Manji, Husseini K., Bowden, Charles L., and Belmaker, Robert H., Eds. Bipolar Medications: Mechanisms of Action. Washington, DC: American Psychiatric Press, 2000. xix + 440 pp. $58.50
For many years lithium has been the mainstay of therapy for bipolar disorder (BPD), but since the mid-1980s, there has been a marked growth in the range of drug treatments available for this illness, resembling and even exceeding similar developments in the treatment of other mental illnesses. Paralleling the discovery of new drugs for BPD, there has been a drive to understand their mechanisms of actions. Such knowledge might provide vital clues to the pathophysiology of BPD and assist in further drug development. Mood stabilizers, like many other efficacious medications, were not discovered by way of a sophisticated and detailed understanding of the pathophysiology of the illness they treat but rather were discovered by chance or because they were effective for other indications and then noted as helpful for coexisting BPD. Therefore, research into their mechanisms of action has had to pursue diverse and innovative lines of inquiry, such as putative neuroprotective properties, effects on signaling pathways, and animal behavior models. Although a comprehensive understanding is still lacking, significant strides have been made, particularly in the study of lithium's action.
To keep abreast of this rich and growing body of knowledge, a need has arisen to collect and present these diverse findings in a coherent manner. Bipolar Medications: Mechanisms of Action meets this goal. The editors and the authors of the chapters are the leaders in the field, and they write of their own contributions. Although the chapters are cross-referenced, they read as narratives of the individual investigator's work, making what can be quite dry and technical more readable. The style in which the accounts are written also varies with some more biographical and others reading more like published journal accounts.
Two broad themes are developed in the book. The major one reflects its title, "Mechanisms of Action," and the second theme, occupying the latter part of the book, is the clinical efficacy of the most novel mood stabilizers. The chapters expounding on mechanisms of action reflect the somewhat disparate nature of the field and are therefore reviewed and grouped below into one of several broad areas of research that have emerged in the field over recent years.
One of the major lines of inquiry into lithium's action has been its effect on the phosphatidylinositol (PI) signaling pathway. Much work has focused on determining which of the many observed changes are relevant to the drug's effectiveness. Both the diacylglycerol (DAG)/protein kinase C (PKC) and inositol triphosphate (IP3)/Ca2+ branches of the PI signaling pathway have been the subjects of considerable study. Atack reports on attempts to mimic lithium effects on the PI system by inhibition of inositol monophosphatase with other agents; such effects might confirm a significant role for lithium inhibition of this enzyme. Agam and Shimon examine human evidence for the role of inositol in BPD and mood-stabilizing treatments. Lenox et al. and Manji et al. address the DAG/PKC branch of the PI system. Although the mechanisms remain unclear, and indeed may differ between the two drugs, both lithium and valproic acid (VPA) similarly inhibit PKC isoenzymes and myristoylated alanine-rich C kinase (MARCKS), a PKC substrate and putative modulator of signaling pathway effects on neuroplastic changes. Furthermore, Manji et al. report that tamoxifen, a PKC inhibitor, has been found in clinical studies to possess antimanic properties. GSK-3β, which is regulated by PKC isoenzymes and known to regulate various cytoskeletal processes and nuclear events, has recently been identified as a target for the action of lithium and valproic acid. Manji et al. summarize their work in this field.
Several lines of evidence suggest that effects on G-protein mediated signal transduction may form one piece of the puzzle. Manji, Jope, and Post each have sections on this topic in their chapters. In addition, Rasenick et al. report clues emanating from the effect of antidepressants on the G-protein-adenylyl cyclase signaling system. A body of knowledge focused on G-protein levels and function in BPD may also provide clues, as outlined by Warsh et al. Further upstream, Leslie and Norman present their findings of c-fos potentiation by chronic lithium administration after 5HT-2a receptor activation. The 5-HT2 family of receptors activate phospholipase (PLC) through a G-protein linkage. Also upstream, van Calker et al. review their results indicating that carbamazepine, via adenosine receptor blockade, may modulate an inhibitory effect of adenosine on pathologically overactive neural circuits.
Empirical studies (referred to by Post et al.) showing that early lithium treatment is more effective than treatment after multiple episodes of illness, and recent in vitro work, suggest that lithium may have neuroprotective properties. Manji et al. tell of their investigations in this area, including an association of chronic lithium and VPA administration with increased expression of the transcription factor PEP2β in the frontal cortex; PEP2β promotes transcription of the gene bcl-2 that is known to enhance cell survival. Gilad and Gilad describe their novel approach to investigating lithium and its putative protective role. In their studies, chronic lithium blocks enhanced brain polyamine biosynthesis associated with repeated stressors. Goodwin reports on attempts to understand how prematurely stopping lithium leads to an exacerbation of the illness. In contrast to the protective role of lithium, the work of Hokin et al. suggests a possible mechanism for the toxic effects of lithium. For several years they have investigated the action of mood stabilizers in cerebral cortex slices and have found that higher concentrations of lithium are associated with increasing release and accumulation of glutamate.
A major difficulty in the field has been reconciling seemingly contradictory results, such as reductions in brain inositol levels with lithium treatment, and clinical improvement in depressed patients who are given inositol. Recent evidence has suggested that lithium and other mood stabilizers exert their therapeutic effects not through unidirectional changes but rather by dampening fluctuations in signaling systems. This concept has been examined mostly in the PI system, and Jope et al. present some of the relevant data. Although lithium effects on the adenylyl cyclase/cAMP/protein kinase A system have received less attention, Mørk and Jensen present evidence that mood stabilizers may likewise reduce oscillations within this signaling system also. In keeping with this theme, Hokin et al. report on a stabilization of glutamate uptake into synaptosomes in mice chronically treated with lithium.
One of the major difficulties investigating therapeutic mechanisms of action is distinguishing incidental and compensatory changes from those forming the basis of therapeutic action. Antagonists at biochemical sites known to be perturbed can be used to reverse the effects of a drug and so test the significance of that site. Kofman et al. describe their attempts to reverse behavioral effects of lithium by using agents to counteract 2 major effects by lithium on signal transduction-at the PLC-linked second messenger system and at the adenylyl cyclase second-messenger system.
The book's last four chapters are comprehensive summaries of the clinical efficacy of VPA, lamotrigine, the atypical neuroleptics, and calcium channel blockers in the treatment of BPD. Bowden examines the efficacy of VPA compared with lithium in mania. Calabrese presents preliminary data on the efficacy of lamotrigine especially for bipolar depression. Recent attention has focused on the efficacy of atypical neuroleptics for bipolar disorder. Tohen and Tollefson review this area and suggest the atypicals are superior to the typical neuroleptics for BPD, even after accounting for their improved side effect profile. Finally, Goodnick and Benitez present data on the calcium channel blockers, especially verapamil and nimodipine, and suggest their reduced teratogenicity, the absence of blood monitoring and the lack of side effects associated with standard treatments may encourage further research into and use of these drugs.
As may be gleaned from this review, Bipolar Medications: Mechanisms of Action, is a collection of state-of-the-art essays on the science of mood stabilizers. The book makes a significant contribution to the field through its scholarship and as a comprehensive collection of the rich and diverse paths of research. In approaching the book, it is important to keep in mind broad areas of research being pursued by the field, as outlined in the review. I would recommend it to both researchers and clinicians who have an interest in BPD and are keen to learn of the latest developments in its pharmacotherapy.
Irving M. Reti, MBBS
Department of Psychiatry; Johns Hopkins University