Bipolar Medications: Mechanisms of Action

First, let’s get one thing straight. This is not a book for most clinicians, unless one needs a sure cure for insomnia. Granted, there are four clinical chapters tacked on at the end (on valproate, lamotrigine, atypical antipsychotics, and calcium channel blockers), but they represent only 12% of the text and appear to be well-written afterthoughts. This is a book for serious scientific types (some of whom may also be clinicians), who will find it as engrossing as the recent presidential election. These are the readers who derive meaning from observations such as, “Incubation of intact human neuroblastoma SH-SY5Y cells with VPA results in an increase in the subsequent in vitro recombinant GSK-3β-mediated [³²P] incorporation into two putative GSK-3 substrates (molecular weight ~85 kDa and 200 kDa), compatible with inhibition of endogenous GSK-3β by VPA” (p. 159).

The editors have assembled an impressive cast of contributors (including themselves) who delve deeply into the mechanisms (emphasis on the plural) of action of bipolar medications. Chapters include erudite discussions of topics such as phosphatidylinositol signaling, the brain polyamine-stress response, the effects of lithium on synaptosomal glutamate uptake, antidepressant effects on the G protein-adenylyl cyclase axis, regulation of signal transduction pathways, mood stabilizer regulation of MARCKS (the myristoylated alanine-rich kinase C substrate), potentiation of immediate-early gene c-fos expression, guanine nucleotide binding disturbances, and adenosine regulation of neuronal excitability. References abound, and many chapters of this year 2000 publication are referenced well into 1999.

Lithium, the most thoroughly researched bipolar medication, is mentioned by name in the titles of 10 of the 19 chapters. It is eminently clear that lithium has many “mechanisms of action,” or, as succinctly put by Mogens Schou, “Since the key is so small, it fits into many locks” (1). If something affects virtually everything, determining which aspect(s) of this multiplicity of mechanisms is responsible for antimanic, antidepressant, and prophylactic properties is a daunting challenge. The search would be simplified greatly, of course, if the etiology of bipolar disorder were not such a mystery.

In the mid-1500s, Levinus Lemnius ascribed mental ill-health to “grosse vapours” adversely affecting the brain (he recommended shaving the head to allow these vapors to “fume oute”) (2, p. 22). The flaw of basing treatment on presumed rather than true etiology should be quite apparent. Basing treatment of mania on the assumption that it was caused by the ego bounding out of control after having escaped the harsh constrictions of the superego was equally unproductive. The problems with both these interventions were etiologies assumed to be true and treatments assumed to be effective. The quantum leap forward that provided the foundation for Bipolar Medications: Mechanisms of Action was fueled by the scientific rigor that established the effectiveness of the involved drugs. Anyone reading this book will be impressed by the progress made toward a more complete unraveling of the mysteries of bipolar disorder and its treatments. Without doubt, this book is the most comprehensive compilation of information in this area.