Current Drug Targets - Volume 7, Issue 2, 2006

It was my great honor and pleasure to be suggested for the guest editing of the theme issue in Current Drug Targets and to prepare this issue entitled "Recent strategies for potentiation and facilitation of antidepressant treatment". Major depression is a severe and dangerous mental disorder with a lifetime prevalence of 20%. Throughout over 50 years of research and drug development, different classes of medications were developed and showed efficacy in the treatment of major depression. However, the main limitations of most antidepressant drugs are a long delay between the beginning of treatment and the onset of the therapeutic effect of the treatment, a high percentage of patients do not respond to the treatment and a high risk of rapid relapse to depression even after effective treatment. Therefore, understanding the mechanisms of action of antidepressant drugs and developing new strategies for potentiation and facilitation of the treatment of depression is one of the main targets of current psychopharmacological research. The aim of the issue was to summarize the current research in the area of neuropharmacological mechanism of antidepressant response and novel strategies used to enhance it. I would like to thank to the authors of the Issue for their outstanding review manuscripts in their area of expertise, such as augmentation and facilitation of antidepressant treatment by pindolol, thyroid hormone, lithium or neurokenin, catecholaminergic strategies for the treatment of major depression and the role of serotonin-dopamine interaction in the antidepressant response. Especial acknowledgement should be given to my mentors, Michael E. Newman, Ph.D., Gal Yadid, Ph.D., and Pierre Blier, M.D., Ph.D., for their help and guidance during the Issue preparation, to Bernard Lerer, M.D. for his introduction to the Issue, to the Editor-in-chief, Francis J. Castellino, Ph.D., for his kind invitation, to the reviewers, and to the Issue Manager, Ms. Saima Ghaffar Rao, for coordinating the entire project.

Depression is one of the major challenges facing clinical medicine. Unipolar depression was ranked fifth among the leading causes of disability worldwide in 2000 and projections indicate that by 2020 it will be ranked second only to ischemic heart disease [1]. Recognition and effective treatment of depression is an important concern. Data from the US National Comorbidity Survey indicate that almost half of those who suffer from depression go untreated and that treatment is adequate in only about 41% of cases [2]. Treatment approaches for depression that are supported by evidence from randomized, controlled trials include antidepressant drugs and specific psychotherapeutic approaches based on interpersonal or cognitive-behavioral techniques. The data supporting efficacy of antidepressant drugs are considerable and this modality is the most widely used, for this reason and because it is accessible to clinicians who are not psychiatrists and do not have expertise in psychotherapy. Has the efficacy of antidepressant medication increased appreciably since the first drugs of this type were introduced almost half a century ago? Response rates to active drug and placebo in controlled trials of antidepressants suggest that there has been little change in this regard. While response to active drug and placebo varies, a differential of 20-30% between active drug and placebo remains constant over scores of trials [3]. Since about 40% of responders to active drug in antidepressant trials could well be placebo responders, the true efficacy of currently available medications is a matter of serious concern. These considerations lead to the conclusion that an important challenge facing contemporary psychopharmacology is to develop antidepressant drugs that are effective in the ∼40% of patients who do not respond to current treatment. This will require novel concepts beyond the current templates for drug development that are essentially based on the mechanism of action of existing agents. Whether blockbuster approaches based on the development of "one size fits all" agents are the correct direction is open to serious debate. Progress in the development of new drugs could well depend on phenomenological dissection of clinical subtypes and the identification of core, drug responsive diagnostic entities. Pharmacogenetic approaches could prove pivotal in this regard [4]. A further challenge that is as yet unmet is the delay 2-4 weeks in onset of action of antidepressants and the lengthy period of 6-8 weeks required for drugs to be fully effective. There is very little evidence to suggest that any of the currently available drugs act faster than the others and this latency of effect is a major difficulty facing clinicians who treat depressed patients. On this background, the current issue of explores the pivotally important strategy of supplementation of antidepressant action and is most timely. The concept underlying this collection of papers is that addition of a second therapeutic agent to an antidepressant drug can have augmenting or accelerating effects. Augmentation implies an increase in efficacy i.e. a stronger therapeutic effect, which would convert non- or partial responders to full responders. Accelerating effects imply an earlier onset of action and more rapid achievement of maximal therapeutic action. Both these objectives are fully congruent with the major challenges facing antidepressant drug development. Supplementary treatments currently being explored involve harnessing neurotransmitter systems other than those acted upon by the primary antidepressant drug (such as dopamine), stimulating or blocking mechanistically relevant receptors whose effect is to enhance the action of the primary agent (such as 5-HT1A receptors) or the addition of substances for which there is clinical evidence but whose mechanism of action in depression is not fully understood (such as triiodothyronine). From the point of view of therapeutics two drugs may well be better than one and the current series of papers seeks to explore whether and how this might be so. In the clinic, each additional agent carries with it further risks of adverse effects, the potential for pharmacokinetic interactions and problems with compliance, which are directly related to the number of pills the patient has to take and the frequency with which he needs to take them. Nevertheless, research on strategies for potentiation and facilitation of antidepressant treatment can have very great potential impact, at the clinical level and also as a basis for the development of novel antidepressant drugs based on the mechanisms identified. REFERENCES [1] Murray, C.J., Lopez, A.D. (1997) Lancet, 349, 1498-1504. [2] Kessler, R.C., Berglund, P., Demler, O., Jin, R., Koretz, D., Merikangas, K.R., Rush, A.J., Walters, E.E., Wang, P.S. (2003) JAMA, 289, 3095-3105. [3] Davis, J.M., Wang, Z., Janicak, P.G. (1993) Psychopharmacol. Bull., 29, 175-81. [4] Lerer, B., Macciardi, F. (2002) Int. J. Neuropsychopharmacol., 5, 255-275.

Pindolol, a partial ß-adrenoceptor/5-HT 1A receptor antagonist was first used to accelerate the onset of action of antidepressant drugs in 1994. Since then, it has been used in more than a dozen controlled trials to examine whether it can reduce the lag to clinical improvement, and/or improve the clinical response in treatment-resistant patients. A recent metaanalysis concluded that pindolol accelerates the antidepressant response but does not increase the effectiveness of SSRIs in unresponsive patients. Several studies have examined the pharmacology of pindolol to clarify the neurobiological basis of its clinical action. Pindolol was initially used due to its ability to block 5-HT1A receptor-mediated responses and to enhance the neurochemical effects of SSRIs. In transfected cells, however, pindolol is a weak (20-25%) partial agonist at 5-HT1A receptors and, as such, its actions greatly depend on the system used. In line with this, other reports have also shown that pindolol can reduce serotonergic cell firing when given alone. Positron emission tomography (PET) scan studies have shown that pindolol displays a preferential occupancy of pre- vs. postsynaptic 5-HT1A receptors, although the overall occupancy is lower than desirable, which suggests that higher doses (e.g., 15 mg/day) may be more effective than the currently used 7.5 mg daily dosage. However, given the complex pharmacology of pindolol, it is hoped that new developments in this field can proceed through the use of a) selective and silent 5-HT1A receptor antagonists in combination with SSRIs, or b) dual action agents (SSRI + 5-HT1A receptor blockers).

Although the selective serotonin reuptake inhibitors have become the first line medications for the treatment of depression, drugs primarily targeting the norepinephrine (NE) and/or the dopamine catecholaminergic systems are also effective. These include selective NE reuptake inhibitors, such as desipramine and reboxetine, the NE releaser bupropion and the α2-adrenergic antagonists mianserin and mirtazapine. Dopamine type 2 agonists are also effective in treating depression, although they are rarely used. Since the NE, dopamine and serotonin systems have reciprocal interactions, it is virtually impossible to act on a specific neuronal element without affecting in a cascade effect the two other systems. In this review, the primary actions of the catecholaminergic strategies upon their acute and long-term administration are described, as well as their impact on other systems. Their use in treatment-resistant depressed patients is also addressed.

In the last decade, many augmentation strategies have been developed to increase the activity of antidepressant drugs or to reduce their long onset of action by acting on different targets. One of the first augmentation strategy used in psychiatric disorders is coadministration of lithium and antidepressant drugs. However, the underlaying mechanism of action involved in the potentiatory effect of lithium is still unclear and many hypotheses have been suggested such as activity on BDNF, ACTH, thyroid hormones and serotonin neurotransmission. All these systems being embedded in each other, we focused on the 5-HT neurotransmission-increase induced by lithium treatment. Based on neurobiochemical and behavioral results we tried to better understand its mechanism of action and we concluded that effect of lithium on 5-HT neurotransmission could be linked to a partial agonist activity on 5-HT1B autoreceptors, or to a modulatory activity on these receptors, located in the cortical area in the case of a short term treatment, or in the hippocampus in the case of a long term treatment. We also suggested that the anti-manic effect of lithium was linked to this activity on 5-HT1B receptors, occurring this time on 5-HT1B postsynaptic (heteroreceptors on dopaminergic pathways) receptors levels.

Dopaminergic mesolimbic and mesocortical systems are fundamental in hedonia and motivation. Therefore their regulation should be central in understanding depression treatment. This review highlights the dopaminergic activity in relation to depressive behavior and suggests two putative receptors as potential targets for research and development of future antidepressants. In this article we review data that describe the role of serotonin in regulating dopamine release, via 5HT2C and 5HT3 receptors. This action of serotonin appears to be linked to depressive-like behavior and to onset of behavioral effects of antidepressants in an animal model of depression. We suggest that drugs or strategies that decrease 5HT2C and increase 5HT3 receptor-mediated dopamine release in the limbic areas of the brain may provide a fast onset of therapeutic effect. Clinical and basic research data supporting this hypothesis are discussed.

Central serotonergic and dopaminergic systems play a critical role in the regulation of normal and abnormal behavior. Recent evidence suggests that a dysfunction of dopamine (DA) and serotonin (5-HT) neurotransmitter systems contributes to various pathological conditions. Among the multiple classes of 5-HT receptors described in the central nervous system, much attention has been devoted to the role of 5-HT2 receptor family in the control of central dopaminergic activity, because of the moderate to dense localization of both transcript and protein for 5-HT2A and 5-HT2C receptors in the substantia nigra (SN) and ventral tegmental area (VTA), as well as their terminal regions. Moreover, modulation of 5-HT2 receptor function by various drugs that has been shown to influence DA function in these brain areas is thought to be important in motor activation, motivation, and reward. Indeed, a number of electrophysiological and biochemical data have shown that 5-HT2C receptor agonists decrease, while 5-HT2C receptor antagonists enhance mesocorticolimbic DA function. Recent studies have focused on the functional interaction between the serotonergic and dopaminergic systems to explain the mechanism of the antidepressant action of SSRIs and 5-HT2 antagonists. In this article, the most relevant data regarding the role of these receptors in the control of brain DA function are reviewed, and the importance of this subject in the search of new antidepressant drugs is discussed.

Classical antidepressant drugs such as Selective Serotonin Reuptake Inhibitors (SSRIs) display several disadvantages, e.g., the onset of action (2 to 3 weeks) to start clinical benefits is too long, and a significant proportion of patients do not respond to this monotherapy. Several strategies have been proposed to overcome these problems, notably the use of potentiating agents, which combined with SSRIs, augment or accelerate their established antidepressant activity. Recent clinical trials proposed that compounds with dual action on both central serotonin (5-HT) and noradrenaline (NA) systems would have a faster action than SSRIs alone. Preclinical electrophysiological and neurochemical studies demonstrated that the putative new class of antidepressants, substance P (neurokinin 1) NK1 receptor antagonists, enhance brain monoaminergic neurotransmissions by reducing the sensitivity of 5-HT1A autoreceptors in the Dorsal Raphe Nucleus, and possibly α2 autoreceptors in the Locus Coeruleus. However, in several clinical studies, a similar delay of therapeutic effects has been reported with NK1 receptor antagonists and SSRIs. Recently intracerebral in vivo microdialysis studies were performed to examine the effects of genetic or pharmacological blockade of Substance P (SP)/ NK1 neurotransmission on SSRIs-induced increases in extracellular 5-HT levels in awake, freely moving mice. New evidences suggest that the combination of a NK1 receptor antagonist with a SSRI should benefit to depressed patients. This review describes our current knowledge of the role of SP and its preferred NK1 receptors mainly in the modulation of brain serotonergic activity.

The thyroid hormone triiodothyronine (T3) has been used both to augment and accelerate the clinical effects of antidepressants, particularly the tricyclics. More recent work indicates that it may have similar actions with regard to the SSRIs. Two main mechanisms have been put forward to explain its antidepressant actions, (a) an action at the nuclear level involving stimulation of gene transcription, (b) an action at the cell membrane level involving potentiation of neurotransmission. In particular, there is considerable evidence for potentiation by T3 of the actions of the neurotransmitter 5- HT or serotonin. This evidence, which is mainly based on in vivo microdialysis studies, is reviewed, and evidence based on human and animal neuroendocrine studies considered. The effects of T3, alone and together with the SSRI fluoxetine, on mRNA levels for the 5-HT1A and 5-HT1B autoreceptors, which mediate serotonergic neurotransmission by feedback actions at the levels of cell firing(somatodendritic 5-HT1A autoreceptors) and neurotransmitter release (nerve terminal 5- HT1B autoreceptors) were also determined. Administration of a combination of fluoxetine and T3 induced reductions in the transcription of these autoreceptors, which may explain the clinical potentiating effects of this combination, and thus link the nuclear and neurotransmitter hypotheses of T3 action.

Background: Type 2 diabetes mellitus (T2DM) is a common disease that is associated with an increased risk of vascular complications. The incidence of T2DM is also increasing. It follows that T2DM prevention is important. Methods: Relevant articles (review articles, randomised studies and large cohort and case-control studies) were identified through a Medline search (up to March 2005). Results: The first trials on T2DM prevention were based on lifestyle intervention. The results of these studies were impressive since they demonstrated that even a small reduction in weight could significantly reduce the incidence of T2DM. However, the main disadvantage of lifestyle measures is that they are difficult to achieve and sustain. Therefore, pharmacological interventions have also been evaluated. The results of trials using metformin, orlistat, nateglinide, acarbose, thiazolidinediones, hormone replacement therapy, statins or fibrates are either encouraging or require more extensive evaluation. In addition, studies using antihypertensive drugs (mainly angiotensinconverting enzyme inhibitors and angiotensin II receptor antagonists) showed that these drugs could also reduce the progression to T2DM in high risk individuals. Conclusions: T2DM has major quality of life and cost implications. Therefore, more research is needed to establish safe and cost effective ways to prevent this modern epidemic.

The application of macromolecules as vehicles for anticancer drug delivery is a burgeoning field of interest. One of the hallmarks of using such systems, however, is that they must be capable of site-specific drug delivery. As such, augmenting the targeting of drug delivery systems to specified sites is paramount. To date, a number of synthetic strategies have been utilized to introduce targeting moieties to macromolecular drug delivery systems to enhance specific targeting. This scheme frequently involves the introduction of some type of biologically recognizable marker to the delivery system. Biological evaluations have substantiated the rationale that introducing targeting groups can significantly increase specificity. This concise review will attempt to encompass what strategies have been done to increase the specificity of macromolecular anticancer drug delivery systems along with their biological activities.