Medical Management of Depression
http://www.100md.com
《新英格兰医药杂志》
To the Editor: In his otherwise comprehensive and well-referenced review of the medical management of depression, Mann (Oct. 27 issue)1 notes both in the text and in the treatment algorithm (Figure 2 in the article) the use of thyroid hormone supplements "even in the absence of clinical hypothyroidism for the purpose of enhancing antidepressant action." This statement has not a single reference to substantiate it.
When a person who is euthyroid takes thyroid supplements, all he or she does is replace the endogenous production of thyroid hormone, with no resultant change in the patient's thyroid status or function. Thus, I wonder on what basis this statement was made, and what possible mechanism of action thyroid administration might have in this setting.
It seems to me to be an invitation for the indiscriminate use of thyroid hormone by clinicians, which is unlikely to be the intent of the author.
Martin M. Grajower, M.D.
Albert Einstein College of Medicine
Bronx, NY 10463
grajower@msn.com
References
Mann JJ. The medical management of depression. N Engl J Med 2005;353:1819-1834.
To the Editor: We think that in comparing nefazodone with other selective serotonin-reuptake inhibitors, Mann overlooked a serious adverse effect of this drug. The cumulative reported incidence of hepatotoxicity for nefazodone was the highest among the antidepressants evaluated (28.96 cases per 100,000 patient-years as compared with 1.28 cases for sertraline and 4.00 for clomipramine).1 There are no relevant advantages to the use of nefazodone, and because of the association with severe hepatic risk, the drug actually has been withdrawn in Europe and Canada. Furthermore, the Food and Drug Administration (FDA) has issued a black-box warning.1,2,3 The manufacturer now recommends educating patients appropriately and discontinuing this medication if hepatic aminotransferase levels increase to three or more times the upper limit of normal.
Similarly, the FDA recently issued a warning regarding duloxetine hydrochloride (Cymbalta), on the basis of postmarketing reports of hepatic injury along with the recommendation that it should not ordinarily be prescribed for patients with a history of alcohol abuse or evidence of chronic liver disease.4
We think that clinicians should be aware of the potentially fatal adverse effects of this drug and that treatment should be individualized.
Ashok K. Malani, M.D.
Hussam Ammar, M.D.
Heartlands Regional Medical Center
St. Joseph, MO 64507
drmalani@yahoo.com
References
Lucena MI, Carvajal A, Andrade RJ, Velasco A. Antidepressant-induced hepatotoxicity. Expert Opin Drug Saf 2003;2:249-262.
FDA safety information and adverse event reporting program: 2003 Safety Alert — nefazodone hydrochloride. (Accessed January 19, 2006, at http://www.fda.gov/medwatch/safety/2003/serzone-squibb.htm.)
Edwards IR. Withdrawing drugs: nefazodone, the start of the latest saga. Lancet 2003;361:1240-1240.
FDA safety information and adverse event reporting program: 2005 Safety Alert — duloxetine hydrochloride. (Accessed January 19, 2006, at http://www.fda.gov/medwatch/safety/2005/cymbalta-pi.pdf.)
To the Editor: Mann's thoughtful review of the medical management of depression includes a nice summary of prescription medications, psychotherapy, and electroconvulsive therapy but omits descriptions or assessment of the safety and efficacy of complementary therapies widely used to treat depression. Patients with mental health problems are among the most frequent users of complementary therapies.1 These treatments include biochemical therapies (B vitamins, calcium, fish oil, S-adenosylmethionine , 5-hydroxy-tryptophan , St. John's wort, and so on), lifestyle therapies (exercise, sunlight, music, tai chi, yoga, and meditation), biomechanical therapies (massage), and biofield therapies, which are treatments based on a belief in energy fields (acupuncture, prayer, and homeopathy).
I realize that the Journal has space limitations that constrain full discussion of every potential therapy, but it would be helpful, particularly in an era in which physicians are sometimes thought to be simply front men (and women) for the pharmaceutical industry, to include at least some references to widely used complementary therapies.
Kathi J. Kemper, M.D., M.P.H.
Wake Forest University School of Medicine
Winston-Salem, NC 27157
References
Barnes PM, Powell-Griner E, McFann K, Nahin RL. Complementary and alternative medicine use among adults: United States, 2002. Adv Data 2004;343:1-19.
Dr. Mann replies: Dr. Grajower points out correctly that thyroid hormones are listed as an option for medication supplementation in depressed patients with an otherwise inadequate treatment response. There is a substantial body of literature that discusses the use of triiodothyronine to accelerate antidepressant effects and free thyroxine as an adjunctive antidepressant treatment in the absence of traditionally defined hypothyroidism.1 Some studies of thyroid function in mood disorders have reported abnormalities in the release of thyrotropin from the pituitary gland in response to the administration of thyrotropin-releasing hormone. The degree to which this response is blunted may predict the response to antidepressant treatment. Other studies have reported low cerebrospinal fluid levels of transthyretin, a protein involved in the transport of thyroid hormone across the blood–brain barrier, which may result in intracerebral thyroid deficiency and explain why thyroid supplements help in the absence of elevated plasma levels of thyrotropin and in low plasma levels of thyroid hormones. Despite the interesting potential mechanisms involved, the approach is not popular, and so these details were not discussed in my review.
Drs. Malani and Ammar correctly draw attention to the potential adverse hepatic effects of nefazodone and duloxetine and suggest that before patients begin these drugs, liver-enzyme levels should be measured and the drugs should be avoided if aminotransferase levels are three times the normal level. I agree, and I would further state that measuring liver enzymes before initiating such antidepressants also helps determine whether a subsequently observed elevated level of liver enzymes actually antedated the commencement of the drug.
Dr. Kemper makes the point that there are many antidepressant treatments used from alternative medicine. She cites one review, and I would also refer the reader to other useful reviews.2,3,4,5 My own view is that most of these treatments fall outside the rubric of medical treatments, but the clinician is advised to have some knowledge of what can work and what can be harmful. A sustained antidepressant response has been proved in controlled clinical trials of n–3 fatty acids in bipolar disorder and bright-light therapy in seasonal depression, a mood disorder that appears in the fall, when there are fewer hours of daylight. The efficacy of the other treatments remains unproven in what the FDA requires, namely, at least two randomized, controlled clinical trials involving patients with major depression.
J. John Mann, M.D.
Columbia University
New York, NY 10032
jjm@columbia.edu
Since publication of his article, Dr. Mann reports receiving payment from Lilly for attending a scientific advisory meeting.
References
Prange AJ Jr. Novel uses of thyroid hormones in patients with affective disorders. Thyroid 1996;6:537-543.
Peet M, Stokes C. Omega-3 fatty acids in the treatment of psychiatric disorders. Drugs 2005;65:1051-1059.
Lawlor DA, Hopker SW. The effectiveness of exercise as an intervention in the management of depression: systematic review and meta-regression analysis of randomised controlled trials. BMJ 2001;322:763-767.
Terman M, Terman JS. Light therapy for seasonal and nonseasonal depression: efficacy, protocol, safety, and side effects. CNS Spectr 2005;10:647-663.
Linde K, Mulrow CD, Berner M, Egger M. St John's wort for depression. Cochrane Database Syst Rev 2005;2:CD000448-CD000448.
When a person who is euthyroid takes thyroid supplements, all he or she does is replace the endogenous production of thyroid hormone, with no resultant change in the patient's thyroid status or function. Thus, I wonder on what basis this statement was made, and what possible mechanism of action thyroid administration might have in this setting.
It seems to me to be an invitation for the indiscriminate use of thyroid hormone by clinicians, which is unlikely to be the intent of the author.
Martin M. Grajower, M.D.
Albert Einstein College of Medicine
Bronx, NY 10463
grajower@msn.com
References
Mann JJ. The medical management of depression. N Engl J Med 2005;353:1819-1834.
To the Editor: We think that in comparing nefazodone with other selective serotonin-reuptake inhibitors, Mann overlooked a serious adverse effect of this drug. The cumulative reported incidence of hepatotoxicity for nefazodone was the highest among the antidepressants evaluated (28.96 cases per 100,000 patient-years as compared with 1.28 cases for sertraline and 4.00 for clomipramine).1 There are no relevant advantages to the use of nefazodone, and because of the association with severe hepatic risk, the drug actually has been withdrawn in Europe and Canada. Furthermore, the Food and Drug Administration (FDA) has issued a black-box warning.1,2,3 The manufacturer now recommends educating patients appropriately and discontinuing this medication if hepatic aminotransferase levels increase to three or more times the upper limit of normal.
Similarly, the FDA recently issued a warning regarding duloxetine hydrochloride (Cymbalta), on the basis of postmarketing reports of hepatic injury along with the recommendation that it should not ordinarily be prescribed for patients with a history of alcohol abuse or evidence of chronic liver disease.4
We think that clinicians should be aware of the potentially fatal adverse effects of this drug and that treatment should be individualized.
Ashok K. Malani, M.D.
Hussam Ammar, M.D.
Heartlands Regional Medical Center
St. Joseph, MO 64507
drmalani@yahoo.com
References
Lucena MI, Carvajal A, Andrade RJ, Velasco A. Antidepressant-induced hepatotoxicity. Expert Opin Drug Saf 2003;2:249-262.
FDA safety information and adverse event reporting program: 2003 Safety Alert — nefazodone hydrochloride. (Accessed January 19, 2006, at http://www.fda.gov/medwatch/safety/2003/serzone-squibb.htm.)
Edwards IR. Withdrawing drugs: nefazodone, the start of the latest saga. Lancet 2003;361:1240-1240.
FDA safety information and adverse event reporting program: 2005 Safety Alert — duloxetine hydrochloride. (Accessed January 19, 2006, at http://www.fda.gov/medwatch/safety/2005/cymbalta-pi.pdf.)
To the Editor: Mann's thoughtful review of the medical management of depression includes a nice summary of prescription medications, psychotherapy, and electroconvulsive therapy but omits descriptions or assessment of the safety and efficacy of complementary therapies widely used to treat depression. Patients with mental health problems are among the most frequent users of complementary therapies.1 These treatments include biochemical therapies (B vitamins, calcium, fish oil, S-adenosylmethionine , 5-hydroxy-tryptophan , St. John's wort, and so on), lifestyle therapies (exercise, sunlight, music, tai chi, yoga, and meditation), biomechanical therapies (massage), and biofield therapies, which are treatments based on a belief in energy fields (acupuncture, prayer, and homeopathy).
I realize that the Journal has space limitations that constrain full discussion of every potential therapy, but it would be helpful, particularly in an era in which physicians are sometimes thought to be simply front men (and women) for the pharmaceutical industry, to include at least some references to widely used complementary therapies.
Kathi J. Kemper, M.D., M.P.H.
Wake Forest University School of Medicine
Winston-Salem, NC 27157
References
Barnes PM, Powell-Griner E, McFann K, Nahin RL. Complementary and alternative medicine use among adults: United States, 2002. Adv Data 2004;343:1-19.
Dr. Mann replies: Dr. Grajower points out correctly that thyroid hormones are listed as an option for medication supplementation in depressed patients with an otherwise inadequate treatment response. There is a substantial body of literature that discusses the use of triiodothyronine to accelerate antidepressant effects and free thyroxine as an adjunctive antidepressant treatment in the absence of traditionally defined hypothyroidism.1 Some studies of thyroid function in mood disorders have reported abnormalities in the release of thyrotropin from the pituitary gland in response to the administration of thyrotropin-releasing hormone. The degree to which this response is blunted may predict the response to antidepressant treatment. Other studies have reported low cerebrospinal fluid levels of transthyretin, a protein involved in the transport of thyroid hormone across the blood–brain barrier, which may result in intracerebral thyroid deficiency and explain why thyroid supplements help in the absence of elevated plasma levels of thyrotropin and in low plasma levels of thyroid hormones. Despite the interesting potential mechanisms involved, the approach is not popular, and so these details were not discussed in my review.
Drs. Malani and Ammar correctly draw attention to the potential adverse hepatic effects of nefazodone and duloxetine and suggest that before patients begin these drugs, liver-enzyme levels should be measured and the drugs should be avoided if aminotransferase levels are three times the normal level. I agree, and I would further state that measuring liver enzymes before initiating such antidepressants also helps determine whether a subsequently observed elevated level of liver enzymes actually antedated the commencement of the drug.
Dr. Kemper makes the point that there are many antidepressant treatments used from alternative medicine. She cites one review, and I would also refer the reader to other useful reviews.2,3,4,5 My own view is that most of these treatments fall outside the rubric of medical treatments, but the clinician is advised to have some knowledge of what can work and what can be harmful. A sustained antidepressant response has been proved in controlled clinical trials of n–3 fatty acids in bipolar disorder and bright-light therapy in seasonal depression, a mood disorder that appears in the fall, when there are fewer hours of daylight. The efficacy of the other treatments remains unproven in what the FDA requires, namely, at least two randomized, controlled clinical trials involving patients with major depression.
J. John Mann, M.D.
Columbia University
New York, NY 10032
jjm@columbia.edu
Since publication of his article, Dr. Mann reports receiving payment from Lilly for attending a scientific advisory meeting.
References
Prange AJ Jr. Novel uses of thyroid hormones in patients with affective disorders. Thyroid 1996;6:537-543.
Peet M, Stokes C. Omega-3 fatty acids in the treatment of psychiatric disorders. Drugs 2005;65:1051-1059.
Lawlor DA, Hopker SW. The effectiveness of exercise as an intervention in the management of depression: systematic review and meta-regression analysis of randomised controlled trials. BMJ 2001;322:763-767.
Terman M, Terman JS. Light therapy for seasonal and nonseasonal depression: efficacy, protocol, safety, and side effects. CNS Spectr 2005;10:647-663.
Linde K, Mulrow CD, Berner M, Egger M. St John's wort for depression. Cochrane Database Syst Rev 2005;2:CD000448-CD000448.