Discontinuing Antidepressant Drugs: Lesson from a Failed Trial and Extensive Clinical Experience

Fava, Giovanni A.; Belaise, Carlotta

doi:10.1159/000492693

Cited by 58 publications

(79 citation statements)

References 67 publications

(130 reference statements)

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“…The explanatory power of pharmacokinetics is limited for these phenomena, even if we take zero-order kinetics into account (only a fixed amount of drug is eliminated in a given interval of time because enzymes for biotransformation and elimination are saturated). Tapering does not appear to affect the occurrence of withdrawal reactions with antidepressant drugs [39, 40] and persistent postwithdrawal disorders months after discontinuation may occur [41]. Further, dosage increase is unlikely to restore response after loss of clinical effect [42].…”

Section: The Concept Of Behavioral Toxicitymentioning

confidence: 99%

“…A pharmacodynamic consideration of the clinical phenomena related to antidepressant treatment was presented for the first time in this journal in 1995 [46] and was subsequently updated with an increasing number of studies supporting the model [41, 42, 47, 48]. According to the oppositional model of tolerance, continued drug treatment may recruit processes that oppose the initial acute effects of a drug.…”

Section: Pathophysiological Mechanisms Of Behavioral Toxicitymentioning

confidence: 99%

“…These processes may also propel the illness to a more malignant and treatment-unresponsive course, as with bipolar manifestations or paradoxical reactions. When drug treatment ends, oppositional processes may encounter no more resistance, resulting in the appearance of new withdrawal symptoms, rebound symptomatology, persistent postwithdrawal disorders, hypomania, and resistance to treatment if it is reinstituted [41, 42]. In the long run, antidepressant drugs may increase chronicity, vulnerability to depressive disorders, and comorbidity.…”

Section: Pathophysiological Mechanisms Of Behavioral Toxicitymentioning

confidence: 99%

“…If it is an adaptive response that mediates therapeutic actions at 2–4 weeks [49], it is also conceivable that further adaptive changes may occur at some later point in time. Such adaptive changes may take place through 5-HT1A autoreceptor activity [41], and/or be associated with the allosteric modulation of the serotonin transporter protein, which was recently detected with SSRIs such as paroxetine and escitalopram [50]. Genetic polymorphism in serotonin receptors such as 5-HT1A, 5-HT1B, and 5-HT2 may modulate the extent of opposing and compensatory processes to the initial effects of drugs [51].…”

Section: Pathophysiological Mechanisms Of Behavioral Toxicitymentioning

confidence: 99%

“…Second, withdrawal symptoms are likely to be misunderstood as indicators of impending relapse and may lead to unnecessary reinstitution of treatment [41]. Even when the nature of symptoms is correctly interpreted, the renewed prescription of the same antidepressant drug or a switch to fluoxetine, which is less likely to induce withdrawal problems and is commonly suggested [59], may worsen the state of behavioral toxicity with subsequent episodes of refractoriness to treatment.…”

Section: Cascade Iatrogenesismentioning

confidence: 99%

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Iatrogenic Factors in Psychopathology

Fava

Rafanelli

2019

Psychother Psychosom

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Section: The Concept Of Behavioral Toxicitymentioning

confidence: 99%

Section: Pathophysiological Mechanisms Of Behavioral Toxicitymentioning

confidence: 99%

Section: Pathophysiological Mechanisms Of Behavioral Toxicitymentioning

confidence: 99%

Section: Pathophysiological Mechanisms Of Behavioral Toxicitymentioning

confidence: 99%

Section: Cascade Iatrogenesismentioning

confidence: 99%

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Iatrogenic Factors in Psychopathology

Fava

Rafanelli

2019

Psychother Psychosom

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Sequential Combination of Pharmacotherapy and Psychotherapy in Major Depressive Disorder

Guidi

Fava

2021

JAMA Psychiatry

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IMPORTANCEThe sequential model emerged from the awareness that the persistence of residual symptoms and the frequent occurrence of psychiatric comorbidity were both associated with poor long-term outcome of major depressive disorder (MDD).OBJECTIVE To conduct an updated meta-analysis to examine the association of the sequential combination of pharmacotherapy and psychotherapy with reduced risk of relapse and recurrence in MDD.DATA SOURCES Keyword searches were conducted in PubMed, PsycInfo, Web of Science, and the Cochrane Library from inception of each database through November 2019. Reference lists from relevant studies were examined using the following keywords: sequential treatment, drugs and psychotherapy, combined treatment, continuation or maintenance, relapse or recurrence and prevention, and depress* or major depress*, selecting adults and randomized controlled trials as additional limits. Authors of selected articles were contacted if needed.STUDY SELECTION Randomized clinical trials examining the effectiveness of the sequential use of psychotherapy following response to acute-phase pharmacotherapy in the treatment of adult remitted patients with MDD were selected independently by 2 reviewers. DATA EXTRACTION AND SYNTHESISThe methods used fulfilled the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data extraction and methodologic quality assessment were conducted independently by the reviewers. Examination of the pooled results was performed based on the random-effects model. Heterogeneity between study results and likelihood of significant publication bias were assessed. Sensitivity analyses and meta-regressions were also run. MAIN OUTCOMES AND MEASURESThe primary outcome measures were relapse or recurrence rates of MDD, as defined by study investigators, at the longest available follow-up. RESULTSSeventeen randomized clinical trials met criteria for inclusion in the meta-analysis, with 1 study yielding 2 comparisons (2283 patients overall, with 1208 patients in a sequential treatment arm and 1075 in a control arm). The pooled risk ratio for relapse/recurrence of MDD was 0.84 (95% CI, 0.74-0.94), suggesting a relative advantage in preventing relapse/recurrence for the sequential combination of treatments compared with control conditions. CONCLUSIONS AND RELEVANCEThe results of this systematic review and meta-analysis indicate that the sequential integration of psychotherapy following response to acute-phase pharmacotherapy, alone or combined with antidepressant medication, was associated with reduced risk of relapse and recurrence in MDD. The preventive value of the sequential strategy relies on abatement of residual symptoms and/or increase in psychological well-being. The steps for implementing the sequential approach in remitted patients with recurrent MDD are provided.

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Exploring characteristics associated with first benzodiazepine prescription in patients with affective disorders and related diagnoses

Carlo

Grancini

Vismara

et al. 2019

Human Psychopharmacology

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Objective: In patients with affective disorders, benzodiazepines (BZDs) are frequently administered at the onset, sometimes inappropriately. We sought to identify clinical variables associated with first BZD prescription in a large sample of patients with affective disorders.Methods: Four hundred sixty patients with mood or anxiety disorders attending different psychiatric services were assessed comparing those who received BZD as first treatment (BZD w/) and those who did not (BZD w/o).Results: More than one third (35.7%) of the total sample had received BZDs as first prescription. In relation to mood disorders, BZD w/ subjects more frequently (a) had not a psychiatrist as first therapist, (b) had anxious symptoms at onset, (c) had adjustment disorder as first diagnosis, (d) were treated as outpatients. In relation to specific diagnoses, (a) personal decision of treatment for major depressive disorder, (b) outpatient status for bipolar disorder and (c) longer duration of untreated illness for adjustment disorder were more frequently associated with first BZD prescription. For anxiety disorders, the presence of stressful life events and the diagnoses of panic disorder or specific phobias were more frequently observed in BZD w/ patients. Conclusion:Patients with affective disorders frequently received BZDs as first prescription with significant differences between and within mood and anxiety disorders.

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Discontinuing Antidepressant Drugs: Lesson from a Failed Trial and Extensive Clinical Experience

Cited by 58 publications

References 67 publications

Iatrogenic Factors in Psychopathology

Iatrogenic Factors in Psychopathology

Sequential Combination of Pharmacotherapy and Psychotherapy in Major Depressive Disorder

Exploring characteristics associated with first benzodiazepine prescription in patients with affective disorders and related diagnoses

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