481 Novel strategies for pharmacotherapy of depression Karen A Maubach*t, Nadia MJ Rupniak*$ Mark S Kramertand Raymond G Hill*# Modulating monoamine activity as a therapeutic strategy continues to dominate antidepressant research, with a recent emphasis on agents with multiple targets, including combined serotonin/noradrenaline re-uptake inhibitors and numerous serotonin receptor ligands. An important new development has been the emergence of potential novel mechanisms of action, notably modulation of the activity of neuropeptides substance P and corticotrophin-releasing factor, and the intracellular messenger cyclic adenosine monophosphate. Efforts in this area have recently been rewarded by the demonstration of antidepressant efficacy of the substance P receptor antagonist MK-0869. Addresses *Merck Sharp & Dohme Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK +Merck Research Laboratories, West Point, PA 19456, USA :e-mail: karen-maubach@merck.com se-mail: nadia-rupniak@merck.com #e-mail: ray-hill@merck.com Current Opinion in Chemical Biology 1999, 3:481-488 http://biomednet.com/elecref/1367593100300481 0 Elsevier Science Ltd ISSN 1367-5931 Abbreviations 5-HT serotonin ACTH adrenocorticotropic hormone BDNF brain-derived neurotrophic factor CREB CAMP-response-element-binding protein CRF corticotrophin-releasing factor CRFR CRF receptor GABA yaminobutyric acid HTT serotonin transporter mGluR metabotropic glutamate receptor MOAI monoamine oxidase inhibitor NK neurokinin PDE phosphodiesterase SP substance P SPA SP receptor antagonist SSRI serotonin re-uptake inhibitor TCA tricyclic antidepressant Introduction The introduction of the monoamine oxidase inhibitors (MAOIs) and the tricyclic antidepressants (TCAs) in the 1950s followed by the selective serotonin (5HT) re-uptake inhibitors (SSRIs) in the 1980s has revolutionised and rede- fined the treatment of depression [l] (Figure 1). The primary disorder, once thought to be due to psychodynamic factors and limited to patients with severe symptoms, is now viewed as biologically determined. Antidepressants are used to treat both outpatients and inpatients with a wide range of symptoms and severity of illness [Z]. Following the serendipitous discovery of the antidepres- sant efficacy of the MAO1 iproniazid and the TCA imipramine, the pharmacological actions of these drugs were explored and this formed the basis of subsequent refinements, particularly with respect to their safety and tolerabihty. The success of this strategy is shown by the SSRIs, which have become the most widely prescribed antidepressant treatments because of their comparative safety in overdose and improved side-effect profile com- pared with earlier TCAs [3]. They have also been successfully employed for treating anxiety-disorders, such as obsessive-compulsive and panic attack [3]. Although SSRIs are clinically effective, adverse effects such as nausea, sexual dysfunction and sleep disorders continue to hinder compliance [4]. Furthermore, the full therapeutic effects of these drugs require weeks to appear and approximately 30% of patients fail to benefit from treatment [S]. Consequently, the search for new antide- pressants continues and has been focused on providing solutions to the deficiences of existing medication. The discovery of novel drugs to treat depression has been constrained by our poor understanding of the pathophysi- ology of mental illness. Therapies designed to enhance monoamine function may all be marred, to various degrees, by problems with treatment resistance, delayed onset and tolerability, potentially resulting in only minor improve- ments in therapy. Alternative, but more speculative, mechanisms may thus prove more successful in the long run. In this review, therefore, we will deal with advances from monoamine-based treatment strategies, but the main focus will be on new emerging approaches targeting neu- ropeptides and excitatory amino acids. Modulation of monoamine systems Serotonin/noradrenaline re-uptake inhibitors The TCAs, such as imipramine, have a dual action on sero- tonin and noradrenaline re-uptake systems [6], but also bind to several other receptor sites [7] that are thought to contribute to their dose-limiting adverse effect profile. Clinical trials with the recently developed selective com- bined serotonin/noradrenaline re-uptake inhibitors (SNRIs, e.g. venlafaxine, Figure Z), suggest that they are effective in depression and they are also being explored for the treatment of anxiety [8,9,10’,11,12,13’]. At present there is insufficient evidence to decide whether they have improved antidepressant activity, but compared with the prototype TCAs they have a modestly improved tolerabil- ity profile as anticipated from their more selective preclinical pharmacology [10’,13’]. The serotonin transporter The serotonin transporter (HTT) plays a key role in the termination of serotonergic neurotransmission and is the