Figure 6 Selective serotonin reuptake inhibitors (SSRIs) and the selective norepinephrine reuptake inhibitor, nisoxetine.

due to their improved tolerability and safety on overdose as compared to the BZs. Clinical studies have expanded the indications for the SSRIs and they are currently being used to treat a variety of anxiety disorders including SAD, panic disorder, OCD, and social phobia.87 For panic disorder, SSRIs are first line therapy but if an accelerated response is necessary (SSRIs require at least 2-3 weeks to achieve efficacy) the combination of an SSRI (sertraline) and a fast-acting BZ (clonazepam) has proven effective with clonazepam being given for the first 4 weeks and then tapered over a 3 week period to minimize side effects.

Like their use in depression, use of antidepressants for anxiety requires 4-6 weeks to achieve desired efficacy. From a disease mechanism point of view, the slow onset of efficacy observed across the spectrum of monoamine reuptake inhibitors is inconsistent with their primary mechanism of action, the blockade of reuptake of neurotransmitters that occurs within minutes/hours following compound administration. A plausible hypothesis for this inconsistency could be that as the levels of monoamines increase in the synapse, activation of presynaptic autoreceptors (by the monoamine) acts against the activity of the reuptake inhibition, thus counteracting the initial increase in synaptic neurotransmitter concentration. Only following long-term use of the reuptake inhibitor do these presynaptic autoreceptors (for example

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