Bipolar Disorders 2000: 2: 77–92 Printed in Ireland. All rights resered I-Shin Shiah a,b and Lakshmi N Yatham a a Division of Mood Disorders, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada, b Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC Key words: anticonvulsants – bipolar disorder – 5-HT – lithium – mania – mood stabilizers – serotonin Received 7 May 1999, revised and accepted for publication 9 July 1999 Corresponding author: Lakshmi N Yatham, MBBS, FRCPC, MRC Psych (UK), Associ- ate Professor in Psychiatry and Director, Mood Disorders Clinical Research Unit, De- partment of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 2A1, Canada. Fax: +1 604 8227922; e-mail: yatham@unixg.ubc.ca Review Serotonin in mania and in the mechanism of action of mood stabilizers: a review of clinical studies Shiah I-S, Yatham LN. Serotonin in mania and in the mechanism of action of mood stabilizers: a review of clinical studies. Bipolar Disord 2000: 2: 77–92. © Munksgaard, 2000 Objecties: Serotonin (5-hydroxytryptamine, 5-HT) was implicated in the pathophysiology of manic-depressive illness as early as 1958. Al- though extensive evidence has accumulated since then to support 5- HT’s role in depression, relatively fewer studies examined its role in mania. The purpose of this paper was to review and summarize the current state of knowledge on the role of 5-HT in mania and its treat- ment. Methods: We systemically reviewed clinical studies of 1) 5-HT function in mania and 2) 5-HT in the mechanism of action of mood stabilizers, including lithium and anticonvulsants. Results: Review showed that cerebrospinal fluid, postmortem, platelet, neuroendocrine challenge, and tryptophan depletion studies provided some evidence to support the hypothesis that a 5-HT deficit is involved in mania and that enhancement of 5-HT neurotransmission exerts a mood-stabilizing effect. Conclusions: There is some evidence from clinical studies for the contri- bution of 5-HT in mania and in the mechanism of action of mood stabilizers. However, it is very likely that other neurotransmitters also play important roles. Future directions for research include 1) in io study of 5-HT receptor subtypes using positron emission tomography, 2) investigation of the interaction between 5-HT and other neurotrans- mitter systems, and 3) determination of the relationships between diag- nostic subtypes of mania and 5-HT function and other neurotransmitter systems. Serotonin (5-hydroxytryptamine, 5-HT) is an im- portant neurotransmitter within the central ner- vous system (CNS). The amount of 5-HT in the CNS is about 1–2% of that in the body (1). Be- cause this indoleamine transmitter cannot cross the blood–brain barrier, all the neuronal 5-HT is syn- thesized locally (1, 2). The synthesis of 5-HT in the brain involves 1) uptake of the essential amino acid L-tryptophan, which is a primary substrate for the synthesis, from plasma into serotonergic neurons, 2) hydroxylation of L-tryptophan to 5-hydroxy- tryptophan (5-HTP) via the enzyme tryptophan hydroxylase, and 3) decarboxylation of 5-HTP to 5-HT through the enzyme aromatic amino acid decarboxylase (2). It appears that 5-HT can be synthesized in both cell bodies and nerve terminals (2). 5-HT synthesized in the cell body is trans- ported into the terminals of dendrites and axons for release. Following its release, 5-HT is either inactivated by re-uptake into serotonergic nerve terminals, or interacts with a complex system of receptors. Once back inside the serotonergic neu- ron, this neurotransmitter is either re-stored in the vesicles or metabolized by the enzyme monoamine oxidase (MAO) and then converted into an inac- tive metabolite, 5-hydroxyindoleacetic acid (5- HIAA). To date, based on pharmacological or molecular properties, at least 14 types of 5-HT 77