hollyduck
04-05-08, 11:14 PM
Tamoxifen Shows Promise as Antimania Agent in Bipolar Disorder
Pauline Anderson
Medscape Medical News 2008. © 2008 Medscape
April 2, 2008 — New research shows that the breast cancer drug tamoxifen has an antimania effect similar to that of lithium that was well tolerated in both men and women with bipolar I disorder (BPD).
The study found that about 48% of patients taking tamoxifen, a selective estrogen-receptor modulator, had at least a 50% improvement of mania ratings after 21 days compared with only 5% of patients taking placebo.
Previous research suggested that tamoxifen corrects abnormal protein kinase C (PKC) activity in the brain. Excessive PKC activation can disrupt prefrontal cortical regulation of behavior, possibly contributing to impaired judgment, impulsivity, and other characteristics of BPD, particularly during mania.
"This is the first reported proof-of-concept study on the role of [PKC] in the development and treatment of mania with an adequate design and statistical power," Dr. Aysegul Yildiz, associate professor of psychiatry at Dokuz Eylül University, in Izmir, Turkey, noted. The study improves understanding of the pathophysiology of bipolar disorder, which affects millions of people worldwide, said Dr. Yildiz.
The findings were published in the March issue of the Archives of General Psychiatry.
First Reported Proof
The 3-week randomized, double-blind, single-site trial included patients with BPD aged 18 to 60 years who were in a manic or mixed-episode state and admitted to the psychiatric unit at Dokuz Eylül University Medical Center. Most of the subjects, who entered the study from April 7, 2003 to June 28, 2006, were referred because they were difficult to treat. Their initial Young Mania Rating Scale (YMRS) scores averaged 38, with some as high as 49, out of a maximum possible rating of 60.
The 66 participants were randomly assigned to receive tamoxifen or placebo. The 2 groups were matched for demographic and clinical characteristics and initial symptom ratings. Subjects who needed to be "rescued" with risperidone were dropped from the study (but ratings from their last assessment before the rescue were included in the analysis).
As well as the YMRS, researchers used the Clinical Global Impressions-Mania (CGI-Mania) scale, Positive and Negative Syndrome Scale (PANSS) for psychotic symptoms, depression rating scales, and adverse-effects questionnaires as assessment tools.
Of the 35 patients receiving tamoxifen, 29 (83%) completed the study, as did 21 of the 31 patients assigned to placebo (68%).
Greater Psychosis Improvement
After 3 weeks, rates of response, defined as a 50% or greater reduction in YMRS scores from baseline, were 48% (14 of 29) with tamoxifen vs 5% (1 of 21) with placebo. As the trial progressed, the gap between mean improvement of subjects on tamoxifen and those on placebo widened. "Tamoxifen resulted in an 18.3-point mean improvement (47.4% improvement relative to the baseline score) in a mania rating scale, in contrast to a 2.9-point worsening (7.8% worsening relative to the baseline score) with placebo," said Dr. Yildiz in an email interview, adding that by the end of the study, there was a difference of 21.2 points between the drug and placebo groups.
PANNS total scores showed greater improvement with tamoxifen than with placebo, and changes in depression scores also tended to be greater with tamoxifen. There were low rates of adverse events in both groups.
Rapid Antimania Effect
Understanding the biochemical targets of BPD treatments is important for the development of new therapeutic strategies, the authors note. The rapid antimanic characteristic of such therapies is a plus for patients. "With such rapidly acting treatments, patients may have the chance of preventing the emergence of full-blown mania once they sense a manic episode coming on and better functioning in their normal lives," said Dr. Yildiz
So should psychiatrists now be considering tamoxifen for their bipolar patients with mania? Not yet, said Dr. Yildiz. "Although effective and quite safe for short-term treatment of mania, long-term use of tamoxifen is not recommended due to potential side effects," such as transient thrombocytopenia, that are related to the drug's estrogen-blocking properties.
"Psychiatrists should wait for development of new central nervous system–penetrant selective PKC inhibitors with no hormonal effect," he said. However, he added, a patient being treated with tamoxifen for breast cancer who develops BPD may benefit from tamoxifen's antimanic properties, with lithium and/or divalproex treatment being monitored accordingly.
Lack of Response With Placebo Surprising
In an accompanying editorial, Mauricio Tohen, MD, DrPH, from Lilly Research Laboratories, commented that the worsening of manic symptoms in patients who received placebo was surprising, since, in most contemporary studies in acute mania, patients receiving placebo show improvement. This lack of response, he said, may be due to the single-site nature of the study, to the fact that some patients had not responded to previous treatments, or because the high retention rate allowed the documentation of symptoms worsening.
Tamoxifen's antiestrogen effects are likely to present a safety challenge, especially in long-term use, said Dr. Tohen. He also pointed out that the study results may not be generalized to non–treatment-resistant patients and that symptomatic improvement is not equivalent to functional improvement.
The study was supported by a grant from the Stanley Medical Research Institute. No financial disclosure was reported by the study authors. Dr. Tohen is a full-time employee and stockholder of Eli Lilly.
Arch Gen Psychiatry. 2008;65:255-263
http://www.medscape.com/viewarticle/572410
[hollyduck says: I also checked prices on the net, and found it surprisingly modestly priced. Looks like something to keep an eye on.]
Pauline Anderson
Medscape Medical News 2008. © 2008 Medscape
April 2, 2008 — New research shows that the breast cancer drug tamoxifen has an antimania effect similar to that of lithium that was well tolerated in both men and women with bipolar I disorder (BPD).
The study found that about 48% of patients taking tamoxifen, a selective estrogen-receptor modulator, had at least a 50% improvement of mania ratings after 21 days compared with only 5% of patients taking placebo.
Previous research suggested that tamoxifen corrects abnormal protein kinase C (PKC) activity in the brain. Excessive PKC activation can disrupt prefrontal cortical regulation of behavior, possibly contributing to impaired judgment, impulsivity, and other characteristics of BPD, particularly during mania.
"This is the first reported proof-of-concept study on the role of [PKC] in the development and treatment of mania with an adequate design and statistical power," Dr. Aysegul Yildiz, associate professor of psychiatry at Dokuz Eylül University, in Izmir, Turkey, noted. The study improves understanding of the pathophysiology of bipolar disorder, which affects millions of people worldwide, said Dr. Yildiz.
The findings were published in the March issue of the Archives of General Psychiatry.
First Reported Proof
The 3-week randomized, double-blind, single-site trial included patients with BPD aged 18 to 60 years who were in a manic or mixed-episode state and admitted to the psychiatric unit at Dokuz Eylül University Medical Center. Most of the subjects, who entered the study from April 7, 2003 to June 28, 2006, were referred because they were difficult to treat. Their initial Young Mania Rating Scale (YMRS) scores averaged 38, with some as high as 49, out of a maximum possible rating of 60.
The 66 participants were randomly assigned to receive tamoxifen or placebo. The 2 groups were matched for demographic and clinical characteristics and initial symptom ratings. Subjects who needed to be "rescued" with risperidone were dropped from the study (but ratings from their last assessment before the rescue were included in the analysis).
As well as the YMRS, researchers used the Clinical Global Impressions-Mania (CGI-Mania) scale, Positive and Negative Syndrome Scale (PANSS) for psychotic symptoms, depression rating scales, and adverse-effects questionnaires as assessment tools.
Of the 35 patients receiving tamoxifen, 29 (83%) completed the study, as did 21 of the 31 patients assigned to placebo (68%).
Greater Psychosis Improvement
After 3 weeks, rates of response, defined as a 50% or greater reduction in YMRS scores from baseline, were 48% (14 of 29) with tamoxifen vs 5% (1 of 21) with placebo. As the trial progressed, the gap between mean improvement of subjects on tamoxifen and those on placebo widened. "Tamoxifen resulted in an 18.3-point mean improvement (47.4% improvement relative to the baseline score) in a mania rating scale, in contrast to a 2.9-point worsening (7.8% worsening relative to the baseline score) with placebo," said Dr. Yildiz in an email interview, adding that by the end of the study, there was a difference of 21.2 points between the drug and placebo groups.
PANNS total scores showed greater improvement with tamoxifen than with placebo, and changes in depression scores also tended to be greater with tamoxifen. There were low rates of adverse events in both groups.
Rapid Antimania Effect
Understanding the biochemical targets of BPD treatments is important for the development of new therapeutic strategies, the authors note. The rapid antimanic characteristic of such therapies is a plus for patients. "With such rapidly acting treatments, patients may have the chance of preventing the emergence of full-blown mania once they sense a manic episode coming on and better functioning in their normal lives," said Dr. Yildiz
So should psychiatrists now be considering tamoxifen for their bipolar patients with mania? Not yet, said Dr. Yildiz. "Although effective and quite safe for short-term treatment of mania, long-term use of tamoxifen is not recommended due to potential side effects," such as transient thrombocytopenia, that are related to the drug's estrogen-blocking properties.
"Psychiatrists should wait for development of new central nervous system–penetrant selective PKC inhibitors with no hormonal effect," he said. However, he added, a patient being treated with tamoxifen for breast cancer who develops BPD may benefit from tamoxifen's antimanic properties, with lithium and/or divalproex treatment being monitored accordingly.
Lack of Response With Placebo Surprising
In an accompanying editorial, Mauricio Tohen, MD, DrPH, from Lilly Research Laboratories, commented that the worsening of manic symptoms in patients who received placebo was surprising, since, in most contemporary studies in acute mania, patients receiving placebo show improvement. This lack of response, he said, may be due to the single-site nature of the study, to the fact that some patients had not responded to previous treatments, or because the high retention rate allowed the documentation of symptoms worsening.
Tamoxifen's antiestrogen effects are likely to present a safety challenge, especially in long-term use, said Dr. Tohen. He also pointed out that the study results may not be generalized to non–treatment-resistant patients and that symptomatic improvement is not equivalent to functional improvement.
The study was supported by a grant from the Stanley Medical Research Institute. No financial disclosure was reported by the study authors. Dr. Tohen is a full-time employee and stockholder of Eli Lilly.
Arch Gen Psychiatry. 2008;65:255-263
http://www.medscape.com/viewarticle/572410
[hollyduck says: I also checked prices on the net, and found it surprisingly modestly priced. Looks like something to keep an eye on.]