Can loss of agency and oppositional perturbation associated with antidepressant monotherapy and low-fidelity psychological treatment dilute the benefits of guideline-consistent depression treatment at the population level?

Abstract

Despite major expansions of evidence-based treatments of common mental disorders in recent decades, especially antidepressant medication, the point prevalence of depression has not decreased; instead it probably increased in young adults. We question whether antidepressants (AD)-monotherapy and low-fidelity-to-guideline psychological treatment (PT) might have no effect or even adverse effects in some patients and contexts that dilute the benefits of treatment at the population level, making it harder for population-based studies to detect treatment-driven prevalence reductions. Randomized Clinical Trial (RCT)s have not identified these effects because AD-monotherapy and low-fidelity PT are uncommon in RCTs where treatment protocols are specified and carefully monitored, unlike treatment in real-world settings. Second, RCTs may have missed the bigger picture of ultimate outcomes due to too short follow-ups. We elaborate two mechanisms through which AD-monotherapy and low-fidelity PT could produce adverse effects on long-term illness course. Both mechanisms are speculative and we outline how to test. Major depressive disorder is a common, highly heterogeneous disorder. To reduce its enormous burden [1], Western countries have expanded their mental health expenditures in specialty and primary care settings since the 1980s [2], providing more treatment for more people, primarily with antidepressants (AD) and, to a lesser extent, psychological treatments (PTs) [3,4]. Both Antidepressant (AD)s and PTs are well-established, evidence-based treatments with roughly similar modest short-term efficacy. Surprisingly, the point-prevalence of depression in the general population has not decreased since the wide-scale use of AD [5]; instead, the prevalence has probably increased, particularly in young people [6]. In addition, the prevalence of recurrentchronic and treatment-resistant depression seems to have risen [7]. One obvious explanation for this "treatment-prevalence paradox" is increased first incidence, offsetting a treatment-driven prevalence drop. But population-based incidence studies do not find such an increase [4,8]. What else could explain the paradox? Explaining the Treatment-Prevalence Paradox We question whether AD-monotherapy and low-fidelity-to-guideline PT might have no effect or even adverse effects in some patients and contexts that dilute the benefits of treatment at the population level, making it harder for population-based studies to detect treatment-driven prevalence reductions. The hypothesized mechanisms through which AD-monotherapy and low-fidelity PT could produce adverse effects on long-term illness course include Loss of Agency [9] and Oppositional Perturbation [10] or Tolerance [11,12]. Both mechanisms are speculative and need rigorous testing. RCTs have not identified these effects because AD-monotherapy and low-fidelity PT are uncommon in RCTs where treatment protocols are specified and carefully monitored, unlike treatment in real-world settings. In addition, AD-withdrawal studies may have m...

Mental Health in Australia: Psychological Distress Reported in Six Consecutive Cross-Sectional National Surveys From 2001 to 2018

“…In turn, these problems may have compromised effectiveness of Australia's mental health service delivery system quality (28,29), impacted by inequity in service delivery and forms of iatrogenesis (17,75). A lack of data precludes the analysis of service quality across much of the service system and this itself is a problem (62).…”

“…Perhaps inequitable and lower quality treatment for mental health problems may actually do some harm as well as good. It has been suggested that iatrogenic influences based on a loss of agency arising from medicalization might perhaps negate the relatively modest effect of antidepressant monotherapy (17,75,76). It also has been proposed that antidepressants themselves may have a significant property of oppositional perturbation, so increasing the rates of depression among those who have been prescribed them above the rates that would have been observed had they never been exposed to this therapy (75).…”

“…It has been suggested that iatrogenic influences based on a loss of agency arising from medicalization might perhaps negate the relatively modest effect of antidepressant monotherapy (17,75,76). It also has been proposed that antidepressants themselves may have a significant property of oppositional perturbation, so increasing the rates of depression among those who have been prescribed them above the rates that would have been observed had they never been exposed to this therapy (75). Between them, these two explanations constitute a possible route for understanding why undoubted therapeutic benefits that may flow to some individuals fortunate enough to get access to comprehensive and appropriate care, may be offset by what can be seen as iatrogenic harms for those receiving more limited forms of care, and so constituting a failure of quaternary prevention (77,78).…”

More Treatment, but Not Less Anxiety and Mood Disorders: Why? Seven Hypotheses and Their Evaluation

“…How frequently these adverse effects occur and outbalance the benefits of treatment is less clear. In particular, medication has been associated with a variety of adverse effects: paradoxical effects, manifestations of tolerance (loss of clinical effect, refractoriness), withdrawal symptoms and disorders [78][79][80][81]. Significant adverse effects of psychological treatments have been noted as well [82,83].…”

“…Behavioral "toxicity" including oppositional perturbation: behavioral toxicity refers to the "pharmacological actions of a drug that, within the dose range in which it has been found to possess clinical utility, may produce alterations in mood, perceptual, cognitive and psychomotor functions, that limit the capacity of the individual or constitute a hazard to his/her well-being" ( [77], p.130). An important form of behavioral toxicity is "oppositional perturbation" that seeks to account for unintended and unwanted effects of medication on illness course, including symptom return after discontinuation, and a progressive loss of effectiveness (tachyphylaxis) across repeated anti-depressant medication trials [78][79][80][81]. Importantly, direct evidence for oppositional perturbation is lacking, but intriguing indirect evidence is available [78,79].…”