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Mood Stabilizers

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Applied Clinical Pharmacokinetics and Pharmacodynamics of Psychopharmacological Agents

Abstract

Mood stabilizers have been used to primarily treat bipolar and schizoaffective disorders. However, these agents are also employed as adjunctive treatments for schizophrenia, depression, and other psychiatric illnesses. Lithium has been a mainstay of therapy for bipolar disorders for over 50 years. Lithium’s pharmacokinetic profile is well known as this agent is primarily excreted from the body by the kidney, which is about 20 % of the glomerular filtration rate. The antiepileptic agents evolved as mood stabilizers; however, the regulatory agencies have only approved the following agents – carbamazepine, valproic acid, and lamotrigine. Other antiepileptics have been used “off-label.” Carbamazepine undergoes autoinduction for the first month of therapy and is a well-known hepatic CYP enzyme inducer. Valproic acid metabolism mainly takes place via glucuronide conjugation by the UGT and mitochondrial β-oxidation. CYP metabolism accounts for 10 % of valproic acid metabolism primarily by CYP2C9. Lamotrigine is also largely metabolized by glucuronidation to three main metabolites. A small amount of autoinduction of 17 % was found to occur with lamotrigine serum concentrations that were determined to be clinically insignificant. Therapeutic plasma or serum concentrations have been established for lithium, carbamazepine, and valproic acid, while a threshold of 3.0 μg/mL for lamotrigine was recommended. Incidence of lamotrigine toxicity significantly increased with >15 μg/mL. Mood stabilizers have complex pharmacodynamic profiles that involve various receptors, ion channels, and secondary messenger systems. Lithium adverse events due to intoxication are linked to toxic plasma concentrations and decreased renal function. Carbamazepine plasma concentrations >14 μg/mL are associated with a variety of adverse effects with symptom severity increasing with rising drug concentrations that include coma and death. Valproic acid has a wider therapeutic range, and hyperammonemic encephalopathy correlations with serum concentrations are poor. Lamotrigine skin rashes are associated with large initial doses, rapid dose escalation, and concurrent valproic acid usage.

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  1. Department of Clinical and Experimental Medicine, University of Messina, Policlinico Universitario, Via Consolare Valeria, Messina, 98125, Italy

    Edoardo Spina MD, PhD & Domenico Italiano MD, PhD

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  1. Edoardo Spina MD, PhD
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  2. Domenico Italiano MD, PhD
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Correspondence to Edoardo Spina MD, PhD .

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  1. Univ. North Texas Sys, Col Pharmacy, Department of Pharmacotherapy, FORT WORTH, Texas, USA

    Michael W. Jann

  2. Department of Pharmacotherapy, Univ. North Texas Sys, Col Pharm, FORT WORTH, Texas, USA

    Scott R. Penzak

  3. Department of Pharmacotherapy, Univ. North Texas Sys, Col Pharm., FORT WORTH, Texas, USA

    Lawrence J. Cohen

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Spina, E., Italiano, D. (2016). Mood Stabilizers. In: Jann, M., Penzak, S., Cohen, L. (eds) Applied Clinical Pharmacokinetics and Pharmacodynamics of Psychopharmacological Agents. Adis, Cham. https://doi.org/10.1007/978-3-319-27883-4_8

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