Pubmed Search Terms and Procedures

Supplementary material

Appendix A

PubMed Search Terms and Procedures

To create Table 1, a PubMed search was conducted to locate articles published between 1980 and 2014 classified under the PubMed Medical Subject Heading (MeSH) terms “major depressive disorder” NOT “postpartum depression” NOT “seasonal affective disorder” AND the complete search terms listed below. Relevancy reflects the percentage of relevant articles listed in the first 40 results.

Heading in Table / Complete Search Terms / Relevancy %
Cognitive bias / “attentional bias” OR “attentional biases” OR “cognitive bias” OR “cognitive biases” OR “attributional style” OR “schema” / 80%
Rumination / “rumination” OR “ruminative” / 82.5%
Memory / “working memory” OR “episodic memory” / 85%
Social isolation / “social isolation” OR “rejection sensitivity” OR “social stress” OR “psychosocial stress” / 62.5%
Financial stress / “financial stress” OR “financial strain” OR “work stress” OR “job loss” OR “productivity” / 75%
Immune response / “immune response” OR “immune system” OR “inflammation” OR “inflammatory” NOT “inflammatory bowel” / 85%
Cortisol / “cortisol” / 87.5%
Hippocampus / “hippocampus atrophy” OR “hippocampal volume” OR “hippocampal structure” / 92.5%
Sleep / “sleep” / 80%
Gene / “gene” / 95%
Personality disorder / “personality disorder” / 77.5%
Diet / “dietary” OR “fatty acid” NOT “MAOIs” NOT “eating disorder” / 80%
Exercise / “exercise” OR “sedentary” / 77.5%
Early adverse experiences / “early adverse experiences” OR “early life stress” OR “childhood trauma” OR “childhood maltreatment” OR “childhood adversity” OR “adverse childhood experiences” / 82.5%

Appendix B

Full Equations for Fig. 1 and Model Replication Instructions

Simulation Model Equations

Environmental Stress=
PinkNoise+MeanPN
Units: Stressor/Day
EnvirStdevParameter=
1
Units: Stressor/Day
Erosion Sensitivity to MDD=
3
Units: Dmnl
FINAL TIME = 100
Units: Month
The final time for the simulation.
iid Noise IN=
RANDOM NORMAL(-1e+006, 1e+006, 0, 1, Noise
Seed)*EnvirStdevParameter*((2-TIME STEP/Noise Smoothing Time)/(TIME
STEP/Noise Smoothing Time))^0.5
Units: Stressor/Day
The iid noise stream that drives the autocorrelated environmental stressors.
INITIAL TIME = 0
Units: Month
The initial time for the simulation.
MDD=
Min(1,Max(0,"Stress-Capability Gap"))
Units: Dmnl
MeanPN=
0
Units: Stressor/Day
Noise Seed=
1
Units: Dmnl
Noise Smoothing Time=
12
Units: Month
PinkNoise= INTEG (
(iid Noise IN-PinkNoise)/Noise Smoothing Time,
RANDOM NORMAL(-100, 100 , 0, 1 , Noise Seed )*EnvirStdevParameter)
Units: Stressor/Day
The first-order auto-correlated noise is generated used iid normal
random numbers with the desired standard deviation.
Regulatory Resources= INTEG (
Resource Development-Resource Erosion,
1)
Units: Stressor/Day
Resource Development=
Max(0,1-4*("Stress-Capability Gap"-0.5)^2)*(1-SWNoFeedback)
Units: Stressor/(Day*Month)
Resource Erosion=
if then else(Regulatory Resources>0,Max(0,MDD)*Erosion Sensitivity to
MDD,0)*(1-SWNoFeedback)
Units: Stressor/Day/Month
SAVEPER = 0.0625
Units: Month
The frequency with which output is stored.
"Stress-Capability Gap"=
Environmental Stress-Regulatory Resources
Units: Stressor/Day
SWNoFeedback=
0
Units: Dmnl
TIME STEP = 0.0625
Units: Month
The time step for the simulation.

Instructions for Replicating the Results

The equations above would allow one to replicate the model in the simulation environment of their choice. The simulations reported include two scenarios:

With Feedback: In this scenario all model parameters remain as in the equations above. The parameter “Noise Seed” is changed between 1 and 1000 to create 1000 different trajectories for environmental stressors. The histograms in Figure 1 show the distribution of variable MDD at the end of simulation time over these 1000 simulated trajectories.

Without Feedback: This scenario is identical to “With Feedback” except that the parameter “SWNoFeedback” is set to one, removing the impact of feedback loops. Again, histograms from 1000 simulations are reported.

To further assist with replication of the results, this online appendix also includes SimpleExample.zip file containing the Vensim ™ model and required files for replicating the simulation results reported in Figure 1 using Vensim modeling language. You may download and install the free Vensim “Model Reader” from do simple analysis on the model or use the professional or DSS versions of the software to do more diverse analyses.

Once you unzip the package you will find the following files:

SimpleExample-Submit.vpm: The model package which can be opened in Vensim model reader.

SimpleExample-Submit.mdl: The model file used for conducting the analysis using the following additional files. You will need the professional Vensim for conducting the analysis using this file and the following additional settings (where as the package above contains all the necessary components). However this model allows you to make changes and conduct additional analyses.

AutomatedSims.cmd: The command file used for generating the results in figure 1. This file can be used in conjunction with .mdl file, and run from File menu inside the Vensim when the mdl and other files below are in the same folder.

SimpleExample.vsc: The sensitivity control file used for conducting 1000 simulations with different noise seeds.

SimpleExample.lst: The savelist used for storing only a subset of variables during the sensitivity run.

You can open the mdl model or the .vpm package and analyze them using the user friendly simulation environment provided by Vensim Model Reader. Variable names are consistent with the notation in the Figure 1, with some additional variables included in the model to facilitate the analysis process.

You can view the equation for each variable by selecting that variable and clicking the “Document” button in the left toolbar. You can follow the procedure below for simulating and analyzing the model behavior:

-First choose a name for your simulation and enter it in the field for simulation name in the middle of the top toolbar:

-Click on the SET button to the left of this name. The model parameters become highlighted.

-Now change the parameters of the model as desired. The current values of the parameters are shown if you click on each parameter.

-Simulate the model by clicking the Run or Synthesim buttons in the top toolbar: .

Examining the behavior:

-You can also use the tools in the left toolbar to see the behavior of different variables. Select a variable by clicking on it and then click on the desired tool. A graph or table of the variable of interest will be shown.

However, you can not edit the model in the Vensim Model Reader. For that purpose you will need to use Vensim (any version, including the free PLE, would allow you to edit this model). The other files included in the .zip file are useful for replicating the analysis using the command scripts provided. These files will significantly simplify the replication of the results and additional analysis. A DSS or Professional version of Vensim is required for using these capabilities.

Appendix C

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Appendix D

Following is the name, purpose, and variables of each reinforcing feedback loop labeled in Figs 2–4.

R1. Consolidation of negative cognitive representations

Negative cognitive representations  biased attention and processing  perceived stress  negative affect, interpretation, and processing  encoding of negative thoughts  negative cognitive representations

Purpose: This loop explains how negative cognitive representation caused by early adversity affectsperception of stress stimuli, contributes to negative affect, interpretation, and processing, and eventually intensifies the negative cognitive representation.

R2.Rumination

Perceived stress negative affect, interpretation, and processing ruminationperceived stress

Purpose: The rumination loop shows the pathway in whichruminative style increases sensitivity to stressors.

R3.Cognitive deficit

Negative affect, interpretation, and processing dysfunctional behaviors negative cognitive representations  biased attention and processing  perceived stress  negative affect, interpretation, and processing

Purpose: This loop illustrates how negative affect contributes to dysfunctional behaviors which intensifies negative cognitive representations and reinforces negative affect.

R4. Impaired working memory

Negative affect, interpretation, and processing deficiency of working memorycognitive performancedysfunctional behaviors negative cognitive representations  biased attention and processing  perceived stress  negative affect, interpretation, and processing

Purpose: This loop depicts the pathway through which negative affect hinders the efficiency of working memory leading to declines in cognitive performance and contributing to dysfunctional behaviors which further intensifies negative affect.

R5. Social isolation

Dysfunctional behaviorsinterpersonal relationshipstress stimuli negative cognitive representations  biased attention and processing  perceived stress  negative affect, interpretation, and processingdysfunctional behaviors

Purpose: This loop captures the social isolation caused by dysfunctional behaviors.

R6. Financial stress

Economic statusstress stimuli negative cognitive representations  biased attention and processing  perceived stress  negative affect, interpretation, and processingdysfunctional behaviorseconomic status

And/or

Economic statusstress stimuli negative cognitive representations  biased attention and processing  perceived stress  negative affect, interpretation, and processingdeficiency of working memorycognitive performancedysfunctional behaviorseconomic status

Purpose: R6 shows how the economic status of depressed patients deteriorates through dysfunctional behaviors and/or less optimum levels of cognitive performance.

R7. Elevated cortisol response

Cortisoleffective GRfeedback inhibition of HPAcortisol

Purpose: R7 depicts the process in which the HPA axis may become impaired.

R8. Exaggerated immune response

Cytokineeffective GRinhibitory effect of glucocorticoid on cytokinecytokine

Purpose: This loop shows why some depressed patients have inflammation.

R9. Impaired memory

Cortisolmonoamineslearning, reward processing, and memorycognitive performancedysfunctional behaviorsNegative cognitive representations  biased attention and processing  perceived stress cortisol

Or/and

Cortisolmonoamineslearning, reward processing, and memorycognitive performanceEconomic statusstress stimuliNegative cognitive representations  biased attention and processing  perceived stress cortisol