Anxiety Disorders and Serotonin: Insights on Effects of rTMS

Abstract

Anxiety disorder patients display chronic hypervigilance towards threatening stimuli, which could result from hyperexcitability of fear circuitry. Repetitive transcranial magnetic stimulation (rTMS) might normalize functioning of the fear circuitry by affecting serotonergic content, receptors, and transporters. In panic disorder patients, increased sensitivity of inhibitory autoreceptors could underly increased sensitivity and hyperactivity. High-frequency stimulation of the frontal cortex should increase 5HT1A receptor sensitivity, normalize serotonin turnover, and decrease activity in dorsal raphe nuclei. In social anxiety disorder, hyperactivity can be caused by decreased functioning of 5HT1A inhibitory autoreceptor. Low-frequency rTMS stimulation of left frontal areas could be an effective treatment. Reduced functioning of the serotonin transporter may underly hyperactivity of fear circuitry in generalized anxiety and post-traumatic stress disorder. Low frequency stimulation of the frontal cortex should increase transporter mRNA, thereby decreasing activity. Obsessive-compulsive disorder is characterized by hyperactivity of basal ganglia, thalamus, orbitofrontal and medial frontal cortices, and is possibly caused by decreased serotonin transporter activity. Low-frequency stimulation of the frontopolar cortex could prove to be effective. Thus, low-frequency rTMS could normalize HPA-axis functioning by increasing serotonin transporter functioning, eventually also affecting functioning of inhibitory autoreceptors. Hereby, feedback of the frontal cortex on the limbic system and HPA-axis is increased. Moreover, sensitivity to environmental factors of the HPA-axis might decrease. A functionally guided, well controlled PET study needs to be performed to compare patients to healthy controls, and to compare the effects of active stimulation versus sham to investigate the effects of frontal rTMS on the serotonergic system.