The involvement of serotonin in anxiety disorders has been long known and already has implications in the treatment of many anxiety disorder patients. However, the exact mechanism of action of serotonin in these disorders remains to be illuminated.

Serotonin is involved in stress response and can inhibit aversive responses in humans, but the mode of action of serotonin remains unclear. Data in rodents suggest that global serotonin depletion may specifically increase long-duration bed nucleus of the stria terminalis (BNST)-mediated aversive responses (i.e. anxiety), but not short-duration BNST-independent responses (i.e. fear). Robinson et al (2012, Neuropsychopharmacology) investigated these findings further by testing the effect of ATD in healthy human subjects. Aversive states were tested by translational acoustic startle measures. Long-duration anxiety-potentiated startle was significantly increased by ATD as compared to a balanced control mixture, but ATD showed no effect on short-duration fear-potentiated startle. These results parallel findings in rodents, where serotonin depletion selectively increases anxiety but not fear. Translational frameworks support the theory that ATD disinhibits dorsal raphe-originating serotonergic control of corticotropin-releasing hormone-mediated excitation of the BNST. This not only provides a model explaining the connection between serotonin and anxiety but may also lead towards a clarification of the origin of mood and anxiety disorders.

Selective serotonin reuptake inhibitors (SSRIs) are first-line treatments for generalized anxiety disorder (GAD); however, it is unknown whether SSRI efficacy depends on synaptic serotonin (5-HT) availability. Hood et al (2010, Psychopharmacology) tested whether temporary reduction in central 5-HT transmission through ATD in male patients, would reverse the therapeutic effect of the SSRIs in GAD patients. At the peak time of depletion, the participants inhaled 7.5% CO2 or air in random order for at least 12 min each. Free plasma tryptophan to large neutral amino acid (LNAA) ratio decreased by 92% on the ATD day and decreased by 2% on the control day. Irrespective of condition (ATD or balanced control mixture), 7.5% CO2 inhalation significantly increased Spielberger State Anxiety Inventory (STAI-S) and GAD-symptom visual analogue scales scores compared with air inhalation. This allows for the conclusion that despite the fact that SSRIs treat GAD effectively, the mechanism of action is different to that seen in panic, social anxiety, and post-traumatic stress disorders. Successful treatment of GAD using SSRIs may involve long-term receptor changes or alterations in other neurotransmitter systems downstream of serotonin.

In generalized social anxiety disorder (gSAD), serotonergic dysfunctions abnormalities of the autonomic nervous system (ANS) in basal conditions and of the hypothalamic pituitary adrenal (HPA) axis in response to psychological challenges can be found. Van Veen et al (2009, Psychoneuroendocrinology) designed a study to find out whether these phenomena are interrelated. They used two groups with gSAD patients already successfully treated with am SSRI and treated them with ATD or a balanced control mixture which was combined with a public speaking task in order to pose a psychological challenge. ANS responses (measured via salivary alpha-amylase) increased significantly under ATD, reflecting hyperresponsivity of the ANS. No effect was seen in HPA-axis responses (measured via salivary cortisol). These results allow for the preliminary conclusion that in gSAD the ANS is more vulnerable to serotonergic manipulation more than the HPA-axis.

Overall, the involvement of serotonin in anxiety disorders is undisputed. However, ATD should not be forgotten as an investigative tool with little side effects and reliable effects on brain serotonin.