Current Pharmaceutical Design - Volume 11, Issue 12, 2005

Major depressive disorder (MDD) poses a significant health problem and is estimated to be the third most costly and disabling disorder in the United States. Pharmacotherapy of depression has been successful, but improvements in response rates, remission rates, side effects, compliance and faster onset of therapeutic action have become prime objectives in drug development. There is considerable support for the hypothesis that dysfunctional serotonergic or noradrenergic neurotransmission may be etiological in depressed patients. Duloxetine is a balanced and potent reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE) being studied as an antidepressant medication. In this review, we highlight the preclinical pharmacology, pharmacokinetic profile, and effects of duloxetine in the pharmacotherapy of depression. Evidence for 5-HT and NE reuptake inhibition by duloxetine comes from in vitro and in vivo transporter binding and functional uptake studies. Taken together with efficacy data from in vivo microdialysis, electrophysiological and behavioral studies, it is evident that duloxetine is balanced as a dual serotonin norepinephrine uptake inhibitor in vivo. The clinical efficacy and safety of duloxetine in the treatment of MDD has been studied in 6 multicenter, randomized, double-blind, placebo-controlled trials. In these studies, duloxetine was found to be effective in the treatment of emotional/psychological and painful physical symptoms associated with depression. More importantly, duloxetine appears to have better response rates and remission from depressive symptoms, perhaps due to its ability to treat a wider range of symptoms.

Brain-derived neurotrophic factor (BDNF) is a member of the structurally and functionally homologous neurotrophin family. It is the most widely distributed trophic factor in the brain, and participates in neuronal growth, maintenance, and use-dependent plasticity mechanisms such as long-term potentiation and learning. There are several lines of evidence supporting a role for BDNF in the treatment of depression. This paper reviews the neurotrophin hypothesis of antidepressant action, and examines our current understanding of activity-dependent mechanisms of BDNF expression and function in limbic regions of the brain. Our discussion starts with the original observations of monoaminergic neurotransmitter dysfunction that served as the basis for early antidepressant drug development, and outlines evidence for neurodegeneration and functional deficits existing with chronic stress and depression. We continue with evidence that enhancement in neurotrophic support and associated augmentation in synaptic plasticity and function may form the basis for antidepressant efficacy, and serve as a current and future focus in the quest for more rapid-acting and effective medication treatments. Finally, we follow the current search for the intracellular mechanisms of antidepressant interventions that may bring the monoaminergic and neurotrophic hypotheses together, and help us to more fully understand the roles of both neurotransmitter and growth factor. Principal challenges to the neurotrophin hypothesis, and inconsistencies between clinical and preclinical research results, are also pointed out, as these also guide future experiments that will refine our understanding of treatment mechanisms.

Depression affects a large percentage of the general population and can produce devastating consequences to affected individuals, families and society. Although the treatment of depression has been advanced by traditional antidepressants, improvements are needed across several dimensions (e.g., overall treatment efficacy, therapeutic onset time, and side effect profile). The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor has an allosteric modulatory site(s) for which potent positive modulators (potentiators) have been designed. These compounds produce antidepressant-like effects in animal models, increase levels of brain-derived neurotrophic factor (BDNF) and engender neurogenesis in vivo. Although these effects are also produced by traditional antidepressants, AMPA receptor potentiators appear to produce their effects through a novel mechanism.

Research on Substance P (SP) has, until recently, focused on its role in pain and inflammation. However, a report that NK1 receptor antagonists have utility in the treatment of depression has stimulated research into the function of SP and the NK1 receptor in anxiety and depression. The distribution of SP and the NK1 receptor in brain areas implicated in anxiety and depression is initially reviewed. This is followed by evaluation of the preclinical data obtained for SP and NK1 receptor antagonists in behavioral models of depression as well as the phenotype of genetically modified animals lacking the genes encoding for the NK1 receptor or for SP. The weight of the evidence supports antidepressant and anxiolytic activity of NK1 receptor antagonists. However, many of the studies do not control for nonspecific effects of the compounds, and when enantiomers that lack activity at the NK1 receptor are included, the results, in some cases, suggest that blockade of NK1 receptors does not account for the observed behavioral activity. Finally, clinical studies in depressed patients assessing SP levels in plasma and cerebrospinal fluid as well as the effect of NK1 receptor antagonists are reviewed. The clinical studies are a mixture of positive, failed and negative studies on the antidepressant activity of NK1 receptor antagonists, not unlike the early clinical results obtained with selective serotonin reuptake inhibitors.

Since vasopressin has been shown to be critical for adaptation of the hypothalamo-pituitary-adrenal axis during stress through its ability to potentiate the stimulatory effect of CRF, it has been hypothesized that this peptide may provide a good opportunity for pharmacological treatment of stress-related disorders. The availability of the first orally active nonpeptide V1b receptor antagonist, SSR149415, opened a new era for examining the role of vasopressin in animal models of anxiety and depression. In rats, SSR149415 blocked several endocrine (i.e. ACTH release), neurochemical (i.e. noradrenaline release) and autonomic (i.e. hyperthermia) responses following various stress exposures. Moreover, the drug was able to attenuate some but not all stress-related behaviors in rodents. While the antidepressant-like activity of the compound was comparable to that of reference antidepressants, the overall profile displayed in anxiety tests was different from that of classical anxiolytics, such as benzodiazepines. These latter were highly effective and reliably produced robust effects in most anxiety tests, while SSR149415 showed clear-cut effects only in particularly stressful situations. Experiments with mice or hamsters indicated that V1b receptor blockade is associated with reduced aggressiveness, suggesting that SSR149415 could prove useful for treating aggressive behavior. It is important to note that SSR149415 is devoid of adverse effects on motor functions or cognitive processes, and it did not produce tolerance to its anxiolytic- or antidepressant-like activity. Altogether, these findings suggest that V1b receptor antagonists represent a promising alternative to agents currently used for the treatment of depression and some forms of anxiety disorders.

Seven forms of congenital long QT syndrome (LQTS) caused by mutations in ion channel genes have been identified. Genotype-phenotype correlation in clinical and experimental studies involving arterially-perfused canine left ventricular wedges suggest that β-blockers are protective in LQT1, less so in LQT2, but not protective in LQT3. A class IB sodium channel blocker, mexiletine, is most effective in abbreviating QT interval in LQT3, but effectively reduces transmural dispersion of repolarization (TDR) and prevents the development of Torsade de Pointes (TdP) in all 3 models, suggesting its potential as an adjunctive therapy in LQT1 and LQT2. High concentrations of intravenous nicorandil, a potassium channel opener, have been shown to be capable of decreasing QT and TDR, and preventing TdP in LQT1 and LQT2 but not in LQT3. The calcium channel blocker, verapamil, has also been suggested as adjunctive therapy for LQT1, LQT2 and possibly LQT3. Experimental data using right ventricular wedge preparations suggest that a prominent transient outward current (Ito )-mediated action potential (AP) notch and a loss of AP dome in epicardium, but not in endocardium, give rise to a transmural voltage gradient, resulting in ST segment elevation and the induction of ventricular fibrillation (VF), characteristics of the Brugada syndrome. Since the maintenance of the AP dome is determined by the balance of currents active at the end of phase 1 of the AP, any intervention that reduces the outward current or boosts inward current at the end of phase 1 may normalize the ST segment elevation and suppress VF. Such interventions are candidates for pharmacological therapy of the Brugada syndrome. The infusion of isoproterenol, a β-adrenergic stimulant, strongly augments L-type calcium current (ICa-L), and is the first choice for suppressing electrical storms associated with Brugada syndrome. Quinidine, by virtue of its actions to block Ito, has been proposed as adjunctive therapy, with an implantable cardioverter defibrillator as backup. Oral denopamine, atropine or cilostazol all increase ICa-L, and for this reason may be effective in reducing episodes of VF.

The isolation and purification of somatostatin (SS), exactly 30 years ago, has led to the elucidation of physiologic actions of SS. This cyclic peptide is produced in the hypothalamus, throughout the central nervous system, as well as in most major peripheral organs and inhibits hormone release from the anterior pituitary gland, pancreas and the gastro-intestinal tract. The potent inhibitory actions of SS not only led to the clinical application of this peptide, but also resulted in the development of SS-analogues, among which octreotide and lanreotide are most well known and clinically used for several distinct disorders. Almost ten years ago, five different SS receptor subtypes (sst1-5) were identified. These receptor subtypes are variably expressed in distinct tissues and bind with varying affinity to the different SS-analogues, providing an excellent tool to unravel the (patho-) physiological function of the five sst subtypes. Following an overview upon the latest developments in SS receptor physiology and established diagnostic and therapeutic efficacy of SSanalogues in several challenging neuroendocrine disorders, this review predominantly focuses upon the latest developments of (clinically) potential novel sst subtype specific analogues as well as universal binding SS-peptides. Also, the role of potential SS antagonists is assessed. Furthermore, the most recent insights concerning targeted sst-mediated chemo- or radiotherapy are discussed, which offers new therapeutic and diagnostic opportunities for patients harbouring sst-positive neuroendocrine diseases. Finally, acknowledged side effects and possible pitfalls of the use of SS-analogues are discussed.