de Jonge, P.

Zuidersma, M.

Proceedings - University of Groningen

   University of GroningenThe effects of treatment-resistant depression and first-ever depression on mortality followingacute coronary syndromeZuidersma, M.; de Jonge, P.Published in:American Journal of PsychiatryIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2009Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Zuidersma, M., & de Jonge, P. (2009). The effects of treatment-resistant depression and first-everdepression on mortality following acute coronary syndrome: interactive or independent? American Journalof Psychiatry, 166(7), 828-829.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Letters to the Editor828 Am J Psychiatry 166:7, July 2009ajp.psychiatryonline.orgMore Aggressive Treatment for Depression?TO THE EDITOR: In the April 2009 issue of the Journal, RobertM. Carney, Ph.D., and Kenneth E. Freedland, Ph.D. (1) notedthat depressed patients in an intervention group who did notexperience treatment response had a higher risk of late mor-tality (which was described as incidence of death ≥6 monthsfollowing acute myocardial infarction) compared with pa-tients who responded to treatment. The authors pointed outthat this relationship was not significant in the usual care armof the study. They also reported that in the interventiongroup, there was a lack of improvement, although subjects re-ceived 6 months of aggressive treatment. However, only ap-proximately 15% of patients in the usual care group receivedany form of nonstudy treatment during the first 6 months.Among patients in the usual care arm who did not experienceimprovement, less than 15% had received any treatment fortheir depression.Drs. Carney and Freedland stated that it is not immediatelyevident why major depression that is not responsive to treat-ment is associated with a higher risk of cardiac-related mor-tality and morbidity and concluded that major depressionmay warrant more aggressive treatment.It seems to me likely that less improvement of depressionwould tend to lead to more aggressive treatment. Perhaps, atleast in part, the explanation for why the greater risk of car-diac-related morbidity and mortality is “not immediately ap-parent” is because we do not wish to think that our efforts attreatment, even aggressive treatment, might have harmed ourpatients. Psychotropic drugs certainly do affect other organsystems—and not always beneficially. A more apt conclusionmight be that less aggressive treatment is better, at least withregard to the treatments that were used in the study, while wesearch for different treatments, a search that the authorsrightly advocate.Reference1. Carney RM, Freedland KE: Treatment-resistant depression andmortality after acute coronary syndrome. Am J Psychiatry2009; 166:410–417JAMES R. NICHOLAS, M.D.Ely, Minn.The author reports no competing interests.This letter (doi: 10.1176/appi.ajp.2009.09040520) was acceptedfor publication in May 2009.The Effects of Treatment-Resistant Depression and First-Ever Depression on Mortality Following Acute Coronary Syndrome: Interactive or Independent?TO THE EDITOR: Drs. Carney and Freedland (1) presented afascinating review on treatment-resistant depression andmortality following acute coronary syndrome. As a possiblemechanism explaining the association between treatment-resistant depression and mortality in acute coronary syn-drome patients, the authors suggested the presence of first-ever depressive episodes, which are associated with bothtreatment resistance and increased risk of cardiac events.We therefore explored the association between treatment-resistant depression, first-ever depression, and cardiovascularprognosis using data from the Myocardial INfarction and De-pression Intervention Trial (MIND-IT), a multi-center ran-domized controlled trial on the treatment of post-acute coro-nary syndrome depression. We previously reported (2), usingCox regression analysis, that patients who did not respond totreatment had an unadjusted hazard ratio of 4.89 (95% confi-dence interval [CI]=1.08–22.10) for new cardiovascular eventsrelative to patients who responded to treatment. Testing thehypothesis of Drs. Carney and Freedland, we adjusted for thepresence of first episodes. However, adjusting hardly affectedthe association (hazard ratio=4.42; 95% CI=0.97–20.10), whichis indicative of no support for the hypothesis. An explanationmay be that in our sample first episodes were not associatedwith new cardiovascular events or treatment resistance. How-ever, they are associated with both new cardiovascular events(hazard ratio=4.12 [95% CI=0.53–31.77]) and with treatmentresistance (odds ratio=2.57 [95% CI=0.82–8.03]). The numberof patients in each subgroup and their associated risk of car-diac events are shown in Table 1.Our tentative conclusion is that first depressive episodesand treatment resistance are two independent risk factors forworse outcomes that do not interact but add up indepen-dently. Our results do not support the hypothesis that first de-pressive episodes would underlie the association betweentreatment-resistant depression and negative cardiac out-comes. Since cell numbers in our study were very low, how-ever, we feel that caution is warranted and no firm conclusionscan yet be determined.We agree with Drs. Carney and Freedland that treatment-resistant depression is likely a marker of an underlying car-diac risk factor associated with treatment resistance in pa-tients with coronary heart disease and that researchersshould investigate this factor. One possible risk factor that isoften overlooked is treatment nonadherence, which is associ-ated with both depression and cardiac prognosis. Treatmentnonadherence is one of the reasons for treatment resistancein depressed patients, and it is likely that a patient who isnonadherent to antidepressant treatment is also nonadher-ent to cardiac aftercare.References1. Carney RM, Freedland KE: Treatment-resistant depression andmortality after acute coronary syndrome. Am J Psychiatry2009; 166:410–4172. de Jonge P, Honig A, van Melle JP, Schene AH, Kuyper AM, Tul-ner D, Schins A, Ormel J: Nonresponse to treatment for depres-sion following myocardial infarction: association with subse-quent cardiac events. Am J Psychiatry 2007; 164:1371–1378MARIJ ZUIDERSMA, M.Sc.Groningen, the NetherlandsPETER DE JONGE, PH.D.Groningen and Tilburg, the NetherlandsPresented in part at the annual meeting of the European Asso-ciation for Consultation-Liaison Psychiatry and Psychosomat-ics (EACLPP), Zaragoza, Spain, June 27, 2008. Drs. ZuidersmaAm J Psychiatry 166:7, July 2009 829LETTERS TO THE EDITORajp.psychiatryonline.organd de Jonge receive VIDI grant support from the Dutch Medi-cal Research Council (grant # 016.086.397).This letter (doi: 10.1176/appi.ajp.2009.09040482) was acceptedfor publication in May 2009.Drs. Carney and Freedland ReplyTO THE EDITOR: Our review article on treatment-resistant de-pression and mortality following acute coronary syndromewas intended to inspire new studies and secondary analysesof relevant databases. We are delighted that Drs. Zuidersmaand de Jonge have included a secondary analysis of data fromthe MIND-IT clinical trial to explore a point we raised in ourreview. However, we respectfully disagree with their state-ment that we “hypothesized” that the increased risk for car-diac morbidity and mortality in depressed patients with coro-nary heart disease is a result of the presence of a higherproportion of treatment-resistant cases among patientswhose first episode of major depression coincides with anacute coronary syndrome than among those with a recurrentmajor depressive episode around the time of an acute coro-nary syndrome. Actually, we noted that we found no relation-ship between response to treatment and the type of depres-sive episode (initial versus recurrent) in the EnhancingRecovery in Coronary Heart Disease (ENRICHD) clinical trial.In ENRICHD, patients with either treatment-resistant or first-episode depression were at higher risk for mortality thanthose with treatment-responsive or recurrent depression. Be-cause other studies of depression in patients with coronaryheart disease have found initial episodes to be less responsiveto treatment than recurrent episodes, we suggested that thispotential relationship “deserves more careful study” (p. 414).For this reason, we are pleased that Drs. Zuidersma and deJonge examined the MIND-IT data to determine whetherthese subgroups overlap or, as in the ENRICHD trial, whetherthey were independent risk factors for cardiac events. Eventhough first depressive episodes were relatively unresponsiveto treatment in the MIND-IT study, first episodes of depres-sion and nonresponse to treatment were independently asso-ciated with the incidence of cardiac events. The small size ofthe subgroups precludes strong conclusions, but the goal ofthe analysis was hypothesis generation.We also agree with the authors that poor adherence to thedepression and cardiac treatment regimens may explain bothpoor response to antidepressant treatment and a higher inci-dence of cardiac events. We have previously suggested thatpoor adherence to the medical treatment regimen is likely toat least partially explain why depression is associated with anincreased risk of cardiac events (1), and we agree that it de-serves more careful study.In his letter, Dr. Nicholas suggests that an initially inade-quate response may prompt more aggressive depression treat-ment, which may prove to be harmful for patients with coro-nary heart disease. Patients who did not respond to treatmentin the ENRICHD clinical trial did not receive more sessions ofcognitive behavioral therapy than those patients who re-sponded to treatment, but they were more likely to be given anantidepressant. However, treatment with an antidepressantwas associated with improved survival in the ENRICHD trial(2). Although it is not known whether the psychotherapy ses-sions were more stressful or longer for patients who did not re-spond to treatment, we do not find support for Dr. Nicholas’conjecture in the ENRICHD trial data. Nevertheless, the possi-bility that initial nonresponse to depression treatment leads tomore aggressive treatment, and in turn, to greater cardiacmorbidity and mortality, deserves further consideration.References1. Skala JA, Freedland KE, Carney RM: Coronary heart disease anddepression: a review of recent mechanistic research. Can J Psy-chiatry 2006; 51:738–7452. Taylor CB, Youngblood ME, Veith RC, Carney RM, Burg MM,Kaufmann PG, Shuster J, Mellman T, Blumenthal JA, Krishnan R,Jaffe AS; ENRICHD Investigators: Effects of antidepressant med-ication on morbidity and mortality in depressed patients aftermyocardial infarction. Arch Gen Psychiatry 2005; 62:792–798ROBERT M. CARNEY, PH.D.KENNETH E. FREEDLAND, PH.D.St. Louis, Mo.The authors’ disclosures accompany the original article.This letter (doi: 10.1176/appi.ajp.2009.09040482r) was acceptedfor publication in May  2009.The Use of Short Half-Life Antidepressants in the Treatment of Bipolar DepressionTO THE EDITOR: In the February 2009 issue of the Journal,Mark A. Frye, M.D., et al. (1), and Joseph F. Goldberg, M.D., etal. (2) examined the predictors of treatment-emergent maniaand mixed states in depressed bipolar patients. I would en-courage both groups of investigators to review their data toexamine two variables that have not been reported. The firstis the diurnal variation of mood, which I find to be more ex-treme in patients who have bipolar depression and may be apredictor of a response to a mood stabilizer in unipolar pa-tients. The second variable is the form of antidepressant givento patients. A convention in publishing is to use the genericnames of medications, but this does not distinguish amongthe three preparations of bupropion (immediate release, 12-hour release, and 24-hour release) and two forms of venlafax-ine (immediate- and time-release). Although time-releasepreparations technically have the same half-life of the under-lying compound, their sustained presence keeps blood andTABLE 1. Patients in Each Subgroup With New Cardiovascular EventsAssociated Risk FactorGroupSubjects Responding to Treatment Subjects Not Responding to Treatment TotalN % N % N %First episode 2/18 11 10/36 28 12/54 22Recurrent episode 0/9 0 1/7 14 1/16 6Total 2/27 7 11/43 26 13/70 19

English

The effects of treatment-resistant depression and first-ever depression on mortality following acute coronary syndrome:interactive or independent?

University of Groningen Research Database

  
 University of Groningen
The effects of treatment-resistant depression and first-ever depression on mortality following
acute coronary syndrome
Zuidersma, Marij; de Jonge, Peter
Published in:
American Journal of Psychiatry
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
2009
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Zuidersma, M., & de Jonge, P. (2009). The effects of treatment-resistant depression and first-ever
depression on mortality following acute coronary syndrome: interactive or independent? American Journal
of Psychiatry, 166(7), 828-829.
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the
author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately
and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the
number of authors shown on this cover page is limited to 10 maximum.
Download date: 10-02-2018
Letters to the Editor
828 Am J Psychiatry 166:7, July 2009ajp.psychiatryonline.org
More Aggressive Treatment for Depression?
TO THE EDITOR: In the April 2009 issue of the Journal, Robert
M. Carney, Ph.D., and Kenneth E. Freedland, Ph.D. (1) noted
that depressed patients in an intervention group who did not
experience treatment response had a higher risk of late mor-
tality (which was described as incidence of death ≥6 months
following acute myocardial infarction) compared with pa-
tients who responded to treatment. The authors pointed out
that this relationship was not significant in the usual care arm
of the study. They also reported that in the intervention
group, there was a lack of improvement, although subjects re-
ceived 6 months of aggressive treatment. However, only ap-
proximately 15% of patients in the usual care group received
any form of nonstudy treatment during the first 6 months.
Among patients in the usual care arm who did not experience
improvement, less than 15% had received any treatment for
their depression.
Drs. Carney and Freedland stated that it is not immediately
evident why major depression that is not responsive to treat-
ment is associated with a higher risk of cardiac-related mor-
tality and morbidity and concluded that major depression
may warrant more aggressive treatment.
It seems to me likely that less improvement of depression
would tend to lead to more aggressive treatment. Perhaps, at
least in part, the explanation for why the greater risk of car-
diac-related morbidity and mortality is “not immediately ap-
parent” is because we do not wish to think that our efforts at
treatment, even aggressive treatment, might have harmed our
patients. Psychotropic drugs certainly do affect other organ
systems—and not always beneficially. A more apt conclusion
might be that less aggressive treatment is better, at least with
regard to the treatments that were used in the study, while we
search for different treatments, a search that the authors
rightly advocate.
Reference
1. Carney RM, Freedland KE: Treatment-resistant depression and
mortality after acute coronary syndrome. Am J Psychiatry
2009; 166:410–417
JAMES R. NICHOLAS, M.D.
Ely, Minn.
The author reports no competing interests.
This letter (doi: 10.1176/appi.ajp.2009.09040520) was accepted
for publication in May 2009.
The Effects of Treatment-Resistant Depression 
and First-Ever Depression on Mortality 
Following Acute Coronary Syndrome: 
Interactive or Independent?
TO THE EDITOR: Drs. Carney and Freedland (1) presented a
fascinating review on treatment-resistant depression and
mortality following acute coronary syndrome. As a possible
mechanism explaining the association between treatment-
resistant depression and mortality in acute coronary syn-
drome patients, the authors suggested the presence of first-
ever depressive episodes, which are associated with both
treatment resistance and increased risk of cardiac events.
We therefore explored the association between treatment-
resistant depression, first-ever depression, and cardiovascular
prognosis using data from the Myocardial INfarction and De-
pression Intervention Trial (MIND-IT), a multi-center ran-
domized controlled trial on the treatment of post-acute coro-
nary syndrome depression. We previously reported (2), using
Cox regression analysis, that patients who did not respond to
treatment had an unadjusted hazard ratio of 4.89 (95% confi-
dence interval [CI]=1.08–22.10) for new cardiovascular events
relative to patients who responded to treatment. Testing the
hypothesis of Drs. Carney and Freedland, we adjusted for the
presence of first episodes. However, adjusting hardly affected
the association (hazard ratio=4.42; 95% CI=0.97–20.10), which
is indicative of no support for the hypothesis. An explanation
may be that in our sample first episodes were not associated
with new cardiovascular events or treatment resistance. How-
ever, they are associated with both new cardiovascular events
(hazard ratio=4.12 [95% CI=0.53–31.77]) and with treatment
resistance (odds ratio=2.57 [95% CI=0.82–8.03]). The number
of patients in each subgroup and their associated risk of car-
diac events are shown in Table 1.
Our tentative conclusion is that first depressive episodes
and treatment resistance are two independent risk factors for
worse outcomes that do not interact but add up indepen-
dently. Our results do not support the hypothesis that first de-
pressive episodes would underlie the association between
treatment-resistant depression and negative cardiac out-
comes. Since cell numbers in our study were very low, how-
ever, we feel that caution is warranted and no firm conclusions
can yet be determined.
We agree with Drs. Carney and Freedland that treatment-
resistant depression is likely a marker of an underlying car-
diac risk factor associated with treatment resistance in pa-
tients with coronary heart disease and that researchers
should investigate this factor. One possible risk factor that is
often overlooked is treatment nonadherence, which is associ-
ated with both depression and cardiac prognosis. Treatment
nonadherence is one of the reasons for treatment resistance
in depressed patients, and it is likely that a patient who is
nonadherent to antidepressant treatment is also nonadher-
ent to cardiac aftercare.
References
1. Carney RM, Freedland KE: Treatment-resistant depression and
mortality after acute coronary syndrome. Am J Psychiatry
2009; 166:410–417
2. de Jonge P, Honig A, van Melle JP, Schene AH, Kuyper AM, Tul-
ner D, Schins A, Ormel J: Nonresponse to treatment for depres-
sion following myocardial infarction: association with subse-
quent cardiac events. Am J Psychiatry 2007; 164:1371–1378
MARIJ ZUIDERSMA, M.Sc.
Groningen, the Netherlands
PETER DE JONGE, PH.D.
Groningen and Tilburg, the Netherlands
Presented in part at the annual meeting of the European Asso-
ciation for Consultation-Liaison Psychiatry and Psychosomat-
ics (EACLPP), Zaragoza, Spain, June 27, 2008. Drs. Zuidersma
Am J Psychiatry 166:7, July 2009 829
LETTERS TO THE EDITOR
ajp.psychiatryonline.org
and de Jonge receive VIDI grant support from the Dutch Medi-
cal Research Council (grant # 016.086.397).
This letter (doi: 10.1176/appi.ajp.2009.09040482) was accepted
for publication in May 2009.
Drs. Carney and Freedland Reply
TO THE EDITOR: Our review article on treatment-resistant de-
pression and mortality following acute coronary syndrome
was intended to inspire new studies and secondary analyses
of relevant databases. We are delighted that Drs. Zuidersma
and de Jonge have included a secondary analysis of data from
the MIND-IT clinical trial to explore a point we raised in our
review. However, we respectfully disagree with their state-
ment that we “hypothesized” that the increased risk for car-
diac morbidity and mortality in depressed patients with coro-
nary heart disease is a result of the presence of a higher
proportion of treatment-resistant cases among patients
whose first episode of major depression coincides with an
acute coronary syndrome than among those with a recurrent
major depressive episode around the time of an acute coro-
nary syndrome. Actually, we noted that we found no relation-
ship between response to treatment and the type of depres-
sive episode (initial versus recurrent) in the Enhancing
Recovery in Coronary Heart Disease (ENRICHD) clinical trial.
In ENRICHD, patients with either treatment-resistant or first-
episode depression were at higher risk for mortality than
those with treatment-responsive or recurrent depression. Be-
cause other studies of depression in patients with coronary
heart disease have found initial episodes to be less responsive
to treatment than recurrent episodes, we suggested that this
potential relationship “deserves more careful study” (p. 414).
For this reason, we are pleased that Drs. Zuidersma and de
Jonge examined the MIND-IT data to determine whether
these subgroups overlap or, as in the ENRICHD trial, whether
they were independent risk factors for cardiac events. Even
though first depressive episodes were relatively unresponsive
to treatment in the MIND-IT study, first episodes of depres-
sion and nonresponse to treatment were independently asso-
ciated with the incidence of cardiac events. The small size of
the subgroups precludes strong conclusions, but the goal of
the analysis was hypothesis generation.
We also agree with the authors that poor adherence to the
depression and cardiac treatment regimens may explain both
poor response to antidepressant treatment and a higher inci-
dence of cardiac events. We have previously suggested that
poor adherence to the medical treatment regimen is likely to
at least partially explain why depression is associated with an
increased risk of cardiac events (1), and we agree that it de-
serves more careful study.
In his letter, Dr. Nicholas suggests that an initially inade-
quate response may prompt more aggressive depression treat-
ment, which may prove to be harmful for patients with coro-
nary heart disease. Patients who did not respond to treatment
in the ENRICHD clinical trial did not receive more sessions of
cognitive behavioral therapy than those patients who re-
sponded to treatment, but they were more likely to be given an
antidepressant. However, treatment with an antidepressant
was associated with improved survival in the ENRICHD trial
(2). Although it is not known whether the psychotherapy ses-
sions were more stressful or longer for patients who did not re-
spond to treatment, we do not find support for Dr. Nicholas’
conjecture in the ENRICHD trial data. Nevertheless, the possi-
bility that initial nonresponse to depression treatment leads to
more aggressive treatment, and in turn, to greater cardiac
morbidity and mortality, deserves further consideration.
References
1. Skala JA, Freedland KE, Carney RM: Coronary heart disease and
depression: a review of recent mechanistic research. Can J Psy-
chiatry 2006; 51:738–745
2. Taylor CB, Youngblood ME, Veith RC, Carney RM, Burg MM,
Kaufmann PG, Shuster J, Mellman T, Blumenthal JA, Krishnan R,
Jaffe AS; ENRICHD Investigators: Effects of antidepressant med-
ication on morbidity and mortality in depressed patients after
myocardial infarction. Arch Gen Psychiatry 2005; 62:792–798
ROBERT M. CARNEY, PH.D.
KENNETH E. FREEDLAND, PH.D.
St. Louis, Mo.
The authors’ disclosures accompany the original article.
This letter (doi: 10.1176/appi.ajp.2009.09040482r) was accepted
for publication in May  2009.
The Use of Short Half-Life Antidepressants in 
the Treatment of Bipolar Depression
TO THE EDITOR: In the February 2009 issue of the Journal,
Mark A. Frye, M.D., et al. (1), and Joseph F. Goldberg, M.D., et
al. (2) examined the predictors of treatment-emergent mania
and mixed states in depressed bipolar patients. I would en-
courage both groups of investigators to review their data to
examine two variables that have not been reported. The first
is the diurnal variation of mood, which I find to be more ex-
treme in patients who have bipolar depression and may be a
predictor of a response to a mood stabilizer in unipolar pa-
tients. The second variable is the form of antidepressant given
to patients. A convention in publishing is to use the generic
names of medications, but this does not distinguish among
the three preparations of bupropion (immediate release, 12-
hour release, and 24-hour release) and two forms of venlafax-
ine (immediate- and time-release). Although time-release
preparations technically have the same half-life of the under-
lying compound, their sustained presence keeps blood and
TABLE 1. Patients in Each Subgroup With New Cardiovascular Events
Associated Risk Factor
Group
Subjects Responding to Treatment Subjects Not Responding to Treatment Total
N % N % N %
First episode 2/18 11 10/36 28 12/54 22
Recurrent episode 0/9 0 1/7 14 1/16 6
Total 2/27 7 11/43 26 13/70 19


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The effects of treatment-resistant depression and first-ever depression on mortality following acute coronary syndrome: interactive or independent?

ARTS repository - University of Groningen

University of Groningen

   University of GroningenThe effects of treatment-resistant depression and first-ever depression on mortality followingacute coronary syndromeZuidersma, M.; de Jonge, P.Published in:American Journal of PsychiatryIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2009Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Zuidersma, M., & de Jonge, P. (2009). The effects of treatment-resistant depression and first-everdepression on mortality following acute coronary syndrome: interactive or independent? American Journalof Psychiatry, 166(7), 828-829.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 12-11-2019Letters to the Editor828 Am J Psychiatry 166:7, July 2009ajp.psychiatryonline.orgMore Aggressive Treatment for Depression?TO THE EDITOR: In the April 2009 issue of the Journal, RobertM. Carney, Ph.D., and Kenneth E. Freedland, Ph.D. (1) notedthat depressed patients in an intervention group who did notexperience treatment response had a higher risk of late mor-tality (which was described as incidence of death ≥6 monthsfollowing acute myocardial infarction) compared with pa-tients who responded to treatment. The authors pointed outthat this relationship was not significant in the usual care armof the study. They also reported that in the interventiongroup, there was a lack of improvement, although subjects re-ceived 6 months of aggressive treatment. However, only ap-proximately 15% of patients in the usual care group receivedany form of nonstudy treatment during the first 6 months.Among patients in the usual care arm who did not experienceimprovement, less than 15% had received any treatment fortheir depression.Drs. Carney and Freedland stated that it is not immediatelyevident why major depression that is not responsive to treat-ment is associated with a higher risk of cardiac-related mor-tality and morbidity and concluded that major depressionmay warrant more aggressive treatment.It seems to me likely that less improvement of depressionwould tend to lead to more aggressive treatment. Perhaps, atleast in part, the explanation for why the greater risk of car-diac-related morbidity and mortality is “not immediately ap-parent” is because we do not wish to think that our efforts attreatment, even aggressive treatment, might have harmed ourpatients. Psychotropic drugs certainly do affect other organsystems—and not always beneficially. A more apt conclusionmight be that less aggressive treatment is better, at least withregard to the treatments that were used in the study, while wesearch for different treatments, a search that the authorsrightly advocate.Reference1. Carney RM, Freedland KE: Treatment-resistant depression andmortality after acute coronary syndrome. Am J Psychiatry2009; 166:410–417JAMES R. NICHOLAS, M.D.Ely, Minn.The author reports no competing interests.This letter (doi: 10.1176/appi.ajp.2009.09040520) was acceptedfor publication in May 2009.The Effects of Treatment-Resistant Depression and First-Ever Depression on Mortality Following Acute Coronary Syndrome: Interactive or Independent?TO THE EDITOR: Drs. Carney and Freedland (1) presented afascinating review on treatment-resistant depression andmortality following acute coronary syndrome. As a possiblemechanism explaining the association between treatment-resistant depression and mortality in acute coronary syn-drome patients, the authors suggested the presence of first-ever depressive episodes, which are associated with bothtreatment resistance and increased risk of cardiac events.We therefore explored the association between treatment-resistant depression, first-ever depression, and cardiovascularprognosis using data from the Myocardial INfarction and De-pression Intervention Trial (MIND-IT), a multi-center ran-domized controlled trial on the treatment of post-acute coro-nary syndrome depression. We previously reported (2), usingCox regression analysis, that patients who did not respond totreatment had an unadjusted hazard ratio of 4.89 (95% confi-dence interval [CI]=1.08–22.10) for new cardiovascular eventsrelative to patients who responded to treatment. Testing thehypothesis of Drs. Carney and Freedland, we adjusted for thepresence of first episodes. However, adjusting hardly affectedthe association (hazard ratio=4.42; 95% CI=0.97–20.10), whichis indicative of no support for the hypothesis. An explanationmay be that in our sample first episodes were not associatedwith new cardiovascular events or treatment resistance. How-ever, they are associated with both new cardiovascular events(hazard ratio=4.12 [95% CI=0.53–31.77]) and with treatmentresistance (odds ratio=2.57 [95% CI=0.82–8.03]). The numberof patients in each subgroup and their associated risk of car-diac events are shown in Table 1.Our tentative conclusion is that first depressive episodesand treatment resistance are two independent risk factors forworse outcomes that do not interact but add up indepen-dently. Our results do not support the hypothesis that first de-pressive episodes would underlie the association betweentreatment-resistant depression and negative cardiac out-comes. Since cell numbers in our study were very low, how-ever, we feel that caution is warranted and no firm conclusionscan yet be determined.We agree with Drs. Carney and Freedland that treatment-resistant depression is likely a marker of an underlying car-diac risk factor associated with treatment resistance in pa-tients with coronary heart disease and that researchersshould investigate this factor. One possible risk factor that isoften overlooked is treatment nonadherence, which is associ-ated with both depression and cardiac prognosis. Treatmentnonadherence is one of the reasons for treatment resistancein depressed patients, and it is likely that a patient who isnonadherent to antidepressant treatment is also nonadher-ent to cardiac aftercare.References1. Carney RM, Freedland KE: Treatment-resistant depression andmortality after acute coronary syndrome. Am J Psychiatry2009; 166:410–4172. de Jonge P, Honig A, van Melle JP, Schene AH, Kuyper AM, Tul-ner D, Schins A, Ormel J: Nonresponse to treatment for depres-sion following myocardial infarction: association with subse-quent cardiac events. Am J Psychiatry 2007; 164:1371–1378MARIJ ZUIDERSMA, M.Sc.Groningen, the NetherlandsPETER DE JONGE, PH.D.Groningen and Tilburg, the NetherlandsPresented in part at the annual meeting of the European Asso-ciation for Consultation-Liaison Psychiatry and Psychosomat-ics (EACLPP), Zaragoza, Spain, June 27, 2008. Drs. ZuidersmaAm J Psychiatry 166:7, July 2009 829LETTERS TO THE EDITORajp.psychiatryonline.organd de Jonge receive VIDI grant support from the Dutch Medi-cal Research Council (grant # 016.086.397).This letter (doi: 10.1176/appi.ajp.2009.09040482) was acceptedfor publication in May 2009.Drs. Carney and Freedland ReplyTO THE EDITOR: Our review article on treatment-resistant de-pression and mortality following acute coronary syndromewas intended to inspire new studies and secondary analysesof relevant databases. We are delighted that Drs. Zuidersmaand de Jonge have included a secondary analysis of data fromthe MIND-IT clinical trial to explore a point we raised in ourreview. However, we respectfully disagree with their state-ment that we “hypothesized” that the increased risk for car-diac morbidity and mortality in depressed patients with coro-nary heart disease is a result of the presence of a higherproportion of treatment-resistant cases among patientswhose first episode of major depression coincides with anacute coronary syndrome than among those with a recurrentmajor depressive episode around the time of an acute coro-nary syndrome. Actually, we noted that we found no relation-ship between response to treatment and the type of depres-sive episode (initial versus recurrent) in the EnhancingRecovery in Coronary Heart Disease (ENRICHD) clinical trial.In ENRICHD, patients with either treatment-resistant or first-episode depression were at higher risk for mortality thanthose with treatment-responsive or recurrent depression. Be-cause other studies of depression in patients with coronaryheart disease have found initial episodes to be less responsiveto treatment than recurrent episodes, we suggested that thispotential relationship “deserves more careful study” (p. 414).For this reason, we are pleased that Drs. Zuidersma and deJonge examined the MIND-IT data to determine whetherthese subgroups overlap or, as in the ENRICHD trial, whetherthey were independent risk factors for cardiac events. Eventhough first depressive episodes were relatively unresponsiveto treatment in the MIND-IT study, first episodes of depres-sion and nonresponse to treatment were independently asso-ciated with the incidence of cardiac events. The small size ofthe subgroups precludes strong conclusions, but the goal ofthe analysis was hypothesis generation.We also agree with the authors that poor adherence to thedepression and cardiac treatment regimens may explain bothpoor response to antidepressant treatment and a higher inci-dence of cardiac events. We have previously suggested thatpoor adherence to the medical treatment regimen is likely toat least partially explain why depression is associated with anincreased risk of cardiac events (1), and we agree that it de-serves more careful study.In his letter, Dr. Nicholas suggests that an initially inade-quate response may prompt more aggressive depression treat-ment, which may prove to be harmful for patients with coro-nary heart disease. Patients who did not respond to treatmentin the ENRICHD clinical trial did not receive more sessions ofcognitive behavioral therapy than those patients who re-sponded to treatment, but they were more likely to be given anantidepressant. However, treatment with an antidepressantwas associated with improved survival in the ENRICHD trial(2). Although it is not known whether the psychotherapy ses-sions were more stressful or longer for patients who did not re-spond to treatment, we do not find support for Dr. Nicholas’conjecture in the ENRICHD trial data. Nevertheless, the possi-bility that initial nonresponse to depression treatment leads tomore aggressive treatment, and in turn, to greater cardiacmorbidity and mortality, deserves further consideration.References1. Skala JA, Freedland KE, Carney RM: Coronary heart disease anddepression: a review of recent mechanistic research. Can J Psy-chiatry 2006; 51:738–7452. Taylor CB, Youngblood ME, Veith RC, Carney RM, Burg MM,Kaufmann PG, Shuster J, Mellman T, Blumenthal JA, Krishnan R,Jaffe AS; ENRICHD Investigators: Effects of antidepressant med-ication on morbidity and mortality in depressed patients aftermyocardial infarction. Arch Gen Psychiatry 2005; 62:792–798ROBERT M. CARNEY, PH.D.KENNETH E. FREEDLAND, PH.D.St. Louis, Mo.The authors’ disclosures accompany the original article.This letter (doi: 10.1176/appi.ajp.2009.09040482r) was acceptedfor publication in May  2009.The Use of Short Half-Life Antidepressants in the Treatment of Bipolar DepressionTO THE EDITOR: In the February 2009 issue of the Journal,Mark A. Frye, M.D., et al. (1), and Joseph F. Goldberg, M.D., etal. (2) examined the predictors of treatment-emergent maniaand mixed states in depressed bipolar patients. I would en-courage both groups of investigators to review their data toexamine two variables that have not been reported. The firstis the diurnal variation of mood, which I find to be more ex-treme in patients who have bipolar depression and may be apredictor of a response to a mood stabilizer in unipolar pa-tients. The second variable is the form of antidepressant givento patients. A convention in publishing is to use the genericnames of medications, but this does not distinguish amongthe three preparations of bupropion (immediate release, 12-hour release, and 24-hour release) and two forms of venlafax-ine (immediate- and time-release). Although time-releasepreparations technically have the same half-life of the under-lying compound, their sustained presence keeps blood andTABLE 1. Patients in Each Subgroup With New Cardiovascular EventsAssociated Risk FactorGroupSubjects Responding to Treatment Subjects Not Responding to Treatment TotalN % N % N %First episode 2/18 11 10/36 28 12/54 22Recurrent episode 0/9 0 1/7 14 1/16 6Total 2/27 7 11/43 26 13/70 19

The effects of treatment-resistant depression and first-ever depression on mortality following acute coronary syndrome:interactive or independent?

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