Depression as a systemic syndrome: mapping the feedback loops of major depressive disorder

May combine two claims.

The review identified reinforcing loops that could be relevant for understanding the etiology of depression and candidate stock variables that may regulate the strength and dynamics of these loops.

“In our review, we identified the reinforcing loops that could be relevant for understanding the etiology of depression and candidate stock variables that may regulate the strength and dynamics of these loops.”

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

Under certain conditions, reinforcing feedback loops can amplify small variations among individuals, leading to significant population-level heterogeneity from much smaller variations in exogenous influences such as genetics and environmental factors.

“First, under certain conditions, reinforcing feedback loops can amplify small variations among individuals, leading to significant population-level heterogeneity from much smaller variations in exogenous influences such as genetics and environmental factors.”

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

The strength of feedback loops and the resulting dynamics are highly dependent on the sources of inertia on the causal pathways (stock or state variables) and the speed in which they change.

“Second, the strength of the loops and the resulting dynamics are highly dependent on the sources of inertia on the causal pathways (i.e. stock or state variables) and the speed in which they change.”

May combine two claims.

In depression, feedback loops include homeostatic balancing processes and reinforcing loops that cut across different domains.

“In the context of depression, they include not only the homeostatic (balancing) processes that keep various neurotransmitters, hormones and other biological mechanisms in approximate balance, but also feedback loops that cut across different domains and may be of a reinforcing1† nature.”

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

Only half of psychotherapy patients recover after their first course of treatment.

“only half of psychotherapy patients recover after their first course of treatment (e.g. Barber et al. 2012; Carter et al. 2013).”

• cites Barber et al. 2012Not checked yet

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• cites Carter et al. 2013Not checked yet

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May combine two claims.

Economic hardship and depressive symptoms form a reinforcing loop: economic hardship increases depressive symptoms, and increased depressive symptoms can cause loss of motivation and economic wellbeing, e.g. job loss.

“For example, economic hardship is a stressor that can increase depressive symptoms. On the other hand, one consequence of increased depressive symptoms is loss of motivation and an increased chance of hurting one’s economic wellbeing, e.g. due to job loss. Together, the two causal links create a reinforcing loop, which may trap an individual in increasing financial hardship and depression.”

May combine two claims.

Narrow perspectives of depression are common and are reflected in theories of pathogenesis ranging from cognitive theory to HPA axis dysfunction, inflammation, neurodegenerative, and stress generation theories.

“Narrow perspectives of depression are common and are reflected in the theories of pathogenesis that range from cognitive theory (Beck, 2008) to the hypothalamic– pituitary–adrenal (HPA) axis dysfunction theory (Pariante & Lightman, 2008), inflammation theory (Miller et al. 2009), neurodegenerative theory (Wainwright & Galea, 2013) and stress generation theory (Hammen, 2006), among others.”

• cites Beck, 2008Not checked yet

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• cites Pariante & Lightman, 2008Not checked yet

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• cites Miller et al. 2009Not checked yet

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Probably not a substantial claim: may not pass S2 (checkable).

System dynamic modeling is a useful tool for understanding how diverse causal feedback mechanisms create a systemic syndrome with heterogeneous patient trajectories.

“System dynamic modeling is a useful tool for understanding how diverse causal feedback mechanisms create a systemic syndrome with heterogeneous patient trajectories (Sterman, 2000).”

• cites Sterman, 2000Not checked yet

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Classified as probably not a substantial claim.

Kendler et al. recommended a shift from seeking an essence directly responsible for a mental disorder to delineating the complex causal mechanisms that underlie psychiatric syndromes.

“Kendler et al. (2011) recommended a shift from seeking an ‘essence’ that is directly responsible for a mental disorder to delineating the complex causal mechanisms that underlie psychiatric syndromes.”

• cites Kendler et al. 2011Not checked yet

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May combine two claims.

Traditional psychometric approaches often assume a linear and latent variable model and cannot estimate intra-individual effects.

“traditional psychometric approaches often assume a linear and latent variable model and cannot estimate intra-individual effects.”

• cites Borsboom & Cramer, 2013Not checked yet

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• cites van De Leemput et al. 2014Not checked yet

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May combine two claims. The quote only partly states this claim.

R4 is a reinforcing feedback loop (impaired working memory) in which increased negative affect inhibits working memory efficiency, leading to less optimal cognitive performance; cognitive performance is weakened by impaired memory and sleep problems and contributes to dysfunctional behaviors; dysfunctional behaviors reinforce negative cognitive representations and lead to biased attentional and m

“As R4 (impaired working memory) illustrates, increased negative affect inhibits the efficiency of one’s working memory (De Lissnyder et al. 2012), leading to less optimal cognitive performance.”

• Also stated in: § Cognitive dimensions · plain

  “Dysfunctional behaviors reinforce negative cognitive representations and lead to biased attentional processes, increased perceptions of stress, negative affect and interpretations, and further inhibit the efficiency of working memory.”

• cites De Lissnyder et al. 2012Not checked yet

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• cites Van Dongen et al. 2003Not checked yet

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• cites McCall& Dunn, 2003Not checked yet

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May combine two claims.

R8 is a reinforcing feedback loop (exaggerated immune response) in which stress or chronic illness releases pro-inflammatory cytokines, cytokines inhibit GR function, and when chronic stress sustains cortisol response and GRs become overburdened, cortisol signaling becomes insufficient to reduce immune responses, leading to inflammation.

“During increased periods of stress or chronic illness, pro-inflammatory cytokines are released. Cytokines are known to inhibit GR function. Although cortisol is a key anti-inflammatory hormone, when chronic stress sustains cortisol response and GRs become overburdened, cortisol signaling becomes insufficient and unable to reduce immune responses, which leads to inflammation (Miller et al. 2009).”

• cites Miller et al. 2009Not checked yet

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May combine two claims.

Sleep is vital to long-term memory consolidation, which is necessary for learning, and sleep problems can disrupt this process.

“Sleep is vital to long-term memory consolidation, which is necessary for learning, and sleep problems can disrupt this process (Choi & Abel, 2013).”

• cites Choi & Abel, 2013Not checked yet

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May combine two claims.

The second loop for physical health relates to the deteriorating health (R13) one can experience when poor behaviors such as physical inactivity due to loss of motivation contributes to chronic medical problems, affecting immune functioning, HPA axis reactivity, and sleep and eventually reinforcing declines in health.

“The second loop for physical health relates to the deteriorating health (R13) one can experience when poor behaviors such as physical inactivity due to loss of motivation contributes to chronic medical problems (Ye et al. 2013), affecting immune functioning, HPA axis reactivity, and sleep and eventually reinforcing declines in health.”

• cites Ye et al. 2013Not checked yet

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May combine two claims.

Negative cognitive representations are key candidates for the inertia driving depression within the cognitive sector and are important targets of change in cognitive theories of depression.

“Negative cognitive representations are key candidates for the inertia driving depression within the cognitive sector of the model and are important targets of change in cognitive theories of depression.”

May combine two claims.

R3 is a reinforcing feedback loop (cognitive deficit) in which negative affect and interpretations contribute to dysfunctional behaviors and strengthen negative cognitive models.

“In R3 (cognitive deficit), negative affect and interpretations contribute to dysfunctional behaviors (Hamilton et al. 2013) and strengthen negative cognitive models (Pettit & Joiner, 2006).”

• cites Hamilton et al. 2013Not checked yet

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• cites Pettit & Joiner, 2006Not checked yet

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May combine two claims.

R2 is a reinforcing feedback loop (rumination) in which negative affect and interpretations intensify ruminative thought, which compounds perceptions of stress and increases negative affect.

“In R2 (rumination), negative affect and interpretations intensify one’s propensity for ruminative thought which further compounds perceptions of stress and increases negative affect (Nolen-Hoeksema & Morrow, 1991).”

• cites Nolen-Hoeksema & Morrow, 1991Not checked yet

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

The study assessed the strength of empirical support for each mechanism, prioritized mechanisms that had been validated, and revised its conceptual structure.

“We assessed the strength of empirical support for each mechanism, prioritized mechanisms that had been validated, and revised our conceptual structure.”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

Social support and financial resources could be important stock variables in the feedback loops; personal economics and social networks typically build over years but can be depleted more quickly than they accumulate, an asymmetry that can exacerbate reinforcing loops.

“Social support and financial resources could be important stock variables in the feedback loops described above. An individual’s personal economics and social networks typically build over the span of years, but have the potential to be depleted more quickly than they accumulate, an asymmetry that can exacerbate these reinforcing loops when they act as vicious cycles.”

Classified as probably not a substantial claim.

The study used a structured approach to incorporate findings from the literature into a conceptual model.

“We used a structured approach to incorporate findings from the literature into a conceptual model (e.g. see Hu et al. 2011).”

• cites Hu et al. 2011Not checked yet

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

There is more uncertainty about potential stock variables within this portion of the model.

“There is more uncertainty about potential stock variables within this portion of the model.”

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

Various random events such as accidents, the loss of loved ones, and early adverse events are relevant exogenous factors.

“Also relevant are various random events such as accidents, the loss of loved ones, and early adverse events (which are partially identified in our model).”

May combine two claims.

Declining physical health can limit an individual's capacity to engage in physical activity and physical inactivity increases cortisol concentrations.

“Also, declining physical health can limit an individual’s capacity to engage in physical activity and physical inactivity increases cortisol concentrations (Paddon-Jones, 2006).”

• cites Paddon-Jones, 2006 sourceNot checked yet

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

The interaction between exogenous factors and feedback loops creates the potential for endogeneity through epigenetics.

“The interaction between exogenous factors and feedback loops also creates the potential for endogeneity through epigenetics.”

May combine two claims.

R7 is a reinforcing feedback loop (elevated cortisol response) in which perceived psychosocial stress activates the HPA axis, increases cortisol, overburdens glucocorticoid receptors, and excess cortisol, cortisol reactivity, and altered GR function inhibit the HPA system and reinforce HPA dysregulation.

“In R7 (elevated cortisol response), perceived psychosocial stress activates the central nervous system by inducing the secretion of corticotrophin-releasing hormone and vasopressin in the hypothalamus that stimulates adrenocorticotrophin hormone in the anterior pituitary and, in turn, releases cortisol in the adrenal cortex.”

• Also stated in: § Biological dimensions · plain

  “Excess cortisol, cortisol reactivity, and altered GR function inhibit the HPA system and reinforce HPA dysregulation which has negative consequences for an individual’s physical and mental health.”

• cites Strüber et al. 2014Not checked yet

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

These loops are often triggered through various factors that are exogenous to the boundary of our model, including genes, personality, gender, socio-economic status, nutritional environment, and the built environment that influences opportunities for exercise.

“These loops, in turn, are often triggered through various factors that are exogenous to the boundary of our model. Those include, among others, genes, personality (e.g. neuroticism), gender, socio-economic status, nutritional environment, and the built environment that influences opportunities for exercise.”

May combine two claims.

Dysfunctional behaviors such as medication non-adherence and poor diet have a negative effect on one's health and perceived stress.

“As an illustration, dysfunctional behaviors such as medication non-adherence (DiMatteo et al. 2000) and poor diet (e.g. diets low in omega-3 essential fatty acids or polyunsaturated fatty acids) have a negative effect on one’s health and perceived stress.”

• cites DiMatteo et al. 2000Not checked yet

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

Not all pathways are active for all depressed individuals, so each empirical case may best be explained by a subset of these loops.

“We note that not all pathways are active for all depressed individuals so each empirical case may best be explained by a subset of these loops.”

Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

Understanding a complex system requires mapping feedback processes and identifying key inertial factors, their speed of change, and potential asymmetries in growth versus decline mechanisms.

“Therefore, understanding a complex system requires not only the mapping of feedback processes, but also the identification of key inertial factors, their speed of change and the potential asymmetries in their growth v. decline mechanisms.”

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

Five experts in unique areas of MDD research were invited to critique the model and suggest additional literature, informing further model revisions.

“Next, we invited five experts in unique areas of MDD research to critique our model and suggest additional literature, informing further model revisions.”

May combine two claims.

Serotonin deficiency reduces the brain's regulatory capacity by not adequately modulating amygdala response to negative stimuli, leading to sustained emotional responding in the face of stress and reinforcing negative cognitive and emotional processes in R1, R2 and R3.

“Serotonin deficiency reduces the brain’s regulatory capacity by not adequately modulating amygdala response to negative stimuli which leads to sustained emotional responding in the face of stress (De Raedt & Koster, 2010) and plays a key role in reinforcing negative cognitive and emotional processes in the R1, R2 and R3 feedback loops.”

• cites De Raedt & Koster, 2010Not checked yet

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May combine two claims.

High levels of cortisol and cytokines in the context of GR resistance act to suppress neurogenesis and promote neuronal death that leads to hippocampal atrophy.

“Relevant to R10 (hippocampus atrophy), high levels of cortisol and cytokines in the context of GR resistance act to suppress neurogenesis and promote neuronal death that leads to hippocampal atrophy (Sapolsky, 2000).”

• cites Sapolsky, 2000Not checked yet

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May combine two claims.

Negative cognitive representations are patterns embedded in neural connections in the brain that accumulate over months and years and are expected to change slowly in many cases.

“Negative cognitive representations are, in essence, patterns embedded in neural connections in the brain that accumulate over months and years (Beck, 2008).”

• Also stated in: § Cognitive dimensions · hedged

  “Negative cognitive representations are expected to change slowly in many cases, making these loops most relevant for dynamics that unfold over longer time horizons (Padesky, 1994).”

• cites Beck, 2008Not checked yet

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• cites Padesky, 1994Not checked yet

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May combine two claims. The quote only partly states this claim.

R1 is a reinforcing feedback loop (consolidation of negative cognitive representations) in which early adversity is processed and stored as negative cognitive representations, which bias attention and processing, increase perceived stress and negative affect, and are further strengthened by memory encoding.

“As Fig. 2 illustrates in reinforcing feedback loop 1, or R1 (consolidation of negative cognitive representations), early adversity such as abuse or neglect of a child is processed and stored in the form of negative cognitive representations within an individual’s memory (McGinn et al. 2005).”

• Also stated in: § Cognitive dimensions · plain

  “The processing of negative thoughts and affect is encoded and stored in one’s memory, further strengthening existing negative cognitive representations (Cole et al. 2014).”

• cites McGinn et al. 2005Not checked yet

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• cites Cole et al. 2014Not checked yet

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

The strength and relevance of different loops depend heavily on the stock variables on each loop and their speeds of change.

“Second, the strength and relevance of different loops depend heavily on the stock variables on each loop and their speeds of change.”

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

The final database used to develop the model included 594 publications.

“The final database used to develop the model included 594 publications.”

May combine two claims.

Various reinforcing loops, activated by exogenous factors, will push some individuals towards a trajectory of increasingly negative cognitive representations, declining social, economic, and health resources, and various perturbations in hormones, immune response and neurotransmitters.

“Various reinforcing loops, activated by exogenous factors, will push some individuals towards a trajectory of increasingly negative cognitive representations, declining social, economic, and health resources, and various perturbations in hormones, immune response and neurotransmitters.”

May combine two claims. The quote only partly states this claim.

R6 is a reinforcing feedback loop (financial stress) in which economic status can be depleted through poor cognitive performance or behaviors at work, absenteeism or presenteeism can lead to job loss or underemployment, and financial stress produces negative affect and problematic behavioral responses that increase economic adversity and reinforce negative mental models.

“One’s economic status, including material assets, income and reputation, can be depleted through the effects of poor cognitive performance (McIntyre et al. 2013) or behaviors at work and beyond (Stewart et al. 2003) as shown in R6 (financial stress).”

• Also stated in: § Social and environmental dimensions · plain

  “Financial stress can produce negative affect and problematic behavioral responses that increase economic adversity and reinforce negative mental models (Hobfoll et al. 2003).”

• cites McIntyre et al. 2013Not checked yet

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• cites Stewart et al. 2003Not checked yet

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• cites Hobfoll et al. 2003Not checked yet

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

Cortisol changes over minutes.

“cortisol (changing over minutes; Gruenewald et al. 2004)”

• cites Gruenewald et al. 2004Not checked yet

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

Many of the relevant dynamics in understanding depression unfold over longer time horizons, and thus some of the stock variables may not represent the most viable candidates for explaining longer-term dynamics.

“Many of the relevant dynamics in understanding depression unfold over longer time horizons, and thus some of the stock variables may not represent the most viable candidates for explaining longer-term dynamics.”

May combine two claims. The quote only partly states this claim.

R5 is a reinforcing feedback loop (social isolation) in which dysfunctional behaviors contribute to weakened social networks, interpersonal stress contributes to negative affect and processing, problematic responses deplete relationship quality, and isolation reinforces negative cognitive representations.

“Affected by cognitive actors, R5 (social isolation) depicts how dysfunctional behaviors contribute to weakened social networks in the form of poor interpersonal relationship quality or social isolation (Lovejoy et al. 2000).”

• Also stated in: § Social and environmental dimensions · plain

  “As depressed patients become further plagued by challenging relationships or isolation, their negative cognitive representations are reinforced.”

• cites Lovejoy et al. 2000Not checked yet

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• cites Joiner et al. 2005Not checked yet

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May combine two claims.

Brief periods of stress on cortisol are often adaptive and resolve autonomously, but chronic stress is what drives illness.

“For clarity, the effects of brief periods of stress on cortisol are often adaptive and resolve autonomously, but chronic stress is what drives illness (Herbert et al. 2006).”

• cites Herbert et al. 2006Not checked yet

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Probably not a substantial claim: may not pass S2 (checkable).

The model demonstrates a feasible path towards a causal-based understanding of the systemic syndrome of depression.

“The model demonstrates a feasible path towards a causal-based understanding of the systemic syndrome of depression.”

Classified as probably not a substantial claim.

The broad scope of this project led us to focus solely on reinforcing loops.

“Finally, the broad scope of this project led us to focus solely on reinforcing loops.”

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

Focusing on reinforcing mechanisms in the absence of homeostatic mechanisms may lead to overestimating the role of reinforcing loops and the heterogeneity that a system produces.

“Focusing on reinforcing mechanisms in the absence of homeostatic mechanisms may lead to overestimating the role of reinforcing loops and the heterogeneity that a system produces.”

Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

Many mechanisms, particularly biological ones, are not well understood and studies do not often explicate causal drivers and their intersections.

“many mechanisms, particularly biological ones, are not well understood and studies do not often explicate causal drivers and their intersections.”

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

Being a qualitative study, other limitations inherent to this mode of inquiry are relevant here as well, e.g. investigator bias and limits to replicability.

“Being a qualitative study, other limitations inherent to this mode of inquiry are relevant here as well, e.g. investigator bias and limits to replicability.”

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

Some patients may be kept down by cognitive feedbacks, others by social ones, some by biological feedbacks, and others by combinations.

“Some patients may be kept down by cognitive feedbacks, others by social ones, some by biological feedbacks, and others by combinations.”