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Abstract Background For decades, lithium carbonate has remained one of the most effective agents for treatment of patients suffering from bipolar disorder (manic depressive psychosis). Lithium acts by altering intraneuronal metabolism of catecholamines, inhibition of noradrenaline sensitive adenylate cyclase, and reduction in synaptic transmission and increase in neuronal excitability with modification of central nervous system (CNS) amine levels. Recently, studies have also shown that lithium holds promise against Alzheimer’s disease. However, lithium has many side effects. Over dosage of lithium can cause acute Li+ intoxication, which occurs quite often due to its narrow therapeutic index. For example, serum Li+ levels over 1.5 mM (12 hours after a dose) usually indicate a significant risk of intoxication. Therefore, the timely and accurate monitoring of serum levels of lithium after a therapeutic dosage is critical. Methods Lithium is determined spectrophotometrically through a formation of a lithium/chromogen complex. When a sample containing lithium ion is mixed with the reagent containing porphyrin derivative at an alkaline pH, the lithium/chromogen complex is formed, resulting in a change in absorbance which is directly proportional to the concentration of lithium in the sample. The development of the colorimetric assay provided a cost-effective and easy-to-use method for determining lithium concentration in a variety of sample matrices, compared to traditional methods like ion selective electrode (ISE). The assay is in a single reagent format, and the reaction takes less than a minute. Results The Diazyme colorimetric lithium assay is developed and validated on the Roche cobas c701 chemistry analyzer, and the Beckman Coulter AU680 clinical chemistry analyzer. The assay has a measuring range from 0.10 mmol/L – 3.00 mmol/L, with a Limit of Quantification (LOQ) of 0.10 mM lithium. Substances normally present in the serum were tested and found no interference to the colorimetric lithium assay. In the past, the high pH of the reagent has posed a challenge to the on-board stability of the colorimetric lithium assay. In this study, a chemical stabilizer, compound X, was found to be extremely effective in maintaining the pH of the reagent, and therefore resulting in a significantly enhanced on-board stability of the assay. Conclusion An improved colorimetric lithium assay was developed and validated on common chemistry analyzers with enhanced on-board stability, better assay precision and accuracy across the clinical range.