Current Pharmaceutical Design - Volume 11, Issue 2, 2005

The birth of new neurons, or neurogenesis, in the hippocampal formation has been demonstrated throughout the lifetime of multiple species including humans. A major finding in the field of depression is that treatment with antidepressant drugs increases hippocampal neurogenesis. This review presents a current summary of this field of study and presents the hypothesis that increasing adult hippocampal neurogenesis may be a new drug target or mechanism for future antidepressant drugs. It has been demonstrated that multiple classes of antidepressant drugs increase hippocampal cell proliferation and neurogenesis in a chronic and not acute time course, which corresponds to the therapeutic time course necessary for effects. Conversely, animal models of depression or stress paradigms decrease cell proliferation. Clinically, there is evidence of reduced hippocampal volume in patients with major depressive disorder or other affective disorders. Taken together, this data indicates that reduced hippocampal cell number may be involved in the pathophysiology of depression and reversal of this may be one way the antidepressant drugs exert their effects. We hypothesize that the next generation of antidepressant drugs will, in addition to their effects on known transmitter or second messenger systems, involve either direct or indirect targeting of neurogenic factors. In addition, the ability of novel compounds to be tested for the neurogenic potential may become an additional way to evaluate a compound for putative antidepressant effects.

Over the past several years, research has indicated that an individual's genetic makeup strongly influences not only their likelihood of developing depression, but also whether or not they will respond well to a particular antidepressant treatment. Identifying those genes regulating susceptibility to depression will increase our understanding of disease pathophysiology and direct the development of treatments that correct underlying neurobiological pathology related to stress-related psychiatric illnesses. Pharmacologically, the identification of genes regulating treatment response can lead to the design of novel pharmacological treatments and allow for more individualized, rational and successful drug treatments. Unfortunately, complex environmental and genetic mechanisms at play in depression and drug response make the discovery of susceptibility genes in humans quite difficult. Animal models may provide a more desirable system in which to discover susceptibility genes because environmental factors and tests can be regulated and more informative genetic methods can be used. Furthermore, a unique genetic opportunity exists with animal models of depression and antidepressant response because several rodent strains have been identified, or selectively bred, that display exaggerated depressive phenotypes on stress-related behavioral tests or divergent responses to antidepressant drugs. This paper reviews several of these rodent strains and illustrates the genetic strategies available to discover the long-sought susceptibility genes regulating these phenotypes.

A wide diversity of animal models has been used to examine antidepressant activity. These range from relatively simple models sensitive to acute treatment, to highly sophisticated models that reputedly model some aspect of depressive illness and which yield a positive response to prolonged, chronic, drug treatment. In recent years antidepressant drug research has focused on the search for antidepressant therapy that has a more rapid onset of action. To be relevant, therefore, animal models must measure the time course of drug action. This review examines the claims of animal models to be sensitive to chronic drug treatment and considers their relevance. First, the review addresses the criteria necessary to examine the validity of animal models of depressive illness. Second, those animal models sensitive to chronic antidepressant treatment are reviewed with respect to their validity as animal models of either depressive illness and / or antidepressant activity. In particular, the development and utility of two 'ethologically-relevant' animal models, the resident-intruder and social hierarchy paradigms, are described in detail. These models of rodent social and agonistic behaviour demonstrate that acute and chronic treatment with antidepressant drugs (regardless of their acute pharmacological activity) induce diametrically opposite changes in rodent agonistic behaviour. It is argued that the common ability of chronic treatment to increase rodent aggression (which in turn results in increased hierarchical status in closed social groups) most likely reflects the increased assertiveness and associated externalization of emotions expressed during recovery from depressive illness. Finally, findings that relate observed behavioural changes to underlying neurochemical changes are briefly reviewed.

Arginine vasopressin (AVP) is a cyclic nonapeptide synthesized exclusively by neurosecretory cells of the central nervous system (CNS). Two functionally distinct vasopressinergic systems can be defined based on differences in the sites of action and release of AVP. The peripheral vasopressinergic system encompasses the sites of action for AVP released into peripheral circulation (e.g. vascular smooth muscle, liver, kidney) from nerve terminals in the posterior pituitary. Peripherally circulating AVP is responsible for the classic endocrine functions ascribed to this neurohormone (e.g. vasoconstriction, glycogen metabolism, antidiuresis). The central vasopressinergic system, on the other hand, includes the sites of AVP synthesis and release within the CNS, where AVP acts as a neuromodulator / neurotransmitter regulating an array of CNS-mediated functions (e.g. learning and memory, neuroendocrine reactivity, social behaviors, circadian rhythmicity, thermoregulation, and autonomic function). Historically, pharmaceutical interest has focused on drug development efforts that sought to exploit the peripheral effects of AVP. Evidence, however, from clinical studies and animal models of CNS disorders has directly implicated disturbances in vasopressinergic activity in the pathophysiology of a number of human psychiatric disorders (mood, anxiety, and cognitive disorders). This review will examine the available evidence of central vasopressinergic system involvement in psychiatric disorders, and the potential opportunities for development of novel psychopharmaceuticals around this system will be discussed. Specific lines of evidence will be presented which rationalize each AVP receptor subtype (V1R or V1a, V2R, V3R or V1b) as a molecular target for particular psychiatric indications.

Improving our knowledge of the development, course and treatment of major depression is among the most pressing public health concerns in medicine. It is therefore satisfying to observe that critical advances have been made in our fundamental understanding of this illness and related conditions in the past several years. Among the areas of major change have been advances in nosology and disease classification, an improved understanding of risk factors for the development of major depression, advances in the standards of clinical practice, enhanced societal acceptance of patients with the disease and their treatment, and a substantial increase in our understanding of the underlying neurobiology of this common, disabling, and potentially lethal illness. It is sobering, in contrast, to observe that we still use methods of clinical study to explore new treatments with this condition that employ study designs and measurement tools which have changed very little over the past three decades. In this selective review, several key areas of interest relevant to the clinical development of antidepressants are examined. These areas point to some suggested topics for attention in the future.

Hypericin is a naturally occurring substance found in the common St. Johns Wort (Hypericum species) and can also be synthesized from the anthraquinone derivative emodin. As the main component of Hypericum perforatum, it has traditionally been used throughout the history of folk medicine. In the last three decades, hypericin has also become the subject of intensive biochemical research and is proving to be a multifunctional agent in drug and medicinal applications. Recent studies report antidepressive, antineoplastic, antitumor and antiviral (human immunodeficiency and hepatitis C virus) activities of hypericin; intriguing information even if confirmation of data is incomplete and mechanisms of these activities still remain largely unexplained. In other contemporary studies, screening hypericin for inhibitory effects on various pharmaceutically important enzymes such as MAO (monoaminoxidase), PKC (protein kinase C), dopamine-betahydroxylase, reverse transcriptase, telomerase and CYP (cytochrome P450), has yielded results supporting therapeutic potential. Research of hypericin and its effect on GABA-activated (gamma amino butyric acid) currents and NMDA (Nmethyl- D-aspartat) receptors also indicate the therapeutic potential of this substance whereby new insights in stroke research (apoplexy) are expected. Also in the relatively newly established fields of medical photochemistry and photobiology, intensive research reveals hypericin to be a promizing novel therapeutic and diagnostic agent in treatment and detection of cancer (photodynamic activation of free radical production). Hypericin is not new to the research community, but it is achieving a new and promizing status as an effective agent in medical diagnostic and therapeutic applications. New, although controversial data, over the recent years dictate further research, re-evaluation and discussion of this substance. Our up-to-date summary of hypericin, its activities and potentials, is aimed to contribute to this process.

The original treatment indicated for those suffering from neurotic anxiety was to employ psychotherapy to facilitate changes in behavior and coping with stressful events. A spectrum of somatic treatments “from cathartics and emetics to opium and “strengthening tonics”, from atropine and digitalis to potassium bromide and chloral hydrate, from barbiturates to benzodiazepines”, to serotonergics, came to be used as well [1]. The Food and Drug Administration originally approved many gamma-aminobutyric acid (GABA) facilitating drugs since the 1960s for anxiety treatment. The 1980s evidenced the approval of a few serotonergic treatments that cornered the prescribing market and the front line of most treatment protocols. More recently, GABAergic drugs are making a return in the treatment of anxiety disorders. The following paper details the pharmacodynamic history of treating anxiety and also updates the reader as to the newer GABA-based approaches mentioned above.

Recent advances in molecular biology have identified numerous steps and proteins involved in malignant transformation as targets of anticancer therapy. Many molecular targeted agents are now undergoing clinical development. Successful developments of trastuzumab in treating breast cancer, imatinib in chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs), and bevacizumab in colorectal cancer, have validated the concept of molecular targeting and raised expectations of patients and oncologists alike. Despite these successes, many agents, notably matrix metalloproteinase inhibitors (MMPIs), have failed in their development. In this review, we will address several issues related to tumor biology and clinical trial design that might have contributed to these successes and failures, and discuss strategies to best optimize the development of these novel agents.

Psoriasis is a chronic skin disorder that affects approximately 2% of the US and European population. Over the last several years, one of the major focuses in psoriasis research has been the development of biologic therapies for this disease. The aim of these therapies is to provide selective, immunologically directed intervention with fewer side effects than traditional therapies. The goal of this article is to review the progress of the biologic agents which are available, or under investigation for clinical use: infliximab, etanercept, efalizumab, alefacept, and adalimumab. In addition, two other investigational therapies, oral tazarotene and oral pimecrolimus will be discussed. Clinical data for these agents, including the most recent phase II and / or III study results, will be discussed, as well as the most recent safety data