Mental disorders affect 44.3 million Americans in a given year. According to analysts the current global CNS therapeutics market is estimated at $40-55 billion, accounting for around 15% of the total global pharmaceuticals market. From a geographical perspective, the US accounts for about two-thirds of this revenue. Affective disorders (including depression) and anxiety are amongst the 10 leading causes of disability in the US and other developed countries, affecting 9.5% and 15% of the US population respectively. Due to the size of the CNS market and the inadequacies of currently available products the pharmaceutical industry continues to place considerable emphasis on the development of new approaches to indications such as anxiety and depression (see our recent feature "CNS 2002" for a full analysis of this therapeutic area). Other than side-effects one of the major problems associated with current treatment options in speed of onset. This can be a serious problem in depressed and suicidal patients. This problem is largely associated with selective serotonin reuptake inhibitors (SSRIs). Although these molecules rapidly block serotonin (5-HT) reuptake, their therapeutic action is delayed. The increase in synaptic 5-HT activates feedback mechanisms mediated by 5-HT1A (cell body) and 5-HT1B (terminal) autoreceptors, which, respectively, reduce the firing in 5-HT neurons and decrease the amount of 5-HT released per action potential resulting in attenuated 5-HT neurotransmission. Long-term treatment desensitizes the inhibitory 5-HT1 autoreceptors, and 5-HT neurotransmission is enhanced, however the onset of clinical activity can be significantly delayed which presents a serious problem especially if the patient is suicidal. The addition of pindolol, which blocks 5-HT1A receptors, to SSRI treatment uncouples the feedback inhibition of 5-HT neuron firing and accelerates and enhances the antidepressant response however this situation remains far from ideal and the identification of monotherapies with a fast onset would be of use. Such monotherapies are likely to exploit molecules with novel modes of action or alternatively molecules with dual 5-HT1A/SSRI activity. We have recently focused on one particularly exciting target, the renin-angiotensin system (click here for "Angiotensin as a potential target in the modification of cognition, anxiety and depression"). As an alternative, Spanish field-leaders have developed a series of novel molecules that have dual affinities for the 5-HT1A receptor and the serotonin reuptake transporter. This group's lead molecule has nanomolar affinity for both proteins. A large number of SSRIs have been developed over past decades and this has been followed more recently by the development of 5-HT1 antagonists. The molecules reported here are however amongst the first to combine activities. Their further development thus offers excellent therapeutic and commercial opportunities for improved treatment of depression or anxiety.

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