Low-frequency rTMS inhibits the anti-depressive effect of ECT. A pilot study.

OBJECTIVE: Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the prefrontal cortex has been shown to have a statistically and clinically significant anti-depressant effect. The present pilot study was carried out to investigate if right prefrontal low-frequency rTMS as an add-on to electroconvulsive therapy (ECT) accelerates the anti-depressant effect and reduces cognitive side effects. METHODS: In this randomised, controlled, double-blind study, thirty-five patients with major depression were allocated to ECT+placebo or ECT+low-frequency right prefrontal rTMS. The severity of depression was evaluated during the course using the Hamilton scale for depression (the 17-item as well as the 6-item scale) and the major depression inventory (MDI). Furthermore, neuropsychological assessment of cognitive function was carried out. RESULTS: The study revealed no significant difference between the two groups for any of the outcomes, but with a visible trend to lower scores for MDI after treatment in the placebo group. The negative impact of ECT on neurocognitive functions was short-lived, and scores on logical memory were significantly improved compared to baseline 4 weeks after last treatment. The ECT-rTMS group revealed generally less impairment of cognitive functions than the ECT-placebo group. CONCLUSION: The addition of low-frequency rTMS as an add-on to ECT treatment did not result in an accelerated response. On the contrary, the results suggest that low-frequency rTMS could inhibit the anti-depressant effect of ECT.

Conformational dynamics of the estrogen receptor alpha: molecular dynamics simulations of the influence of binding site structure on protein dynamics.

We present 158 ns of unrestrained all-atom molecular dynamics (MD) simulations of the human estrogen receptor alpha ligand binding domain (ERalpha LBD) sampling the conformational changes upon binding of estradiol. The pivotal role of His524 in maintaining the protein structure in the biologically active agonist conformation is elucidated. With His524 modeled as the epsilon-tautomer, a conserved hydrogen bond to the ligand is found in the active complex. Helices 3 and 11 are held together by a hydrogen-bonding network from His524 to Glu339 via Glu419 and Lys531, arresting the ligand in the binding pocket and creating the "mouse trap" binding site for helix 12 (H12). The simulations reveal how His524 serves as a communication point between the two. When estradiol is bound, His524 is positioned correctly for the hydrogen bond network to be established. H12 is then positioned for interaction with the co-activator protein, leading to the biologically active complex. The conformational dynamics of ERalpha LBD is further investigated from simulations of antagonist and apo conformations of the protein. These simulations suggest a likely sequence of events for the transition from the inactive apo structure to the transcriptionally active conformation of ERalpha LBD. Stable conformations are identified where H12 is placed neither in the "mouse trap" nor in the co-activator binding groove, as is the case for antagonist structures of ERalpha LBD. Finally, the influence of such conformations on the biological function of ERalpha is discussed in relationship to the interaction with selective estrogen receptor modulators and endocrine-disrupting compounds.