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In terms of world-wide sales, the current antidepressant of choice is the selective serotonin re-uptake inhibitor (SSRI), leading examples of which include Wyeth’s Effexor (venlafaxine) and Pfizer’s Zoloft (sertraline). Even modern treatments, however, fail to treat major depressive disorder effectively: only 22.6% of patients achieve clinical remission after their first treatment with an antidepressant.

Of the new generation of antidepressants, GlaxoSmithKline's noradrenaline and dopamine re-uptake inhibitor, bupropion (Wellbutrin), the only currently-marketed drug that targets dopamine, appears to be more effective at alleviating certain residual symptoms, compared with SSRIs, including sleepiness and fatigue, whilst not causing the side-effects of weight gain and sexual dysfunction that can affect compliance with SSRI treatment.

Bupropion, however, along with all other currently-marketed drugs for depression (and several in late-stage development), targets the monoamine system, acting on serotonin, noradrenaline and/or dopamine receptors. Each compound has a slightly different pharmacological profile, with varying activity on some or all of the monoamine pathways. The increased number and variety of therapies that will result from new monoamine-targeting drugs reaching the market will broaden the range of options available to patients – increasing the chances that they will find a suitable treatment – but they are likely to suffer from the same problems and the high rate of relapse that SSRIs do.

Drugs in late-stage development

One of the major drawbacks of SSRIs is their delayed onset of action. It has been proposed that the therapeutic actions of SSRIs are caused by long-term changes in certain neurotransmitter pathways. Modulating post-synaptic 5-HT1A receptors is expected to target the mechanism that augments serotonergic transmission directly, rather than via the indirect pathways targeted by SSRIs.

According to IMS LifeCycle R&D focus antidepressants in development that target 5-HT1A receptors include: gepirone, which is being evaluated in Phase III trials, and vilazodone, which entered Phase III trials in January 2006. Both drugs have met with development problems, however: the US Food and Drug Administration determined that gepirone ER was not approvable in 2004 and the original New Drug Application was withdrawn (Fabre Kramer plans to submit an amended NDA), while vilazodone failed to demonstrate efficacy against placebo in trials, but demonstrated efficacy comparable with a currently-marketed antidepressant.

The complexity of changes in the serotonergic system in depressed patients and during treatment may limit the potential of compounds targeting serotonin alone: companies are therefore exploring compounds with alternative mechanisms of action in an attempt to overcome some of the problems experienced with the monoamine-targeting agents.

Table 1 - Drugs in late-stage development for depression

Source: IMS LifeCycle R&D focus

Agomelatine, a melatonin agonist, shows efficacy against depressive symptoms, and improves disrupted sleep patterns in depressed patients without affecting daytime alertness. Compounds that selectively target the neurokinin receptors, including saredutant and casopitant, also have efficacy in the treatment of anxiety disorders. Neurokinin antagonists have had problems with efficacy, however, and Merck & Co’s Emend (aprepitant) was discontinued for the treatment of depression in late 2003 after it failed to show efficacy in a Phase III trial.

Other types of compounds that several companies are focusing on include those that antagonise the CRF1 receptor, and Type II and IV phosphodiesterase inhibitors. If they reach the market, these compounds will offer new classes of antidepressants, and will increase options available to patients who don’t respond to other classes. In addition, they may have increased efficacy against residual symptoms, such as sleep disorders and anxiety.

Novel approaches

At the 35th Annual Meeting of the Society for Neuroscience companies such as Karo Bio, which is developing oestrogen receptor beta agonists, reported on new approaches for treating depression. In addition, data were presented for novel formulations of compounds to provide more convenient dosing, with the aim of increasing compliance, such as Minnesota University's intranasal formulation of a thyrotropin-releasing hormone analogue. In addition, companies are trying to refine currently-marketed compounds, to capture their therapeutic potential whilst minimising their side-effect profiles, such as The Mayo Clinic's programme to develop venlafaxine analogues.

R&D focus lists numerous early Phase I and preclinical programmes that are under way to evaluate compounds targeting a range of receptors and regulating hormones. All programmes are supported by research suggesting a role for these receptors and pathways in depression, but the high attrition rate of preclinical programmes and the lack of efficacy data for the compounds makes it impossible to predict whether these compounds will have any antidepressant activity in humans, in addition to acceptable side-effect and pharmacokinetic profiles. In addition, of the new compounds that are being evaluated, a large number will initially be developed for multiple indications rather than specifically for depression, and it is impossible to estimate which programmes will eventually produce effective depression therapies.

Gene screening programmes

Gene screening programs are being conducted in an attempt to discover the mechanisms that underlie the manifest symptoms of depression and to identify new targets for drug discovery, including genes and regulating proteins. Biotech companies are conducting screening programmes to support drug discovery:

• Biocortech's programme is based on the development of therapies to restore neuronal pathways and deficient brain receptors, by controlling receptor mRNA editing mechanisms
• Psychiatric Genomics is identifying gene expression patterns associated with psychiatric diseases, using samples from diseased, normal and drug-treated patients, and incorporating this data into its Multi-Parameter High-Throughput Screen to rapidly discover new therapeutic compounds
• Lexicon Genetics is using knockout mice to investigate the functions of genes, and the physiological and behavioural effects of losing the function of that gene, to identify potential novel drug targets. This approach reveals the side-effects, as well as the therapeutic potential of modulating a specific target, before drug screening has begun
• ChemGenex is using a combination of animal models and human sample collections to identify and characterise novel targets for the treatment of depression. The company is evaluating several, including proteins involved in neuronal signal transduction, homeostasis and biogenesis
• Proteome Sciences has developed several proteomics technologies to analyse differential protein expression in disease and therapy.

In the future, research programmes may permit the identification of specific receptor regions and receptor subtypes involved in depression, and novel non-receptor targets and signalling pathways, in order to develop drugs with more specific mechanisms of action and fewer side-effects. In addition, a greater understanding of differences in patient etiology, and how these can be identified with gene or biochemical markers, will allow tailored treatments.

Depression, however, is a genetically-complex disorder with a number of predisposing genes, and behaviour is complex and multi-factorial. It is possible that depression will never be reduced to a series of genes and molecular mechanisms, and this complexity, combined with the infancy of these biotech programmes, means that a ground-breaking pharmacological therapy or the use of tailored therapies for depression is a long-way off, and may never be possible at all.

This article was written by Kate George, an Editor of IMS LifeCycle R&D focus, a powerful tool for the evaluation of the progress of experimental compounds, licensing deals and the identification of new business opportunities. For more information, please contact Stephanie Earle via e-mail, or call +44 207 393 5757.