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Past, Present, and Future Directions for Defining Optimal Treatment Outcome in Depression

Past, Present, and Future Directions for Defining Optimal Treatment Outcome in Depression During the past decade, evidence from research on mood disorders has demonstrated that remission is the optimal outcome of treatment. However, there continues to be considerable variability in the specific characteristics that are accepted as indicators of remission. Increasing knowledge of mood disorders and their underlying mechanisms may allow for the development of a new diagnostic and assessment system that no longer is based solely on symptoms and other descriptive phenomena. Continued advances in neuroscience may allow for more knowledge of the underlying neurobiological status and more accurate assessments of the underlying disease state and response to treatment, thus enabling physicians to use treatments that will most effectively bring patients back to euthymia and a truly disease-free healthy state. Until then, remission should continue to be based on the descriptive and experiential phenomena of symptoms and psychosocial functioning.The evaluation and quantification of improvements in chronic medical illnesses have evolved as understanding of the disease processes and underlying pathophysiology of the conditions has increased. Depression is a chronic and recurrent illnessand is associated with significant functional impairment,morbidity, and mortality.Like other chronic medical conditions, depressive disorders are most often reported to and managed by a primary care physician, unless the severity of the illness is such that it requires care from a specialist.However, unlike many other chronic medical illnesses, a measurable critical end point of treatment for depression has yet to be clearly established. In diabetes, hypertension, or hypothyroidism, for example, specific criteria define satisfactory control of the disease and the achievement of a healthy state.In conditions such as hypercholesterolemia, treatment guidelines identify specific courses of action for patients with varying degrees of illness.Moreover, treatment is continued until the outcome criteria have been met and patients continue on maintenance treatment to prevent the return of the condition. Asthma, which frequently has a chronic and recurring course similar to that of depression, also has clearly defined outcomes as well as guidelines to address maintenance therapy and management of exacerbations.Unambiguous outcome goals can assist the physician not only in managing treatment, but also in communicating with patients. Patients frequently ask questions such as "How will I know when I am well?" If outcome goals have been established, the physician can address these issues with specific answers (eg, target blood cholesterol levels) rather than with vague, descriptive answers.Although clearly defined treatment goals are useful and necessary, they are not the sole indicator of a remitted state (ie, a state of optimal health and functioning). Achievement of a remitted state does not imply simply that a given laboratory value is within the normal range or that the severity of a symptom has decreased. For example, a patient with heart disease may experience resolution of chest pain when treated with sublingual nitroglycerin, but would not be considered truly well if there were still evidence of extensive occlusion of coronary arteries, if the patient were still unable to return to work, or if any of a number of other factors indicated an incomplete resolution of the disease state. Wellness must be determined by evaluating a combination of 3 key domains: symptoms, functional status, and pathophysiological changes.Remission has become widely recognized as the optimal outcome of treatment for depression and other mood disorders.However, changes in the disease state are largely noted by changes in number and severity of symptoms, which are based on descriptive phenomena rather than measurable results of specific tests or procedures. Although the state of symptoms has shown to be very relevant in predicting the future course of mood disorders, there remain high rates of relapse and other poor outcomes even after remission has been achieved.It therefore seems likely that there are other crucial, as yet unknown, aspects of brain neurophysiology that are powerful predictors of the course of illness. Nevertheless, characterizing remission based on symptom assessments is an important first step in defining wellness.At this time, the precise meaning of remission and what constitutes a healthy state for patients with mood disorders has not yet been standardized, and several questions remain to be answered. Are the definitions of remission currently used most often sufficient? Are additional criteria necessary? Should we have different classifications within remission to more clearly describe the patient's status?EVOLUTION OF OPERATIONAL CRITERIA FOR TREATMENT OUTCOMEPast Definitions: Symptom SeverityAlthough reduction of depressive symptoms has long been a goal of treatment, only in the last decade or so have attempts been made to establish standardized definitions and operational criteria for treatment outcomes. Until the early 1990s, outcome terms, definitions, and criteria reported in the scientific literature were considerably inconsistent.Some consistency was observed during the 1980s, as research from the Collaborative Depression Studyused 1 set of operational criteria to evaluate and describe changes in symptom severity in several clinical trials. These studies used the Psychiatric Status Ratings (PSR) and Research Diagnostic Criteria for a Selected Group of Functional Disordersfor episodic mood disorders (Table 1), including depressive disorders, and defined recovery as a period of 8 consecutive weeks at a PSR of 1 or 2 (presence of no symptoms or 1 to 2 symptoms to a mild degree).Table 1.Psychiatric Status Ratings*CodeTermDefinition6Definite criteria-severeRDC definite criteria and prominent psychotic symptoms or extreme impairment5Definite criteriaRDC definite criteria4MarkedNot RDC definite criteria but major symptoms of impairment3Partial remissionConsiderably less psychopathology than full RDC criteria, only moderate impairment, but still obvious evidence of disorder2Residual≥1 Symptoms to a mild degree1Usual selfNo residual symptoms; may have significant symptomatology of other disorderAbbreviation: RDC, Research Diagnostic Criteria for a Selected Group of Functional Disorders.*Adapted with permission from Keller and Shapiro.The RDC criteria are described in Spitzer et al.Other studies during that time used varying categories of outcome criteria based on a number of assessments, including standardized rating scales such as the Hamilton Rating Scale for Depression (HAM-D)(ie, percentage change from baseline or reduction to a predefined cutoff score).Although various rating scales have been validated, they often place emphasis on different symptoms and factors, thereby rendering accurate comparisons among study results more difficult.Other assessments included functional criteria (eg, hospital discharge or admission), return to usual functioning, or clinical judgment.Definition in the 1990s: Response, Remission, RecoveryIn 1991, Frank et alproposed definitions for outcomes (Box) in an effort to facilitate the creation of a uniform terminology that would provide a structure for clear communication among physicians and would enable useful and consistent comparisons of results from different clinical trials. Along with conceptual definitions, operational criteria were proposed based on ranges of scores of standardized assessment tools as well as time factors (Table 2). In addition, the group called for others to research the proposed criteria to better establish definitions. These definitions and criteria continue to provide a reliable means of identifying patients who have achieved remission.Box. Definitions of Outcomes in Depression*ResponsePatient no longer fully symptomatic but evidence of more than minimal symptomsRemissionPatient no longer meets syndromal criteria and has no or minimal symptomsRelapseReturn to fully symptomatic state that occurs during remission; reemergence of current episodeRecoveryExtended period of remission; indicates end of current episodeRecurrenceAppearance of new episode of major depression; occurs only during recovery*Data from Frank et al.Table 2.Operational Criteria for Outcomes in Depression*SADSHAM-D17BDIAsymptomatic≤2 SymptomsScore ≤7Score ≤8Fully symptomatic≥5 SymptomsScore ≥15Score ≥15Episode≥4 Weeks symptomatic≥2 Weeks fully symptomatic≥4 Weeks fully symptomaticFull remission≥2 Weeks to <8 weeks asymptomatic≥2 Weeks to <6 months asymptomatic≥3 Weeks to <4 months asymptomaticRecovery≥8 Weeks asymptomatic≥6 Months asymptomatic≥4 Months asymptomaticAbbreviations: BDI, Beck Depression Inventory (21-item); HAM-D17, 17-Item Hamilton Rating Scale for Depression; SADS, Schedule for Affective Disorders and Schizophrenia.*Data from Frank et al.Through most of the 1990s, the way improvement in depression was assessed and reported in the scientific literature remained somewhat inconsistent. In addition, few randomized controlled trials of acute treatment with antidepressant medications addressed remission,despite the fact that as early as 1993, treatment guidelines had begun to identify remission as the goal of treatment.Descriptions of outcomes included terms such as response, full response, or partial response; remission or partial remission; and recovery or partial/incomplete recovery. Criteria for these outcomes, including the assessment scale (eg, HAM-D, Montgomery Asberg Depression Rating Scale [MADRS], Clinical Global Impressions-Improvement [CGI-I]), the score (or change in score) used as a marker for symptomatic improvement, and the time factors used (particularly in terms of defining remission and recovery), frequently varied from study to study.Response, typically defined as more than a 50% decrease from baseline score for a standardized scale (eg, HAM-D, MADRS), is one of the more consistently defined terms and has been widely used as the critical end point for defining improvement in acute treatment studies. This and other criteria, including a HAM-D score of 6 or less, CGI-I score of 1 or 2, Beck Depression Inventory score of 9 or less, and a MADRS score of 15 or less, have also been used to designate a full response, which has been used interchangeably with remission.When remission was distinguished from a response or full response, criteria were frequently based on 17-item HAM-D (HAM-D17) scores but were inconsistent, with cutoff scores ranging from 7 to 11.In longitudinal studies, recovery was somewhat consistently defined as the presence of only 1 or minimal symptoms of major depression to a mild degree or a complete absence of symptoms for at least 2 months.Present Status Definition: Toward Standardized CriteriaCurrently there is not a universally accepted definition for remission. Generally, remission describes a state of minimal to no symptoms and return to normal functioning,but specific criteria for these end points vary.Definitions of remission used in clinical trials of psychotherapy and antidepressant therapy are typically based on scores of symptomatic rating scales and have included HAM-D17scores of 12 or less to 6 or less,a MADRS score of 15 or less to 8 or less,and a CGI-I score of 1 (very much improved).Of these, the HAM-D score of 7 or less, MADRS score of 10 or less, and CGI-I score equal to 1 criteria are being used with the greatest frequency in clinical trials of antidepressant medications.It has been demonstrated that using a HAM-D17score of 7 or less provides reliable differentiation between patients with depression and patients without depression. Because the mean (SD) HAM-D17score at intake for a group of outpatients with depression generally ranges between 18 and 22 (4), it is improbable that someone with a HAM-D17score of 7 or less would meet criteria for the diagnosis of major depressive disorder. For example, if the sample's mean HAM-D score were 20, less than 1% of the population would fall below a score of 7 (ie, 3 SD units below the mean). Similarly, because the mean (SD) HAM-D score of a typical nondepressed control group ranges from 1 to 3 (2), it is unlikely for a person without depression to score more than 7 on the HAM-D scale.Thus, this criterion provides a useful and reliable marker for remission.The clinical use of some of these scales, particularly the HAM-D17, has been questioned,which has prompted the development of briefer versions of the scale such as the Toronto HAM-D7.These shorter scales may provide a reliable tool for evaluating the core symptoms of depression, but the sensitivity and specificity of most of these scales remain to be validated.WHY REMISSION?Long-term Symptomatic and Syndromal OutcomesUse of the term remission to describe a distinct end point in randomized controlled trials and a standard of treatment began around 1992and has steadily increased since then.The focus of treatment outcomes shifted as evidence accumulated, suggesting that achieving remission is associated with better long-term outcomes compared with achieving response without remission.This finding was true regardless of how outcomes were described (ie, remission vs recovery vs absence of residual symptoms).Studies that compared the risk for relapse in patients who achieved full remission with those who achieved partial remission demonstrated that patients who achieved only partial remission were significantly more likely to experience relapse within the first 10 to 15 months after remission.A study comparing patients who had a full recovery (HAM-D score ≤6 for 2 months) with those who had only a partial recovery reported similar results, with a significantly greater risk of relapse in patients who had not fully recovered.Similarly, studies of patients with and without residual subthreshold symptoms demonstrated that residual symptoms are a strong predictor of early relapseand are associated with a shorter duration between depressive episodes.Specifically, relapse was about 3 times more likely in patients with residual symptoms, and these patients relapsed about 3 times faster than asymptomatic patients.Quality of LifeIn addition to the effects on outcomes related to depressive illness, partial remission and residual depressive symptoms are associated with impaired psychosocial functioning and quality of life.A study of psychosocial functioning in patients with chronic forms of major depression evaluated impairment in multiple domains of functioning (overall psychosocial adjustment, quality of life, work functioning, interpersonal functioning, and physical health) before and after 12 weeks of antidepressant therapy with sertraline or imipramine.Results demonstrated significantly greater improvement across all domains of functioning for patients who had achieved remission compared with patients who had achieved only a therapeutic response. Furthermore, responders continued to experience impairment after treatment, while remitters had levels of functioning that approached or matched that of healthy controls. An evaluation of Epidemiological Catchment Area data collected among more than 20 000 adults at 5 major psychiatric research centers across the United States revealed that patients with subsyndromal depressive symptoms experienced levels of impairment in multiple domains of functioning that were similar to those of patients with major depression.A retrospective evaluation of work outcomes in patients with depression demonstrated consistently better outcomes in both functional (absenteeism, decreased productivity, interpersonal friction) and affective (distress, disinterest, and dissatisfaction in the workplace) impairment for patients who achieved remission compared with those who did not.Analysis of data from a longitudinal study of depression in primary care revealed that, compared with remitters, patients who did not achieve remission had a lower probability of paid employment and were likely to miss more days of work due to illness or health care visits.In addition, the data suggested that remission might be associated with lower health care costs.Morbidity and MortalityFailure to achieve remission of symptoms has the potential to adversely affect physical health. Depressive symptoms have been associated with an increased risk for cardiac morbidity and mortality,poor glycemic control in type 1 or 2 diabetes mellitus,human immunodeficiency virus disease progression,increased risk of stroke mortality,and increased all-cause mortality.Neuroimaging StudiesNeuroimaging studies have shown decreased hippocampal volumes in patients with severe depression.Moreover, the degree to which hippocampal volume is decreased is correlated with the duration of the depressive episodes.The mechanism by which this occurs is unclear, but chronic activation of the stress response system, and hence chronically elevated glucocorticoid levels, is believed to have a role.Other research, however, has demonstrated no structural changes in the brains of patients with depression.Thus, the matter remains to be further studied and the findings replicated. Nevertheless, some evidence suggests that depression may, in fact, have cumulative and lasting deleterious effects on the brain, and that patients with prolonged periods of depression might be at an even higher risk for a chronic, recurrent course of depression. Achievement of remission, therefore, is critical for the successful long-term treatment of depression and should be considered the goal of therapy for depression as well as other mood disorders.CURRENT DIRECTIONS IN DEFINING REMISSIONDepressive SymptomatologyCurrent criteria distinguish between different degrees of improvement by using terms such as remission, response, and nonresponse. However, many questions remain unanswered. Is more specificity in identifying treatment outcomes warranted? For example, it may be beneficial to distinguish remitted patients who are asymptomatic from those who experience residual symptoms, thereby creating subtypes of remission. Most criteria (ie, HAM-D score ≤7; MADRS score ≤10) do not require that patients be asymptomatic to be considered in remission.However, there is evidence that among patients who meet remission criteria, those who report residual symptoms are likely to experience a more chronic course of illness,shorter time between episodes,more symptomatic weeks during follow-up,a decreased likelihood of recovery over time,and increased psychosocial and socioeconomic impairment.Furthermore, the presence of residual symptoms is associated with an increased likelihood of and shorter time to relapsecompared with asymptomatic remission and may also be associated with more frequent depressive episodes over time if untreated.Thus, the presence of even a minimal number of residual symptoms can have implications for treatment decisions, and the distinction between asymptomatic remission and remission with residual symptoms may warrant clarification.Psychosocial FunctioningA return to healthy functioning is part of the conceptual definition of remission.Is it reasonable to expect psychosocial impairment to resolve as a function of symptomatic improvement, or should specific measures of psychosocial functioning be included? In a study of the effects of sertraline and imipramine on functional impairment in patients with depression, the degree of improvement in psychosocial functioning was correlated with the degree of improvement of symptoms.Also, a study that evaluated work performance in patients with depression showed that impairment decreased substantially with the resolution of depressive symptoms.However, other evidence suggests that improvements in psychosocial functioning do not necessarily occur at the same rate as the amelioration of symptoms.An 8-month follow-up study of women with depression who had responded to treatment with imipramine found that considerable improvement in social adjustment did occur but more slowly than symptomatic improvement.Similar results were found in a 12-week acute treatment study that evaluated changes in depressive symptoms and in various domains of psychosocial functioning in patients with chronic forms of major depression in response to treatment with nefazodone, psychotherapy, or combination therapy.Prolonged psychosocial impairment may be more likely in patients with a chronic course of disease and those with higher HAM-D scores and functional impairment at baseline.Psychosocial functioning is an important outcome measure related to the level of remission that has been achieved. Because functioning may improve independently of depressive symptoms, it may warrant separate evaluation to determine whether patients have truly achieved a state of wellness.Relapse and RecurrenceShould the definition of remission include additional criteria to designate the duration of remission? Would separate classifications of short-term vs sustained remission be valid or practical for predicting outcomes such as relapse or recurrence?Currently, there is not a way to reliably predict which patients will have a relapse or recurrence or when this might occur.A 15-month longitudinal study of remitted patients reported a 40% rate of relapse but noted that all occurred during the first 10 months of follow-up.Naturalistic follow-up studies have reported relapse and recurrence rates for remitted patients of 19% at 6 months,37% within 1 year,from 25% to 40% within 2 years,and a cumulative rate of up to 85% after 15 years.Recent unpublished data suggest that a 4-week asymptomatic period is a strong predictor of a significantly lower probability of relapse (Lewis Judd, MD, unpublished data, January 10, 2003).Investigations have attempted to identify characteristics of recovered or remitted patients that are associated with an increased risk of relapse and recurrence. However, few variables have been identified. Residual depressive symptoms are probably one of the more reliable predictors of relapse or recurrence. Residual symptoms are relatively common and were reported in one study as present in 32% of remitters.As discussed earlier, residual symptomatology is strongly correlated with many poor outcomes, including increased risks for relapse or recurrence and shorter times between depressive episodes.Among asymptomatic patients, predicting the return of depressive illness is more difficult because there are few other factors that are highly correlated with relapse or recurrence.Some predictive characteristics were identified by naturalistic longitudinal studies from the Collaborative Program on the Psychobiology of Depression. This research has been following patients with mood disorders for more than 20 years with a prospective, naturalistic design and interview intervals of 6 months for 5 years and annually thereafter and has found that most patients have had multiple observed recoveries, relapses, and recurrences. Using the PSR scale, recovered patients include asymptomatic patients as well as those who experienced 1 or 2 symptoms to a mild degree.In these studies, an increased risk of relapse was associated with the presence of an underlying chronic depression for at least 2 years,and with an increased number of symptoms recalled from the worst previous episode.History of multiple previous episodes of depression was associated with an increased risk of relapse, a shorter time to relapse after recovery, and therefore an increased risk of multiple relapses.The association between multiple episodes of depression and an increased risk for relapse or recurrence was also demonstrated in a 10-year follow-up study that reported that the risk of recurrence increased 16% with each successive episode.Similar findings were demonstrated in a primary care population.Furthermore, there is evidence to suggest that with multiple episodes, the brain becomes more sensitized to the depressive state and the onset of future episodes is less related to stressful life events.Predicting outcomes in asymptomatic patients is further complicated by the return of subthreshold symptoms. For example, Collaborative Program on the Psychobiology of Depression data demonstrated that only 30% of recovered patients remained in recovery and symptom-free during 1 year of follow-up.Therefore, the risk for relapse may change over time as patients technically remain in remission but mild symptoms appear.Another factor in determining the probability of relapse or recurrence is the time course following discontinuation of treatment (either antidepressant treatment or psychotherapy). Evidence suggests that the risk for relapse is greatest shortly after recovery and decreases over time.Specifically, the risk of relapse is greatest during the first 3 to 6 months following recovery and declines slowly thereafter.Results of continuation and maintenance phase studies of antidepressant therapy have demonstrated that patients who had responded to an antidepressant and continued treatment with the full therapeutic dose were less likely to relapse than those who had their dose decreasedor who discontinued the drug.Thus, continuation and maintenance therapy with antidepressant medications has become accepted as the standard of care.Evidence also suggests that after 6 months, the risk for relapse or recurrence for patients whose treatment has been discontinued is not significantly more than that of patients who receive maintenance therapy.These data have prompted the observation that perhaps the value of maintenance therapy is limited.However, patients who have experienced multiple recurrences are at a significantly increased risk for future recurrences and would likely benefit from continued antidepressant therapy beyond 6 months after recovery.In addition, a 5-year study of maintenance treatment with imipramine demonstrated that patients who discontinued treatment after 3 years were at an increased risk of recurrence, and that treatment beyond 3 years continued to demonstrate a prophylactic effect.Currently, it is unclear whether maintenance therapy is associated with any benefits beyond a decreased risk of relapse or recurrence.PathophysiologyOne of the major obstacles to determining the best course of treatment for patients with depression or other mood disorders is the absence of a more comprehensive understanding of the pathophysiology of depressive illness, forcing physicians to rely on resolution of symptoms as a primary indicator of improvement. However, as is true for other chronic medical illnesses, it is important to view the symptom experience of the condition in the context of the complete disease state and overall function, as well as individual biological factors that may influence the long-term risk for poor outcomes.There is currently no objective way to evaluate a patient's underlying disease state. For example, unlike other disease states, there is no blood test or neuroimaging study that can determine if the treatment is merely controlling the symptoms of the condition or if the disease has been truly eliminated. Thus, we are unable to distinguish between an asymptomatic patient whose illness is being suppressed by medication and one who is disease-free. As knowledge of the neurobiology of depression and other mood disorders increases, advances can be made in diagnosis and assessment of treatment response.Current Recommendation for Remission as a Definition of Optimal Treatment OutcomeBecause there are currently limitations in the ability to assess pathophysiology, a system that gives primary consideration to symptoms but takes into account psychosocial functioning is recommended as the best approach to defining remission at this time. Thus, remission will continue to be based on descriptive and experiential phenomena until assessments of clinical status can be augmented with knowledge of the underlying neurobiological status. The proposed criteria for this recommendation are based on the data reviewed in this article on the impact of the presence and severity of residual symptoms and functioning on future psychopathological course and psychosocial functioning.Remission criteria should continue to be based primarily on significant reduction in the number and severity of symptoms, based on specific end points of either a HAM-D total score of 7 or less or a MADRS total score of 10 or less. However, a patient's status would be further classified based on the absence or presence of residual symptoms and the level of impairment of psychosocial functioning.The optimal outcome would be remission with the absence of both symptoms and functional impairment. Specifically, the remitted patient would be completely asymptomatic for at least 4 weeks (Lewis Judd, MD, unpublished data, January 10, 2003) and would experience restoration of healthy and complete functional status. A second classification would be included to identify patients who achieve remission with no symptoms but who have minimal impairment in psychosocial functioning. A third would include patients who achieve remission but continue to experience both symptoms and impairment in functioning to a mild degree. Currently, there are no data to suggest that a specific duration cutoff time to distinguish short-term vs sustained remission would be warranted to add additional predictive value.FUTURE DIRECTIONSResearch into associations between symptoms of mood disorders and biological processes has included attempts to identify potential markers of genetic risk for depression. Results of some studies have suggested that familial risk is most consistently associated with the recurrent subtype of major depression,and that patients who experience an early first onset of depression (ie, during childhood or adolescence) may be more likely to experience a recurrence during adulthood.In addition, several persistent biological perturbations have been investigated. Disturbances in the onset and duration of rapid eye movement sleep,dysfunction of the hypothalamic-pituitary-adrenal system,and elevated levels of corticotropin-releasing hormone in the cerebrospinal fluidhave been observed in patients with depression or other mood disorders.However, tests of these factors as potential diagnostic markers or as markers of response to treatment have produced variable findings. Thus, reliable and valid assessment tools based on biological markers remain to be identified.The focus of neurobiological research on depression and other mood disorders has shifted from the interaction between neurotransmitters and cell surface receptors to gene expression and structural and functional changes within the brain. Advances in genetics made possible by new tools and technology (eg, high-throughput genotyping via mass spectrometry, draft sequence of the human genome; comprehensive catalog of human genetic variation; intermediate phenotypes; biological traits, disease subtypes, and symptom clusters; new statistical methods; and large data sets) may provide a biological basis for a completely new diagnostic and classification system for mood disorders.Neuroimaging studies have thus far demonstrated structural and functional changes associated with depression (eg, decreased hippocampal volumes), but have not yet determined the clinical consequences of these findings. New structural and functional imaging techniques can provide a deeper understanding of brain disturbances related to depression and other disorders and, if used in conjunction with genetic research, may eventually identify patterns of brain function linked to particular genotypes.Future definitions of optimal treatment outcomes ideally will include 2 additional dimensions: pathophysiology and genetic modifiers. The latter would not be an outcome but an important way to categorize patients. Ultimately, remission criteria should include assessments of pathophysiological signs to evaluate the disease state and symptomatic and psychosocial improvement as well as genetics to discern who is disease-free vs who is merely improved for an interval, and who within the disease-free category remains at different levels of increased genetic risk of disease. Indeed, there may come a time when remission not only refers to the absence of symptoms, but also indicates a truly disease-free state based on neuroimaging and other types of assessments of brain structure and functioning.CONCLUSIONTreatment to remission is a concept that is not unique to mood disorders. The goals of treatment for various chronic medical illnesses essentially define remission for those disease states by serving as markers of wellness. Remission of symptoms serves as a marker of wellness for patients with mood disorders, and therefore remains the optimal treatment outcome for mood disorders.Continued work in descriptions of phenomenology as well as research in basic science may lead to a better diagnostic system and the ability to measure the underlying disease states of mood disorders. 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Bull.1996;32:33-40.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=8927672ESPaykelMMWeissmanSocial adjustment and depression: a longitudinal study.Arch Gen Psychiatry.1973;28:659-663.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=4700679RMHirschfeldDLDunnerGKeitnerDoes psychosocial functioning improve independent of depressive symptoms? a comparison of nefazodone, psychotherapy, and their combination.Biol Psychiatry.2002;51:123-133.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=11822991VAgostiPredictors of persistent social impairment among recovered depressed outpatients.J Affect Disord.1999;55:215-219.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=10628890RRamanaESPaykelZCooperRemission and relapse in major depression: a two-year prospective follow-up study.Psychol Med.1995;25:1161-1170.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=8637946WCoryellJEndicottMBKellerPredictors of relapse into major depressive disorder in a nonclinical population.Am J Psychiatry.1991;148:1353-1358.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=1897616DASolomonMBKellerACLeonMultiple recurrences of major depressive disorder.Am J Psychiatry.2000;157:229-233.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=10671391KSKendlerLMThorntonCOGardnerStressful life events and previous episodes in the etiology of major depression in women: an evaluation of the "kindling" hypotheses.Am J Psychiatry.2000;157:1243-1251.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=10910786PWLavoriMBKellerGLKlermanRelapse in affective disorders: a reanalysis of the literature using life table methods.J Psychiatr Res.1984;18:13-25.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=6716315EFrankDJKupferJMPerelComparison of full-dose versus half-dose pharmacotherapy in the maintenance treatment of recurrent depression.J Affect Disord.1993;27:139-145.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=8478502EDPeselowDLDunnerRRFieveCDifigliaThe prophylactic efficacy of tricyclic antidepressants: a five-year follow up.Prog Neuropsychopharmacol Biol Psychiatry.1991;15:71-82.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=2008541DPDooganVCaillardSertraline in the prevention of depression.Br J Psychiatry.1992;160:217-222.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=1540762MDEvansSDHollonRJDeRubeisDifferential relapse following cognitive therapy and pharmacotherapy for depression.Arch Gen Psychiatry.1992;49:802-808.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=1417433JWStewartFMQuitkinPJMcGrathUse of pattern analysis to predict differential relapse of remitted patients with major depression during 1 year of treatment with fluoxetine or placebo.Arch Gen Psychiatry.1998;55:334-343.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=9554429RDawsonPWLavoriWHCoryellMaintenance strategies for unipolar depression: an observational study of levels of treatment and recurrence.J Affect Disord.1998;49:31-44.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=9574858SAMontgomeryGDunbarParoxetine is better than placebo in relapse prevention and the prophylaxis of recurrent depression.Int Clin Psychopharmacol.1993;8:189-195.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=8263317SAMontgomeryJGRasmussenPTanghojA 24-week study of 20 mg citalopram, 40 mg citalopram, and placebo in the prevention of relapse of major depression.Int Clin Psychopharmacol.1993;8:181-188.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=8263316EFrankDJKupferJMPerelThree-year outcomes for maintenance therapies in recurrent depression.Arch Gen Psychiatry.1990;47:1093-1099.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=2244793FWReimherrJDAmsterdamFMQuitkinOptimal length of continuation therapy in depression: a prospective assessment during long-term fluoxetine treatment.Am J Psychiatry.1998;155:1247-1253.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=9734550METhaseRedefining antidepressant efficacy toward long-term recovery.J Clin Psychiatry.1999;60(suppl 6):15-19.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=10235120AREntsuahRLRudolphDHackettSMiskaEfficacy of venlafaxine and placebo during long-term treatment of depression: a pooled analysis of relapse rates.Int Clin Psychopharmacol.1996;11:137-145.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=8803651MBKellerJHKocsisMEThaseMaintenance phase efficacy of sertraline for chronic depression.JAMA.1998;280:1665-1672.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=9831997RJBaldessariniACVigueraRelapse of depressive symptoms after discontinuing sertraline.JAMA.1999;281:323-324.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=9929081DJKupferEFrankJMPerelFive-year outcome for maintenance therapies in recurrent depression.Arch Gen Psychiatry.1992;49:769-773.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=1417428DSCharneyDHBarlowKBotteronNeuroscience research agenda to guide development of a pathophysiologically based classification system.In: Kupfer DJ, First MV, Reiger GA, eds. A Research Agenda for DSM-V. Washington, DC: American Psychiatric Association; 2002:31-83.PFSullivanMCNealeKSKendlerGenetic epidemiology of major depression: review and meta-analysis.Am J Psychiatry.2000;157:1552-1562.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=11007705PJWickramaratneVWarnerMMWeissmanSelecting early onset MDD probands for genetic studies: results from a longitudinal high-risk study.Am J Med Genet.2000;96:93-101.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=10686560EANofzingerMKeshavanDJBuysseThe neurobiology of sleep in relation to mental illness.In: Charney DS, Nestler EJ, Bunney BS, eds. Neurobiology of Mental Illness.New York, NY: Oxford University Press; 1999:915-929.FHolsboerAnimal models of mood disorders.In: Charney DS, Nestler EJ, Bunney BS, eds. Neurobiology of Mental Illness. New York, NY: Oxford University Press; 1999:317-332.SJGarlowDLMusselmanCBNemeroffThe neurochemistry of mood disorders: clinical studies.In: Charney DS, Nestler EJ, Bunney BS, eds. Neurobiology of Mental Illnesss.New York, NY: Oxford University Press; 1999:348-364.Corresponding Author and Reprints:Martin B. Keller, MD, Department of Psychiatry and Human Behavior, Brown University, Box G-BH, Sawyer Bldg, 345 Blackstone Blvd, Providence, RI 02906 (e-mail: martin_keller@brown.edu).Acknowledgment:I thank Sherri D. Jones, PharmD, who assisted with literature research and provided writing and editorial assistance.Financial Disclosure:Dr Keller has received consultant fees, honoraria, and research grants from, and has served on advisory boards for, a number of pharmaceutical companies. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Past, Present, and Future Directions for Defining Optimal Treatment Outcome in Depression

JAMA , Volume 289 (23) – Jun 18, 2003

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References (113)

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American Medical Association
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Copyright 2003 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
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0098-7484
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1538-3598
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10.1001/jama.289.23.3152
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12813121
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Abstract

During the past decade, evidence from research on mood disorders has demonstrated that remission is the optimal outcome of treatment. However, there continues to be considerable variability in the specific characteristics that are accepted as indicators of remission. Increasing knowledge of mood disorders and their underlying mechanisms may allow for the development of a new diagnostic and assessment system that no longer is based solely on symptoms and other descriptive phenomena. Continued advances in neuroscience may allow for more knowledge of the underlying neurobiological status and more accurate assessments of the underlying disease state and response to treatment, thus enabling physicians to use treatments that will most effectively bring patients back to euthymia and a truly disease-free healthy state. Until then, remission should continue to be based on the descriptive and experiential phenomena of symptoms and psychosocial functioning.The evaluation and quantification of improvements in chronic medical illnesses have evolved as understanding of the disease processes and underlying pathophysiology of the conditions has increased. Depression is a chronic and recurrent illnessand is associated with significant functional impairment,morbidity, and mortality.Like other chronic medical conditions, depressive disorders are most often reported to and managed by a primary care physician, unless the severity of the illness is such that it requires care from a specialist.However, unlike many other chronic medical illnesses, a measurable critical end point of treatment for depression has yet to be clearly established. In diabetes, hypertension, or hypothyroidism, for example, specific criteria define satisfactory control of the disease and the achievement of a healthy state.In conditions such as hypercholesterolemia, treatment guidelines identify specific courses of action for patients with varying degrees of illness.Moreover, treatment is continued until the outcome criteria have been met and patients continue on maintenance treatment to prevent the return of the condition. Asthma, which frequently has a chronic and recurring course similar to that of depression, also has clearly defined outcomes as well as guidelines to address maintenance therapy and management of exacerbations.Unambiguous outcome goals can assist the physician not only in managing treatment, but also in communicating with patients. Patients frequently ask questions such as "How will I know when I am well?" If outcome goals have been established, the physician can address these issues with specific answers (eg, target blood cholesterol levels) rather than with vague, descriptive answers.Although clearly defined treatment goals are useful and necessary, they are not the sole indicator of a remitted state (ie, a state of optimal health and functioning). Achievement of a remitted state does not imply simply that a given laboratory value is within the normal range or that the severity of a symptom has decreased. For example, a patient with heart disease may experience resolution of chest pain when treated with sublingual nitroglycerin, but would not be considered truly well if there were still evidence of extensive occlusion of coronary arteries, if the patient were still unable to return to work, or if any of a number of other factors indicated an incomplete resolution of the disease state. Wellness must be determined by evaluating a combination of 3 key domains: symptoms, functional status, and pathophysiological changes.Remission has become widely recognized as the optimal outcome of treatment for depression and other mood disorders.However, changes in the disease state are largely noted by changes in number and severity of symptoms, which are based on descriptive phenomena rather than measurable results of specific tests or procedures. Although the state of symptoms has shown to be very relevant in predicting the future course of mood disorders, there remain high rates of relapse and other poor outcomes even after remission has been achieved.It therefore seems likely that there are other crucial, as yet unknown, aspects of brain neurophysiology that are powerful predictors of the course of illness. Nevertheless, characterizing remission based on symptom assessments is an important first step in defining wellness.At this time, the precise meaning of remission and what constitutes a healthy state for patients with mood disorders has not yet been standardized, and several questions remain to be answered. Are the definitions of remission currently used most often sufficient? Are additional criteria necessary? Should we have different classifications within remission to more clearly describe the patient's status?EVOLUTION OF OPERATIONAL CRITERIA FOR TREATMENT OUTCOMEPast Definitions: Symptom SeverityAlthough reduction of depressive symptoms has long been a goal of treatment, only in the last decade or so have attempts been made to establish standardized definitions and operational criteria for treatment outcomes. Until the early 1990s, outcome terms, definitions, and criteria reported in the scientific literature were considerably inconsistent.Some consistency was observed during the 1980s, as research from the Collaborative Depression Studyused 1 set of operational criteria to evaluate and describe changes in symptom severity in several clinical trials. These studies used the Psychiatric Status Ratings (PSR) and Research Diagnostic Criteria for a Selected Group of Functional Disordersfor episodic mood disorders (Table 1), including depressive disorders, and defined recovery as a period of 8 consecutive weeks at a PSR of 1 or 2 (presence of no symptoms or 1 to 2 symptoms to a mild degree).Table 1.Psychiatric Status Ratings*CodeTermDefinition6Definite criteria-severeRDC definite criteria and prominent psychotic symptoms or extreme impairment5Definite criteriaRDC definite criteria4MarkedNot RDC definite criteria but major symptoms of impairment3Partial remissionConsiderably less psychopathology than full RDC criteria, only moderate impairment, but still obvious evidence of disorder2Residual≥1 Symptoms to a mild degree1Usual selfNo residual symptoms; may have significant symptomatology of other disorderAbbreviation: RDC, Research Diagnostic Criteria for a Selected Group of Functional Disorders.*Adapted with permission from Keller and Shapiro.The RDC criteria are described in Spitzer et al.Other studies during that time used varying categories of outcome criteria based on a number of assessments, including standardized rating scales such as the Hamilton Rating Scale for Depression (HAM-D)(ie, percentage change from baseline or reduction to a predefined cutoff score).Although various rating scales have been validated, they often place emphasis on different symptoms and factors, thereby rendering accurate comparisons among study results more difficult.Other assessments included functional criteria (eg, hospital discharge or admission), return to usual functioning, or clinical judgment.Definition in the 1990s: Response, Remission, RecoveryIn 1991, Frank et alproposed definitions for outcomes (Box) in an effort to facilitate the creation of a uniform terminology that would provide a structure for clear communication among physicians and would enable useful and consistent comparisons of results from different clinical trials. Along with conceptual definitions, operational criteria were proposed based on ranges of scores of standardized assessment tools as well as time factors (Table 2). In addition, the group called for others to research the proposed criteria to better establish definitions. These definitions and criteria continue to provide a reliable means of identifying patients who have achieved remission.Box. Definitions of Outcomes in Depression*ResponsePatient no longer fully symptomatic but evidence of more than minimal symptomsRemissionPatient no longer meets syndromal criteria and has no or minimal symptomsRelapseReturn to fully symptomatic state that occurs during remission; reemergence of current episodeRecoveryExtended period of remission; indicates end of current episodeRecurrenceAppearance of new episode of major depression; occurs only during recovery*Data from Frank et al.Table 2.Operational Criteria for Outcomes in Depression*SADSHAM-D17BDIAsymptomatic≤2 SymptomsScore ≤7Score ≤8Fully symptomatic≥5 SymptomsScore ≥15Score ≥15Episode≥4 Weeks symptomatic≥2 Weeks fully symptomatic≥4 Weeks fully symptomaticFull remission≥2 Weeks to <8 weeks asymptomatic≥2 Weeks to <6 months asymptomatic≥3 Weeks to <4 months asymptomaticRecovery≥8 Weeks asymptomatic≥6 Months asymptomatic≥4 Months asymptomaticAbbreviations: BDI, Beck Depression Inventory (21-item); HAM-D17, 17-Item Hamilton Rating Scale for Depression; SADS, Schedule for Affective Disorders and Schizophrenia.*Data from Frank et al.Through most of the 1990s, the way improvement in depression was assessed and reported in the scientific literature remained somewhat inconsistent. In addition, few randomized controlled trials of acute treatment with antidepressant medications addressed remission,despite the fact that as early as 1993, treatment guidelines had begun to identify remission as the goal of treatment.Descriptions of outcomes included terms such as response, full response, or partial response; remission or partial remission; and recovery or partial/incomplete recovery. Criteria for these outcomes, including the assessment scale (eg, HAM-D, Montgomery Asberg Depression Rating Scale [MADRS], Clinical Global Impressions-Improvement [CGI-I]), the score (or change in score) used as a marker for symptomatic improvement, and the time factors used (particularly in terms of defining remission and recovery), frequently varied from study to study.Response, typically defined as more than a 50% decrease from baseline score for a standardized scale (eg, HAM-D, MADRS), is one of the more consistently defined terms and has been widely used as the critical end point for defining improvement in acute treatment studies. This and other criteria, including a HAM-D score of 6 or less, CGI-I score of 1 or 2, Beck Depression Inventory score of 9 or less, and a MADRS score of 15 or less, have also been used to designate a full response, which has been used interchangeably with remission.When remission was distinguished from a response or full response, criteria were frequently based on 17-item HAM-D (HAM-D17) scores but were inconsistent, with cutoff scores ranging from 7 to 11.In longitudinal studies, recovery was somewhat consistently defined as the presence of only 1 or minimal symptoms of major depression to a mild degree or a complete absence of symptoms for at least 2 months.Present Status Definition: Toward Standardized CriteriaCurrently there is not a universally accepted definition for remission. Generally, remission describes a state of minimal to no symptoms and return to normal functioning,but specific criteria for these end points vary.Definitions of remission used in clinical trials of psychotherapy and antidepressant therapy are typically based on scores of symptomatic rating scales and have included HAM-D17scores of 12 or less to 6 or less,a MADRS score of 15 or less to 8 or less,and a CGI-I score of 1 (very much improved).Of these, the HAM-D score of 7 or less, MADRS score of 10 or less, and CGI-I score equal to 1 criteria are being used with the greatest frequency in clinical trials of antidepressant medications.It has been demonstrated that using a HAM-D17score of 7 or less provides reliable differentiation between patients with depression and patients without depression. Because the mean (SD) HAM-D17score at intake for a group of outpatients with depression generally ranges between 18 and 22 (4), it is improbable that someone with a HAM-D17score of 7 or less would meet criteria for the diagnosis of major depressive disorder. For example, if the sample's mean HAM-D score were 20, less than 1% of the population would fall below a score of 7 (ie, 3 SD units below the mean). Similarly, because the mean (SD) HAM-D score of a typical nondepressed control group ranges from 1 to 3 (2), it is unlikely for a person without depression to score more than 7 on the HAM-D scale.Thus, this criterion provides a useful and reliable marker for remission.The clinical use of some of these scales, particularly the HAM-D17, has been questioned,which has prompted the development of briefer versions of the scale such as the Toronto HAM-D7.These shorter scales may provide a reliable tool for evaluating the core symptoms of depression, but the sensitivity and specificity of most of these scales remain to be validated.WHY REMISSION?Long-term Symptomatic and Syndromal OutcomesUse of the term remission to describe a distinct end point in randomized controlled trials and a standard of treatment began around 1992and has steadily increased since then.The focus of treatment outcomes shifted as evidence accumulated, suggesting that achieving remission is associated with better long-term outcomes compared with achieving response without remission.This finding was true regardless of how outcomes were described (ie, remission vs recovery vs absence of residual symptoms).Studies that compared the risk for relapse in patients who achieved full remission with those who achieved partial remission demonstrated that patients who achieved only partial remission were significantly more likely to experience relapse within the first 10 to 15 months after remission.A study comparing patients who had a full recovery (HAM-D score ≤6 for 2 months) with those who had only a partial recovery reported similar results, with a significantly greater risk of relapse in patients who had not fully recovered.Similarly, studies of patients with and without residual subthreshold symptoms demonstrated that residual symptoms are a strong predictor of early relapseand are associated with a shorter duration between depressive episodes.Specifically, relapse was about 3 times more likely in patients with residual symptoms, and these patients relapsed about 3 times faster than asymptomatic patients.Quality of LifeIn addition to the effects on outcomes related to depressive illness, partial remission and residual depressive symptoms are associated with impaired psychosocial functioning and quality of life.A study of psychosocial functioning in patients with chronic forms of major depression evaluated impairment in multiple domains of functioning (overall psychosocial adjustment, quality of life, work functioning, interpersonal functioning, and physical health) before and after 12 weeks of antidepressant therapy with sertraline or imipramine.Results demonstrated significantly greater improvement across all domains of functioning for patients who had achieved remission compared with patients who had achieved only a therapeutic response. Furthermore, responders continued to experience impairment after treatment, while remitters had levels of functioning that approached or matched that of healthy controls. An evaluation of Epidemiological Catchment Area data collected among more than 20 000 adults at 5 major psychiatric research centers across the United States revealed that patients with subsyndromal depressive symptoms experienced levels of impairment in multiple domains of functioning that were similar to those of patients with major depression.A retrospective evaluation of work outcomes in patients with depression demonstrated consistently better outcomes in both functional (absenteeism, decreased productivity, interpersonal friction) and affective (distress, disinterest, and dissatisfaction in the workplace) impairment for patients who achieved remission compared with those who did not.Analysis of data from a longitudinal study of depression in primary care revealed that, compared with remitters, patients who did not achieve remission had a lower probability of paid employment and were likely to miss more days of work due to illness or health care visits.In addition, the data suggested that remission might be associated with lower health care costs.Morbidity and MortalityFailure to achieve remission of symptoms has the potential to adversely affect physical health. Depressive symptoms have been associated with an increased risk for cardiac morbidity and mortality,poor glycemic control in type 1 or 2 diabetes mellitus,human immunodeficiency virus disease progression,increased risk of stroke mortality,and increased all-cause mortality.Neuroimaging StudiesNeuroimaging studies have shown decreased hippocampal volumes in patients with severe depression.Moreover, the degree to which hippocampal volume is decreased is correlated with the duration of the depressive episodes.The mechanism by which this occurs is unclear, but chronic activation of the stress response system, and hence chronically elevated glucocorticoid levels, is believed to have a role.Other research, however, has demonstrated no structural changes in the brains of patients with depression.Thus, the matter remains to be further studied and the findings replicated. Nevertheless, some evidence suggests that depression may, in fact, have cumulative and lasting deleterious effects on the brain, and that patients with prolonged periods of depression might be at an even higher risk for a chronic, recurrent course of depression. Achievement of remission, therefore, is critical for the successful long-term treatment of depression and should be considered the goal of therapy for depression as well as other mood disorders.CURRENT DIRECTIONS IN DEFINING REMISSIONDepressive SymptomatologyCurrent criteria distinguish between different degrees of improvement by using terms such as remission, response, and nonresponse. However, many questions remain unanswered. Is more specificity in identifying treatment outcomes warranted? For example, it may be beneficial to distinguish remitted patients who are asymptomatic from those who experience residual symptoms, thereby creating subtypes of remission. Most criteria (ie, HAM-D score ≤7; MADRS score ≤10) do not require that patients be asymptomatic to be considered in remission.However, there is evidence that among patients who meet remission criteria, those who report residual symptoms are likely to experience a more chronic course of illness,shorter time between episodes,more symptomatic weeks during follow-up,a decreased likelihood of recovery over time,and increased psychosocial and socioeconomic impairment.Furthermore, the presence of residual symptoms is associated with an increased likelihood of and shorter time to relapsecompared with asymptomatic remission and may also be associated with more frequent depressive episodes over time if untreated.Thus, the presence of even a minimal number of residual symptoms can have implications for treatment decisions, and the distinction between asymptomatic remission and remission with residual symptoms may warrant clarification.Psychosocial FunctioningA return to healthy functioning is part of the conceptual definition of remission.Is it reasonable to expect psychosocial impairment to resolve as a function of symptomatic improvement, or should specific measures of psychosocial functioning be included? In a study of the effects of sertraline and imipramine on functional impairment in patients with depression, the degree of improvement in psychosocial functioning was correlated with the degree of improvement of symptoms.Also, a study that evaluated work performance in patients with depression showed that impairment decreased substantially with the resolution of depressive symptoms.However, other evidence suggests that improvements in psychosocial functioning do not necessarily occur at the same rate as the amelioration of symptoms.An 8-month follow-up study of women with depression who had responded to treatment with imipramine found that considerable improvement in social adjustment did occur but more slowly than symptomatic improvement.Similar results were found in a 12-week acute treatment study that evaluated changes in depressive symptoms and in various domains of psychosocial functioning in patients with chronic forms of major depression in response to treatment with nefazodone, psychotherapy, or combination therapy.Prolonged psychosocial impairment may be more likely in patients with a chronic course of disease and those with higher HAM-D scores and functional impairment at baseline.Psychosocial functioning is an important outcome measure related to the level of remission that has been achieved. Because functioning may improve independently of depressive symptoms, it may warrant separate evaluation to determine whether patients have truly achieved a state of wellness.Relapse and RecurrenceShould the definition of remission include additional criteria to designate the duration of remission? Would separate classifications of short-term vs sustained remission be valid or practical for predicting outcomes such as relapse or recurrence?Currently, there is not a way to reliably predict which patients will have a relapse or recurrence or when this might occur.A 15-month longitudinal study of remitted patients reported a 40% rate of relapse but noted that all occurred during the first 10 months of follow-up.Naturalistic follow-up studies have reported relapse and recurrence rates for remitted patients of 19% at 6 months,37% within 1 year,from 25% to 40% within 2 years,and a cumulative rate of up to 85% after 15 years.Recent unpublished data suggest that a 4-week asymptomatic period is a strong predictor of a significantly lower probability of relapse (Lewis Judd, MD, unpublished data, January 10, 2003).Investigations have attempted to identify characteristics of recovered or remitted patients that are associated with an increased risk of relapse and recurrence. However, few variables have been identified. Residual depressive symptoms are probably one of the more reliable predictors of relapse or recurrence. Residual symptoms are relatively common and were reported in one study as present in 32% of remitters.As discussed earlier, residual symptomatology is strongly correlated with many poor outcomes, including increased risks for relapse or recurrence and shorter times between depressive episodes.Among asymptomatic patients, predicting the return of depressive illness is more difficult because there are few other factors that are highly correlated with relapse or recurrence.Some predictive characteristics were identified by naturalistic longitudinal studies from the Collaborative Program on the Psychobiology of Depression. This research has been following patients with mood disorders for more than 20 years with a prospective, naturalistic design and interview intervals of 6 months for 5 years and annually thereafter and has found that most patients have had multiple observed recoveries, relapses, and recurrences. Using the PSR scale, recovered patients include asymptomatic patients as well as those who experienced 1 or 2 symptoms to a mild degree.In these studies, an increased risk of relapse was associated with the presence of an underlying chronic depression for at least 2 years,and with an increased number of symptoms recalled from the worst previous episode.History of multiple previous episodes of depression was associated with an increased risk of relapse, a shorter time to relapse after recovery, and therefore an increased risk of multiple relapses.The association between multiple episodes of depression and an increased risk for relapse or recurrence was also demonstrated in a 10-year follow-up study that reported that the risk of recurrence increased 16% with each successive episode.Similar findings were demonstrated in a primary care population.Furthermore, there is evidence to suggest that with multiple episodes, the brain becomes more sensitized to the depressive state and the onset of future episodes is less related to stressful life events.Predicting outcomes in asymptomatic patients is further complicated by the return of subthreshold symptoms. For example, Collaborative Program on the Psychobiology of Depression data demonstrated that only 30% of recovered patients remained in recovery and symptom-free during 1 year of follow-up.Therefore, the risk for relapse may change over time as patients technically remain in remission but mild symptoms appear.Another factor in determining the probability of relapse or recurrence is the time course following discontinuation of treatment (either antidepressant treatment or psychotherapy). Evidence suggests that the risk for relapse is greatest shortly after recovery and decreases over time.Specifically, the risk of relapse is greatest during the first 3 to 6 months following recovery and declines slowly thereafter.Results of continuation and maintenance phase studies of antidepressant therapy have demonstrated that patients who had responded to an antidepressant and continued treatment with the full therapeutic dose were less likely to relapse than those who had their dose decreasedor who discontinued the drug.Thus, continuation and maintenance therapy with antidepressant medications has become accepted as the standard of care.Evidence also suggests that after 6 months, the risk for relapse or recurrence for patients whose treatment has been discontinued is not significantly more than that of patients who receive maintenance therapy.These data have prompted the observation that perhaps the value of maintenance therapy is limited.However, patients who have experienced multiple recurrences are at a significantly increased risk for future recurrences and would likely benefit from continued antidepressant therapy beyond 6 months after recovery.In addition, a 5-year study of maintenance treatment with imipramine demonstrated that patients who discontinued treatment after 3 years were at an increased risk of recurrence, and that treatment beyond 3 years continued to demonstrate a prophylactic effect.Currently, it is unclear whether maintenance therapy is associated with any benefits beyond a decreased risk of relapse or recurrence.PathophysiologyOne of the major obstacles to determining the best course of treatment for patients with depression or other mood disorders is the absence of a more comprehensive understanding of the pathophysiology of depressive illness, forcing physicians to rely on resolution of symptoms as a primary indicator of improvement. However, as is true for other chronic medical illnesses, it is important to view the symptom experience of the condition in the context of the complete disease state and overall function, as well as individual biological factors that may influence the long-term risk for poor outcomes.There is currently no objective way to evaluate a patient's underlying disease state. For example, unlike other disease states, there is no blood test or neuroimaging study that can determine if the treatment is merely controlling the symptoms of the condition or if the disease has been truly eliminated. Thus, we are unable to distinguish between an asymptomatic patient whose illness is being suppressed by medication and one who is disease-free. As knowledge of the neurobiology of depression and other mood disorders increases, advances can be made in diagnosis and assessment of treatment response.Current Recommendation for Remission as a Definition of Optimal Treatment OutcomeBecause there are currently limitations in the ability to assess pathophysiology, a system that gives primary consideration to symptoms but takes into account psychosocial functioning is recommended as the best approach to defining remission at this time. Thus, remission will continue to be based on descriptive and experiential phenomena until assessments of clinical status can be augmented with knowledge of the underlying neurobiological status. The proposed criteria for this recommendation are based on the data reviewed in this article on the impact of the presence and severity of residual symptoms and functioning on future psychopathological course and psychosocial functioning.Remission criteria should continue to be based primarily on significant reduction in the number and severity of symptoms, based on specific end points of either a HAM-D total score of 7 or less or a MADRS total score of 10 or less. However, a patient's status would be further classified based on the absence or presence of residual symptoms and the level of impairment of psychosocial functioning.The optimal outcome would be remission with the absence of both symptoms and functional impairment. Specifically, the remitted patient would be completely asymptomatic for at least 4 weeks (Lewis Judd, MD, unpublished data, January 10, 2003) and would experience restoration of healthy and complete functional status. A second classification would be included to identify patients who achieve remission with no symptoms but who have minimal impairment in psychosocial functioning. A third would include patients who achieve remission but continue to experience both symptoms and impairment in functioning to a mild degree. Currently, there are no data to suggest that a specific duration cutoff time to distinguish short-term vs sustained remission would be warranted to add additional predictive value.FUTURE DIRECTIONSResearch into associations between symptoms of mood disorders and biological processes has included attempts to identify potential markers of genetic risk for depression. Results of some studies have suggested that familial risk is most consistently associated with the recurrent subtype of major depression,and that patients who experience an early first onset of depression (ie, during childhood or adolescence) may be more likely to experience a recurrence during adulthood.In addition, several persistent biological perturbations have been investigated. Disturbances in the onset and duration of rapid eye movement sleep,dysfunction of the hypothalamic-pituitary-adrenal system,and elevated levels of corticotropin-releasing hormone in the cerebrospinal fluidhave been observed in patients with depression or other mood disorders.However, tests of these factors as potential diagnostic markers or as markers of response to treatment have produced variable findings. Thus, reliable and valid assessment tools based on biological markers remain to be identified.The focus of neurobiological research on depression and other mood disorders has shifted from the interaction between neurotransmitters and cell surface receptors to gene expression and structural and functional changes within the brain. Advances in genetics made possible by new tools and technology (eg, high-throughput genotyping via mass spectrometry, draft sequence of the human genome; comprehensive catalog of human genetic variation; intermediate phenotypes; biological traits, disease subtypes, and symptom clusters; new statistical methods; and large data sets) may provide a biological basis for a completely new diagnostic and classification system for mood disorders.Neuroimaging studies have thus far demonstrated structural and functional changes associated with depression (eg, decreased hippocampal volumes), but have not yet determined the clinical consequences of these findings. New structural and functional imaging techniques can provide a deeper understanding of brain disturbances related to depression and other disorders and, if used in conjunction with genetic research, may eventually identify patterns of brain function linked to particular genotypes.Future definitions of optimal treatment outcomes ideally will include 2 additional dimensions: pathophysiology and genetic modifiers. The latter would not be an outcome but an important way to categorize patients. Ultimately, remission criteria should include assessments of pathophysiological signs to evaluate the disease state and symptomatic and psychosocial improvement as well as genetics to discern who is disease-free vs who is merely improved for an interval, and who within the disease-free category remains at different levels of increased genetic risk of disease. Indeed, there may come a time when remission not only refers to the absence of symptoms, but also indicates a truly disease-free state based on neuroimaging and other types of assessments of brain structure and functioning.CONCLUSIONTreatment to remission is a concept that is not unique to mood disorders. The goals of treatment for various chronic medical illnesses essentially define remission for those disease states by serving as markers of wellness. Remission of symptoms serves as a marker of wellness for patients with mood disorders, and therefore remains the optimal treatment outcome for mood disorders.Continued work in descriptions of phenomenology as well as research in basic science may lead to a better diagnostic system and the ability to measure the underlying disease states of mood disorders. 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New York, NY: Oxford University Press; 1999:317-332.SJGarlowDLMusselmanCBNemeroffThe neurochemistry of mood disorders: clinical studies.In: Charney DS, Nestler EJ, Bunney BS, eds. Neurobiology of Mental Illnesss.New York, NY: Oxford University Press; 1999:348-364.Corresponding Author and Reprints:Martin B. Keller, MD, Department of Psychiatry and Human Behavior, Brown University, Box G-BH, Sawyer Bldg, 345 Blackstone Blvd, Providence, RI 02906 (e-mail: martin_keller@brown.edu).Acknowledgment:I thank Sherri D. Jones, PharmD, who assisted with literature research and provided writing and editorial assistance.Financial Disclosure:Dr Keller has received consultant fees, honoraria, and research grants from, and has served on advisory boards for, a number of pharmaceutical companies.

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JAMAAmerican Medical Association

Published: Jun 18, 2003

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