Escitalopram—translating molecular properties into clinical benefit: reviewing the evidence in major depression

The majority of currently marketed drugs contain a mixture of enantiomers; however, recent evidence suggests that individual enantiomers can have pharmacological properties that differ importantly from enantiomer mixtures. Escitalopram, the S-enantiomer of citalopram, displays markedly different pharmacological activity to the R-enantiomer. This review aims to evaluate whether these differences confer any significant clinical advantage for escitalopram over either citalopram or other frequently used antidepressants. Searches were conducted using PubMed and EMBASE (up to January 2009). Abstracts of the retrieved studies were reviewed independently by both authors for inclusion. Only those studies relating to depression or major depressive disorder were included. The search identified over 250 citations, of which 21 studies and 18 pooled or meta-analyses studies were deemed suitable for inclusion. These studies reveal that escitalopram has some efficacy advantage over citalopram and paroxetine, but no consistent advantage over other selective serotonin reuptake inhibitors. Escitalopram has at least comparable efficacy to available serotonin-norepinephrine reuptake inhibitors, venlafaxine XR and duloxetine, and may offer some tolerability advantages over these agents. This review suggests that the mechanistic advantages of escitalopram over citalopram translate into clinical efficacy advantages. Escitalopram may have a favourable benefit-risk ratio compared with citalopram and possibly with several other antidepressant agents

Chronic Citalopram Administration Causes a Sustained Suppression of Serotonin Synthesis in the Mouse Forebrain

BACKGROUND:Serotonin (5-HT) is a neurotransmitter with important roles in the regulation of neurobehavioral processes, particularly those regulating affect in humans. Drugs that potentiate serotonergic neurotransmission by selectively inhibiting the reuptake of serotonin (SSRIs) are widely used for the treatment of psychiatric disorders. Although the regulation of serotonin synthesis may be an factor in SSRI efficacy, the effect of chronic SSRI administration on 5-HT synthesis is not well understood. Here, we describe effects of chronic administration of the SSRI citalopram (CIT) on 5-HT synthesis and content in the mouse forebrain. METHODOLOGY/PRINCIPAL FINDINGS:Citalopram was administered continuously to adult male C57BL/6J mice via osmotic minipump for 2 days, 14 days or 28 days. Plasma citalopram levels were found to be within the clinical range. 5-HT synthesis was assessed using the decarboxylase inhibition method. Citalopram administration caused a suppression of 5-HT synthesis at all time points. CIT treatment also caused a reduction in forebrain 5-HIAA content. Following chronic CIT treatment, forebrain 5-HT stores were more sensitive to the depleting effects of acute decarboxylase inhibition. CONCLUSIONS/SIGNIFICANCE:Taken together, these results demonstrate that chronic citalopram administration causes a sustained suppression of serotonin synthesis in the mouse forebrain. Furthermore, our results indicate that chronic 5-HT reuptake inhibition renders 5-HT brain stores more sensitive to alterations in serotonin synthesis. These results suggest that the regulation of 5-HT synthesis warrants consideration in efforts to develop novel antidepressant strategies

Regulation of the release of serotonin in the dorsal raphe nucleus by alpha(1) and alpha(2) adrenoceptors

To investigate the modulation of serotonin release in the dorsal raphe nucleus (DRN) by alpha(1) and alpha(2) adrenoceptors, dual-probe microdialysis was performed in conscious rats. The specific alpha(1) and alpha(2) adrenoceptor agonists and antagonists were locally infused into the DRN via retrograde microdialysis. The release of serotonin was simultaneously sampled from the DRN and prefrontal cortex (PFC). Infusion of the a, adrenoceptor agonist cirazoline into the DRN (100 muM) produced an increase in the release of serotonin in the DRN to 200% of the basal levels, but no effect was seen in the PFC. After infusion of the alpha(1) adrenoceptor antagonist prazosin into the DRN (100 mum) the release of serotonin decreased in the DRN and PFC to about 40% and 65% of the basal levels, respectively. Infusion of the alpha(2) adrenoceptor agonist clonidine into the DRN (100 mum) slightly but significantly decreased the level of serotonin in the DRN as well as in the PFC to about 70% of the basal levels. Infusion of the alpha(2A) adrenoceptor antagonist BRL 44408 into the DRN (100 mum) caused an increase of serotonin release in the DRN to 270% of the basal levels, but at the same time no changes were seen in the extracellular levels of serotonin in the PFC. The present study demonstrates that alpha(1) as well as alpha(2) adrenoceptors in the DRN modulate the release of serotonin in the DRN, and that a, adrenoceptors in the DRN are maximally stimulated during resting conditions. (C) 2003 Wiley-Liss, Inc

The interaction between the locus coeruleus and dorsal raphe nucleus studied with dual-probe microdialysis

The interaction between the locus coeruleus and dorsal raphe nucleus was investigated by means of dual-probe microdialysis in conscious rats. The release of noradrenaline and 5-hydroxytryptamine (5-HT) after inhibition or stimulation of locus cocruleus and dorsal raphe activity was sampled in both nuclei and analysed by high-pressure liquid chromatography (HPLC). The inhibition of locus coeruleus activity by the infusion of the alpha2-adrenoceptor agonist clonidine (100 muM) decreased the release of noradrenaline to 20% in the locus coeruleus and 30% in the dorsal raphe, whilst the release of 5-HT decreased to 80% of control in the two brain areas, The excitation of locus coeruleus activity by the muscarinic receptor agonist carbachol (100 muM) led to an increase in the release of noradrenaline to 240% and 220% of control in the locus coeruleus and dorsal raphe, respectively, The release of 5-HT in both nuclei did not respond to the carbachol infusion into the locus coeruleus. Infusion of the 5-HT1A receptor agonist flesinoxan into the dorsal raphe (1 muM) significantly decreased the release of 5-HT in the dorsal raphe and locus coeruleus to 45% and 65% of control, respectively. The release of noradrenaline was decreased in the dorsal raphe to 45% by flesinoxan, whereas no changes were seen in the release of noradrenaline in the locus coeruleus. In conclusion, the innervation of the dorsal raphe by the locus coeruleus has a slight excitatory effect on the release of 5-HT in the dorsal raphe. The dorsal raphe does not exert a direct inhibitory influence on the release of noradrenaline in the locus cocruleus. Finally, the release of noradrenaline in the dorsal raphe may be locally regulated by 5-HT1A receptors. (C) 2002 Published by Elsevier Science B.V