The Effectiveness of Lithium in the Treatment of Bipolar Disorder and Its Potential Health Risk

Abstract

Lithium carbonate is one of the most prescribed mood stabilizers worldwide and remains the first-line pharmacological treatment for bipolar disorder (BD). Its therapeutic efficacy is well established; however, lithium (Li) has a narrow therapeutic index, and prolonged or excessive intake can cause renal, neurological, or endocrine toxicity. In Brazil and globally, lithium-based formulations are widely commercialized; however, only Brazil adopts a specific regulatory classification distinguishing reference, generic, and similar medicines. Despite its extensive clinical use, studies monitoring the actual Li concentration in pharmaceutical products are extremely scarce. This study quantified Li concentrations in different formulations available in Brazil to evaluate their chemical uniformity, estimated daily intake, and potential health risks. Samples were digested and analyzed using Inductively Coupled Plasma Optical Emission Spectrometry (ICP OES). Statistical analysis with the Kruskal–Wallis test revealed significant differences among formulations (p = 0.012), confirming non-uniform Li content. Measured concentrations ranged from 245.47 to 315.24 mg/kg, with generic products showing the highest values. The calculated daily intake (DI) and chronic daily intake (CDI) increased with therapeutic dose (600–1800 mg/day), and higher-dose regimens frequently exceeded the permitted daily exposure (PDE) value for Li established by International Council for Harmonisation Guideline for Elemental Impurities (Revision 2) (ICH Q3D (R2) (0.55 mg/day). Moreover, hazard quotient (HQ) values above 1 in some scenarios indicated potential health risks associated with excessive or long-term Li exposure. As one of the first studies to quantify Li in marketed formulations, this work underscores the need for systematic monitoring and stricter quality control to ensure therapeutic safety.

1. Introduction

Bipolar disorder (BD) is a chronic and severe psychiatric illness characterized by recurrent episodes of mania, hypomania, and depression that profoundly impair patients’ functionality and quality of life [1,2,3]. According to the World Health Organization (WHO), mental disorders are among the leading causes of disability worldwide, placing a substantial burden on healthcare systems and affecting millions of individuals [4]. The Global Burden of Disease (GBD 2019) study estimates a lifetime prevalence of approximately 2.4% for BD [5]. In Brazil, more than four million people are estimated to live with BD, many of whom face stigma, diagnostic delays, and limited access to adequate treatment [6,7].

The social and economic burden of BD is significant, affecting interpersonal relationships, occupational performance, and overall functionality. Approximately 30% of individuals with BD experience severe occupational impairment and are at an increased risk of suicide [1,8,9]. Beyond individual consequences, BD generates substantial public health costs due to its chronic course, recurrent episodes, and lifelong pharmacological management [5,10,11].

Pharmacotherapy remains the cornerstone of BD management, with lithium carbonate recognized as the gold standard for mood stabilization and relapse prevention [12,13,14]. Long-term therapy, often extending over decades, requires continuous clinical and laboratory monitoring to adjust dosage and minimize adverse effects [15,16,17]. Maintenance therapy focuses on dose optimization and personalized adjustment under medical supervision to balance therapeutic efficacy and safety [14,18,19].

Over the past decades, lithium carbonate has demonstrated robust clinical efficacy in reducing mood fluctuations and preventing suicide [8,20,21]. However, its narrow therapeutic index means that small variations in serum concentration can lead to toxicity [22,23,24]. Chronic exposure or high cumulative doses, especially without adequate clinical monitoring, may cause neurological, renal, thyroid, and cardiovascular effects [25,26,27].

In recent years, several countries have reported clinical cases of Li intoxication associated with both acute overdose and chronic therapeutic use. These cases frequently involve neurological impairment, renal dysfunction, or cardiac complications and may occur even at therapeutic serum levels [28,29,30,31]. Large-scale surveillance data, such as that from the California Poison Control System, also revealed that, while mortality remains low, a considerable proportion of patients develop severe complications requiring hemodialysis [22]. Despite its widespread therapeutic use, few studies have quantified Li concentrations directly in pharmaceutical formulations [32], particularly in medications used for the treatment of BD, and such investigations remain scarce. Moreover, toxicological risk assessments that consider the variability of lithium carbonate dosages commonly prescribed during BD maintenance therapy remain scarce. This lack of analytical and risk-based studies represents a critical gap in the scientific literature, as prolonged exposure to Li can lead to bioaccumulation and health effects that depend on both formulation quality and dosage regimen [12,28,33].

In Brazil, the pharmaceutical market includes reference, generic, and similar formulations, all of which must comply with the National Health Surveillance Agency (ANVISA) requirements for quality, safety, and therapeutic efficacy [34,35,36]. A reference medicine is the original patented formulation proven to be safe and effective through clinical trials. Once the patent expires, generic formulations containing the same active ingredient, dosage, and bioequivalence profile are authorized for commercialization. Similar formulations also contain the same active ingredient and demonstrate therapeutic equivalence but may differ in characteristics such as shape, color, packaging, or shelf life [34,37,38].

In contrast, most other countries, such as the United States, Canada, India, China, Russia, South Africa, and members of the European Union, recognize only two main categories of medicines: reference and generic drugs. In these jurisdictions, generic formulations must fall within 80–125% of the reference product’s pharmacokinetic parameters and comply with rigorous quality, safety, and efficacy standards before market authorization [39,40]. Scientific evidence on brand-name and generic cardiovascular and antidiabetic agents consistently demonstrates that, when bioequivalence criteria are met, generic formulations perform clinically equivalently to their reference medicines [40,41]. However, in low- and middle-income countries, variations in manufacturing practices and regulatory enforcement can lead to inconsistencies in product quality, underscoring the importance of continuous post-marketing surveillance [40,41]. In contrast, although lithium carbonate is widely used to treat BD in several countries, there are no published studies quantifying Li concentrations in generic, similar, and reference formulations of BD medications.

Regulatory frameworks such as those outlined by the Brazilian [42] and the International Council for Harmonisation (ICH) [43] establish specific limits for elemental impurities, including Li, to minimize chronic exposure to potentially toxic substances [32,44]. Nevertheless, systematic evaluations of Li content in pharmaceutical products remain scarce in the literature, and studies assessing the cumulative health risks associated with therapeutic doses are virtually absent [32,33].

In this context, the present study aims to quantify Li concentrations in reference, generic, and similar lithium carbonate medicines commercialized in Brazil for BD treatment using Inductively Coupled Plasma Optical Emission Spectrometry (ICP OES). Additionally, it seeks to compare the measured concentrations with international regulatory limits and to estimate chronic oral exposure and non-carcinogenic risk associated with different therapeutic doses. By integrating chemical analysis with toxicological risk assessment, this study addresses a critical knowledge gap and contributes to the scientific and regulatory understanding of Li safety and quality in pharmaceutical formulations.

2. Materials and Methods

2.1. Sample Collection and Identification

A total of 35 boxes of lithium carbonate were purchased, each containing 60 tablets, from seven different manufacturers and production batches. The pharmaceutical samples were obtained through direct purchase from retail pharmacies located in the city of Campo Grande, Mato Grosso do Sul, Brazil, during September 2024. All purchases were made upon presentation of medical prescriptions, in accordance with Ordinance No. 344 of 12 May 1998, issued by the Brazilian Ministry of Health. The selection of brands and manufacturers was based on the availability of products for purchase in major pharmacy and drugstore chains within the municipality of Campo Grande, MS, Brazil.

For sample identification, each medication was labeled using a code composed of the letter M (for medication), followed by a sequential number (1 to 7) and an initial indicating the drug classification: R for reference, S for similar, and G for generic. Accordingly, the sampling included five boxes of each medication, each containing 60 tablets, as follows: one reference drug (M1R); three similar drugs from different brands and manufacturers (M2S, M3S, and M4S); and three generic drugs produced by distinct laboratories (M5G, M6G, and M7G). For each sample, the identification code, chemical compound, drug classification, and number of tablets analyzed are listed in

Table 1. Identification and classification of lithium carbonate pharmaceutical samples.

Sample ID	Drug Classification	Number of Tablets Per Box	Total Number of Tablets
M1R	Reference	60	300
M2S	Similar	60	300
M3S	Similar	60	300
M4S	Similar	60	300
M5G	Generic	60	300
M6G	Generic	60	300
M7G	Generic	60	300

Each sample was coded using the letter M (for medication), followed by a sequential number (1–7) and a letter representing its classification: R = Reference, S = Similar, and G = Generic.

.

2.2. Preparation of Materials for Analysis

All materials used in the analyses, including Falcon-type plastic tubes and glassware, were chemically demineralized prior to use. The items were immersed in a 5% (v/v) Extran solution and 10% nitric acid (HNO₃, Merck) for a minimum period of 24 h. Subsequently, all materials were thoroughly rinsed with ultrapure water (H₂O; resistivity 18.2 MΩ·cm, Millipore Biocel, Darmstadt, Hesse, Germany) and dried in an oven at 42 °C.

2.3. Acid Digestion of Samples

A quantity of 300 tablets from each of the seven representative samples was individually crushed and homogenized. Subsequently, an amount of approximately 0.25 g of each sample was weighed using an analytical balance and placed in glass test tubes. To each of the tubes the following was added: 1.0 mL of ultrapure water (conductivity 18.2 MΩ cm, ultrapure, Merck, Darmstadt, Germany), 1.0 mL of hydrogen peroxide (H₂O₂, 30%, Merck, Darmstadt, Germany) and 2.5 mL of nitric acid (HNO₃, 65%, ultrapure, Merck, Darmstadt, Germany). Subsequently, each solution was homogenized in a vortex (Biomixer, QL-901, Curitiba, PR, Brazil) and subjected to acid digestion in a digestion block (Tecnal, TE-041/25, Piracicaba, SP, Brazil). The digestion process using the digester block was carried out in 3 stages and steps (cycling) according to

Table 2. Programmed stages and steps for the digestion procedure using the digestion block (cycling method).

Stages	Temperature °C	TRamp (min)	THold (min)
1	100	15	60
2	130	15	120
3	150	15	60

.

After acid digestion, the resulting solutions were filtered through 9 µm filter paper (Whatman No. 40, GE Healthcare, São Paulo, SP, Brazil) and diluted to a final volume of 10 mL with ultrapure water (conductivity 18.2 MΩ cm, ultrapure, Merck, Darmstadt, Germany). Subsequently, the digested samples were transferred from the glass test tubes to Falcon-type polypropylene tubes for storage and subsequent elemental quantification by ICP OES.

2.4. Instrumental and Operational Parameters for ICP OES Analysis

The quantification of Li in the seven studied samples was performed using ICP OES (Thermo Scientific, Waltham, MA, USA, model iCAP 6300^®, Thermo Scientific iTEVA, software, version 2.8.0.96) under optimized instrumental conditions to ensure accuracy and precision. The ICP OES was operated with a radiofrequency (RF) power of 1250 W and a sample flow rate of 0.45 L/min. The plasma gas flow rate was maintained at 12 L/min, with a nebulizer pressure of 20 psi and axial plasma viewing configuration. Each analysis was performed in triplicate to assess analytical repeatability. The integration time was set at 15 s, and a stabilization period of 20 s was used between readings to ensure signal consistency. The analytical wavelength used for Li determination was 670.784 nm, selected based on its sensitivity and minimal spectral interference.

2.5. Analytical Calibration and Detection Limits

External calibration curves were prepared using a monoelemental Li standard solution (Specsol, São Paulo, Brazil). For the calibration, one analytical blank and eight concentration levels were employed: 0.007, 0.015, 0.031, 0.062, 0.10, 0.25, 0.50, and 1.00 ppm. The calibration parameters demonstrated excellent linearity, confirming the reliability of the analytical procedure.

The limit of detection (LOD) and limit of quantification (LOQ) for Li were determined according to the criteria established by the International Union of Pure and Applied Chemistry (IUPAC) [45]. The LOD values were calculated by multiplying the standard deviation (SD) of the blank signal by three and dividing by the slope of the calibration curve, whereas the LOQ values were obtained by multiplying the SD by ten and dividing by the same slope.

The calibration curve parameters for the analyte, including the external calibration equation (y = ax + b), the LOD, LOQ, and the correlation coefficient (R²), are presented in

Table 3. Calibration curve parameters: calibration equations (y = ax + b), limit of detection (LOD), limit of quantification (LOQ), and correlation coefficient (R²).

Analyte	Calibration Equations (y = ax + b)	LOD (µg/g)	LOQ (µg/g)	R2
Li	y = 127,666x + 1241.5	0.0019	0.0063	0.9992

y = absorbance of signal; a = slope; x = concentration (g/kg); b = intercept.

. The obtained values for LOD, LOQ, and R² were 0.0019 µg/g, 0.0063 µg/g, and 0.9992, respectively, indicating excellent sensitivity, precision, and linearity of the analytical method. To assess method accuracy and possible matrix effects, spike-recovery tests were performed by fortifying representative sample aliquots with known amounts of the Li standard solution at three concentration levels within the calibration range: 0.10 mg/L (low), 0.50 mg/L (medium), and 0.90 mg/L (high). Each spiked and unspiked sample was subjected to the same digestion and analytical procedures described above. The accuracy, expressed as recovery percentage (R%), ranged from 93% to 109%, confirming the reliability of the analytical procedure and the absence of significant matrix interference.

These parameters (Table 3) confirm that the ICP OES method is reliable and robust for the quantitative determination of Li at trace levels in pharmaceutical matrices. The high R² and low detection limits demonstrate the method’s suitability for ensuring the analytical quality control of pharmaceutical-grade lithium carbonate, minimizing uncertainty and ensuring data reproducibility in accordance with IUPAC and International Council for Harmonisation Guideline for Elemental Impurities (Revision 2), ICH Q3D(R2) validation guidelines.

2.6. Daily Intake

The daily intake (DI) (mg/day) of Li resulting from the consumption of lithium carbonate medication was calculated using Equation (1) (adapted from [43,46,47]).

$$\mathrm{D}\mathrm{I}\left({\displaystyle \frac{\mathrm{m}\mathrm{g}}{\mathrm{d}\mathrm{a}\mathrm{y}}}\right)=\mathrm{C}(\mathrm{m}\mathrm{g}/\mathrm{k}\mathrm{g})\times \mathrm{M}(\mathrm{k}\mathrm{g}/\mathrm{d}\mathrm{a}\mathrm{y})$$

(1)

where C (mg/kg) represents the measured concentration of the analyte, and M (kg) corresponds to the daily mass of the tablet ingested by an adult under standard therapeutic conditions. This estimation provides a quantitative basis for assessing the total Li exposure from pharmaceutical use. To obtain M (kg), corresponding to the mass (kg) of tablets ingested per day by an adult, the average weight of one tablet of each analyzed medicine was multiplied by the number of tablets administered daily. The average tablet mass for each sample and the resulting M (kg) per day calculated based on this dose are presented in

Table 4. Average weight of lithium carbonate tablets in each sample and total mass (M, kg/day) corresponding to the daily maintenance dose.

Sample	Mass M (kg) Dose: 600 mg (2 Tablets)	Mass M (kg) Dose: 900 mg (3 Tablets)	Mass M (kg) Dose: 1200 mg (4 Tablets)	Mass M (kg) Dose: 1500 mg (5 Tablets)	Mass M (kg) Dose: 1800 mg (6 Tablets)
M1R	8.1448 × 10−4	1.2217 × 10−3	1.6289 × 10−3	2.0362 × 10−3	2.4434 × 10−3
M2S	7.6086 × 10−4	1.1413 × 10−3	1.5217 × 10−3	1.9022 × 10−3	2.2826 × 10−3
M3S	7.9834 × 10−4	1.1975 × 10−3	1.5967 × 10−3	1.9959 × 10−3	2.3950 × 10−3
M4S	7.9978 × 10−4	1.1997 × 10−3	1.5996 × 10−3	1.9995 × 10−3	2.3993 × 10−3
M5G	8.1522 × 10−4	1.2228 × 10−3	1.6304 × 10−3	2.0381 × 10−3	2.4457 × 10−3
M6G	8.0140 × 10−4	1.2021 × 10−3	1.6028 × 10−3	2.0004 × 10−3	2.4042 × 10−3
M7G	1.0315 × 10−3	1.5473 × 10−3	2.0630 × 10−3	2.5788 × 10−3	3.0945 × 10−3

.

To obtain the total daily mass (M, kg) of lithium carbonate tablets ingested by an adult, the average mass of one tablet from each analyzed medicine was determined and multiplied by the number of tablets administered per day, according to the prescribed therapeutic dose. The following dose regimens were considered: 600 mg/day (2 tablets per day), 900 mg/day (3 tablets per day), 1200 mg/day (4 tablets per day), 1500 mg/day (5 tablets per day), and 1800 mg/day (6 tablets per day). Thus, the total daily mass (M) reflects the actual amount of lithium carbonate ingested, based on the measured tablet weight and the corresponding therapeutic dosage.

According to the manufacturer’s information [48], each tablet contains 300 mg of lithium carbonate. The therapeutic serum level of Li for the maintenance phase in the treatment of BD ranges from 0.6 to 1.2 mEq/L, which is typically achieved in adults with daily doses between 600 mg and 1800 mg [25,48,49].

In this study, for the estimation of DI (mg/day), five therapeutic dose scenarios were considered: 600, 900, 1200, 1500, and 1800 mg/day of lithium carbonate. Among these, the 900 mg/day dose equivalent to the ingestion of three tablets of 300 mg each was adopted as the reference maintenance dose, since most patients in maintenance therapy are stabilized with this regimen, according to the manufacturer and supporting literature [12,25,48,50,51].

The average tablet mass for each sample and the corresponding total daily mass (M, kg/day), calculated for each therapeutic dose (600–1800 mg/day), are presented in Table 4, which served as the basis for calculating the DI (C × M) of Li using the concentration values (C) described in Table 5, with the resulting DI values presented in Table 6.

2.7. Calculation of Chronic Daily Intake

The chronic daily intake (CDI) of Li was estimated to assess potential health risks associated with the continuous use of lithium carbonate medication. The CDI (mg/kg/day) was calculated according to Equation (2) [46,52,53].

$$\mathrm{C}\mathrm{D}\mathrm{I}={\displaystyle \frac{\mathrm{C}\times \mathrm{I}\mathrm{R}\times {\mathrm{E}\mathrm{F}}_{\mathrm{r}}\times \mathrm{E}\mathrm{D}}{\mathrm{A}\mathrm{T}\times \mathrm{B}\mathrm{W}}}$$

(2)

The parameters and the exact values adopted in this study are: Li in lithium carbonate tablets, here, C (mg/kg) is the Li concentration quantified by ICP OES for each sample (reported in the analytical results table); Ingestion Rate (IR) (kg/day): three maintenance-therapy scenarios: 0.0006 kg/day (600 mg/day; 2 tablets of 300 mg); 0.0009 kg/day (900 mg/day; 3 tablets of 300 mg) and 0.0012 kg/day (1200 mg/day; 4 tablets of 300 mg)—The values mass of tablets for each sample are presented in Table 4. In this study, the CDI was simulated for three therapeutic intake scenarios (IR) = 600 mg/day, 900 mg/day, and 1200 mg/day, corresponding respectively to two, three, and four 300 mg tablets per day [48].

The therapeutic serum Li concentrations for long-term maintenance typically range between 0.50–0.60 mEq/L and 0.80–1.00 mEq/L. These levels may vary according to individual response and tolerance, emphasizing the need for regular serum monitoring [25,48,54]; EF corresponds to Exposure frequency (days/year): EF = 360 days/year (accounts for occasional missed doses); Exposure duration (ED) (years): 30 years (long-term, chronic management) [52,55]. Since BD is a chronic condition, medication must be maintained long-term after diagnosis due to the therapeutic benefits of Li including its well-documented anti-suicidal effects while not neglecting its potential adverse effects [10,49,56,57]. Body weight (BW) (kg): 70 kg (adult default) [58]; Averaging time (AT) (days): 21,900 days (60 years × 365 days) [59]. Therapeutic context (for interpretation): Typical maintenance serum Li range 0.50–0.60 to 0.80–1.00 mEq/L with routine monitoring. For the calculation of AT, corresponding to a period of 60 years × 365 days/year = 21,900 days was considered, representing the lifetime exposure period for an adult aged 60 years [59]; this value was adopted because individuals with BD often have a reduced life expectancy [1,2,9]. According to the literature, the diagnosis of BD tends to be delayed by approximately 6 to 10 years, and the first symptoms usually appear between 18 and 25 years of age [1,60,61]. Therefore, in the present study, the CDI was estimated assuming continuous exposure to Li through lithium carbonate therapy for 30 years (ED) in a 60-year-old adult.

The non-carcinogenic risk associated with Li intake was evaluated using the hazard quotient (HQ), as described by Equation (3) below [46,52,55].

$$\mathrm{H}\mathrm{Q}={\displaystyle \frac{\mathrm{C}\mathrm{D}\mathrm{I}}{\mathrm{R}\mathrm{f}\mathrm{D}}}$$

(3)

In Equation (3), CDI (mg/kg/day) represents the CDI of Li previously calculated (Equation (2)), and RfD is the reference dose, adopted as 0.002 mg/kg/day [62]. When HQ > 1, there is a potential health risk, whereas HQ < 1 indicates an acceptable exposure level, suggesting that adverse health effects are unlikely to occur in consumers [52,53,63].

2.8. Statistical Analysis

All analytical determinations were performed in triplicate, and the results are expressed as mean ± SD. Prior to comparison, the data were assessed for normality using the Shapiro–Wilk test and for homogeneity of variances using Levene’s test. Since the data did not meet the assumptions of normality and homoscedasticity, a nonparametric Kruskal–Wallis test was applied to evaluate whether significant differences existed among the Li concentrations of the reference, generic, and similar formulations. When significant differences were detected by the Kruskal–Wallis test (p < 0.05), pairwise comparisons were performed using Dunn’s post hoc test, which identified significant differences between the reference and one of the non-reference formulations (p < 0.05). All statistical analyses were performed using GraphPad Prism, version 10.0.0 (GraphPad Software, LLC, San Diego, CA, USA) and R software, version 4.3.1 (R Foundation for Statistical Computing, Vienna, Austria). The significance level was set at α = 0.05.

3. Results

3.1. Lithium Concentration in Analyzed Samples

Table 5 presents the concentrations of Li obtained in the analyzed lithium carbonate samples using ICP OES. The results show measurable differences among the products from different manufacturers, which include reference, similar, and generic formulations as described in Table 1. The Li concentrations ranged from 245.47 ± 4.02 mg/kg (M3S) to 315.24 ± 4.82 mg/kg (M7G). Among the analyzed samples, with the exception of M5G, the generic formulations (M6G, M7G) exhibited the highest lithium concentrations, followed by the similar medicines (M2S, M4S, M3S) and finally the reference product (M1R). The observed variations reflect the differences among manufacturers and formulation types, even though all products contain lithium carbonate as the declared active pharmaceutical ingredient (API). These findings demonstrate that the elemental quantification by ICP OES allowed precise differentiation of Li content across the various marketed pharmaceutical categories.

Table 5. Concentrations (mg/kg) obtained for each element in lithium carbonate samples.

Element	M1R	M2S	M3S	M4S	M5G	M6G	M7G
Li	247.40 ± 6.25	264.81 ± 2.34	245.47 ± 4.02	263.64 ± 1.27	257.96 ± 9.20	285.37 ± 9.60	315.24 ± 4.82

Table 5. Concentrations (mg/kg) obtained for each element in lithium carbonate samples.

Element	M1R	M2S	M3S	M4S	M5G	M6G	M7G
Li	247.40 ± 6.25	264.81 ± 2.34	245.47 ± 4.02	263.64 ± 1.27	257.96 ± 9.20	285.37 ± 9.60	315.24 ± 4.82

3.2. Estimated Daily Intake

Table 6 presents the calculated DI (mg/day) of Li, obtained from the product between the measured Li concentration (C) (mg/kg) in each sample and the corresponding daily ingested mass (M, kg/day) of lithium carbonate. Six therapeutic dose scenarios were simulated at 300, 600, 900, 1200, 1500, and 1800 mg/day, corresponding respectively to the ingestion of one, two, three, four, five, and six 300 mg tablets per day. These doses represent the typical range of regimens commonly prescribed for the maintenance treatment of BD.

Across all samples, the DI of Li increased proportionally with the administered dose. The ID values ranged from 1.01 × 10⁻¹ mg/day (M1R and M2S, 300 mg) to 9.76 × 10⁻¹ mg/day (M7 G, 1800 mg), demonstrating a clear dose–response relationship. Samples M6 G and M7 G consistently showed the highest estimated intakes, reflecting their relatively higher Li concentrations determined by ICP OES.

The data also show that doubling the administered dose approximately doubled the estimated DI, confirming the linearity of Li accumulation with respect to the ingested tablet mass (M). This finding supports the accuracy of the applied equation (DI = C × M) and the homogeneity of the concentration levels across different samples and manufacturers.

Overall, the calculated DI values provide a quantitative basis for assessing potential differences in Li exposure among patients under varying therapeutic regimens. These values were subsequently used to estimate the CDI and HQ parameters for health risk assessment presented in the following tables.

Table 6. Calculation of daily intake (DI = C × M) of lithium (Li) based on the determined concentrations (C, mg/kg—Table 5) and daily ingested mass (M, kg/day—Table 4) for different therapeutic doses of lithium carbonate (300, 600, 900, 1200, 1500, and 1800 mg).

Sample	ID (mg/Day) Dose: 300 mg	ID (mg/Day) Dose: 600 mg	ID (mg/Day) Dose: 900 mg	ID (mg/Day) Dose: 1200 mg	ID (mg/Day) Dose: 1500 mg	ID (mg/Day) Dose: 1800 mg
M1 R	1.01 × 10−1	2.02 × 10−1	3.02 × 10−1	4.03 × 10−1	5.04 × 10−1	6.05 × 10−1
M2 S	1.01 × 10−1	2.01 × 10−1	3.02 × 10−1	4.03 × 10−1	5.04 × 10−1	6.04 × 10−1
M3 S	9.80 × 10−2	1.96 × 10−1	2.94 × 10−1	3.92 × 10−1	4.90 × 10−1	5.88 × 10−1
M4 S	1.05 × 10−1	2.11 × 10−1	3.16 × 10−1	4.22 × 10−1	5.27 × 10−1	6.33 × 10−1
M5 G	1.05 × 10−1	2.10 × 10−1	3.15 × 10−1	4.21 × 10−1	5.26 × 10−1	6.31 × 10−1
M6 G	1.14 × 10−1	2.29 × 10−1	3.43 × 10−1	4.57 × 10−1	5.72 × 10−1	6.86 × 10−1
M7 G	1.63 × 10−1	3.25 × 10−1	4.88 × 10−1	6.50 × 10−1	8.13 × 10−1	9.76 × 10−1

Table 6. Calculation of daily intake (DI = C × M) of lithium (Li) based on the determined concentrations (C, mg/kg—Table 5) and daily ingested mass (M, kg/day—Table 4) for different therapeutic doses of lithium carbonate (300, 600, 900, 1200, 1500, and 1800 mg).

Sample	ID (mg/Day) Dose: 300 mg	ID (mg/Day) Dose: 600 mg	ID (mg/Day) Dose: 900 mg	ID (mg/Day) Dose: 1200 mg	ID (mg/Day) Dose: 1500 mg	ID (mg/Day) Dose: 1800 mg
M1 R	1.01 × 10−1	2.02 × 10−1	3.02 × 10−1	4.03 × 10−1	5.04 × 10−1	6.05 × 10−1
M2 S	1.01 × 10−1	2.01 × 10−1	3.02 × 10−1	4.03 × 10−1	5.04 × 10−1	6.04 × 10−1
M3 S	9.80 × 10−2	1.96 × 10−1	2.94 × 10−1	3.92 × 10−1	4.90 × 10−1	5.88 × 10−1
M4 S	1.05 × 10−1	2.11 × 10−1	3.16 × 10−1	4.22 × 10−1	5.27 × 10−1	6.33 × 10−1
M5 G	1.05 × 10−1	2.10 × 10−1	3.15 × 10−1	4.21 × 10−1	5.26 × 10−1	6.31 × 10−1
M6 G	1.14 × 10−1	2.29 × 10−1	3.43 × 10−1	4.57 × 10−1	5.72 × 10−1	6.86 × 10−1
M7 G	1.63 × 10−1	3.25 × 10−1	4.88 × 10−1	6.50 × 10−1	8.13 × 10−1	9.76 × 10−1

3.3. Result of Chronic Daily Intake and Hazard Quotient

The resulting CDI and HQ values for each sample are summarized in

Table 7. Chronic Daily Intake (CDI, mg/kg/day) and Hazard Quotient (HQ) for lithium according to ingestion rate (IR) and dose scenario.

Sample	IR (kg/Day) Dose: 600 mg	CDI (mg/kg/Day) Dose: 600 mg	HQ Dose: 600 mg	IR (kg/Day) Dose: 900 mg	CDI (mg/kg/Day) Dose: 900 mg	HQ Dose: 900 mg	IR (kg/Day) Dose: 1200 mg	CDI (mg/kg/Day) Dose: 1200 mg	HQ Dose: 1200 mg
M1 R	8.1448 × 10−4	1.4196 × 10−3	0.7098	1.2217 × 10−3	2.1294 × 10−3	1.0647	1.6290 × 10−3	2.8392 × 10−3	1.4196
M2 S	7.6086 × 10−4	1.4194 × 10−3	0.7097	1.1422 × 10−3	2.1291 × 10−3	1.0646	1.5217 × 10−3	2.8389 × 10−3	1.4194
M3 S	7.9834 × 10−4	1.3806 × 10−3	0.6903	1.1975 × 10−3	2.0709 × 10−3	1.0345	1.5967 × 10−3	2.7611 × 10−3	1.3806
M4 S	7.9978 × 10−4	1.4855 × 10−3	0.7427	1.1997 × 10−3	2.2282 × 10−3	1.1141	1.5996 × 10−3	2.9709 × 10−3	1.4855
M5 G	8.1522 × 10−4	1.4815 × 10−3	0.7407	1.2218 × 10−3	2.2223 × 10−3	1.1111	1.6304 × 10−3	2.9630 × 10−3	1.4815
M6 G	8.0140 × 10−4	1.6112 × 10−3	0.8056	1.2210 × 10−3	2.4168 × 10−3	1.2084	1.6028 × 10−3	3.2224 × 10−3	1.6112
M7 G	1.0315 × 10−3	2.2909 × 10−3	1.1454	1.5472 × 10−3	3.4363 × 10−3	1.7181	2.0630 × 10−3	4.5817 × 10−3	2.2908

, which illustrates the individual contribution of Li concentration and dosage regimen to total chronic intake. These findings provide quantitative evidence that small variations in Li dosage significantly influence the estimated chronic intake, emphasizing the importance of individualized dose monitoring in long-term pharmacotherapy.

The CDI values were calculated for each medication sample based on the experimentally determined Li concentrations and the three IR scenarios (600, 900, and 1200 mg/day).

Across all samples, CDI values increased proportionally with the administered dose. The lowest exposure scenario (600 mg/day) yielded the smallest CDI estimates, while the highest dose (1200 mg/day) produced approximately double the CDI, reflecting a direct correlation between the prescribed dose and the potential systemic exposure to Li. In addition, the HQ values increased proportionally with the administered dose, reflecting the expected dose–response relationship. Among the evaluated samples, the generic formulations (M6 G and M7 G) exhibited higher HQ values compared to the reference (M1 R) and similar (M2 S, M3 S, M4 S, M5 G) medicines across all dose levels.

4. Discussion

This section discusses the results obtained from the quantification of Li in pharmaceutical formulations, the estimation of DI, and the health risk assessment expressed through CDI and HQ. The discussion integrates the findings presented in Table 5, Table 6 and Table 7, comparing them with published literature, pharmacological data, and regulatory standards.

4.1. Lithium Concentrations in Pharmaceutical Formulations

The quantitative analysis of lithium carbonate tablets (Table 5) revealed considerable variation in Li concentrations among the different brands and pharmaceutical types identified in Table 1. The samples were organized in descending order of Li content as follows: M7G > M6G > M2S > M4S > M5G > M1R > M3S, with measured mean concentrations ranging from 315.24 mg/kg in M7G to 245.47 mg/kg in M3S. The Kruskal–Wallis test revealed significant differences among the formulations (p = 0.012), confirming that the products are not uniform across brands. Pairwise comparisons using Dunn’s post hoc test indicated that at least one non-reference formulation differed significantly from the reference product (p < 0.05). From a clinical perspective, this variation may affect therapeutic efficacy and increase the risk of adverse effects, given the narrow therapeutic range of Li.

Generic formulations (M6G, M7G) presented the highest mean concentrations of Li, particularly M7G, which exceeded the reference sample (M1R) by approximately 27%. This pattern suggests possible differences in the purity of the API or variability in manufacturing processes among generic producers. The similar products (M2S–M4S) displayed intermediate concentrations, with M2S and M4S showing a relatively elevated value (264.81 mg/kg and 263.64 mg/kg), whereas M3S remained close to the lower range of the dataset.

In contrast, the reference formulation (M1R), which is generally expected to represent the standard composition, exhibited a mid-range Li concentration (247.40 mg/kg). Although this value falls within the expected specification limits for lithium carbonate, it indicates that some generic and similar products contain notably higher elemental concentrations than the reference.

These results align with previous studies that have highlighted chemical and manufacturing inconsistencies between reference and generic formulations. Dunne et al. (2013) [64] and Merchant et al. (2020) [65] demonstrated that, even when the active substance is identical, variations in excipients, manufacturing methods, and quality control practices can influence drug stability, purity, and clinical performance. Shen and Song (2024) [66] further emphasized that commercial and regulatory factors, including trademark policies, may indirectly affect market standardization and competitive quality assurance. Together, these findings support the current observation that pharmaceutical equivalence does not necessarily guarantee chemical homogeneity.

Previous international studies have emphasized that, despite regulatory harmonisation, differences may persist between reference and generic formulations, particularly in excipient composition, manufacturing process, and impurity levels [64,65,66]. Such differences can influence drug bioavailability, stability, and ultimately therapeutic performance. These findings align with our observations, suggesting that even products containing the same declared active ingredient may exhibit variations in elemental content, potentially influencing exposure and safety outcomes.

Regarding variability and analytical precision, the standard deviations (±1.27–±9.60 mg/kg) indicate adequate analytical precision for the ICP OES determinations, supporting the reliability of the observed differences. Nonetheless, the magnitude of variation among brands (≈70 mg/kg between the lowest and highest means) highlights significant heterogeneity across marketed formulations. Such differences can affect the actual Li dose delivered per tablet, which is critical for maintaining the narrow therapeutic window of lithium carbonate therapy.

Given that all samples contained lithium carbonate as the declared active ingredient, the observed disparities in Li concentrations may arise from differences in formulation, excipient composition, or manufacturing variability among brands. Because Li therapy requires strict therapeutic monitoring to prevent toxicity, even small deviations in elemental content could result in subtherapeutic or potentially toxic plasma levels in patients. These concentration variations therefore pose a significant risk to patient safety, as reports in the literature have described cases of chronic toxicity in individuals taking a maintenance dose of 300 mg of lithium carbonate per day, a value lower than the minimum dose recommended by the manufacturer in Brazil [27,48,67,68]. Therefore, the observed discrepancies emphasize the need for strict quality control and regulatory oversight to ensure equivalence among reference, similar, and generic Li medications available on the market.

The Li concentrations quantified in the samples were compared with the maximum limits allowed for metals in pharmaceutical products, as established by the Brazilian Pharmacopoeia (FB) [42] and ICH Q3D (R2) guideline [43], for oral administration. According comparison, all mean concentrations of Li in the pharmaceutical samples (Table 5) exceeded the maximum limit established by the ICH Q3D (R2) guideline, which is 55 mg/kg. The FB does not define a maximum permissible limit for this element in pharmaceutical products, reinforcing the absence of standardized criteria for such data. However, it is important to note that the elevated Li concentrations observed in all samples of the present study (Table 6) result from the fact that the API analyzed is lithium carbonate, a compound in which Li is the therapeutic element itself. Furthermore, the mean Li concentrations found here were higher than those reported by Li et al. [63], who analyzed various pharmaceutical excipients and found much lower values (2.47 mg/kg).

The difference in Li content among the various types of medications, all containing lithium carbonate as the API, is noteworthy. In Brazil, according to current legislation, similar and generic medicines must have the same active ingredient, formulation, concentration, route of administration, dosage regimen, and therapeutic indication as the reference product, thereby ensuring equivalent efficacy [34,37,38]. Therefore, the significant differences observed in Li concentrations among brands raise concern, as they may lead to clinical implications for patient treatment. These findings highlight the need for further studies on lithium-based formulations and reinforce the importance of stricter regulatory oversight to ensure product uniformity and therapeutic safety.

The results of the present study (Table 5), which revealed differences in Li concentrations among the three types of medications (generic, similar, and reference), contrast with the findings reported by Santos et al. [69]. In their review, the authors concluded that generic medicines generally present the same concentration as reference products, indicating compliance with the regulatory requirements that mandate identical active ingredient content, formulation, and dosage [69]. The divergence observed in the present study therefore suggests possible inconsistencies among marketed formulations, emphasizing the need for continued monitoring of product equivalence.

The different Li concentrations quantified in the representative samples of the present study are consistent with the findings reported by Santos et al. [70], who, when comparing elemental impurities in captopril-based medicines of generic, similar, and reference types, also identified variations among the analyzed elements. Moreover, the Li concentrations obtained in the present research (Table 6) are in line with the observations of Santos et al. [71], who evaluated the pharmaceutical equivalence of antihypertensive tablets (generic, similar, and reference) based on the concentration of the active ingredient required in the formulation. Their study revealed lower concentrations in similar products (31% below the reference value) and variable results for generics, while even the reference medicine exhibited a higher concentration than that indicated on its package insert [71].

Lithium carbonate is widely used in the treatment of BD and recurrent depression. The use of this medication requires frequent monitoring of serum Li levels, primarily because of the metal’s toxicity and its narrow therapeutic window, which may lead to intoxication even when therapeutic limits are respected. The elevated Li concentration observed in sample M7G may therefore indicate a potential health risk. According to the ICH Q3D (R2) guideline [43], Li is classified as a Class 3 element, characterized by relatively low oral toxicity and a low risk of contamination, which typically occurs only when analytes are intentionally added during the manufacturing process of the pharmaceutical product.

4.2. Estimated Daily Intake of Lithium

In Table 6, the DI values derived from concentrations provide an important insight into the actual exposure of patients under standard therapeutic regimens. For doses between 300 and 1800 mg/day, the calculated intake of Li ranged from approximately 1.01 × 10⁻¹ to 9.76 × 10⁻¹ mg/day, showing that both the concentration of the active compound and the mass of tablets significantly influence the total elemental intake.

Higher-dose regimens (≥1500 mg/day) resulted in markedly elevated Li intakes, approaching or exceeding 5.0 × 10⁻¹ mg/day for several samples. Such differences could have clinical implications, as lithium carbonate has a narrow therapeutic window, and small variations in intake may affect serum Li levels and toxicity risk. Consequently, the analytical verification of elemental content in different commercial formulations is essential for ensuring therapeutic efficacy and patient safety.

These findings are consistent with previous analytical evaluations of elemental impurities and active components in pharmaceutical products [70,71,72,73] reinforcing the need for systematic quality control and inter-brand comparability assessments in lithium-based medications.

When these results are compared with the ICH Q3D (R2) guideline for elemental impurities, which establishes a permitted daily exposure (PDE) of 0.55 mg/day for Li, it becomes evident that some therapeutic scenarios, especially at higher doses, exceed this toxicological safety threshold. Specifically, for the 1800 mg dose, the ID values of samples M1R, M2S, M3S, M4S, M5G, M6G, and M7G ranged from 0.57 mg/day to 0.98 mg/day, all of which surpass the PDE value. Even at the 1200–1500 mg doses, some formulations (notably M7G and M6G) approach or exceed the PDE limit.

These findings suggest that inter-brand variability in Li concentration has direct implications for patient exposure and potential toxicity, particularly during long-term therapy. Given that Li has a narrow therapeutic index and cumulative toxic effects on renal and thyroid function, even small deviations above the PDE can increase the risk of adverse outcomes. Therefore, the results emphasize the importance of routine elemental monitoring and strict adherence to ICH Q3D (R2) limits to ensure the quality and safety of lithium-based pharmaceuticals.

Furthermore, the differences observed among commercial formulations highlight the need for greater regulatory oversight and standardization of manufacturing processes to minimize variability in elemental content. Analytical verification by ICP OES, as applied in this study, provides an essential quality-control tool to support compliance with international guidelines and to safeguard patient health during chronic lithium carbonate therapy.

4.3. Chronic Daily Intake and Hazard Quotient for Lithium

The CDI results obtained in this study indicate that the chronic exposure to Li through therapeutic use of lithium carbonate can be substantial, particularly under higher daily doses (≥900 mg/day). This is consistent with the pharmacological nature of Li as a narrow-therapeutic-index element, where the boundary between therapeutic efficacy and potential toxicity is narrow.

Considering the 30-year exposure scenario, the estimated CDI values approach levels that require close clinical supervision, especially when serum Li concentrations exceed 0.8 mEq/L, a range often associated with adverse effects on renal and thyroid functions [29,31,50,74].

The present findings align with WHO and American Pharmacopoeia (U.S. EPA) risk-assessment frameworks, which emphasize the relevance of long-term exposure parameters such as EF, ED, and AT in determining potential chronic effects [46,47]. Although therapeutic use is controlled and justified, the results highlight that even regulated pharmaceutical exposure can contribute significantly to the total body burden of Li, warranting monitoring of serum levels, renal function, and cumulative exposure throughout treatment [24,27,30,68].

Furthermore, the simulated exposure scenarios (600–1200 mg/day) align with clinical practice guidelines for maintenance therapy in BD. The increasing CDI trend across doses reinforces the necessity of dose individualization and adherence monitoring, particularly for elderly patients or those with pre-existing renal impairment.

The HQ values shown in Table 7 provide an estimate of the potential non-carcinogenic. A clear dose-dependent increase in HQ was observed, demonstrating that higher lithium doses lead to proportionally greater potential risk.

At the 600 mg/day dose, HQ values ranged from 0.69 to 0.81, remaining below unity for all formulations. These values indicate that, under standard therapeutic conditions, lithium exposure remains within acceptable safety limits, suggesting no potential non-carcinogenic risk at this dosage. On the other hand, at 900 mg/day, HQ values increased to 1.03–1.21, with several formulations exceeding the threshold value of 1.0. This finding suggests that moderate dose escalation may elevate the potential for exceeding safe exposure levels, particularly in formulations containing higher lithium concentrations. Finally, at the 1200 mg/day dose, HQ values ranged from 1.38 to 2.29, with the M7 G formulation showing the highest value (HQ = 2.29). These results indicate that, at higher therapeutic doses, some formulations may present increased potential for adverse effects, reinforcing the importance of maintaining strict control over lithium content and uniformity among marketed products. Although HQ values above 1.0 do not directly imply toxicity, they signal a possible health concern under chronic exposure scenarios.

Thus, the HQ analysis demonstrates that, while standard doses of lithium carbonate are generally within safe limits, higher doses substantially increase potential exposure risk, especially when product-to-product variability is considered. These findings underscore the need for rigorous quality assurance, batch monitoring, and patient follow-up to ensure the safety and consistency of lithium-based therapies.

In summary, the CDI assessment demonstrates that the long-term use of lithium carbonate, although clinically beneficial, demands vigilant toxicological and pharmacokinetic monitoring to balance therapeutic efficacy and safety. In fact, Li remains a cornerstone in the treatment of BD and other mood-stabilizing indications owing to its proven efficacy; however, its narrow therapeutic index has been repeatedly underscored in clinical toxicology.

A number of case reports and case series document situations of acute, acute-on-chronic, and chronic Li intoxication, often with severe neurological, renal, cardiac or multiorgan manifestations. For example, de Cates et al. (2017) described a man in his 60s who self-administered 50 × 400 mg lithium carbonate tablets and developed delayed severe neurotoxicity following renal replacement therapy initiation when his Li level was 4.7 mEq/L [26]. Chronic Li toxicity in a 66-year-old woman with underlying chronic kidney disease stage 4 was detailed by another report, emphasizing the subtle onset of neurologic signs and the diagnostic challenge [28]. In addition, there are cases illustrating that even therapeutic Li serum levels may be associated with fatal outcomes: a patient collapsed after vomiting, presenting bradycardia and ST-T changes despite Li levels within the nominal therapeutic range [75]. Rare cardiac manifestations have included complete heart block in the context of Li toxicity, as in the case of a 66-year-old female who required both hemodialysis and pacemaker placement [27]. More recently, an 83-year-old woman on a modest maintenance dose (300 mg/day) experienced acute Li poisoning in association with hypermagnesemia and colonic obstruction, underscoring the role of precipitating factors such as drug–drug/matrix interactions and renal/hydration status [68]. A broader case-series from the California Poison Control System reported 502 hospitalized exposures between 2003–2007, showing that deaths were rare (0.8%), but cardiac complications, albeit uncommon, may arise, especially in chronic toxicity settings requiring hemodialysis in 12.6% of cases [76].

Despite the severity and diversity of these clinical scenarios, a principal limitation for broader understanding remains the lack of systematic quantification of Li in drug formulations in the toxicological literature. Most reports refer to serum Li levels and clinical course, rather than linking the ingested pharmaceutical dosage, elemental composition of the medication, or formulation variability. This gap hampers comparisons of intoxication risk across different formulations (reference, generic, similar) and across regulatory markets. In addition, the classification of medicines as reference, generic and similar as used in Brazil is not uniformly adopted internationally, complicating global harmonisation of formulation quality and comparative risk assessment.

A key limitation of the present study lies in the absence of comparable research in the scientific literature. To date, no studies have been identified that quantify Li concentrations in pharmaceutical formulations, either in Brazil or in other countries. The existing publications primarily address the clinical efficacy, pharmacokinetics, and toxicity of Li therapy, but do not evaluate the actual Li content in marketed drug products. This gap restricts the possibility of comparing our findings with those from other regions and underscores the need for further analytical studies.

It is also important to note that the classification of reference, generic, and similar medicines is a regulatory distinction unique to the Brazilian pharmaceutical system. Many other countries do not adopt this tripartite categorization, which limits direct international comparisons of formulation quality and manufacturing consistency. Consequently, future investigations are essential to expand the analytical database on lithium-based formulations, assess possible inter-manufacturer variations, and support global efforts to ensure the quality, safety, and therapeutic reliability of Li medications used in the treatment of BD.

Lithium carbonate is widely recognized as the first-line pharmacological agent for the long-term management of BD, primarily due to its efficacy in mood stabilization and suicide prevention. However, Li possesses a narrow therapeutic index, which means that even small deviations in serum concentration can lead to toxicity. The balance between therapeutic benefit and toxic effect is delicate, requiring continuous clinical and laboratory monitoring throughout treatment [30,77].

Toxicity can manifest acutely, following an overdose or accidental ingestion, or chronically, due to prolonged accumulation in the body when excretion is impaired. Acute-on-chronic toxicity may also occur in patients undergoing long-term treatment who subsequently ingest excessive doses [22]. Clinically, Li intoxication presents with neurological, gastrointestinal, and renal symptoms, including tremor, ataxia, confusion, vomiting, diarrhea, polyuria, and, in severe cases, coma and cardiac arrhythmias [22,30].

Several real-world case studies have described the clinical consequences of Li intoxication. De Cates et al. (2017) reported a case of delayed severe neurotoxicity following a massive overdose of lithium carbonate, even after hemodialysis, underscoring the drug’s prolonged tissue retention [26]. Similarly, Kobylianskii et al. (2021) described a 54-year-old woman who developed chronic Li toxicity associated with renal dysfunction, highlighting the diagnostic challenge of recognizing subtle neurological manifestations [29]. A broader analysis by Baird-Gunning et al. (2017), which reviewed data from the California Poison Control System, showed that, among 502 hospitalized patients exposed to Li between 2003 and 2007, mortality was low (0.8%), but severe neurological and renal complications were common, and 12.6% of patients required hemodialysis [22].

These clinical observations collectively demonstrate that Li intoxication may occur even within nominally therapeutic serum levels, especially in elderly individuals, patients with renal impairment, or those exposed to drug interactions such as diuretics or nonsteroidal anti-inflammatory drugs (NSAIDs). Thus, continuous therapeutic monitoring and adherence to established serum Li reference ranges (0.6–1.2 mEq/L) are essential to avoid adverse effects [30,77].

Despite the abundance of clinical literature describing Li pharmacokinetics and toxicity, a notable research gap remains: virtually no studies have quantified the actual Li concentration in pharmaceutical formulations themselves. This limitation hinders comparative analysis between marketed products and their potential contribution to interpatient variability and toxicity risk. In Brazil, this issue is particularly relevant because the pharmaceutical market uniquely categorizes medicines as reference, generic, and similar—a distinction not adopted in most other countries. Therefore, analytical studies quantifying Li in commercially available formulations, such as the present research, are crucial to strengthen regulatory oversight and ensure therapeutic safety.

5. Conclusions

To the best of our knowledge, this is one of the first studies to quantitatively demonstrate significant variability in Li concentrations among marketed pharmaceutical formulations, showing that reference, generic, and similar medicines are not chemically equivalent. Generic formulations, particularly samples M6G and M7G, exhibited the highest Li levels, exceeding the reference product by approximately 27%. These differences suggest that variations in excipient composition, active ingredient purity, or manufacturing control may influence the final Li content of each product. Moreover, the calculated DI and CDI values showed that, under higher therapeutic doses (≥1500 mg/day), patient exposure may surpass the PDE of 0.55 mg/day established by the ICH Q3D (R2) guideline. This finding indicates a potential toxicological concern, especially during long-term treatment, given lithium’s narrow therapeutic index and cumulative toxicity. Importantly, this research represents the first quantitative assessment of Li concentrations in pharmaceutical formulations marketed in Brazil, and similar data are still lacking internationally. Therefore, the observed variability underscores the need for stricter quality control, harmonized regulatory standards, and expanded analytical studies to ensure the chemical consistency, safety, and therapeutic reliability of lithium-based medications used in the management of BD.