The importance of serotonin and noradrenaline in anxiety

Abstract

The therapeutics of obsessive-compulsive disorder (OCD) involves the serotonergic system in the brain; the selective serotonin reuptake inhibitors (SSRIs) are the only class of drugs to be consistently effective for this disorder. Preclinical studies in the orbito-frontal cortex – a brain area known to be involved in mediation of OCD symptoms – show that sustained administration of SSRI for 2 months leads to enhanced 5-HT release. Initially, raised 5-HT levels, resulting from serotonin (5-HT) reuptake inhibition, over-activates the cell body 5-HT1A autoreceptor, which has an inhibitory effect on the neuronal firing rate. However, after long-term administration of SSRIs, these 5-HT1A autoreceptors become desensitized to the raised extracellular 5-HT levels, and increase 5-HT transmission. The recovery of neuronal firing rate is faster with escitalopram (the active S-enantiomer of citalopram) than with citalopram, which may be due to different mechanisms of action. The 5-HT system has reciprocal interactions with the noradrenaline (NA) system. Although not a major mediator in the treatment of OCD symptomatology, patients with anxiety disorders such as panic disorder have increased NA reactivity and/or tone. Long-term SSRI administration reduces the firing rate of NA neurones, unlike 5-HT neurones. Evidence indicates that accrued 5-HT levels have an inhibitory modulatory effect on NA transmission, thus indicating the clinical relevance of SSRI treatment for anxiety disorders. The different effectiveness of the SSRIs escitalopram and citalopram in enhancing synaptic 5-HT levels may be due to the inhibitory action of the R-enantiomer in racemic citalopram on S-enantiomer binding to the 5-HT transporter. This allows escitalopram to produce higher extracellular 5-HT levels than can be achieved by the equivalent S-enantiomer dose of citalopram. Escitalopram is therefore a viable front-line treatment option for people with anxiety disorders, and possibly for those who have failed to respond to conventional SSRI therapies.