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To the Editor: Studies have suggested that fast repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex is a promising treatment strategy for major depression (1). Moreover, slow rTMS of the right dorsolateral prefrontal cortex has been also shown to improve symptoms of depression and posttraumatic stress disorder (2). However, studies of its anxiolytic properties are hampered by the complex symptom profile of the anxiety disorders. Thus, the investigation of rTMS in a specific paradigm of experimentally induced anxiety theoretically may be a promising avenue for testing whether rTMS exerts specific anxiolytic effects.
The administration of cholecystokinin tetrapeptide (CCK-4) provokes panic-like symptoms both in healthy volunteers and in patients with panic disorder that can be blocked by use of antipanic agents, such as benzodiazepines and antidepressants (3), and may therefore serve to test the anxiolytic properties of new therapeutic strategies. We report on a patient treated with right prefrontal rTMS who showed a reduction in panic disorder symptoms and improvement in CCK-4–induced panic attacks, associated with blunting of the CCK-4–induced elevation of ACTH and cortisol.
Ms. A, a 52-year-old woman, had been suffering from panic disorder (according to DSM-IV criteria) with six panic attacks per week for 13 months. She had not received any prior treatment and was medication free at the time of admission. Ms. A gave her informed consent for treatment after the procedure had fully been explained to her; she was treated in a pilot investigation with slow rTMS of the right dorsolateral prefrontal cortex for 2 weeks (10 sessions, 1200 stimuli/day, 1 Hz, 110% intensity, which was related to individual motor threshold). At baseline and after rTMS treatment, a CCK-4 challenge was performed to assess the putative effects of rTMS in its ability to induce panic attacks. Panic symptoms were assessed by applying the Acute Panic Inventory (4) and the Panic Symptom Scale (5). Cortisol and ACTH plasma levels were determined during the challenge. Ratings for general anxiety and naturally occurring panic attacks were assigned after use of the Hamilton Anxiety Rating Scale and Bandelow’s Panic and Agoraphobia Scale (6).
After 2 weeks of rTMS, Ms. A reported a marked improvement in her anxiety. Her score on the Hamilton anxiety scale had decreased from 27 to 6 (–78%), and her score on the Panic and Agoraphobia Scale had decreased from 34 to 14 (–59%). Moreover, a marked reduction in her CCK-4–associated panic symptoms was observed after the second challenge. Her maximum scores on the Acute Panic Inventory and the Panic Symptom Scale decreased from 34 to 20 (–41%) and from 38 to 26 (–32%), respectively. Her maximum serum cortisol level CCK-4 challenge decreased from 884 nmol/liter to 0 nmol/liter; her maximum serum ACTH level decreased from 1.47 pmol/liter to 0.35 pmol/liter. At her 4-week follow-up examination, Ms. A’s condition was stable, so she did not require further pharmacotherapy.
This report adds to previous evidence that slow rTMS of the right prefrontal cortex ameliorates the symptoms of major depression and anxiety disorders (1). In contrast, single instances of panic disorder and generalized anxiety disorder have been reported in which panic and anxiety increased after fast rTMS over left or right prefrontal sites (7). However, slow rTMS is hypothesized to be associated with the opposite effect on cortical excitability—namely, putative inhibitory net effects—in contrast to the augmentative effects of fast rTMS (8).
The clinical findings in the present case report are strengthened by the observation of a complete blunting of CCK-4–induced serum cortisol increase after rTMS, despite the occurrence of mild symptoms of anxiety. This is compatible with the putative effect of rTMS on hypothalamic-pituitary-adrenal reactivity to CCK-4 administration. However, in view of the high susceptibility of patients with panic disorder to placebo effects, we must consider the possibility that placebo effects may also have influenced our findings. Future studies should investigate the anxiolytic potential of rTMS in patients with panic disorder under placebo-controlled conditions.
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