With reversible monoamine oxidase-A inhibitor antidepressants such as moclobemide(Drug information on moclobemide) not yet available in the United States, there is interest in the selective monoamine oxidase-B inhibitor approved for Parkinson's disease, selegiline(Drug information on selegiline) (Eldepryl), as a possible alternative for depression with less liability than the monoamine oxidase inhibitor antidepressants for hypertensive drug interactions. A transdermal delivery system for selegiline was investigated by manufacturer Somerset Pharmaceuticals to ascertain whether circumventing the "first-pass" hepatic metabolism of oral administration and delivering higher selegiline levels to the central nervous system also reduced potential for adverse interaction with co-administered pressor drugs or with dietary tyramine.
In the first safety study, 10 healthy volunteers received the selegiline transdermal system (STS) with 20 mg/20 cm2 alone and with pseudoephedrine(Drug information on pseudoephedrine) (Sudafed) in increasing dosage over two weeks. Tolerance of the combination was ascertained through monitoring of vital signs, electrocardiograms (EKGs), physical examinations and clinical laboratory results. Administration of the STS alone had little effect on blood pressure or heart rate, while pseudoephedrine alone raised both. Addition of pseudoephedrine to steady-state administration of STS, however, caused minimal changes in the pressor response indicators; and there were no clinically meaningful changes in other monitored parameters.
In another manufacturer-sponsored safety study, 301 patients with major depression were randomized to receive either the STS or topical placebo over an eight-week period without dietary tyramine restrictions. Safety monitoring revealed adverse effects, most of mild to moderate intensity, in 82.6% of patients with the STS and 77.6% of those with placebo; a statistically insignificant difference. There were no statistically significant differences between the groups in vital signs, physical examination, laboratory or EKG.
A separately reported kinetics study indicated that the STS provided higher and more sustained selegiline blood levels than oral administration, with significantly less metabolite formation. The researchers concluded that the transdermal administration of selegiline is safe for adults with major depression, and they anticipate future trials of efficacy.
The administration of rapid transcranial magnetic stimulation (rTMS) as a possible adjunct or alternative to electroconvulsive therapy (ECT) for major depression has been investigated in a number of open-label and sham-controlled trials. In a study sponsored by the Pritzker Foundation, the treatment was provided to 24 patients with treatment-resistant depression who had failed at least two adequate antidepressant trials and exhibited a HAM-D-17 total score of at least 18.
In the 21 patients completing the trial, involving a total of 120 stimulations over a two-week period, there was a 26% mean improvement in HAM-D total scores and a 37% mean improvement in the Beck Depression Inventory (BDI). In addition, 10 of the 21 patients rated themselves as much or very much improved on the Clinical Global Impression scale (CGI). Response was particularly prominent in women, with 53% having greater than 50% reduction in HAM-D or BDI, while no males achieved this level of response.
Vagus nerve stimulation (VNS), a procedure now indicated for treating severe epileptic seizures, also appeared safe and effective for patients with treatment-resistant depression in a study sponsored by the device manufacturer, Cyberonics. In 60 patients receiving the VNS implant device who completed eight weeks of the procedure while continuing antidepressant medication, 31% demonstrated a 50% reduction on the 28-item HAM-D. Twenty-seven percent had a 25% to 49% reduction, and 15% of patients met criteria for remission at the end of the study. There was congruence between the HAM-D-28 and the MADRS results.
The patients with most severe treatment resistance, indicated by failure to respond in seven or more adequate trials of antidepressant treatment, had a response rate of 6% with VNS, compared to 40% of patients who had failed two to six antidepressant trials. The researchers concluded, "VNS seems to be an effective treatment in patients with moderate treatment resistance and was well-tolerated by a majority of the patients."
This novel procedure, referred to as a "pacemaker for the brain" in some press coverage at the earlier American Psychiatric Association meeting in May, was approved for treatment of resistant depression in Canada in April and in Europe several weeks earlier. The first controlled study of VNS for depression (with implanted but inactivated devices in half of the 210 patients) is being conducted at 21 sites in the United States and Canada and is anticipated to be completed by mid-2002.