CoChat
Sign Up
Cited by 80Treatment of Major DepressionBipolar Disorder and TreatmentPsychological Treatments and Disorders

The emergence of loss of efficacy during antidepressant drug treatment for major depressive disorder: An integrative review of evidence, mechanisms, and clinical implications

Open access
Fornaro, Michele, Anastasia, Annalisa, Novello, Stefano, Fusco, Andrea, Pariano, Riccardo, De Berardis, Domenico, Solmi, Marco, Veronese, Nicola +5 more·2019·Pharmacological Research
DOI 10.1016/j.phrs.2018.10.025
Open this paper in CoChat — free account

Abstract

&NA; The re‐emergence (i.e. ‘breakthrough’) of depressive symptoms despite maintenance treatment of depression with antidepressant drugs is a complex clinical phenomenon referred to as tolerance. Herein we critically appraise evidence from both pre‐clinical and clinical studies, focusing on putative mechanisms as well as clinical correlates and implications of the emergence tolerance during antidepressant treatment for major depressive disorder (MDD). It is firstly unclear to what extent this phenotype reflects a pharmacological effect of an antidepressant, is driven by non‐adherence, is a marker of latent bipolarity or another comorbidity, a marker of neuroprogression of the underlying disorder or the intrusion of the impact of psychosocial variables into the clinical course. The operational definitions of tolerance and its related phenomena have also been largely inconsistent. Several protective clinical indicators have been proposed, including a rapid‐cycling course and comorbid chronic anxiety, whilst poor treatment adherence, proneness to emotional blunting and sub‐threshold bipolarity have been identified as possible correlates of tolerance to antidepressant treatment in MDD. Putative neurobiological underpinnings include adaptations in the hypothalamic–pituitary–adrenal (HPA) axis and the serotonergic system. Due to the clinical and diagnostic challenges imposed by the emergence of tolerance to antidepressants, there is an urgent need for upcoming international guidelines to reach a consensus on operational definitions for this complex clinical phenomenon, thus enabling a more precise appreciation of the incidence and correlates of tolerance to antidepressants. Taken together, the present review underscores the need to cautiously weight benefits and risks prior to considering long‐term antidepressant treatment for patients with MDD as tolerance may emerge in a subset of patients.

AI snapshot

Written from the paper’s full text.

TL;DR

This integrative review critically appraises evidence on loss of efficacy/tolerance during antidepressant maintenance treatment for major depressive disorder (MDD), including definitions, mechanisms, clinical correlates, and implications. It concludes that tolerance may emerge in a subset of patients and contribute to worse outcomes, but inconsistent definitions and limited long-term controlled data prevent precise estimates.

Key findings

  • Return of depressive symptoms during maintenance antidepressant treatment has been reported in 9–33% of patients across published trials; the National Institute of Mental Health Collaborative Depression Study reported tolerance in up to 25% (43 of 171 subsequent episodes) among 103 patients with MDD over a 20-year follow-up.
  • Among 149 non-refractory patients with MDD, the odds of response decreased by 20% after each prior antidepressant treatment exposure; reported cases often had an average duration of remission of approximately 24 weeks.
  • Proposed correlates and warning signs include poor treatment adherence, emotional blunting, subthreshold bipolarity, rapid-cycling course, and comorbid chronic anxiety; putative mechanisms include pharmacokinetic and pharmacodynamic tolerance, serotonergic and HPA-axis adaptations, the oppositional model of tolerance, neuroplasticity changes, and psychosocial stressors.
  • In STAR*D, when sustained recovery was considered, the cumulative rate was only 43%; in steps 3 and 4, nearly half of those remitting subsequently relapsed.

Methods

  • Integrative review. PubMed was searched from inception through July 23, 2018 using terms including “antidepressant tolerance,” “antidepressant poop out/up,” “antidepressant tachyphylaxis,” “loss of efficacy,” “antidepressant withdrawal,” “antidepressant wear-off,” and “breakthrough depression”; the search was manually augmented with “withdrawal,” “sensitization,” “switching,” and “treatment-resistant (depression).” Scopus, ClinicalTrials.gov, Cochrane Library, PsycINFO, and Web of Science were also searched from inception through June 21, 2018.
  • Eligible studies included primary and secondary research providing qualitative or quantitative information about tolerance to drugs used for depression and related phenomena, including both preclinical and clinical studies.
  • The paper narratively and critically synthesizes evidence on definitions, mechanisms, clinical correlates, and implications; no meta-analysis is reported.

Limitations

  • The paper states that operational definitions of tolerance and related phenomena are largely inconsistent; terms such as relapse and recurrence are often used interchangeably, maintenance timeframes are often shorter than 52 weeks, and evidence is largely naturalistic, uncontrolled, retrospective, or anecdotal.
  • The paper states that it could not stratify findings by antidepressant pharmacological class, that head-to-head comparisons across classes are lacking, and that genetic underpinnings of antidepressant tolerance remain unknown.
  • The text makes evident that, as an integrative/narrative review, it does not report a formal risk-of-bias assessment or quantitative synthesis, so conclusions depend on heterogeneous included literature.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.phrs.2018.10.025

Cites

95 of 95 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 80 cited sources checked · 0 supported · 0 flagged

  • Premisecitation
    § ACCEPTED MANUSCRIPT · p. 11

    The occurrence of antidepressant-induced manic switch even among unipolar depressed patients is well documented.

    “The occurrence of the antidepressant-induced manic switch even among unipolar depressed patients is well documented [24]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] source

      Not checked in the free run.

  • Interpretationcitation
    § ACCEPTED MANUSCRIPT · p. 12

    There is a disconnect between mechanisms of possible tolerance and withdrawal.

    “suggesting a disconnect between mechanisms of possible tolerance and withdrawal [32].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] source

      Not checked in the free run.

  • Premisenone given
    § 3. Frequency and clinical correlates of tolerance to antidepressants during the treatment of MDD · p. 10

    Estimates of the rates of tolerance and related phenomena essentially rely on anecdotal reports or naturalistic studies rather than on controlled trials.

    “The estimation of the rates of tolerance and related phenomena essentially rely on anecdotal reports or otherwise naturalistic studies, rather than on controlled trials.”
    Quote in the paperNot a substantial claim
  • Interpretationcitation
    § 3. Frequency and clinical correlates of tolerance to antidepressants during the treatment of MDD · p. 10

    A proportion of depressed patients receiving maintenance treatment with antidepressant drugs appear to develop genuine tolerance to antidepressants.

    “Nevertheless, a proportion of depressed patients receiving maintenance treatment with antidepressant drugs appear to develop 'genuine' tolerance to antidepressants.”
    Quote in the paperSubstantial claim
  • Premisecitation
    § 3. Frequency and clinical correlates of tolerance to antidepressants during the treatment of MDD · p. 10

    The true rates of tachyphylaxis during continuation treatment with drugs for depression for MDD may be lower than once thought.

    “Moreover, the true rates of tachyphylaxis occurring during continuation treatment with drugs for depression for MDD may be lower than once thought [19]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] [19] M. Zimmerman, T. Thongy, How often do SSRIs and other new-generation antidepressants lose their effect during continuation treatment? Evidence suggesting the rate of true tachyphylaxis during continuation treatment is low, The Journal of clinical psychiatry 68(8) (2007) 1271-1276. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 31
  • May combine two claims. 34
  • The quote only partly states this claim. 1

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given
    § 3. Frequency and clinical correlates of tolerance to antidepressants during the treatment of MDD · p. 10

    Many studies of tolerance do not take into account that relapse is driven by a multitude of causes, even in one individual.

    “An important caveat is that many of these studies don not take into account that relapse is driven by a multitude of causes, even in one individual.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § ACCEPTED MANUSCRIPT · p. 11

    Some cases of apparent tolerance may actually be due to long-term withdrawal or dependence, which may be affected by poor compliance to prescribed antidepressants.

    “Yet it has been postulated that some cases of apparent tolerance may actually be due to long-term withdrawal or dependence which may, in turn, be affected by poor compliance to prescribed drugs for depression [2, 6].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] [2] G.A. Fava, E. Offidani, The mechanisms of tolerance in antidepressant action, Progress in NeuroPsychopharmacology and Biological Psychiatry 35(7) (2011) 1593-1602. source

      Not checked in the free run.

    • cites [6] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § ACCEPTED MANUSCRIPT · p. 11

    Lieb and Balter described the emergence of refractoriness in some patients with MDD to previously efficacious antidepressants, and changing treatment to another antidepressant yielded time-limited therapeutic benefits.

    “In 1984, Lieb and Balter [31] described the emergence of refractoriness in some patients with MDD to drugs for depression that had been previously efficacious. Changing treatment to another antidepressant drug yielded some therapeutic benefits, although timelimited.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § ACCEPTED MANUSCRIPT · p. 12

    A potential detrimental manifestation of long-term treatment with antidepressants may be the emotional blunting phenomenon or otherwise depressogenic phenomena.

    “A potential detrimental manifestation of long-term treatment with antidepressants may be the emotional blunting phenomenon (vide infra) or otherwise 'depressogenic' phenomena [33-36].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [33] source

      Not checked in the free run.

    • cites [34] source

      Not checked in the free run.

    • cites [35]

      Not checked in the free run.

    • cites [36] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 3. Frequency and clinical correlates of tolerance to antidepressants during the treatment of MDD · p. 10

    The majority of cases reported in the literature set an average duration of remission of approximately 24 weeks, so that the actual maintenance duration criterion is not consistently met.

    “In addition, the majority of cases reported in the literature set an average duration of remission of approximately 24 weeks [22], so that the actual 'maintenance' duration criterion is not consistently met [23].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] source

      Not checked in the free run.

    • cites [23]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 1. Introduction · p. 6

    The return of depressive symptoms of MDD occurs in 9-33% of patients across published trials, and up to 9-33% of patients with MDD may develop tolerance to antidepressants.

    “with the return of depressive symptoms of MDD occurring in 9-33% of patients across published trials [3].”
    • Also stated in: § 3. Frequency and clinical correlates of tolerance to antidepressants during the treatment of MDD · p. 10 · hedged
      “It has been estimated that up to 9 to 33% of patients with MDD may develop tolerance to antidepressants [3] as formulated by Fava in 1994 [6].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] [3] S.E. Byrne, A.J. Rothschild, Loss of antidepressant efficacy during maintenance therapy: possible mechanisms and treatments, The Journal of clinical psychiatry (1998). [4] L. Franchini, D. Rossini, F. Bongiorno, C. Spagnolo, E. Smeraldi, R. Zanardi, Will a second prophylactic treatment with a higher dosage of the same antidepressant either prevent or delay new depressive episodes?, Psychiatry research 96(1) (2000) 81-85. [5] S. Byrne, A.J. Rothschild, Psychiatrists' responses to failure of maintenance therapy with antidepressants, Psychiatric services (Washington, DC) 48(6) (1997) 835-837. source

      Not checked in the free run.

    • cites [6] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given
    § 4. Potential mechanisms and models of tolerance to antidepressants · p. 13

    Pharmacokinetic and pharmacodynamic adaptations have been repeatedly advocated as a core mechanism of pharmacological tolerance to antidepressants.

    “Specifically, pharmacokinetic and pharmacodynamic adaptations have been repeatedly advocated as a core mechanism of pharmacological tolerance to antidepressants.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § ACCEPTED MANUSCRIPT · p. 16

    Serotonergic receptors operating through auto-receptors (5-HT1A, 5-HT1B, α2-adrenoceptors) and postsynaptic receptors (e.g., 5-HT3) may account for the delayed onset of antidepressant treatment response.

    “operating through auto-receptors (5-HT1A, 5-HT1B, α2-adrenoceptors) and postsynaptic receptors (e.g., 5-HT3) may account for the delayed onset of antidepressant treatment response.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § ACCEPTED MANUSCRIPT · p. 16

    The role of 5HT-1 and 5HT2 receptors in the development of tolerance to drugs for depression has been postulated.

    “the role of 5HT-1 and 5HT2 receptors in the development of tolerance to drugs for depression has been likewise postulated [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] [2] G.A. Fava, E. Offidani, The mechanisms of tolerance in antidepressant action, Progress in NeuroPsychopharmacology and Biological Psychiatry 35(7) (2011) 1593-1602. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 4.2. Pharmacodynamic tolerance · p. 14

    Glutamate is a major tonic/phasic release regulator of serotonin, dopamine, and norepinephrine, meaning that pharmacodynamic tolerance involves more than a handful of monoamines and/or multiple sites, timing and regulators.

    “For example, the glutamate is a major tonic/phasic release regulator or serotonin, dopamine, and norepinephrine, meaning that the phenomenon of pharmacodynamic tolerance takes more than a handful of monoamine, and/or multiple sites, timing and regulators [42].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § ACCEPTED MANUSCRIPT · p. 7

    Most trials assessing the efficacy, safety, and tolerability of antidepressants are of short duration (acute trials), while there is a relative paucity of long-term maintenance antidepressant trials.

    “Moreover, most trials assessing the efficacy, safety, and tolerability of antidepressants are of short duration (i.e., acute trials), while there is a relative paucity of long-term (i.e., maintenance) antidepressant trials.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § ACCEPTED MANUSCRIPT · p. 18

    Hippocampal neurogenesis has been mechanistically implicated in the mechanism of action of drugs for depression, and chronic exposure to drugs for depression may alter this process.

    “neurogenesis has been mechanistically implicated in the mechanism of action of drugs for depression and that the chronic exposure to drugs for depression may alter this process [57, 58].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [57] source

      Not checked in the free run.

    • cites [58] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § ACCEPTED MANUSCRIPT · p. 16

    Down-regulation of 5HT2 post-synaptic receptors, proposed as one final pathway driving therapeutic effects of antidepressants, may facilitate 5HT1 receptor neurotransmission, which may activate the HPA axis with increased ACTH and cortisol.

    “Hence a down-regulation of 5HT2 post-synaptic receptors which has been proposed as one of the final pathways driving therapeutic effects of different antidepressant [50] may facilitate 5HT1 receptor neurotransmission, which in turn may activate the HPA axis with an increased production of adrenocorticotropic hormone (ACTH) and cortisol [51].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [50] source

      Not checked in the free run.

    • cites [51] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § ACCEPTED MANUSCRIPT · p. 15

    Tolerance to antidepressants is a heterogeneous clinical phenomenon, with tolerance to specific side effects or recurrence of specific symptom dimensions depending on the receptor reserve at particular brain networks.

    “This may explain why tolerance to antidepressants is a heterogeneous clinical phenomenon”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § ACCEPTED MANUSCRIPT · p. 11

    The current concept of treatment-resistance to drugs for depression refers to acute treatment of depression and may poorly fit the maintenance phase of MDD treatment.

    “This is compelling taking into consideration that the current concept of treatment-resistance to drugs for depression refers to the acute treatment of depression and may poorly fit the maintenance phase of MDD treatment.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given
    § 4. Potential mechanisms and models of tolerance to antidepressants · p. 13

    The mechanisms of tolerance to antidepressant drugs are yet to be fully elucidated.

    “The mechanisms of tolerance to antidepressant drugs are yet to be fully elucidated.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § ACCEPTED MANUSCRIPT · p. 17

    Depression is characterized by hampered hippocampal neurogenesis and cortical synaptogenesis, with high recurrence rates and chronicity possibly induced by altered trophic support following stressor-induced reduced activity of growth factors, especially BDNF.

    “depression is characterized by hampered hippocampal neurogenesis and cortical synaptogenesis, with high recurrence rates and chronicity possibly induced by altered trophic support following stressor-induced reduced activity of growth factors, especially the brain-derived neurotrophic factor (BDNF) [56].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given
    § ACCEPTED MANUSCRIPT · p. 15

    The function and density of a given receptor may vary depending on the organ system in which it is located.

    “A possible explanation for this latter observation is that the function (inhibitory or excitatory) and density of a given receptor may vary depending on the organ system in which it is located.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § ACCEPTED MANUSCRIPT · p. 15

    In psychopharmacology, a relatively successful model is the loss of effect of antipsychotics linked to dopamine D2 receptor transition from low- to high-affinity state, although a similar model with translational value for antidepressant tolerance is lacking.

    “Notably, in the field of psychopharmacology, a relatively successful model is represented, in the example, by the loss of effect of the antipsychotics linked to dopamine D2 receptor transition from low to high-affinity state [43], although a similar model with potential translational value for antidepressant tolerance is lacking.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § 4. Potential mechanisms and models of tolerance to antidepressants · p. 13

    Activation of processes driving tolerance to antidepressant drugs may occur to varying degrees in every patient receiving antidepressants, and may only manifest and be recognized in patients with chronic and recurrent forms of depression who had previously responded to antidepressant therapy.

    “For instance, it was postulated that the activation of processes driving tolerance to antidepressant drugs may occur to at varying degrees in every patient receiving antidepressants [3], may only manifest themselves and then be recognized in patients with chronic and recurrent forms of depression who had previously responded to antidepressant therapy at some time [37].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] [3] S.E. Byrne, A.J. Rothschild, Loss of antidepressant efficacy during maintenance therapy: possible mechanisms and treatments, The Journal of clinical psychiatry (1998). [4] L. Franchini, D. Rossini, F. Bongiorno, C. Spagnolo, E. Smeraldi, R. Zanardi, Will a second prophylactic treatment with a higher dosage of the same antidepressant either prevent or delay new depressive episodes?, Psychiatry research 96(1) (2000) 81-85. [5] S. Byrne, A.J. Rothschild, Psychiatrists' responses to failure of maintenance therapy with antidepressants, Psychiatric services (Washington, DC) 48(6) (1997) 835-837. source

      Not checked in the free run.

    • cites [37]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § 4.2. Pharmacodynamic tolerance · p. 14

    Tolerance to antidepressant drugs involves multiple pharmacological mechanisms at the receptor and signal transduction level, both at pre- and post-synaptic levels.

    “Tolerance to antidepressant drugs involves multiple pharmacological mechanisms at the receptor and signal transduction level, both at pre- and post-synaptic levels.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Pharmacodynamic tolerance depends only on pharmacological properties of the drug.

  • Probably not a substantial claim: may not pass S1 (asserted). May combine two claims. The quote only partly states this claim.

    Interpretationcitation
    § ACCEPTED MANUSCRIPT · p. 16

    Some neurobiological mechanisms related to the therapeutic effects of drugs for depression (e.g., down-regulation of post-synaptic 5HT2 receptors) may, under specific conditions, trigger changes in post-receptor signal transduction pathways or neuronal architecture, leading to impaired balance and function of serotonin receptors and contributing to tolerance.

    “It has been hypothesized that some neurobiological mechanisms related to the therapeutic effects of drugs for depression (e.g. a down-regulation of post-synaptic 5HT2 receptors) may, under specific conditions, trigger changes in post-receptor signal transduction pathways”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] [2] G.A. Fava, E. Offidani, The mechanisms of tolerance in antidepressant action, Progress in NeuroPsychopharmacology and Biological Psychiatry 35(7) (2011) 1593-1602. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § Abstract · p. 5

    Operational definitions of tolerance and related phenomena are largely inconsistent, with no univocal definitions for tachyphylaxis or other tolerance-related phenomena apart from Rothschild's criteria.

    “The operational definitions of tolerance and its related phenomena have also been largely inconsistent.”
    • Also stated in: § ACCEPTED MANUSCRIPT · p. 7 · plain
      “Apart from the notable exception of the criteria proposed by Rothschild [13] (see Table 1), there are no univocal operational definitions for 'tachyphylaxis' or other tolerance-related phenomena.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13] source

      Not checked in the free run.

    • cites [11]

      Not checked in the free run.

    • cites [14]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given
    § ACCEPTED MANUSCRIPT · p. 15

    There is substantial evidence supporting the role of 5-hydroxytryptamine (5-HT) in the pathophysiology of depression and its pharmacological management.

    “There is substantial evidence supporting the role of 5-hydroxytryptamine (5-HT) in the pathophysiology of depression and its pharmacological management.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § ACCEPTED MANUSCRIPT · p. 17

    Consumption of drugs of abuse and environmental stressors may generate allostasis and deregulate the HPA axis.

    “The consumption of drugs of abuse as well as a wide array of environmental stressors may generate allostasis and deregulate the HPA axis [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § ACCEPTED MANUSCRIPT · p. 17

    Long-term antidepressant actions on the HPA axis may increase sensitization of stressors, which may affect the likelihood of recurrences in a clinical scenario attributed to tolerance.

    “long-term antidepressant actions on the HPA axis (vide supra) may also increase sensitization of stressors [2], which may affect the likelihood of recurrences, in a clinical scenario that would be attributed to the emergence of tolerance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] [2] G.A. Fava, E. Offidani, The mechanisms of tolerance in antidepressant action, Progress in NeuroPsychopharmacology and Biological Psychiatry 35(7) (2011) 1593-1602. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § ACCEPTED MANUSCRIPT · p. 16

    Long-term treatment with antidepressant drugs may activate the HPA axis, resulting in loss of clinical benefits (tolerance) at least partly due to effects on serotonergic neurotransmission.

    “Based on these pharmacodynamic effects it was postulated that the long-term treatment with antidepressant drugs may activate the HPA axis which would result in a loss of clinical benefits (i.e. tolerance) at least partly due to effects on serotonergic neurotransmission [2, 8].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] [2] G.A. Fava, E. Offidani, The mechanisms of tolerance in antidepressant action, Progress in NeuroPsychopharmacology and Biological Psychiatry 35(7) (2011) 1593-1602. source

      Not checked in the free run.

    • cites [8] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 4. Potential mechanisms and models of tolerance to antidepressants · p. 13

    Some depressed patients who developed tolerance during maintenance treatment with fluoxetine 20 mg responded to an increased dose of 40 mg, while other patients failed to respond to this strategy.

    “Hence some depressed patients who developed tolerance during maintenance treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine 20mg responded to an increased dose of 40mg [39], whilst other patients failed to respond to this strategy [31].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [39]

      Not checked in the free run.

    • cites [31] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § ACCEPTED MANUSCRIPT · p. 7

    Many causes of perceived loss of treatment efficacy are not pharmacokinetic in origin.

    “While this paper focuses on the mechanisms of antidepressant tolerance per se, it is important to note that many causes of perceived loss of treatment efficacy and not pharmacokinetic in origin.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: There is a narrow gap between antidepressants and placebo in acute treatment trials, implying that many people who improve while taking antidepressants are placebo responders.
    • Rests on an assumption: Stressors and life events can intrude and cause depression despite previously adequate maintenance efficacy.
    • Rests on an assumption: Neuroprogression of the underlying disorder is associated with treatment resistance.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation
    § ACCEPTED MANUSCRIPT · p. 23

    The rapid cycling phenomenon may be due to a bipolar diathesis or may result from the development of tolerance to antidepressants.

    “Although this phenomenon may be due to the presence of a bipolar diathesis [88], it may also result from the development of tolerance to antidepressants as previously discussed.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning
    § 6. Conclusion and outlook · p. 26

    Tolerance may more likely develop in bipolar disorder simply because depression is more recurrent in that condition than in MDD, although tolerance may be a potential marker of latent bipolarity.

    “tolerance may more likely develop in bipolar disorder simply because depression is more recurrent in that condition than in MDD although tolerance may be a potential marker of latent bipolarity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § ACCEPTED MANUSCRIPT · p. 34

    A score of 7 or greater on the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT) is considered indicative of the presence of antidepressant tachyphylaxis.

    “A score ≥ 7 in the RSAT is considered indicative of the presence of antidepressant tachyphylaxis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § ACCEPTED MANUSCRIPT · p. 22

    While the interplay among different serotonergic receptors and long-term adaptive mechanisms has been implicated in the emergence of tolerance to SSRIs, no head-to-head comparisons are available for alternative classes, especially for newer generation antidepressant drugs.

    “While the interplay among different serotonergic receptors and long-term adaptive mechanisms have been implicated in the emergence of tolerance to SSRIs, no head-to-head comparisons are available for alternative classes, especially for newer generation antidepressant drugs [66, 83].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [66] source

      Not checked in the free run.

    • cites [83] source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § 4.8. Genetic and epigenetic mechanisms · p. 19

    Most genetic studies of treatment loss of response or treatment-resistant depression have been based on a candidate gene approach, and only for a few genes has replication supported associations with treatment-resistant depression.

    “most studies have been based on candidate gene approach, and only for few genes replication supported associations with treatmentresistant depression.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given
    § ACCEPTED MANUSCRIPT · p. 22

    Terms such as relapse and recurrence are often used interchangeably in the literature reporting about tolerance/tachyphylaxis to antidepressants.

    “terms such as 'relapse' and 'recurrence' are often used interchangeably in the handful literature reporting about tolerance/tachyphylaxis to antidepressants.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given
    § 5. Critical appraisal of the evidence · p. 21

    Inconsistency of operational definitions in the literature hinders a rigorous assessment of the phenomenon of tolerance to antidepressants.

    “the inconsistency of the operational definitions appraised in the literature hinders a rigorous assessment of the phenomenon of tolerance to antidepressants.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § ACCEPTED MANUSCRIPT · p. 18

    Emotional blunting may persist even after depressive symptoms have improved and may occur in patients of all ages.

    “Such adverse affective manifestations may persist even after the symptoms of depression have improved and may ensue in patients of all ages [63].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § ACCEPTED MANUSCRIPT · p. 20

    Mediators of adaptation (e.g., cortisol and adrenaline) are released in response to stressors or lifestyle factors, and specific brain regions respond to repeated stimuli with changes in dendritic branching and number of neurons.

    “The mediators of this adaptation (e.g. cortisol and adrenaline) are released in response to stressors or lifestyle factors, and specific brain regions respond to these repeated stimuli with changes in dendritic branching and in the number of neurons [71].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given
    § 6. Conclusion and outlook · p. 26

    There is a lack of consensus in the literature regarding the operational definition for tolerance to antidepressants and its confounds.

    “it outlines a lack of consensus in the literature regarding the operational definition for this complex clinical phenomenon and its confounds.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § ACCEPTED MANUSCRIPT · p. 23

    Comorbid anxiety disorders in patients with MDD may further propel the development of tolerance to antidepressants.

    “Comorbid anxiety disorders in patients with MDD may however further propel the development of tolerance to antidepressants.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation
    § ACCEPTED MANUSCRIPT · p. 25

    Tolerance may contribute to poorer outcomes in people with depression exposed to long-term antidepressant treatment, although there are many confounds of this association.

    “the phenomenon of tolerance may contribute to poorer outcomes in people with depression exposed to long-term antidepressant treatment, although as noted earlier, there are many confounds of this association [95, 96].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [95] source

      Not checked in the free run.

    • cites [96] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § ACCEPTED MANUSCRIPT · p. 34

    Rothschild's conceptualization of antidepressant tachyphylaxis holds that a patient who develops tachyphylaxis does not experience a full-threshold major depressive episode.

    “The conceptualization of antidepressant tachyphylaxis proposed by Rothschild A.J. (2008) stresses out the notion that a patient who develops tachyphylaxis does not experience a full-threshold major depressive episode.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § ACCEPTED MANUSCRIPT · p. 20

    External stressors promote adaptation (allostasis) and lead over time to wear and tear of otherwise compensatory mechanisms (allostatic load).

    “These external stressors promote adaptation (allostasis) and lead over time to 'wear and tear' of otherwise compensatory (i.e. adaptive) mechanisms (allostatic load) [54, 70].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [54] source

      Not checked in the free run.

    • cites [70] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § ACCEPTED MANUSCRIPT · p. 20

    Most preclinical efficacy studies are limited to acute or subacute administration of drugs, while the risk of losing efficacy during long-term treatment is not fully assessed and modelled.

    “most preclinical efficacy studies are limited to the acute or subacute administration of drugs, while the risk of losing efficacy during long-term treatment is not fully assessed and modelled [38].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning
    § 6. Conclusion and outlook · p. 26

    This lack of consensus hinders a more precise appreciation of the frequency and correlates of tolerance to antidepressants.

    “This aspect hinders a more precise appreciation of the frequency and correlates of tolerance to antidepressants.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given
    § 4.8. Genetic and epigenetic mechanisms · p. 19

    The possible genetic underpinnings related to the onset of tolerance to antidepressants remain unknown.

    “However, the possible genetic underpinnings related to the onset of tolerance to antidepressants remain unknown.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § ACCEPTED MANUSCRIPT · p. 23

    Rapid cycling, a bipolar forme fruste, was already noted as a potential concern related to the prescription of antidepressants since the 1980s.

    “rapid cycling, which is a bipolar forme fruste , was already noted as a potential concern related to the prescription of antidepressants since the 1980s [86].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given
    § 6. Conclusion and outlook · p. 26

    Available international guidelines for the management of depression do not give proper consideration to the phenomenon of tolerance and its various potential deleterious consequences.

    “available international guidelines for the management of depression do not give proper consideration to the phenomenon of tolerance to and its various potential deleterious consequences”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning
    § ACCEPTED MANUSCRIPT · p. 23

    MDD patients exposed to antidepressants for a long period of time may be more prone to develop a rapid cycling course over time.

    “MDD patients exposed to antidepressants for a long period of time may be more prone to develop a rapid cycling course over time.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § ACCEPTED MANUSCRIPT · p. 24

    In steps 3 and 4 of STAR*D, in addition to low remission rates, nearly half of those remitting ended up experiencing a relapse.

    “in steps 3 and 4 of the trial, in addition to low remission rates, nearly half of those remitting ended up experiencing a relapse [89].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning
    § 6. Conclusion and outlook · p. 26

    While some guidance exists about the optimal duration of pharmacological trials for depression, even upon achievement of successful maintenance treatment, no clear indication exists about the eventual need to discontinue antidepressant drug treatment after a specific timeframe.

    “while some guidance exists about the 'optimal' duration of pharmacological trials for depression, even upon achievement of successful maintenance treatment, no clear indication exists about the eventual need to discontinue antidepressant drug treatment after a specific timeframe.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 4.8. Genetic and epigenetic mechanisms · p. 19

    GWAS did not detect any genome-wide significant association at the variant level, but signal transduction genes regulating synaptic plasticity, cytoskeleton architecture, and neurogenesis could be associated with treatment-resistant depression according to GWAS of antidepressant response.

    “GWAS (Genome-Wide Association Studies) did not detect any genome-wide significant association at the variant level, however, signal transduction including genes regulating synaptic plasticity, cytoskeleton architecture, and neurogenesis could be associated with treatment-resistant depression, according to the results by genome-wide association studies of antidepressant response [68].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68]

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given
    § ACCEPTED MANUSCRIPT · p. 24

    Reports on tolerance to antidepressants are almost invariably non-controlled, naturalistic, and based on anecdotal retrospective data.

    “the non-controlled nature of the reports on the matter, which are almost invariably naturalistic, and based on anecdotal retrospective data.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given
    § 4.8. Genetic and epigenetic mechanisms · p. 19

    Patients with MDD may be particularly sensitive to interpersonal stressors even after long-term remission of affective symptoms.

    “Patients with MDD may be particularly sensitive to interpersonal stressors even after long-term remission of affective symptoms.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning
    § ACCEPTED MANUSCRIPT · p. 34

    Most alternative definitions of antidepressant tachyphylaxis proposed by other authors differ from Rothschild's conceptualization in that they do not require that a patient who develops tachyphylaxis does not experience a full-threshold major depressive episode.

    “This is in contrast with most of the alternative definitions proposed by other authors (please refer to table S1, available online, for details).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given
    § ACCEPTED MANUSCRIPT · p. 20

    Other factors such as substance abuse may drive treatment non-response, as may non-adherence or partial adherence to medication, which is far more common than many clinicians perceive or patients overtly manifest.

    “Other factors such as substance abuse may drive treatment non response to treatment, as may non-adherence or partial adherence to medication, which is far more common than many clinicians perceive or patients overtly manifest.”
    Quote in the paperNot a substantial claim
56 of 56

  • The paper relies on this without support.

    There is a narrow gap between antidepressants and placebo in acute treatment trials, implying that many people who improve while taking antidepressants are placebo responders.

    “Finally, there is a narrow gap between antidepressants and placebo in acute treatment trials, implying that many people who improve while taking antidepressants are placebo responders.”

  • The paper relies on this without support.

    Stressors and life events can intrude and cause depression despite previously adequate maintenance efficacy.

    “Stressors and life events can intrude, and cause depression despite previously adequate maintenance efficacy.”

  • The paper relies on this without support.

    Neuroprogression of the underlying disorder is associated with treatment resistance.

    “Neuroprogression of the underlying disorder is associated with treatment resistance.”

  • The paper relies on this without support.

    Withdrawal symptoms following antidepressant treatment discontinuation appear to occur during the acute or post-acute phases of treatment of MDD.

    “Moreover, withdrawal symptoms following antidepressant treatment discontinuation appear to occur during the acute or post-acute phases of treatment of MDD.”

  • The authors state this as an assumption.

    Pharmacodynamic tolerance depends only on pharmacological properties of the drug.

    “In this sense, pharmacodynamic tolerance depends only on pharmacological properties of the drug.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting conflict-of-interest disclosures for AdB

    Minor

    The statement that the other authors report no conflicts is immediately followed by a disclosure that AdB received research support and honoraria and served on advisory boards.

1 of 1

Cites

Flagged first, then by citations

4 of the 99 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Möller, 2011, Relapse or recurrence in depression: why has the cutoff been set at 6 months, Medicographia, 33, 125
  2. Santarelli, 2003, Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants, Science (New York, N.Y.), 301, 805, 10.1126/science.1083328 · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Fornaro, M., Anastasia, A., Novello, S., Fusco, A., Pariano, R., De Berardis, D., Solmi, M., Veronese, N., Stubbs, B., Vieta, E., Berk, M., de Bartolomeis, A., & Carvalho, A. F.
Affiliations
  • Federico II University Hospital (IT)
  • University of Padua (IT)
  • National Research Council (IT)
  • King's College London (GB)
  • Centro de Investigación Biomédica en Red de Salud Mental (ES)
  • Barwon Health (AU)
Corresponding author
Fornaro, Michele
ORCID
Venue
Pharmacological Research
Publisher
Elsevier BV
Published
2019-01
Volume
139
Pages
494-502
ISSN
1043-6618 (ISSN-L)
DOI
10.1016/j.phrs.2018.10.025
OpenAlex
W2898836641
Semantic Scholar
d53a290cff780741d82830dc7bf2a2fbf2523412
Cited by
80
References
99
Citations by year
2026: 9 · 2025: 15 · 2024: 11 · 2023: 4 · 2022: 12 · 2021: 8 · 2020: 10 · 2019: 6 · 2018: 5
FWCI
0.85
Type
journal article
Language
en
Open access
Licence
Locations
  • Pharmacological Research (publishedVersion)
  • PubMed (publishedVersion)
  • Figshare (submittedVersion, cc-by)
  • Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion, cc-by-nc-nd)
  • Padua Research Archive (University of Padova) (submittedVersion)
Funders
  • Brain and Behaviour Foundation
  • Spanish Ministry of Science and Innovation (Centro de Investigación Biomédica en Red de Salud Mental)
  • Seventh European Framework Programme (European Network of Bipolar Research Expert Centres)
  • Stanley Medical Research Institute
  • NHMRC Senior Principal Research Fellowship (APP1059660)
  • NIH
  • Cooperative Research Centre
  • Simons Autism Foundation
  • Cancer Council of Victoria, Stanley Medical Research Foundation
  • MBF
  • NHMRC
  • Beyond Blue
  • Rotary Health
  • Meat and Livestock Board
  • Astra Zeneca
  • Woolworths
  • Avant
  • Harry Windsor Foundation
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
  • Social Sciences › Psychology › Clinical Psychology › Psychological Treatments and Disorders
Keywords
major depressive disorder, maintenance therapy, medication adherence, bipolarity, neuroprogression, hypothalamic-pituitary-adrenal axis, serotonergic system, emotional blunting, operational definitions, long-term antidepressant treatment
MeSH terms
Antidepressive Agents, Major Depressive Disorder, Drug Tolerance, Humans, Treatment Outcome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review