.; Nielsen, R.E.; Rybakowski, J.K.; Sani, G.; Schulze, T.G.; Tondo, L.; Bauer, M. Lithium’s antiviral effects: A potential drug for CoViD-19 disease? Int. J. Bipolar Disord. 2020, 8, 1–9.
  8. Birch, N.J. Inorganic Pharmacology of Lithium. Chem. Rev. 1999, 99, 2659–2682.
  9. Gitlin, M. Lithium side effects and toxicity: Prevalence and management strategies. Int. J. Bipolar Disord. 2016, 4, 1–10.
  10. Camus, M.; Baron, G.; Peytavin, G.; Massias, L.; Farinotti, R. Comparison of lithium concentrations in red blood cells and plasma in samples collected for TDM, acute toxicity, or acute-on-chronic toxicity. Eur. J. Clin. Pharmacol. 2003, 59, 583–587.
  11. El Balkhi, S.; Megarbane, B.; Poupon, J.; Baud, F.J.; Galliot-Guilley, M. Lithium poisoning: Is determination of the red blood cell lithium concentration useful? Clin. Toxicol. 2009, 47, 8–13.
  12. Couffignal, C.; Chevillard, L.; El Balkhi, S.; Cisternino, S.; Declèves, X. The Pharmacokinetics of Lithium. In The Science and Practice of Lithium Therapy; Malhi, G.S., Masson, M., Bellivier, F., Eds.; Springer International Publishing: Cham, Switzerland, 2017; pp. 25–53.
  13. Öhlund, L.; Ott, M.; Oja, S.; Bergqvist, M.; Lundqvist, R.; Sandlund, M.; Renberg, E.S.; Werneke, U. Reasons for lithium discontinuation in men and women with bipolar disorder: A retrospective cohort study. BMC Psychiatry 2018, 18, 1–10.
  14. Criscuolo, F.; Cantu, F.; Taurino, I.; Carrara, S.; De Micheli, G. Flexible sweat sensors for non-invasive optimization of lithium dose in psychiatric disorders. In Proceedings of the 2019 IEEE SENSORS, Montreal, QC, Canada, 27-30 October 2019; pp. 1–4.
  15. Novell, M.; Guinovart, T.; Blondeau, P.; Rius, F.X.; Andrade, F.J. A paper-based potentiometric cell for decentralized monitoring of Li levels in whole blood. Lab Chip 2013, 14, 1308–1314.
  16. Constantinou, L.; Triantis, I.; Hickey, M.; Kyriacou, P.A. On the merits of tetrapolar impedance spectroscopy for monitoring lithium concentration variations in human blood plasma. IEEE Trans. Biomed. Eng. 2016, 64, 601–609.
  17. Damborský, P.; Švitel, J.; Katrlík, J. Optical biosensors. Essays Biochem. 2016, 60, 91–100.
  18. Villemin, E.; Raccurt, O. Optical lithium sensors. Coord. Chem. Rev. 2021, 435, 213801.
  19. Aliasgharpour, M.; Hagani, H. Evaluation of lithium determination in three analyzers: Flame emission, flame atomic absorption spectroscopy and ion selective electrode. N. Am. J. Med. Sci. 2009, 1, 4.
  20. Bertholf, R.L.; Savory, M.G.; Winborne, K.H.; Hundley, J.C.; Plummer, G.M.; Savory, J. Lithium determined in serum with an ion-selective electrode. Clin. Chem. 1988, 34, 1500–1502.
  21. Vrouwe, E.X.; Luttge, R.; Berg, A.V.D. Direct measurement of lithium in whole blood using microchip capillary electrophoresis with integrated conductivity detection. Electrophoresis 2004, 25, 1660–1667.
  22. Sawada, S.; Torii, H.; Osakai, T.; Kimoto, T. Pulse Amperometric Detection of Lithium in Artificial Serum Using a Flow Injection System with a Liquid/Liquid-Type Ion-Selective Electrode. Anal. Chem. 1998, 70, 4286–4290.
  23. Hu, J.; Stein, A.; Bühlmann, P. Rational design of all-solid-state ion-selective electrodes and reference electrodes. TrAC Trends Anal. Chem. 2015, 76, 102–114.
  24. Lindner, E.; Gyurcsányi, R.E. Quality control criteria for solid-contact, solvent polymeric membrane ion-selective electrodes. J. Solid State Electrochem. 2008, 13, 51–68.
  25. Kubáň, P.; Hauser, P.C. Evaluation of microchip capillary electrophoresis with external contactless conductivity detection for the determination of major inorganic ions and lithium in serum and urine samples. Lab Chip 2008, 8, 1829–1836.
  26. Vrouwe, E.X.; Luttge, R.; Olthuis, W.; Berg, A.V.D. Microchip analysis of lithium in blood using moving boundary electrophoresis and zone electrophoresis. Electrophoresis 2005, 26, 3032–3042.
  27. Floris, A.; Staal, S.; Lenk, S.; Staijen, E.; Kohlheyer, D.; Eijkel, J.; Berg, A.V.D. A prefilled, ready-to-use electrophoresis based lab-on-a-chip device for monitoring lithium in blood. Lab Chip 2010, 10, 1799–1806.
  28. Komatsu, T.; Maeki, M.; Ishida, A.; Tani, H.; Tokeshi, M. Paper-Based Device for the Facile Colorimetric Determination of Lithium Ions in Human Whole Blood. ACS Sens. 2020, 5, 1287–1294.
  29. Manfro, I.D.; Tegner, M.; Krutzmann, M.E.; Artmann, A.D.C.; Brandeburski, M.R.; Peteffi, G.P.; Linden, R.; Antunes, M.V. Determination of lithium in dried blood spots and dried plasma spots by graphite furnace atomic absorption spectrometry: Method development, validation and clinical application. Talanta 2020, 216, 120907.
  30. Ates, H.C.; Roberts, J.A.; Lipman, J.; Cass, A.E.; Urban, G.A.; Dincer, C. On-Site Therapeutic Drug Monitoring. Trends Biotechnol. 2020, 38, 1262–1277.
  31. Criscuolo, F.; Ny Hanitra, I.; Aiassa, S.; Taurino, I.; Oliva, N.; Carrara, S.; De Micheli, G. Wearable multifunctional sweat-sensing system for efficient healthcare monitoring. Sens. Actuators B Chem. 2020, 328, 129017.
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