APA: Two Drugs No Better than One for Depression - just more side effects

[Guest guest]

http://www.medpagetoday.com/MeetingCoverage/APA/26576

APA: Two Drugs No Better than One for Depression

By Gever, Senior Editor, MedPage Today

Published: May 19, 2011

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of

Medicine, Harvard Medical School, Boston and

Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

HONOLULU -- Combining two antidepressants for patients with chronic or

recurrent major depression does not produce better outcomes than

monotherapy, researchers said here.

In a large trial sponsored by the National Institute of Mental Health

(NIMH), patients who received either of two dual-drug combinations were

no more likely to achieve responses or remission at 12 or 28 weeks than

those treated with a single agent, said Madhukar Trivedi, MD, of the

University of Texas Southwestern Medical Center in Dallas.

In a presentation at the American Psychiatric Association meeting here,

Trivedi said it now appears that efforts to improve on outcomes for

antidepressant monotherapy seen in the landmark STAR*D trial are

probably " futile. "

In the current trial, Trivedi said, the only difference for patients

with combination therapy was to " increase the burden of side effects. "

The findings were also published online shortly before the APA meeting

in the organization's official scientific publication, the American

Journal of Psychiatry.

The federally sponsored STAR*D trial -- which Trivedi helped lead --

shocked many psychiatrists by showing that only about 30% of depressed

patients given standard single-drug antidepressants achieved remission,

and that substituting other drugs increased remission rates by

progressively smaller increments.

These rates were much lower than were seen in company-sponsored trials,

but the inclusion criteria were deliberately set very loose in STAR*D in

order to reflect the types of patients who receive antidepressants in

routine practice.

Those findings then prompted questions about the potential added benefit

of combining different antidepressants.

NIMH agreed to fund a comparative trial, called COMED (Combining

Medications to Enhance Depression Outcomes), which enrolled 660 patients.

The study examined three treatment regimens: escitalopram (Lexapro) plus

placebo; sustained-release bupropion (Wellbutrin, Zyban) plus

escitalopram; and extended-release venlafaxine (Effexor) plus

mirtazapine (Remeron).

Its primary outcome measure was remission on the QIDS-SR16 scale at 12

weeks, with remission defined as two scores of less than eight points on

the scale during the final two evaluations, including at least one score

less than six.

Trivedi explained that this was a relatively rigorous measure in that

patients having " one good week, " as he put it, would not be classed as

having remission.

Other depression and suicidality rating scales were used as secondary

outcome measures.

Although the COMED trial was intended to follow STAR*D's lead in keeping

exclusion criteria to a minimum, the number of different drugs and other

considerations led to a large array of exclusions anyway.

Trivedi listed 22 separate exclusion criteria, many of which were

related to conditions incompatible with the study medications.

But also among them were other psychiatric conditions that could include

depressive components, such as bipolar and schizoaffective disorders.

Patients with a primary diagnosis of obsessive-compulsive disorder,

current psychotic symptoms, and recent histories of anorexia or bulimia

were not allowed, nor were those who had previously failed to respond to

any of the study medications.

On the other hand, the age range for inclusion was relatively broad,

with patients from 18 to 75 allowed in. Patients needed to have Hamilton

scores of at least 16 with a current episode lasting at least two months

and otherwise meeting current DSM-IV criteria for major depression.

Dosing in all three treatment arms started low, with escalations

possible from weeks four and eight based on QIDS scores. The maximum

doses were 20 mg/day for escitalopram, 400 mg/day for bupropion, 300

mg/day for venlafaxine, and 45 mg/day for mirtazapine.

The first medications patients received were open-label for both

patients and clinicians. Second medications (placebo in the case of the

escitalopram monotherapy group) were unknown to patients, but clinicians

knew what they were.

Remission rates at weeks 12 and 28 were nearly identical in all three

groups. At week 12, the primary endpoint was met by 38% to 39% of patients.

At week 28, the venlafaxine-mirtazapine group showed a nonsignificantly

lower rate than the other arms (37% versus 46% to 47%, P=0.38).

Response rates, defined as at least 50% reduction in QIDS scores, were

also nearly the same in all groups at week 12 (52% in all three arms)

and at week 28 (58% to 59%).

Trivedi reported the side-effect burden as percentages of patients in

four categories: no impairment, minimal or mild, moderate or marked, and

severe or intolerable.

About the same fraction of all three groups were rated as having no side

effects, but a larger proportion of the escitalopram monotherapy group

fell into the minimal/mild category whereas the two combination-therapy

arms had more patients rated with severe or intolerable effects.

Specific rates for the latter category at week 12 were as follows:

Escitalopram plus placebo: 4.2%

Venlafaxine plus mirtazapine: 15.2% (P<0.001 versus monotherapy group)

Bupropion plus escitalopram: 10.0% (P=0.06 versus monotherapy group)

Rates at week 28 were very similar to those seen at week 12, Trivedi

reported.

The venlafaxine-mirtazapine arm also had significantly more side effects

worsening over time relative to escitalopram monotherapy. This

particular measure did not differ significantly for the

bupropion-escitalopram group relative to monotherapy.

Limitations of the study included its single-blind design (without

blinding of clinicians), the fact that the population chosen may not

have been representative of all patients with chronic or recurrent major

depression, and the possibility that drug doses in the combination

therapies may not have been high enough.

Trivedi suggested that the remission and response rates in this trial,

as well as in STAR*D, might be as good as they can get.

Following STAR*D, he said he had repeatedly been asked " why we had not

found higher remission rates, " and he expected to hear similar questions

about COMED.

" The basic assumption that people are making, including educated

colleagues, is that there is a much better remission rate to be found,

and we just didn't find it. I think that we have to recognize, and be

humble, that maybe there isn't a much better rate to be found. "

Radwan Haykal, MD, a psychiatrist based in Memphis, Tenn., called COMED

" a superb study " and agreed that combining medications with similar

mechanisms is not likely to produce better outcomes than monotherapy.

He suggested that it could still be possible to improve remission and

response rates by adding drugs from other classes such as mood

stabilizers. But he suggested it was still vital to test the

antidepressant combinations in a rigorous, controlled trial.

" I'm very encouraged by this study and we need to have more of these, "

he said.

The study was funded by the National Institute of Mental Health. Forest

Pharmaceuticals, GlaxoKline, Organon, and Wyeth Pharmaceuticals

provided study medications.

Trivedi reported research support from the Agency for Healthcare

Research and Quality, Corcept, Cyberonics, Merck, NARSAD, the National

Institute of Mental Health, the National Institute on Drug Abuse,

Novartis, Pharmacia & Upjohn, Predix (EPIX), Solvay, and Targacept, and

consulting and speaker fees from Abbott, Abdi Ibrahim, Akzo (Organon),

AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Evotec, Fabre

Kramer, Forest, GlaxoKline, Janssen, & , Mead

, Medtronic, Neuronetics, Otsuka, Parke-, Pfizer, Sepracor,

Shire Development, VantagePoint, and Wyeth.

Primary source: American Journal of Psychiatry

Source reference:

http://ajp.psychiatryonline.org/cgi/content/abstract/appi.ajp.2011.10111645v1

[Guest guest]

http://www.medpagetoday.com/MeetingCoverage/APA/26576

APA: Two Drugs No Better than One for Depression

By Gever, Senior Editor, MedPage Today

Published: May 19, 2011

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of

Medicine, Harvard Medical School, Boston and

Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

HONOLULU -- Combining two antidepressants for patients with chronic or

recurrent major depression does not produce better outcomes than

monotherapy, researchers said here.

In a large trial sponsored by the National Institute of Mental Health

(NIMH), patients who received either of two dual-drug combinations were

no more likely to achieve responses or remission at 12 or 28 weeks than

those treated with a single agent, said Madhukar Trivedi, MD, of the

University of Texas Southwestern Medical Center in Dallas.

In a presentation at the American Psychiatric Association meeting here,

Trivedi said it now appears that efforts to improve on outcomes for

antidepressant monotherapy seen in the landmark STAR*D trial are

probably " futile. "

In the current trial, Trivedi said, the only difference for patients

with combination therapy was to " increase the burden of side effects. "

The findings were also published online shortly before the APA meeting

in the organization's official scientific publication, the American

Journal of Psychiatry.

The federally sponsored STAR*D trial -- which Trivedi helped lead --

shocked many psychiatrists by showing that only about 30% of depressed

patients given standard single-drug antidepressants achieved remission,

and that substituting other drugs increased remission rates by

progressively smaller increments.

These rates were much lower than were seen in company-sponsored trials,

but the inclusion criteria were deliberately set very loose in STAR*D in

order to reflect the types of patients who receive antidepressants in

routine practice.

Those findings then prompted questions about the potential added benefit

of combining different antidepressants.

NIMH agreed to fund a comparative trial, called COMED (Combining

Medications to Enhance Depression Outcomes), which enrolled 660 patients.

The study examined three treatment regimens: escitalopram (Lexapro) plus

placebo; sustained-release bupropion (Wellbutrin, Zyban) plus

escitalopram; and extended-release venlafaxine (Effexor) plus

mirtazapine (Remeron).

Its primary outcome measure was remission on the QIDS-SR16 scale at 12

weeks, with remission defined as two scores of less than eight points on

the scale during the final two evaluations, including at least one score

less than six.

Trivedi explained that this was a relatively rigorous measure in that

patients having " one good week, " as he put it, would not be classed as

having remission.

Other depression and suicidality rating scales were used as secondary

outcome measures.

Although the COMED trial was intended to follow STAR*D's lead in keeping

exclusion criteria to a minimum, the number of different drugs and other

considerations led to a large array of exclusions anyway.

Trivedi listed 22 separate exclusion criteria, many of which were

related to conditions incompatible with the study medications.

But also among them were other psychiatric conditions that could include

depressive components, such as bipolar and schizoaffective disorders.

Patients with a primary diagnosis of obsessive-compulsive disorder,

current psychotic symptoms, and recent histories of anorexia or bulimia

were not allowed, nor were those who had previously failed to respond to

any of the study medications.

On the other hand, the age range for inclusion was relatively broad,

with patients from 18 to 75 allowed in. Patients needed to have Hamilton

scores of at least 16 with a current episode lasting at least two months

and otherwise meeting current DSM-IV criteria for major depression.

Dosing in all three treatment arms started low, with escalations

possible from weeks four and eight based on QIDS scores. The maximum

doses were 20 mg/day for escitalopram, 400 mg/day for bupropion, 300

mg/day for venlafaxine, and 45 mg/day for mirtazapine.

The first medications patients received were open-label for both

patients and clinicians. Second medications (placebo in the case of the

escitalopram monotherapy group) were unknown to patients, but clinicians

knew what they were.

Remission rates at weeks 12 and 28 were nearly identical in all three

groups. At week 12, the primary endpoint was met by 38% to 39% of patients.

At week 28, the venlafaxine-mirtazapine group showed a nonsignificantly

lower rate than the other arms (37% versus 46% to 47%, P=0.38).

Response rates, defined as at least 50% reduction in QIDS scores, were

also nearly the same in all groups at week 12 (52% in all three arms)

and at week 28 (58% to 59%).

Trivedi reported the side-effect burden as percentages of patients in

four categories: no impairment, minimal or mild, moderate or marked, and

severe or intolerable.

About the same fraction of all three groups were rated as having no side

effects, but a larger proportion of the escitalopram monotherapy group

fell into the minimal/mild category whereas the two combination-therapy

arms had more patients rated with severe or intolerable effects.

Specific rates for the latter category at week 12 were as follows:

Escitalopram plus placebo: 4.2%

Venlafaxine plus mirtazapine: 15.2% (P<0.001 versus monotherapy group)

Bupropion plus escitalopram: 10.0% (P=0.06 versus monotherapy group)

Rates at week 28 were very similar to those seen at week 12, Trivedi

reported.

The venlafaxine-mirtazapine arm also had significantly more side effects

worsening over time relative to escitalopram monotherapy. This

particular measure did not differ significantly for the

bupropion-escitalopram group relative to monotherapy.

Limitations of the study included its single-blind design (without

blinding of clinicians), the fact that the population chosen may not

have been representative of all patients with chronic or recurrent major

depression, and the possibility that drug doses in the combination

therapies may not have been high enough.

Trivedi suggested that the remission and response rates in this trial,

as well as in STAR*D, might be as good as they can get.

Following STAR*D, he said he had repeatedly been asked " why we had not

found higher remission rates, " and he expected to hear similar questions

about COMED.

" The basic assumption that people are making, including educated

colleagues, is that there is a much better remission rate to be found,

and we just didn't find it. I think that we have to recognize, and be

humble, that maybe there isn't a much better rate to be found. "

Radwan Haykal, MD, a psychiatrist based in Memphis, Tenn., called COMED

" a superb study " and agreed that combining medications with similar

mechanisms is not likely to produce better outcomes than monotherapy.

He suggested that it could still be possible to improve remission and

response rates by adding drugs from other classes such as mood

stabilizers. But he suggested it was still vital to test the

antidepressant combinations in a rigorous, controlled trial.

" I'm very encouraged by this study and we need to have more of these, "

he said.

The study was funded by the National Institute of Mental Health. Forest

Pharmaceuticals, GlaxoKline, Organon, and Wyeth Pharmaceuticals

provided study medications.

Trivedi reported research support from the Agency for Healthcare

Research and Quality, Corcept, Cyberonics, Merck, NARSAD, the National

Institute of Mental Health, the National Institute on Drug Abuse,

Novartis, Pharmacia & Upjohn, Predix (EPIX), Solvay, and Targacept, and

consulting and speaker fees from Abbott, Abdi Ibrahim, Akzo (Organon),

AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Evotec, Fabre

Kramer, Forest, GlaxoKline, Janssen, & , Mead

, Medtronic, Neuronetics, Otsuka, Parke-, Pfizer, Sepracor,

Shire Development, VantagePoint, and Wyeth.

Primary source: American Journal of Psychiatry

Source reference:

http://ajp.psychiatryonline.org/cgi/content/abstract/appi.ajp.2011.10111645v1

[Guest guest]

http://www.medpagetoday.com/MeetingCoverage/APA/26576

APA: Two Drugs No Better than One for Depression

By Gever, Senior Editor, MedPage Today

Published: May 19, 2011

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of

Medicine, Harvard Medical School, Boston and

Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

HONOLULU -- Combining two antidepressants for patients with chronic or

recurrent major depression does not produce better outcomes than

monotherapy, researchers said here.

In a large trial sponsored by the National Institute of Mental Health

(NIMH), patients who received either of two dual-drug combinations were

no more likely to achieve responses or remission at 12 or 28 weeks than

those treated with a single agent, said Madhukar Trivedi, MD, of the

University of Texas Southwestern Medical Center in Dallas.

In a presentation at the American Psychiatric Association meeting here,

Trivedi said it now appears that efforts to improve on outcomes for

antidepressant monotherapy seen in the landmark STAR*D trial are

probably " futile. "

In the current trial, Trivedi said, the only difference for patients

with combination therapy was to " increase the burden of side effects. "

The findings were also published online shortly before the APA meeting

in the organization's official scientific publication, the American

Journal of Psychiatry.

The federally sponsored STAR*D trial -- which Trivedi helped lead --

shocked many psychiatrists by showing that only about 30% of depressed

patients given standard single-drug antidepressants achieved remission,

and that substituting other drugs increased remission rates by

progressively smaller increments.

These rates were much lower than were seen in company-sponsored trials,

but the inclusion criteria were deliberately set very loose in STAR*D in

order to reflect the types of patients who receive antidepressants in

routine practice.

Those findings then prompted questions about the potential added benefit

of combining different antidepressants.

NIMH agreed to fund a comparative trial, called COMED (Combining

Medications to Enhance Depression Outcomes), which enrolled 660 patients.

The study examined three treatment regimens: escitalopram (Lexapro) plus

placebo; sustained-release bupropion (Wellbutrin, Zyban) plus

escitalopram; and extended-release venlafaxine (Effexor) plus

mirtazapine (Remeron).

Its primary outcome measure was remission on the QIDS-SR16 scale at 12

weeks, with remission defined as two scores of less than eight points on

the scale during the final two evaluations, including at least one score

less than six.

Trivedi explained that this was a relatively rigorous measure in that

patients having " one good week, " as he put it, would not be classed as

having remission.

Other depression and suicidality rating scales were used as secondary

outcome measures.

Although the COMED trial was intended to follow STAR*D's lead in keeping

exclusion criteria to a minimum, the number of different drugs and other

considerations led to a large array of exclusions anyway.

Trivedi listed 22 separate exclusion criteria, many of which were

related to conditions incompatible with the study medications.

But also among them were other psychiatric conditions that could include

depressive components, such as bipolar and schizoaffective disorders.

Patients with a primary diagnosis of obsessive-compulsive disorder,

current psychotic symptoms, and recent histories of anorexia or bulimia

were not allowed, nor were those who had previously failed to respond to

any of the study medications.

On the other hand, the age range for inclusion was relatively broad,

with patients from 18 to 75 allowed in. Patients needed to have Hamilton

scores of at least 16 with a current episode lasting at least two months

and otherwise meeting current DSM-IV criteria for major depression.

Dosing in all three treatment arms started low, with escalations

possible from weeks four and eight based on QIDS scores. The maximum

doses were 20 mg/day for escitalopram, 400 mg/day for bupropion, 300

mg/day for venlafaxine, and 45 mg/day for mirtazapine.

The first medications patients received were open-label for both

patients and clinicians. Second medications (placebo in the case of the

escitalopram monotherapy group) were unknown to patients, but clinicians

knew what they were.

Remission rates at weeks 12 and 28 were nearly identical in all three

groups. At week 12, the primary endpoint was met by 38% to 39% of patients.

At week 28, the venlafaxine-mirtazapine group showed a nonsignificantly

lower rate than the other arms (37% versus 46% to 47%, P=0.38).

Response rates, defined as at least 50% reduction in QIDS scores, were

also nearly the same in all groups at week 12 (52% in all three arms)

and at week 28 (58% to 59%).

Trivedi reported the side-effect burden as percentages of patients in

four categories: no impairment, minimal or mild, moderate or marked, and

severe or intolerable.

About the same fraction of all three groups were rated as having no side

effects, but a larger proportion of the escitalopram monotherapy group

fell into the minimal/mild category whereas the two combination-therapy

arms had more patients rated with severe or intolerable effects.

Specific rates for the latter category at week 12 were as follows:

Escitalopram plus placebo: 4.2%

Venlafaxine plus mirtazapine: 15.2% (P<0.001 versus monotherapy group)

Bupropion plus escitalopram: 10.0% (P=0.06 versus monotherapy group)

Rates at week 28 were very similar to those seen at week 12, Trivedi

reported.

The venlafaxine-mirtazapine arm also had significantly more side effects

worsening over time relative to escitalopram monotherapy. This

particular measure did not differ significantly for the

bupropion-escitalopram group relative to monotherapy.

Limitations of the study included its single-blind design (without

blinding of clinicians), the fact that the population chosen may not

have been representative of all patients with chronic or recurrent major

depression, and the possibility that drug doses in the combination

therapies may not have been high enough.

Trivedi suggested that the remission and response rates in this trial,

as well as in STAR*D, might be as good as they can get.

Following STAR*D, he said he had repeatedly been asked " why we had not

found higher remission rates, " and he expected to hear similar questions

about COMED.

" The basic assumption that people are making, including educated

colleagues, is that there is a much better remission rate to be found,

and we just didn't find it. I think that we have to recognize, and be

humble, that maybe there isn't a much better rate to be found. "

Radwan Haykal, MD, a psychiatrist based in Memphis, Tenn., called COMED

" a superb study " and agreed that combining medications with similar

mechanisms is not likely to produce better outcomes than monotherapy.

He suggested that it could still be possible to improve remission and

response rates by adding drugs from other classes such as mood

stabilizers. But he suggested it was still vital to test the

antidepressant combinations in a rigorous, controlled trial.

" I'm very encouraged by this study and we need to have more of these, "

he said.

The study was funded by the National Institute of Mental Health. Forest

Pharmaceuticals, GlaxoKline, Organon, and Wyeth Pharmaceuticals

provided study medications.

Trivedi reported research support from the Agency for Healthcare

Research and Quality, Corcept, Cyberonics, Merck, NARSAD, the National

Institute of Mental Health, the National Institute on Drug Abuse,

Novartis, Pharmacia & Upjohn, Predix (EPIX), Solvay, and Targacept, and

consulting and speaker fees from Abbott, Abdi Ibrahim, Akzo (Organon),

AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Evotec, Fabre

Kramer, Forest, GlaxoKline, Janssen, & , Mead

, Medtronic, Neuronetics, Otsuka, Parke-, Pfizer, Sepracor,

Shire Development, VantagePoint, and Wyeth.

Primary source: American Journal of Psychiatry

Source reference:

http://ajp.psychiatryonline.org/cgi/content/abstract/appi.ajp.2011.10111645v1

[Guest guest]

http://www.medpagetoday.com/MeetingCoverage/APA/26576

APA: Two Drugs No Better than One for Depression

By Gever, Senior Editor, MedPage Today

Published: May 19, 2011

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of

Medicine, Harvard Medical School, Boston and

Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

HONOLULU -- Combining two antidepressants for patients with chronic or

recurrent major depression does not produce better outcomes than

monotherapy, researchers said here.

In a large trial sponsored by the National Institute of Mental Health

(NIMH), patients who received either of two dual-drug combinations were

no more likely to achieve responses or remission at 12 or 28 weeks than

those treated with a single agent, said Madhukar Trivedi, MD, of the

University of Texas Southwestern Medical Center in Dallas.

In a presentation at the American Psychiatric Association meeting here,

Trivedi said it now appears that efforts to improve on outcomes for

antidepressant monotherapy seen in the landmark STAR*D trial are

probably " futile. "

In the current trial, Trivedi said, the only difference for patients

with combination therapy was to " increase the burden of side effects. "

The findings were also published online shortly before the APA meeting

in the organization's official scientific publication, the American

Journal of Psychiatry.

The federally sponsored STAR*D trial -- which Trivedi helped lead --

shocked many psychiatrists by showing that only about 30% of depressed

patients given standard single-drug antidepressants achieved remission,

and that substituting other drugs increased remission rates by

progressively smaller increments.

These rates were much lower than were seen in company-sponsored trials,

but the inclusion criteria were deliberately set very loose in STAR*D in

order to reflect the types of patients who receive antidepressants in

routine practice.

Those findings then prompted questions about the potential added benefit

of combining different antidepressants.

NIMH agreed to fund a comparative trial, called COMED (Combining

Medications to Enhance Depression Outcomes), which enrolled 660 patients.

The study examined three treatment regimens: escitalopram (Lexapro) plus

placebo; sustained-release bupropion (Wellbutrin, Zyban) plus

escitalopram; and extended-release venlafaxine (Effexor) plus

mirtazapine (Remeron).

Its primary outcome measure was remission on the QIDS-SR16 scale at 12

weeks, with remission defined as two scores of less than eight points on

the scale during the final two evaluations, including at least one score

less than six.

Trivedi explained that this was a relatively rigorous measure in that

patients having " one good week, " as he put it, would not be classed as

having remission.

Other depression and suicidality rating scales were used as secondary

outcome measures.

Although the COMED trial was intended to follow STAR*D's lead in keeping

exclusion criteria to a minimum, the number of different drugs and other

considerations led to a large array of exclusions anyway.

Trivedi listed 22 separate exclusion criteria, many of which were

related to conditions incompatible with the study medications.

But also among them were other psychiatric conditions that could include

depressive components, such as bipolar and schizoaffective disorders.

Patients with a primary diagnosis of obsessive-compulsive disorder,

current psychotic symptoms, and recent histories of anorexia or bulimia

were not allowed, nor were those who had previously failed to respond to

any of the study medications.

On the other hand, the age range for inclusion was relatively broad,

with patients from 18 to 75 allowed in. Patients needed to have Hamilton

scores of at least 16 with a current episode lasting at least two months

and otherwise meeting current DSM-IV criteria for major depression.

Dosing in all three treatment arms started low, with escalations

possible from weeks four and eight based on QIDS scores. The maximum

doses were 20 mg/day for escitalopram, 400 mg/day for bupropion, 300

mg/day for venlafaxine, and 45 mg/day for mirtazapine.

The first medications patients received were open-label for both

patients and clinicians. Second medications (placebo in the case of the

escitalopram monotherapy group) were unknown to patients, but clinicians

knew what they were.

Remission rates at weeks 12 and 28 were nearly identical in all three

groups. At week 12, the primary endpoint was met by 38% to 39% of patients.

At week 28, the venlafaxine-mirtazapine group showed a nonsignificantly

lower rate than the other arms (37% versus 46% to 47%, P=0.38).

Response rates, defined as at least 50% reduction in QIDS scores, were

also nearly the same in all groups at week 12 (52% in all three arms)

and at week 28 (58% to 59%).

Trivedi reported the side-effect burden as percentages of patients in

four categories: no impairment, minimal or mild, moderate or marked, and

severe or intolerable.

About the same fraction of all three groups were rated as having no side

effects, but a larger proportion of the escitalopram monotherapy group

fell into the minimal/mild category whereas the two combination-therapy

arms had more patients rated with severe or intolerable effects.

Specific rates for the latter category at week 12 were as follows:

Escitalopram plus placebo: 4.2%

Venlafaxine plus mirtazapine: 15.2% (P<0.001 versus monotherapy group)

Bupropion plus escitalopram: 10.0% (P=0.06 versus monotherapy group)

Rates at week 28 were very similar to those seen at week 12, Trivedi

reported.

The venlafaxine-mirtazapine arm also had significantly more side effects

worsening over time relative to escitalopram monotherapy. This

particular measure did not differ significantly for the

bupropion-escitalopram group relative to monotherapy.

Limitations of the study included its single-blind design (without

blinding of clinicians), the fact that the population chosen may not

have been representative of all patients with chronic or recurrent major

depression, and the possibility that drug doses in the combination

therapies may not have been high enough.

Trivedi suggested that the remission and response rates in this trial,

as well as in STAR*D, might be as good as they can get.

Following STAR*D, he said he had repeatedly been asked " why we had not

found higher remission rates, " and he expected to hear similar questions

about COMED.

" The basic assumption that people are making, including educated

colleagues, is that there is a much better remission rate to be found,

and we just didn't find it. I think that we have to recognize, and be

humble, that maybe there isn't a much better rate to be found. "

Radwan Haykal, MD, a psychiatrist based in Memphis, Tenn., called COMED

" a superb study " and agreed that combining medications with similar

mechanisms is not likely to produce better outcomes than monotherapy.

He suggested that it could still be possible to improve remission and

response rates by adding drugs from other classes such as mood

stabilizers. But he suggested it was still vital to test the

antidepressant combinations in a rigorous, controlled trial.

" I'm very encouraged by this study and we need to have more of these, "

he said.

The study was funded by the National Institute of Mental Health. Forest

Pharmaceuticals, GlaxoKline, Organon, and Wyeth Pharmaceuticals

provided study medications.

Trivedi reported research support from the Agency for Healthcare

Research and Quality, Corcept, Cyberonics, Merck, NARSAD, the National

Institute of Mental Health, the National Institute on Drug Abuse,

Novartis, Pharmacia & Upjohn, Predix (EPIX), Solvay, and Targacept, and

consulting and speaker fees from Abbott, Abdi Ibrahim, Akzo (Organon),

AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Evotec, Fabre

Kramer, Forest, GlaxoKline, Janssen, & , Mead

, Medtronic, Neuronetics, Otsuka, Parke-, Pfizer, Sepracor,

Shire Development, VantagePoint, and Wyeth.

Primary source: American Journal of Psychiatry

Source reference:

http://ajp.psychiatryonline.org/cgi/content/abstract/appi.ajp.2011.10111645v1