scholarly journals Computational Analysis of Therapeutic Neuroadaptation to Chronic Antidepressant in a Model of the Monoaminergic Neurotransmitter and Stress Hormone Systems

2019 ◽  
Author(s):  
Mariam Bonyadi Camacho ◽  
Warut D. Vijitbenjaronk ◽  
Thomas J Anastasio
Keyword(s):  
Clinical Judgment ◽  
Computational Analysis ◽  
Antidepressant Drugs ◽  
Chronic Administration ◽  
Trial And Error ◽  
Stress Hormone ◽  
Treatment Resistant ◽  
Potential Explanation ◽  
System Components ◽  
Monoaminergic Neurotransmitter

AbstractThe clinical practice of selective serotonin reuptake inhibitor (SSRI) augmentation relies heavily on clinical judgment and trial-and-error. Unfortunately, the drug combinations prescribed today fail to provide relief for all treatment-resistant depressed patients. In order to identify potentially more effective treatments, we developed a computational model of the monoaminergic neurotransmitter and stress-steroid systems that neuroadapts to chronic administration of combinations of antidepressant drugs and hormones by adjusting the strengths of its transmitter-system components (TSCs). We used the model to screen 60 chronically administered drug/hormone pairs and triples, and identified as potentially therapeutic those combinations that raised the monoamines (serotonin, norepinephrine, and dopamine) but lowered cortisol following neuroadaptation in the model. We also evaluated the contributions of individual and pairs of TSCs to therapeutic neuroadaptation with chronic SSRI using sensitivity, correlation, and linear temporal-logic analyses. All three approaches found that therapeutic neuroadaptation to chronic SSRI is an overdetermined process that depends on multiple TSCs, providing a potential explanation for the clinical finding that no single antidepressant regimen alleviates depressive symptoms in all patients.

scholarly journals Computational Analysis of Therapeutic Neuroadaptation to Chronic Antidepressant in a Model of the Monoaminergic Neurotransmitter, Stress Hormone, and Male Sex Hormone Systems

2019 ◽  
Author(s):  
Mariam Bonyadi Camacho ◽  
Warut D. Vijitbenjaronk ◽  
Thomas J Anastasio
Keyword(s):  
Antidepressant Treatment ◽  
Chronic Administration ◽  
Sex Hormone ◽  
Model Parameters ◽  
Depression Treatment ◽  
Stress Hormone ◽  
Large Sets ◽  
Effective Combination ◽  
Male Sex ◽  
Monoaminergic Neurotransmitter

AbstractSecond-line depression treatment involves augmentation with one (rarely two) additional drugs, of chronic administration of a selective serotonin reuptake inhibitor (SSRI), which is the first-line depression treatment. Unfortunately, many depressed patients still fail to respond even after months to years of searching to find an effective combination. To aid in the identification of potentially affective antidepressant combinations, we created a computational model of the monoaminergic neurotransmitter (serotonin, norepinephrine, and dopamine), stress-hormone (cortisol), and male sex-hormone (testosterone) systems. The model was trained via machine learning to represent a broad set of empirical observations. Neuroadaptation to chronic drug administration was simulated through incremental adjustments in model parameters that corresponded to key regulatory components of the neurotransmitter and neurohormone systems. Analysis revealed that neuroadaptation in the model depended on all of the regulatory components in complicated ways, and did not reveal any one or a few specific components that could be targeted in the design of combination antidepressant treatment. We used large sets of neuroadapted states of the model to screen 74 different drug and hormone combinations and identified several combinations that could potentially be therapeutic for a higher proportion of male patients than SSRIs by themselves.

scholarly journals BIOCHEMICAL STUDIES OF HIPPOCAMPAL GENE EXPRESSION OF BRAIN-DERIVED NEUROTROPIC FACTOR AND TOLL-LIKE RECEPTOR-4 IN DIABETIC RATS EXPOSED TO CHRONIC STRESS: EFFECTS OF ANTIDEPRESSANT DRUGS

2018 ◽  
Vol 11 (1) ◽  
pp. 271
Author(s):  
Sawsan Aboul-fotouh ◽  
Doaa Mohamed Hassan ◽  
Mohamed Zaki Eldeen Habib ◽  
Ahmed Ibrahim Amin ◽  
Samar K. Kassim ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Antidepressant Drugs ◽  
Chronic Administration ◽  
Diabetic Rats ◽  
Toll Like Receptor ◽  
Bdnf Expression ◽  
Toll Like Receptor 4 ◽  
Inflammatory State ◽  
Neurotropic Factor ◽  
Factor Α

  Objective: Depression and diabetes are closely associated in a reciprocal manner, leading to significant morbidity and mortality with an evidence of a pro-inflammatory state underlying pathophysiology of both diseases. Unfortunately, little information is available about the effects of antidepressant drugs on hippocampal brain-derived neurotrophic factor (BDNF) and toll-like receptor-4 (TLR-4) expression in diabetes.Methods: We investigated the effect of chronic administration of fluoxetine (FLU) and imipramine (IMIP) on behavioral, metabolic, and inflammatory abnormalities in diabetic and non-diabetic rats exposed to chronic restraint stress (CRS).Results: Both diabetes and CRS induced depressive-like behavior which was more prominent in diabetic/depressed rats; this was reversed by chronic treatment with FLU and IMIP. Diabetic and non-diabetic rats exposed to CRS showed a significant increase in hippocampal expression of TLR-4 and pro-inflammatory cytokines alongside a decrease in BDNF expression. FLU and IMIP ameliorated these inflammatory abnormalities.Conclusion: Diabetes mellitus (DM) and chronic stress induced a depressive-like behavior associated with an increase in hippocampal expression of TLR-4, tumor necrosis factor-α, and interleukin-1ß with a significant correlation to decreased BDNF expression. FLU and IMIP showed comparable effects regards the improvement of depressive and inflammatory abnormalities associated with DM.

Pharmacogenomic testing for treatment resistant depression

2014 ◽  
Vol 4 (5) ◽  
pp. 236-239
Author(s):  
Susan G. Leckband
Keyword(s):  
Genetic Testing ◽  
Genetic Factors ◽  
Poor Response ◽  
Trial And Error ◽  
Treatment Resistant Depression ◽  
Antidepressant Response ◽  
Treatment Resistant ◽  
Dose Selection ◽  
Multiple Trials ◽  
Resistant Depression

The percentage of patients who have failed to completely or partially respond to multiple trials of antidepressants at adequate doses and for an adequate duration of therapy has varied in the literature and is considered substantial. Numerous strategies exist to treat poor antidepressant response, but often medications are selected on a “trial and error” basis. Genetic factors may play a role in poor response or intolerance to treatment with antidepressants which lead to treatment failures. Currently, available genetic testing as well as genetic testing currently under research may help guide clinicians with proper medication and dose selection.

From Trial and Error to Trial Simulation III: A Framework for Interim Analysis in Efficacy Trials With Antidepressant Drugs

2011 ◽  
Vol 89 (4) ◽  
pp. 602-607 ◽  
Author(s):  
G Santen ◽  
E van Zwet ◽  
P Bettica ◽  
R A Gomeni ◽  
M Danhof ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Antidepressant Drugs ◽  
Trial And Error ◽  
Efficacy Trials ◽  
Trial Simulation
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