Antidepressants: New pharmacological strategies

Book reviews

covered in Chapter 13, wlhich also introduces the developmental interactions which may occur between endocrine and autonomic systems. The possibility that endocrine factors (insulin and IGFs) maly affect the development of autonomic nerves is extensively reviewed. The book concludes with a chapter on sexual differentiation of the autonomic nervous system. Each of the chapters contain extensive and up-to-date references as well as more historical references which is to be expected of anatomical work. Although entitled ‘interactions’ the consideration is primarily one way with less on the potential for endocrine factors to modulate central and peripheral autonomic activity. However, for those interested in the neural mechanisms which may regulate the secretory activity of endocrine glands this book will provide a useful text. Cohn D. Ingram Department of Anatomy University of Bristol Bristol, U.K. PII: SOO28-390?3(97)001!~8-6 Antidepressants: New Pharmacological Strategies Edited by Phil Skolnick. IHumana Press, 1997. ISBN 0-896-03469-O. The symptoms of depression are generally considered to be related to a decrease in cerebral monoaminergic systems, particularly noradrenaline (NA) and serotonin (5hydroxytryptamine, 5-HT). The first generation antidepressants, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), which altered the disposition and metabolism of biogenic amines, revolutionized biological psychiatry. However, these drugs were severely limited by their side effect profile. The advent of selective serotonin inhibitors (SSRIs) were as effective as TCAs in the treatment of major depression, but were better tolerated. Despite these advances, approximately 30% of patients still fail to respond satisEsctorily to treatment, and no antidepressant starts to produce its therapeutic effects in less than 2-4 weeks of treatment. Consequently there is still a significant unmet medical. need and scope for improvement. The objective of this book is to being together novel concepts of antidepressant therapy that may or may not be grounded on the biogenic amine hypothesis-from regulation of transmitter levels :and second messenger systems, to gene expression and behaviour. In the first chapter, Romero et al., critically review the evidence that the acute response to an SSRI is limited by activation of somatodendritic 5-HT,, autoreceptors. Experimentally it is clear that augmenting the effect of a 5HT uptake blocker by co-administration of a 5-HT,, autoreceptor antagonist may have a clinical benefit in reducing the time-lag for its clinical effect, as well as improving the response rate. Early signs from the clinic support these experiment.al findings, in that combination of

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an SSRI with (-)-pindolol (a P-adrenoceptor antagonist with modest 5-HT,, antagonist activity) has shown some utility in this regard. Although SSRI’s are better tolerated than TCAs, their efficacy in major depression is no greater, and the delay in onset of action is of a similar duration. There is considerable evidence that increasing NA function has an antidepressant effect. Moret and Briley review the recent tendency towards the development of new antidepressants that selectively and simultaneously inhibit the reuptake of both 5-HT and NA (e.g. milnacipran and venlafaxine), while Glover describes the newest class of antidepressant MAOIs in the clinic-the selective reversible inhibitors of monoamine oxidase A, (RIMAs, e.g. moclobemide). RIMAs are deemed to be safer than the older nonselective irreversible MAOIs, however, they are less effective against metabolism of 5-HT (and dopamine)-a factor which may reduce their antidepressant activity, and imply that nonselective RIMAs may offer an alternative strategy. Calcium channel blockers have become valuable drugs in the treatment of several cardiovascular disorders. Numerous studies have also aimed at characterizing their pharmacodynamic profile with respect to potential psychotropic activity. Calcium channel antagonists have been proposed as possible alternatives to classical antidepressant drugs; being described as mood stabilisers, since they are similar to lithium in their clinical profile. Both preclinical and clinical data support their antimanic effectiveness, while antidepressant effects in animal models appear equivocal in clinical trials for major depression, especially in depressed bipolar patients. Pucilowski reviews the preclinical and clinical data, and hypothesise that L-type calcium channel blockers may have a greater utility as disorder specific (mania/depression) drugs, because of their propensity to act at open/depolarized channels. The role of N-methyl-D-aspartate (NMDA) receptors in depression and in the mode of action of antidepressants are discussed by a number of authors. In animal models of depression and anxiety, functional NMDA antagonists exhibit antidepressant and anxiolytic properties. Trullas explores the potential antidepressant activities of partial agonists or antagonists at the glycine modulatory site (strychnine insensitive glycine site) of the NMDA receptor. Moreover, Huang et al., describe the ability of chronic, but not acute, treatment with antidepressants to reduce the affinity of glycine for this site (leading to a reduction in NMDA receptor function). Although the precise mechanism for the functional adaptation in the NMDA receptor is unknown, the relevance of such an adaptation in viva will depend on whether or not the glycine site is saturated. Studies have also implicated a role for CAMP second messenger cascade in the action of antidepressant treatments. Although early studies consistently showed downregulation of pl-adrenergic receptor stimulated CAMP production, more recently, chronic antidepressant treatment has been shown to evoke an up-regulation of the CAMP intracellular signal transduction cascade. In particular,

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Book reviews

Duman et al., describe the increased expression of BDNF (brain derived neurotropic factor) and TrKB (tyrosine kinase receptor) as well as CREB (CAMP response-element binding protein), and their potential role in the therapeutic action of antidepressants-and as neuroprotective agents. One of the major limitations in the preclinical evaluation of potential antidepressants is the lack of animal models with construct and face validity, but also predictive validity. Willner and Papp describe the merits of one model-chronic mild stress-that has been used to identify a variety of novel antidepressants, but also reveal compounds that may address the issue of onset of action. However, the diversity of depressive disorders necessitates the development of other models that also incorporate chronicity as an essential design feature. Finally Paul et al., describe the use of molecular biology techniques to fully delineate the downstream mechanisms underlying antidepressant drug action and to find genes that determine genetic vulnerability (or susceptibility) to develop major affective disorder. This information may provide novel therapeutic approaches as well as new targets for drug discovery. Stephen Mitchell Lilly Research Centre Eli Lilly & Co Surrey, U.K.

PlI: SOO2S-3908(97)00199-S Excitatory Amino Acids-Clinical Results Antagonists Edited by P Herrling. Academic Press, 1997. ISBN o-12-546820-2.

with

NMDA receptor antagonists have been with us for more than 17 years; their potential clinical applications emerged in the early 1980s. AMPA antagonists have a shorter history. This volume summarizes in 10 chapters the current status of the compounds that have most interested the pharmaceutical industry in terms of their potential application in epilepsy, stroke, traumatic brain injury, pain and motor neurone disease. In spite of the book’s title most of the data presented concern preclinical studies, human pharmacokinetics and side effect profiles rather than clinical efficacy. Two of the compounds with more extensive clinical data (riluzole and remacemide) are also the two whose authenticity as pure EAA antagonists is most in doubt. The AMPA antagonists reviewed (NBQX and LY293558) have either not survived or not entered phase 1 trials. Excellent summaries of the fairly extensive clinical data accumulated for selfotel, and eliprodil are provided. At the time this volume went to press the disappointing outcomes of trials with these compounds in stroke and traumatic brain injury were not known. The front runner among competitive NMDA antagonists is currently D-CPPene (SDZ EAA 494); the outcome of a large scale controlled trial in traumatic brain injury is expected during 1998. The best placed runners among the

low-affinity non-competitive antagonists and glycine site antagonists are currently less well defined. This volume is exceptionally well edited; the chapters have a consistent style and structure and one integrated bibliography is provided. The book thus serves an important purpose in providing an accessible summary of the problems and prospects for clinical application of glutamate antagonists as at the beginning of 1997. It would have been helpful if the authors had provided the dates at which particular trials started and their planned completion dates. Indeed much of the information in this volume would be more useful in an online format with the possibility of continuous updating. Becoming outdated through the appearance of positive clinical data in acute neuroprotection is, however, the most desirable outcome for this publication. Brian S. Meldrum Institute of Psychiatry London, U.K. PII: SOO28-3908(97)00200-l Molecular Biology of the Neuron Edited by R. W. Davies and B. J. Morris. Bios Scientific Publishers, 1997. ISBN l-859962-40-8. By now even the most traditional of neurobiologists can not have failed to notice the growing impact of molecular biology on our understanding of the development, function and pathology of the CNS. The stated aim of this book, the fifth in BIOS’s series “Molecular and Cellular Neurobiology”, is to present an overview of the current state of knowledge of the molecular biology of the neurone, ranging from control of gene expression through to development and disease. The book consists of 14 chapters each prepared by different, mainly European authors. Commendably, this collection of experts avoid the temptation to dwell on the details of their own research and instead provide well written, information-packed, summaries of their allotted subject. The book follows a generally logical progression from chapter to chapter. It starts out with a good introductory chapter that provides an overview of what neuronal genes are, how they are isolated experimentally, and how and where one can obtain information about them. This is followed by a chapter entitled “Molecular Genetics of the Nervous and Neuromuscular Systems”. This is a (very) long chapter covering almost the entire gamut of genetic analysis of the neurone. As such, it is packed with information and, although up to the high standard of the rest of the book, may have been better, for the purposes of digestion, divided into two or three shorter chapters. The next chapter concerns the topic of neurone-specific gene expression. This is covered in lucid and very readable detail by Grant and Wisden, who supplement their contribution with a useful appendix describing the methods used by molecular biologists to study promoter and enhancer function, After these initial chapters on the somewhat more hard-