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Residual Symptoms in Depressed Patients Who Respond Acutely to Fluoxetine
Abstract
BACKGROUND: Antidepressants have unequivocal efficacy as compared with placebo, but many patients have residual symptoms despite a robust response to antidepressant therapy. The purpose of this study is to assess residual symptoms in outpatients who respond acutely to fluoxetine. METHOD: Two hundred and fifteen outpatients with major depressive disorder as assessed with the Structured Clinical Interview for DSM-III-R (SCID-P) were treated openly with fluoxetine 20 mg/day for 8 weeks. One hundred and eight (50.2%) were considered full responders (final 17-item Hamilton Rating Scale for Depression [HAM-D] score < or =7). Percentages of full responders who continued to have subthreshold or full major depressive disorder symptoms were calculated. The relationship between residual symptoms and Axis I and Axis II (assessed with SCID-II for personality disorders) comorbidity was assessed. RESULTS: Of the 108 responders, 19 (17.6%) had no subthreshold or threshold SCID-P major depressive disorder symptoms, while 28 (25.9%) had 1 symptom, and 61 (56.5%) had 2 or more symptoms. No statistically significant relationships were found between number of residual symptoms and selected Axis I comorbid conditions or total number of Axis II disorders. CONCLUSION: Less than 20% of full responders to fluoxetine by HAM-D criteria were free of all SCID-P subthreshold and threshold major depressive disorder symptoms after 8 weeks of treatment. While depressed patients benefit from antidepressants, most continue to have some symptoms of depression. The high prevalence of residual symptoms among antidepressant responders suggests the need for further study including whether residual symptoms abate with longer treatment or increased dose of fluoxetine. Other strategies, such as cognitive behavioral therapy, may be needed to address residual symptoms.
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“Longitudinal studies suggest that insomnia increases the risk of developing a psychiatric condition [6,40,41]; these studies also suggest that the treatment of the psychiatric condition does not necessarily resolve disturbed sleep [42,43].”
From Non-Pharmacological Treatment of Insomnia (2012) · cites this paper as [42]
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BackgroundA randomized clinical trial of exercise to alleviate postpartum depressed mood
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“Residual symptoms such as depression and anxiety are also common, with numerous studies showing that over 50% of patients in remission report two or more residual symptoms (Miller et al., 1998; Nierenberg et al., 1999; Nil et al., 2016).”
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“For example, in a study of 215 patients with major depressive disorder who received fluoxetine for 8 weeks, 108 were found to be in remission (HAMD # 7).(6) Of these, however, only 18% had no threshold or subthreshold symptoms of major depression, while 26% had one residual symptom, and over half (57%) still had 2 or…”
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“Standard medications for these disorders, such as selective serotonin reuptake inhibitors, have demonstrated little effect and may even worsen anhedonia (McCabe, Mishor, Cowen, & Harmer, 2010; McClintock et al., 2011; Nierenberg et al., 1999; Price, Cole, & Goodwin, 2009).”
BackgroundDiagnosis and Management of Insomnia in Older People
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“In fact, insomnia is the most common residual symptom of depression in those who otherwise have been successfully treated with fluoxetine.(9) Although hypnotics and other pharmacological therapies may sometimes be appropriate as first-line intervention for primary insomnia, in most cases, nonpharmacological therapies…”
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“…2014); (3) disturbed sleep moderates depression treatment (Dew et al., 1997); (4) treatment of either one leaves residual symptoms of the other (Lichstein, Wilson, & Johnson, 2000; Nierenberg et al., 1999); and (5) residual subjective poor sleep beckons depression relapse (Buysse et al., 1996).”
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“Second, insomnia is a common residual symptom of SSRI treatment (Nierenberg et al. 1999 ; Iovieno et al. 2011 ; McClintock et al. 2011) and is associated with an increased risk of recurrence of a depressive episode in patients treated with SSRIs (Fava et al. 1990 ; Perlis et al. 1997 ; Riemann &…”
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“For example, in a study of patients with MDD treated with fluoxetine who had fully responded to treatment, at least 20% still had residual symptoms, as identified through the Structured Clinical Interview for DSM-III-R.”
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Zajecka, J., Kornstein, S. G., & Blier, P. (2013) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.12059ah1 · Cited by 65
“The neurochemical rationale for adjunctive treatments for MDD generally involves (1) increasing the effects of 1 or more neurotransmitters (eg, 5-HT, NE, DA, γ-aminobutyric acid, glutamate) and/or (2) modulating the activity of receptors that may affect specific symptomatic and side effect domains, either directly or…”
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“Because of this and because several diagnostic criteria for MDD are not included on the HRSD, a conceptual problem arises in that some patients simultaneously meet criteria for minor depression or MDD and also are considered to be in remission.(32,33) There is something wrong with an outcome tool, or the definition of…”
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BackgroundSelf-citationTreatment of sleep dysfunction and psychiatric disorders
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“A cutoff of 7 on the Hamilton depression scale allows for the presence of residual symptoms, and some patients even qualify for a depressive disorder diagnosis (5).”
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Thase, M. E., Trivedi, M. H., Nelson, J. C., D, M. F. M., Swanink, R., Tran, Q.-V., Pikalov, A., Yang, H., Carlson, B. X., Marcus, R. N., et al. (2008) · The Primary Care Companion to The Journal of Clinical Psychiatry · doi:10.4088/pcc.v10n0603 · Cited by 48
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“patients considered to be treatment ‘responders’ using conventional outcome measures in clinical trials may still present with persistent subthreshold symptoms or clusters of depressive symptoms that ultimately impede their ability to reengage in usual activities (Nierenberg et al., 1999).”
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“Nierenberg and his colleagues assessed the prevalence of residual symptoms in a sample of 215 patients taking open-label fluoxetine 20 mg for 8 weeks; of the original sample, 108 achieved remission (HAMD-17 score≤7), yet 44% continued to complain of problems with sleep (Nierenberg et al., 1999).”
BackgroundLong-term use of hypnotics: Analysis of trends and risk factors
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“In this context, it is noteworthy that a high proportion of both recovered and non-recovered BPD subjects had clinically significant sleep disturbance, suggesting that resolution of sleep disturbance is not required for recovery from BPD, and that comorbid sleep disturbance may be a frequent residual problem in BPD, a…”
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“joint pain are also commonly reported by patients under remission from depression (Opdyke et al., 1996; Nierenberg et al., 1999; Gasto et al., 2003; Carney et al., 2007; Merens et al., 2008).”
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Current Nosology of Treatment Resistant Depression: A Controversy Resistant to Revision
Fornaro, M., & Giosuè, P. (2010) · Clinical Practice and Epidemiology in Mental Health · doi:10.2174/1745017901006010020 · Cited by 43
“Finally, it is also worth noting that while partial or non-response are common, residual symptoms among remitters are also highly prevalent [12, 13], being usually associated with poorer psychosocial functioning [14] as well as an increased relapse rates [15], higher suicidal ideation and attempts, higher number of li…”
BackgroundChung, K., Yu, B. Y.-M., Yung, K.-P., Yeung, W., Ng, T. H., & Ho, F. Y. (2014) · Comprehensive Psychiatry · doi:10.1016/j.comppsych.2014.06.006 · Cited by 42
Insomnia: Prevalence, Impact, Pathogenesis, Differential Diagnosis, and Evaluation
Becker, P. M. (2006) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2006.08.001 · Cited by 44
Vichaya, E. G., Laumet, G. O., Christian, D. L., Grossberg, A. J., Estrada, D. J., Heijnen, C. J., Kavelaars, A., & Dantzer, R. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0075-z · Cited by 42
Development of a clinical global impression scale for fatigue
Targum, S. D., Hassman, H. H., Pinho, M., & D, M. F. M. (2012) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2011.12.001 · Cited by 41
“Fatigue is a common symptom in the general population and often associated with comorbid Axis I psychiatric disorders, particularly depression (Nierenberg et al., 1999; Walker et al., 1993; Fava, 2003; Sevy et al., 2005; McIntyre et al., 2006; Harvey et al., 2009; Ferrentinos et al., 2010).”
BackgroundInfluentialSelf-citationStahl, S. M. (2010) · CNS Spectrums · doi:10.1017/s1092852900027334 · Cited by 40
Impact of sleep disturbance on patients in treatment for mental disorders
Kallestad, H., Hansen, B., Langsrud, K., Ruud, T., Morken, G., Stiles, T. C., & Gråwe, R. W. (2012) · BMC Psychiatry · doi:10.1186/1471-244x-12-179 · Cited by 40
“; licensee BioMed Centr Commons Attribution License (http://creativec reproduction in any medium, provided the or may precede depression [8-10], and 40% to 70% of patients who are successfully treated for depression experience sleep disturbance as a residual symptom [11-13].”
BackgroundTackling sleeplessness: psychological treatment options for insomnia in older adults
McCrae, C. (2010) · Nature and Science of Sleep · doi:10.2147/nss.s7064 · Cited by 40
“24,25 While not routinely recommended as part of the assessment for insomnia, polysomnography (PSG) can be used to diagnose the presence of additional sleep disorders, such as obstructive sleep apnea (OSA) or periodic limb movement disorder (PLMD).”
Cognitive Behavioral Therapy for Insomnia in Older Adults
Bélanger, L., LeBlanc, M., & Morin, C. M. (2011) · Cognitive and Behavioral Practice · doi:10.1016/j.cbpra.2010.10.003 · Cited by 39
“Evidence rather shows that insomnia often persists in patients with chronic conditions receiving standard care (Katz & McHorney, 1998; Nierenberg et al., 1999).”
Chronic insomnia: Recent advances and innovations in treatment developments and dissemination.
Morin, C. M. (2010) · Canadian Psychology/Psychologie canadienne · doi:10.1037/a0018715 · Cited by 39
“Another study found that insomnia (with fatigue) was the most common residual symptom amongst patients treated for major depression (Nierenberg et al., 1999) and some have suggested that persistent sleep disturbances may be a risk factor for future relapse (Perlis, Giles, Buysse, Tu, & Kupfer, 1997).”
BackgroundPineal gland volume in schizophrenia and mood disorders.
Fındıklı, E., İnci, M. F., Gökçe, M., Fındıklı, H. A., Altun, H., & Karaaslan, M. F. (2015) · PubMed · Cited by 38
The Role of Depression in the Uptake and Maintenance of Cigarette Smoking
Audrain-McGovern, J. E., Leventhal, A. M., & Strong, D. R. (2015) · International review of neurobiology · doi:10.1016/bs.irn.2015.07.004 · Cited by 40
“This is not surprising given that 30–50% of those who remit from an episode of MDD will continue to experience depressive symptomatology (Bothwell & Scott, 1997; Fawcett, 1994; Nierenberg et al., 1999).”
BackgroundCircadian rhythms and psychiatric illness
Asarnow, L. D., Soehner, A. M., & Harvey, A. G. (2013) · Current Opinion in Psychiatry · doi:10.1097/yco.0b013e328365a2fa · Cited by 38
“Sleep and circadian disturbances are risk factors for the onset of psychiatric disorders [4], precursors of relapse [5], and associated with residual symptoms [6] and treatment resistance [7].”
Backgroundten Have, M., Penninx, B. W. J. H., van Dorsselaer, S., Tuithof, M., Kleinjan, M., & de Graaf, R. (2016) · Sleep Medicine · doi:10.1016/j.sleep.2016.07.015 · Cited by 40
Rethorst, C. D., GREER, T. L., Toups, M. S. P., Bernstein, I. H., Carmody, T. J., & Trivedi, M. H. (2015) · Translational Psychiatry · doi:10.1038/tp.2015.104 · Cited by 38
Effort-based decision-making is affected by overweight/obesity in major depressive disorder
Mansur, R. B., Subramaniapillai, M., Zuckerman, H., Park, C., Iacobucci, M., Lee, Y. L., Tuineag, M., Hawco, C. S., Frey, B. N., Rasgon, N., et al. (2019) · Journal of Affective Disorders · doi:10.1016/j.jad.2019.06.002 · Cited by 42
Novel tetrahydroisoquinolines are histamine H3 antagonists and serotonin reuptake inhibitors
Letavic, M. A., Keith, J. M., Jablonowski, J. A., et al. (2006) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2006.11.036 · Cited by 36
A Critical Review of Model-Based Economic Studies of Depression
Afzali, H. H. A., Karnon, J. D., & Gray, J. (2012) · PharmacoEconomics · doi:10.2165/11590500-000000000-00000 · Cited by 35
Metadata
- Authors
- Nierenberg, A. A., Keefe, B. R., Leslie, V. C., Alpert, J. E., Pava, J. A., Worthington, J. J., Rosenbaum, J. F., & Fava, M.
- Affiliations
- Massachusetts General Hospital (US)
- Harvard University (US)
- Venue
- The Journal of Clinical Psychiatry
- Publisher
- Physicians Postgraduate Press, Inc
- Published
- 1999-04-15
- Volume
- 60
- Issue
- 4
- Pages
- 221-225
- ISSN
- 0160-6689 (ISSN-L)
- OpenAlex
- W2056454671
- Cited by
- 470
- References
- 0
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 13 · 2023: 13 · 2022: 11 · 2021: 10 · 2020: 9 · 2019: 19 · 2018: 10 · 2017: 8 · 2016: 16 · 2015: 22 · 2014: 17 · 2013: 19 · 2012: 30
- FWCI
- 3.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1r01mh048483-01a1)
- National Institute of Mental Health (R01 MH48483-01)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Health Sciences › Medicine › Psychiatry and Mental health › Mental Health Treatment and Access
- Keywords
- residual depressive symptoms, fluoxetine, major depressive disorder, antidepressant response, subthreshold depression, comorbidities, personality disorders, outpatients, cognitive behavioral therapy
- MeSH terms
- Adult, Ambulatory Care, Depressive Disorder, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Fluoxetine, Humans, Male, Middle Aged, Personality Disorders, Psychiatric Status Rating Scales, Comorbidity, Cognitive Behavioral Therapy, Prevalence, Treatment Outcome, Selective Serotonin Reuptake Inhibitors, Age of Onset
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