Treatment Strategies after SSRI Failure — Good News and Bad News
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《新英格兰医药杂志》
My recent use of that august medical search engine, Google, revealed a publication that identified sin as the cause of depression. Initial amusement quickly gave way to the sobering recognition that this simplistic formulation conveyed a prevalent, if generally unarticulated, belief that depression is not a real illness but, rather, the result of a personal failing — moral, spiritual, or adaptational. How did depression come to be viewed in so pejorative a manner?
Depression certainly cannot be dismissed as rare; its lifetime prevalence is 15 to 20 percent1 (as compared, for example, with a 4 to 6 percent lifetime prevalence of colorectal cancer). And the present burden of major depression is clearly nothing short of staggering. In a series of reports describing the results of the Global Burden of Disease Study,2,3 unipolar depression was the fourth leading cause of temporary and permanent disability in 1990, and the projections for the year 2020 are even more grim. Unipolar depression will be second only to ischemic heart disease as a cause of illness burden worldwide. Among middle-aged women, the presence of depression increases the adjusted risk of dying from heart disease by 50 percent.
Why, then, is depression not at the table with all other "important" diseases? There are several reasons. First, until recently, there were no clear pathological signatures of depression that could be identified in the brain. With the benefit of molecular and imaging technologies, however, we now know that depression is characterized by abnormalities of cell signaling, neuronal and glial survival, and brain-region connectivity and network activation.4,5 Second, many of the symptoms of depression involve behavior with which virtually everyone is intimately acquainted: changes in motivation, mood, experience of pleasure, and concentration. If it is a developmental virtue to learn to regulate and control one's behavior, then the inability to self-regulate — to rise to the task — is seen as a failure, a weakness, if not a vice. Third, frustrated with an inability to demonstrate the cortical lesions that the German psychiatrist Emil Kraepelin insisted underlie the "disease process" that is depression, many psychiatrists in the early 20th century began to search beneath the manifestations of depression for maladaptive behavioral antecedents that might suggest a means of modifying the symptoms. Psychiatry, then, became less about description and more about underlying meaning. This change led to a definition of the cause of depression in behavioral terms — anger turned inward or abnormal reaction types — and suggested treatment that focused on insight or behavioral modification in the context of talk therapy. Depression, thus, was divorced from other medical illnesses. It was the search for new treatments that initiated the reconciliation between psychiatry and medicine, and the current questions surrounding the treatment of depression bring fully into focus our abilities and limitations in reducing the ravages of this disorder.
The treatment studies reported by Rush et al.6 and Trivedi et al.7 in this issue of the Journal are simultaneously illuminating and disconcerting. The reports focus on level 2 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, the level 1 study having involved 4041 outpatients with nonpsychotic depression at 23 psychiatric and 18 primary care sites.8 The level 1 study demonstrated that approximately 30 percent of depressed patients have a remission of symptoms after treatment with the selective serotonin-reuptake inhibitor (SSRI) citalopram at higher doses (mean, 41.8 mg) and for a longer time (mean, 47 days) than common practice would have suggested. The level 2 studies address two strategies for the treatment of patients who do not have a remission — either switching to an alternative therapy or augmenting the ineffective or partially effective antidepressant with other medications.
First, the good news: these "practical trials" or "effectiveness trials," sponsored by the National Institutes of Mental Health, provide real-world data on real-world outcomes (functional impairment) in real-world patients (including their coexisting illnesses). These trials focus on remission rather than simply on a reduction in symptoms, and the results are generalizable and can be directly translated into practice. Furthermore, the characterizations of patients and sample sizes dramatically reduce the effect of uncontrolled variability. The results demonstrate a remission rate of about 25 percent, regardless of the class of antidepressant drug substituted for an SSRI, and a slightly higher remission rate with either of the two augmenting agents (albeit in a cohort of patients with notable differences from those in the switch study). These findings are encouraging, both in the justification for attempting to induce a remission among patients for whom an initial antidepressant trial has failed and in their demonstration that multiple agents may achieve such a remission. These studies confirm that intolerance or failure to respond to an SSRI does not predict a lack of efficacy or intolerance of another SSRI.
However, these carefully performed trials are discouraging for several reasons. First, the results suggest that at least half of patients with depression do not have a remission. Second, if medications with various mechanisms of action are all roughly equivalent, as these trials suggest, what can we possibly infer about the pathophysiology of depression, particularly since there was neither a placebo group nor a group that continued to receive citalopram? This problem might be approached by considering advances in behavioral neuroscience that convincingly reveal behavioral disorders and their components as products of interactions between susceptibility and a precipitant, between gene products and environment. Stated differently, environmental events will have very different long-term and short-term effects in the context of various genetic backgrounds. Although the susceptibility to depression is heritable, it is likely to be encoded at multiple sites in specific gene networks in the brain. The same disorder, then, may involve effectors and response characteristics that vary among patients. This hypothesis suggests that much of the promise of the STAR*D trials may be found in the identification of predictors of response to antidepressant therapies — the differences among patients that should permit the design of more specific, individualized treatment. Third, the ongoing "nature–nurture" dialogue increasingly provides an explanation for what we already know: depression is bad for your health.
In this regard, the characteristics of the patients participating in these two trials are disturbing. From 76 to 79 percent had recurrent depression, with a mean duration of 16 to 17 years. The mean number of episodes among patients was close to 7 in both studies; the proportion of patients who were unemployed was 41 to 49 percent; and 37 to 41 percent of patients had no medical insurance (including Medicare and Medicaid). These statistics dovetail with previous data indicating that more than 60 percent of patients with a mental health disorder receive no treatment during a 12-month period and that the delay before the first treatment for mood disorders ranges from 6 to 8 years.9,10
Affective neuroscience and effectiveness trials such as STAR*D should help us identify new targets for treatment and patients for whom the treatments will be the most effective and best tolerated. However, if we fail to make health care accessible, to make the treatments for depression available, and to destigmatize depression, we will guarantee the continued and unnecessary suffering of millions of our friends and neighbors. Such an abrogation of our responsibility would, indeed, be a sin.
No potential conflict of interest relevant to this article was reported.
Source Information
From the University of North Carolina, Chapel Hill.
References
Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:593-602.
Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet 1997;349:1436-1442.
Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet 1997;349:1498-1504.
Charney DS, DeJesus G, Manji HK. Cellular plasticity and resilience and the pathophysiology of severe mood disorders. Dialogues Clin Neurosci 2004;6:217-25.
Mayberg HS. Modulating limbic-cortical circuits in depression: targets of antidepressant treatments. Semin Clin Neuropsychiatry 2002;7:255-268.
Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006;354:1231-1242.
Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006;354:1243-1252.
Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006;163:28-40.
Wang PS, Lane M, Olfson M, Pincus HA, Wells KB, Kessler RC. Twelve-month use of mental health services in the United States: results from the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:629-640.
Wang PS, Berglund P, Olfson M, Pincus HA, Wells KB, Kessler RC. Failure and delay in initial treatment contact after first onset of mental disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:603-613.(David R. Rubinow, M.D.)
Depression certainly cannot be dismissed as rare; its lifetime prevalence is 15 to 20 percent1 (as compared, for example, with a 4 to 6 percent lifetime prevalence of colorectal cancer). And the present burden of major depression is clearly nothing short of staggering. In a series of reports describing the results of the Global Burden of Disease Study,2,3 unipolar depression was the fourth leading cause of temporary and permanent disability in 1990, and the projections for the year 2020 are even more grim. Unipolar depression will be second only to ischemic heart disease as a cause of illness burden worldwide. Among middle-aged women, the presence of depression increases the adjusted risk of dying from heart disease by 50 percent.
Why, then, is depression not at the table with all other "important" diseases? There are several reasons. First, until recently, there were no clear pathological signatures of depression that could be identified in the brain. With the benefit of molecular and imaging technologies, however, we now know that depression is characterized by abnormalities of cell signaling, neuronal and glial survival, and brain-region connectivity and network activation.4,5 Second, many of the symptoms of depression involve behavior with which virtually everyone is intimately acquainted: changes in motivation, mood, experience of pleasure, and concentration. If it is a developmental virtue to learn to regulate and control one's behavior, then the inability to self-regulate — to rise to the task — is seen as a failure, a weakness, if not a vice. Third, frustrated with an inability to demonstrate the cortical lesions that the German psychiatrist Emil Kraepelin insisted underlie the "disease process" that is depression, many psychiatrists in the early 20th century began to search beneath the manifestations of depression for maladaptive behavioral antecedents that might suggest a means of modifying the symptoms. Psychiatry, then, became less about description and more about underlying meaning. This change led to a definition of the cause of depression in behavioral terms — anger turned inward or abnormal reaction types — and suggested treatment that focused on insight or behavioral modification in the context of talk therapy. Depression, thus, was divorced from other medical illnesses. It was the search for new treatments that initiated the reconciliation between psychiatry and medicine, and the current questions surrounding the treatment of depression bring fully into focus our abilities and limitations in reducing the ravages of this disorder.
The treatment studies reported by Rush et al.6 and Trivedi et al.7 in this issue of the Journal are simultaneously illuminating and disconcerting. The reports focus on level 2 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, the level 1 study having involved 4041 outpatients with nonpsychotic depression at 23 psychiatric and 18 primary care sites.8 The level 1 study demonstrated that approximately 30 percent of depressed patients have a remission of symptoms after treatment with the selective serotonin-reuptake inhibitor (SSRI) citalopram at higher doses (mean, 41.8 mg) and for a longer time (mean, 47 days) than common practice would have suggested. The level 2 studies address two strategies for the treatment of patients who do not have a remission — either switching to an alternative therapy or augmenting the ineffective or partially effective antidepressant with other medications.
First, the good news: these "practical trials" or "effectiveness trials," sponsored by the National Institutes of Mental Health, provide real-world data on real-world outcomes (functional impairment) in real-world patients (including their coexisting illnesses). These trials focus on remission rather than simply on a reduction in symptoms, and the results are generalizable and can be directly translated into practice. Furthermore, the characterizations of patients and sample sizes dramatically reduce the effect of uncontrolled variability. The results demonstrate a remission rate of about 25 percent, regardless of the class of antidepressant drug substituted for an SSRI, and a slightly higher remission rate with either of the two augmenting agents (albeit in a cohort of patients with notable differences from those in the switch study). These findings are encouraging, both in the justification for attempting to induce a remission among patients for whom an initial antidepressant trial has failed and in their demonstration that multiple agents may achieve such a remission. These studies confirm that intolerance or failure to respond to an SSRI does not predict a lack of efficacy or intolerance of another SSRI.
However, these carefully performed trials are discouraging for several reasons. First, the results suggest that at least half of patients with depression do not have a remission. Second, if medications with various mechanisms of action are all roughly equivalent, as these trials suggest, what can we possibly infer about the pathophysiology of depression, particularly since there was neither a placebo group nor a group that continued to receive citalopram? This problem might be approached by considering advances in behavioral neuroscience that convincingly reveal behavioral disorders and their components as products of interactions between susceptibility and a precipitant, between gene products and environment. Stated differently, environmental events will have very different long-term and short-term effects in the context of various genetic backgrounds. Although the susceptibility to depression is heritable, it is likely to be encoded at multiple sites in specific gene networks in the brain. The same disorder, then, may involve effectors and response characteristics that vary among patients. This hypothesis suggests that much of the promise of the STAR*D trials may be found in the identification of predictors of response to antidepressant therapies — the differences among patients that should permit the design of more specific, individualized treatment. Third, the ongoing "nature–nurture" dialogue increasingly provides an explanation for what we already know: depression is bad for your health.
In this regard, the characteristics of the patients participating in these two trials are disturbing. From 76 to 79 percent had recurrent depression, with a mean duration of 16 to 17 years. The mean number of episodes among patients was close to 7 in both studies; the proportion of patients who were unemployed was 41 to 49 percent; and 37 to 41 percent of patients had no medical insurance (including Medicare and Medicaid). These statistics dovetail with previous data indicating that more than 60 percent of patients with a mental health disorder receive no treatment during a 12-month period and that the delay before the first treatment for mood disorders ranges from 6 to 8 years.9,10
Affective neuroscience and effectiveness trials such as STAR*D should help us identify new targets for treatment and patients for whom the treatments will be the most effective and best tolerated. However, if we fail to make health care accessible, to make the treatments for depression available, and to destigmatize depression, we will guarantee the continued and unnecessary suffering of millions of our friends and neighbors. Such an abrogation of our responsibility would, indeed, be a sin.
No potential conflict of interest relevant to this article was reported.
Source Information
From the University of North Carolina, Chapel Hill.
References
Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:593-602.
Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet 1997;349:1436-1442.
Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet 1997;349:1498-1504.
Charney DS, DeJesus G, Manji HK. Cellular plasticity and resilience and the pathophysiology of severe mood disorders. Dialogues Clin Neurosci 2004;6:217-25.
Mayberg HS. Modulating limbic-cortical circuits in depression: targets of antidepressant treatments. Semin Clin Neuropsychiatry 2002;7:255-268.
Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006;354:1231-1242.
Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006;354:1243-1252.
Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006;163:28-40.
Wang PS, Lane M, Olfson M, Pincus HA, Wells KB, Kessler RC. Twelve-month use of mental health services in the United States: results from the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:629-640.
Wang PS, Berglund P, Olfson M, Pincus HA, Wells KB, Kessler RC. Failure and delay in initial treatment contact after first onset of mental disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:603-613.(David R. Rubinow, M.D.)