The sequential integration of pharmacotherapy and psychotherapy in the treatment of major depressive disorder: A meta-analysis of the sequential model and a critical review of the literature
Open accessAbstract
OBJECTIVE: A number of randomized controlled trials in major depressive disorder have employed a sequential model, which consists of the use of pharmacotherapy in the acute phase and of psychotherapy in its residual phase. The aim of this review was to provide an updated meta-analysis of the efficacy of this approach in reducing the risk of relapse in major depressive disorder and to place these findings in the larger context of treatment selection. METHOD: Keyword searches were conducted in MEDLINE, EMBASE, PsycINFO, and Cochrane Library from inception of each database through October 2014. Randomized controlled trials examining the efficacy of the administration of psychotherapy after successful response to acute-phase pharmacotherapy in the treatment of adults with major depressive disorder were considered for inclusion in the meta-analysis. RESULTS: Thirteen high-quality studies with 728 patients in a sequential treatment arm and 682 in a control treatment arm were included. All studies involved cognitive-behavioral therapy (CBT). The pooled risk ratio for relapse/recurrence was 0.781 (95% confidence interval [CI]=0.671-0.909; number needed to treat=8), according to the random-effects model, suggesting a relative advantage in preventing relapse/recurrence compared with control conditions. A significant effect of CBT during continuation of antidepressant drugs compared with antidepressants alone or treatment as usual (risk ratio: 0.811; 95% CI=0.685-0.961; number needed to treat=10) was found. Patients randomly assigned to CBT who had antidepressants tapered and discontinued were significantly less likely to experience relapse/recurrence compared with those assigned to either clinical management or continuation of antidepressant medication (risk ratio: 0.674; 95% CI=0.482-0.943; number needed to treat=5). CONCLUSIONS: The sequential integration of CBT and pharmacotherapy is a viable strategy for preventing relapse in major depressive disorder. The current indications for the application of psychotherapy in major depressive disorder are discussed, with special reference to its integration with pharmacotherapy.
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The studies that used a sequential design clearly indicated that the level of remission obtained by successful pharmacotherapy could be increased by a subsequent psychotherapeutic treatment.
“The studies that used a sequential design clearly indicated that the level of remission obtained by successful pharmacotherapy could be increased by a subsequent psychotherapeutic treatment 72 .”
From The pursuit of euthymia (2020) · cites this paper as [72]
The Sequential Integration of Psychotherapy and Pharmacotherapy section reports that psychotherapy after a successful response to acute-phase pharmacotherapy reduced relapse or recurrence relative to controls. The Sequential Treatment section also discusses improvement of residual symptoms. The paper does not establish that subsequent psychotherapy increased the level of remission achieved by pharmacotherapy; its pooled outcome was relapse or recurrence. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAdding CBT as ADMs are tapered off reduces the risk of subsequent relapse or recurrence.
“Adding CBT as ADMs are tapered off has also been shown to reduce the risk of subsequent relapse or recurrence (Guidi, Tomba, & Fava, 2015)”
From Risk factors for relapse and recurrence of depression in adults and how they operate: A four-phase systematic review and meta-synthesis (2018) · cites this paper as Guidi, Tomba, & Fava, 2015
Meta-analyses focusing on psychological relapse prevention interventions for depressive disorders indicate that these interventions are effective in preventing relapse, with reductions of 22-50% in relapse.
“Meta-analyses focusing on psychological relapse prevention interventions for depressive disorders indicate that these interventions are effective in preventing relapse, with reductions of 22–50% in relapse [18, 44–48].”
From Psychological interventions to prevent relapse in anxiety and depression: A systematic review and meta-analysis (2022) · cites this paper as [45]
The sequential design was subsequently used in a number of randomized controlled trials and was found to entail significant benefits in a meta-analysis.
“This design was subsequently used in a number of randomized controlled trials and was found to entail significant benefits in a meta-analysis 72 .”
From The pursuit of euthymia (2020) · cites this paper as [72]
Risk ratios were chosen because they are more conservative than odds ratios and can be easily compared with other systematic reviews.
“Risk ratios with 95% confidence intervals were chosen, as they are more conservative than odds ratios are [57], and they can be easily compared with other systematic reviews [18, 44–46].”
From Psychological interventions to prevent relapse in anxiety and depression: A systematic review and meta-analysis (2022) · cites this paper as [45]
The Data Synthesis section says the paper calculated risk ratios, but it does not compare them with odds ratios. Its statement that an approach is “more conservative” refers to the random-effects model versus the fixed-effects model, not to risk ratios versus odds ratios. The claim about comparison with other reviews is attributed to different citations in the citing sentence. (LLM, conf=0.76)
Experimental — accuracy not yet measured
When the sequential model involves antidepressant tapering and discontinuation, it presents the advantage of limiting antidepressant exposure.
“When the sequential model involves AD tapering and discontinuation, it presents the advantage of limiting AD exposure.63”
From May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance (2020) · cites this paper as [63]
The benefits of applying psychotherapeutic strategies after pharmacotherapy has yielded its effects become maximal when drug discontinuation by slow tapering is achieved.
“The benefits of applying psychotherapeutic strategies after pharmacotherapy has yielded its effects become maximal when drug discontinuation by slow tapering is achieved.63”
From May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance (2020) · cites this paper as [63]
The time needed for satisfactory remission can be shortened to 3 months before tapering if the sequential combination of pharmacotherapy and psychotherapy is employed.
“This time can be shortened to 3 months before tapering if the sequential combination of pharmacotherapy and psychotherapy is employed.63”
From May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance (2020) · cites this paper as [63]
Reducing or eliminating residual symptoms may improve the long-term outcome of depression.
“If prodromal symptoms may have a pathophysiological role in affective disorders and some residual symptoms may progress to become prodromal symptoms of relapse, then reduction or disappearance of residual symptomatology may entail a more favorable long-term outcome of depression.”
From Iatrogenic Factors in Psychopathology (2019) · cites this paper as [20]
Sequential treatment favorably affected the long-term course of depressive illness and symptom development.
“Sequential treatment was thus able to favorably affect the long-term course of depressive illness and the longitudinal development of symptoms (rollback phenomenon).”
From Iatrogenic Factors in Psychopathology (2019) · cites this paper as [20]
The rollback phenomenon was later supported in mood and anxiety disorder research and inspired sequential treatment.
“The rollback phenomenon was later substantiated in research on mood and anxiety disorders [18,19] and was the basic idea for developing the concept of sequential treatment [20].”
From Iatrogenic Factors in Psychopathology (2019) · cites this paper as [20]
Such vulnerabilities may manifest during treatment administration and/or after its discontinuation.
“Such vulnerabilities may manifest themselves during treatment administration and/or after its discontinuation.”
From The Deceptive Manifestations of Treatment Resistance in Depression: A New Look at the Problem (2020) · cites this paper as [43]
A major weakness of current RCT design is that it pays insufficient attention to prior treatments beyond response rates, especially iatrogenic comorbidity.
“A substantial weakness of the design of current RCT is the insufficient attention to previous treatments aside from response rates, with particular reference to iatrogenic comorbidity [43].”
From The Deceptive Manifestations of Treatment Resistance in Depression: A New Look at the Problem (2020) · cites this paper as [43]
The UKU scale considerably improved the detection of side effects because of its comprehensive nature.
“The UKU [57] is an example of a scale that considerably improved the detection of side effects because of its comprehensive nature.”
From Clinical Pharmacopsychology: Conceptual Foundations and Emerging Tasks (2017) · cites this paper as [57]
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“This has been trialled successfully by adding CBT as ADMs are discontinued (Guidi et al., 2015) and could be considered as a particularly protective option given the suggestion that long term ADM use can in some patients become a contributing factor in increasing risk for recurrence (Fava, 2003).”
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Self-citationEvidence-Based Applications of Combination Psychotherapy and Pharmacotherapy for Depression
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The Deceptive Manifestations of Treatment Resistance in Depression: A New Look at the Problem
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Deletion of serine racemase confers D-serine –dependent resilience to chronic social defeat stress
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Self-citationPoorer Long-Term Outcomes among Persons with Major Depressive Disorder Treated with Medication
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Psychotherapy in recurrent depression: efficacy, pitfalls, and recommendations
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Conceptual and Clinical Innovations of Well-being Therapy
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Depression in the Medically Ill
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Prediction of individual patient outcomes to psychotherapy vs medication for major depression
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Psychotherapie depressiver Störungen
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Time to rethink the approach to recurrent depression
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Self-citationMaking Therapy Widely Available: Clinical Research Triumph or Existential Catastrophe?
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An update on pharmacotherapy for recurrent depression in 2022
Belge, J.-B., Sabbe, A. C. F., & Sabbe, B. (2023) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2023.2223962 · Cited by 5 · see citing works
Supported self-help to prevent relapse or recurrence of depression: Who benefits most?
Dijkstra‐Kersten, S. M. A., Biesheuvel-Leliefeld, K. E. M., van der Wouden, J. C., van Schaik, A., Bosmans, J. E., van Marwijk, H., & van der Horst, H. E. (2019) · Journal of Affective Disorders · doi:10.1016/j.jad.2019.07.006 · Cited by 4 · see citing works
Fava, G. A. (2021) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000001468 · Cited by 4 · see citing works
Self-citationBalon, R. (2022) · Psychotherapy and Psychosomatics · doi:10.1159/000527693 · Cited by 4 · see citing works
Yasar, A. B. (2024) · Dusunen Adam The Journal of Psychiatry and Neurological Sciences · doi:10.14744/dajpns.2024.00232 · Cited by 3 · see citing works
- Authors
- Guidi, J., Tomba, E., & Fava, G. A.
- Affiliations
- University at Buffalo, State University of New York (US)
- Venue
- American Journal of Psychiatry
- Published
- 2016-02-01
- Volume
- 173
- Issue
- 2
- Pages
- 128-137
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- OpenAlex
- W2103319508
- Cited by
- 167
- References
- 85
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 14 · 2023: 8 · 2022: 13 · 2021: 17 · 2020: 20 · 2019: 15 · 2018: 20 · 2017: 32 · 2016: 12 · 2015: 1
- FWCI
- 2.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Social Sciences › Psychology › Clinical Psychology › Psychotherapy Techniques and Applications
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Keywords
- major depressive disorder, sequential therapy, pharmacotherapy, psychotherapy, cognitive behavioral therapy, relapse prevention, antidepressants, treatment selection
- MeSH terms
- Antidepressive Agents, Combined Modality Therapy, Major Depressive Disorder, Humans, Psychotherapy, Recurrence, Cognitive Behavioral Therapy, Secondary Prevention
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