Repetitive transcranial magnetic stimulation (rTMS) has been found to exert modest to substantial antidepressant effects in the majority of prior clinical studies. As effect sizes and stimulation conditions have varied greatly, controversy persists regarding effective stimulation parameters (e.g. intensity, frequency, localization). In the present controlled study, we investigated whether the antidepressant efficacy of rTMS may be related to the stimulation intensity applied. Thirty-one patients suffering from a pharmacotherapy-resistant major depressive episode were randomly assigned to three treatment groups receiving rTMS at different stimulation intensities: (1) intensity at the individual motor threshold (MT); (2) 90% subthreshold intensity; and (3) low intensity of standard sham rTMS. Each patient underwent 10 sessions of 10 Hz rTMS with 1500 stimuli/day over the left dorsolateral prefrontal cortex. Improvement of depressive symptoms after rTMS significantly increased with stimulation intensity across the three groups. A 30% to 33% reduction of baseline depression scores was observed after rTMS at MT intensity. Similarly, groups differed significantly regarding the clinical course after rTMS with the lowest number of antidepressant interventions and the shortest hospital stay in the MT intensity group. These findings support the hypothesis of a relationship between stimulation intensity of rTMS and its antidepressant efficacy.

There is evidence for altered levels of neuroactive steroids in major depression that normalize after successful antidepressant pharmacotherapy. Currently it is not known whether this is a general principle of clinically effective antidepressant therapy or a pharmacological effect of antidepressants. Here, we investigated whether repetitive transcranial magnetic stimulation (rTMS) may affect plasma concentrations of neuroactive steroids in a similarway as antidepressant pharmacotherapy. Progesterone, 3 ␣ ,, 3 ␣ ,, 3 ␤ , NO . 5 Neuroactive Steroids before and after rTMS 875 action (Fleischmann et al. 1995;Zyss et al. 1997;Ben-Shachar et al. 1999;Kole et al. 1999;Keck et al. 2000). Neuroactive steroids interacting with the ␥ -aminobutyric acid type A (GABA A ) benzodiazepine receptor complex have been suggested to be involved in the pathophysiology of major depression and the action of antidepressant pharmacotherapy (George et al. 1994;Romeo et al. 1998;Uzunova et al. 1998;Rupprecht and Holsboer 1999;Rupprecht et al. 2001). Lowered levels of 3 ␣ -reduced neuroactive steroids have been found in plasma and cerebrospinal fluid (CSF) of depressed patients (Romeo et al. 1998;Uzunova et al. 1998), which normalized following successful treatment with fluoxetine (Romeo et al. 1998;Uzunova et al. 1998) and other antidepressant drugs (Romeo et al. 1998). On the other hand, dehydroepiandrosterone (DHEA) has been shown to exert beneficial effects on depressive symptoms in a placebo-controlled study (Wolkowitz et al. 1999). In rodents, 3 ␣ -reduced neuroactive steroids and dehydroepiandrosterone sulfate (DHEAS) have been found to exert antidepressant-like effects in the forced swim test Urani et al. 2001). In addition, the formation of 3 ␣ -reduced neuroactive steroids is enhanced by treatment with selective serotonin reuptake inhibitors (SSRI) (Uzunov et al. 1996;Griffin and Mellon 1999). Currently it is not known whether the normalization of altered neuroactive steroid concentrations is a prerequisite for the alleviation of depressive symptoms or due to a specific pharmacological action of antidepressant drugs. In the present study we therefore investigated whether repetitive transcranial magnetic stimulation (rTMS) as a novel non-pharmacological treatment in major depression affects plasma concentrations of neuroactive steroids. METHODSThirty-seven inpatients were included in an open-label protocol (age: 51.5 Ϯ 14.8 years, 23 women, 14 men). Patients met DSM-IV criteria for a major depressive episode. All patients gave their written informed consent for this study after the procedure had been fully explained. The study was approved by the local ethical committee. Prior to the study, antidepressant medication and benzodiazepines were washed out for at least seven days and patients remained medication-free during the entire study.Repetitive transcranial magnetic stimulation was applied as reported elsewhere (Padberg et al. 2002a). Patients underwent 10 sessions of rTMS (10 Hz, 15 trains of 10 s each, 30 s inter-train in...

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Cholecystokinin-tetrapeptide (CCK-4) induces panic attacks both in patients with panic disorder (PD) and healthy volunteers. It has been shown that panic elicited by CCK-4 is improved after treatment with antidepressants. Moreover, a reduction of CCK-4-induced panic has also been demonstrated after treatment with lorazepam in single subjects and after selective GABAergic treatment with vigabatrin. Although benzodiazepines are widely used as anxiolytics, no controlled study on the effects of benzodiazepines on CCK-4-induced panic symptoms is available so far. Therefore, we investigated the effects of alprazolam and placebo on CCK-4-induced panic symptoms in a double-blind, placebo-controlled study. A total of 30 healthy subjects were challenged with 50 mg CCK-4. Out of these 30 subjects, 26 showed a marked panic response to CCK-4. Subjects were rechallenged after a 7-day interval and treated with 1 mg alprazolam or placebo 1 h prior to the second CCK-4 challenge. Panic was assessed using the acute panic inventory (API) and a DSM-IV-derived panic symptom scale (PSS). Moreover, the number of reported symptoms and self-rated anxiety and arousal were recorded. We found a significant reduction of the API and PSS scores and of the number of reported symptoms compared to placebo. Moreover, compared to placebo the CCK-4-induced ACTH and cortisol release were significantly attenuated during the CCK-4 challenge after alprazolam treatment. However, also placebo treatment reduced CCK-4-induced anxiety and HPA-axis activation to a certain extent. In conclusion, our data show that alprazolam reduces CCK-4-induced panic, which supports the hypothesis of a possible interaction between the GABA and the CCK system.