Stress Sensitivity and Depression for Blood Vessel Function

Overseen By Jody Greaney, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: University of Delaware

Must not be taking: Antidepressants, Antipsychotics, Benzodiazepines, others

Disqualifiers: Neuropsychiatric disease, Suicidal ideation, Chronic disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how stress and depression might affect blood vessel function, focusing on a natural compound in the body called nitric oxide. Researchers are examining both healthy adults and those with major depressive disorder (MDD) to determine if stress impacts their blood vessel function differently. The study uses a treatment called NG-nitro-L-arginine methyl ester (L-NAME) for this investigation. Participants should either be non-depressed and healthy or have symptoms of MDD without other major health issues. As an unphased trial, this study provides a unique opportunity to contribute to understanding the complex relationship between mental health and cardiovascular function.

Will I have to stop taking my current medications?

Yes, you will need to stop taking medications that alter cardiovascular function or are psychoactive, such as antidepressants and antipsychotics, at least 8 weeks before joining the trial.

Is there any evidence suggesting that NG-nitro-L-arginine methyl ester (L-NAME) is likely to be safe for humans?

Research suggests that L-NAME, a compound under study, may help treat mood disorders like depression. Some studies have examined its effects on stress-related depression and found it might improve depressive symptoms. However, detailed information about its safety for humans remains limited.

L-NAME works by influencing the nitric oxide system in the body. While research indicates potential benefits for depression, information about human tolerance and possible side effects is insufficient. The trial phase is "Not Applicable," indicating that detailed safety information might not be fully available yet. Participants should consider this when deciding to join a trial involving L-NAME. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Most treatments for depression, like SSRIs and SNRIs, work by balancing brain chemicals. But NG-nitro-L-arginine methyl ester (L-NAME) takes a different approach. It targets blood vessel function, potentially linking stress sensitivity and depression to how well our blood vessels work. Researchers are excited because this could open up a new pathway for treating depression, especially for those not responding well to traditional medications. This unique angle might offer hope for faster or more effective relief for those struggling with major depressive disorder.

What evidence suggests that NG-nitro-L-arginine methyl ester (L-NAME) might be an effective treatment for depression?

Research has shown that L-NAME affects blood vessel function by influencing a pathway involving nitric oxide (NO). Some studies suggest it might help reduce inflammation related to depression. This trial will compare its effects on blood vessel function between healthy adults and adults with major depressive disorder (MDD). This pathway also plays a role in how some antidepressants work, suggesting potential benefits for mood disorders like MDD. However, results vary; some studies show it can both increase and decrease anxiety-like behaviors. This mixed evidence indicates that its effectiveness can differ, necessitating further research to understand its potential benefits for depression and blood vessel function. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for working-age adults who may experience heightened negative emotional responses to daily stress. It's specifically looking at those with or without major depressive disorder (MDD) to understand how their blood vessels respond.

Inclusion Criteria

I don't have any long-term health issues like heart or autoimmune diseases.

Non-depressed health adults (HA) with no evidence of current or lifetime history of major psychiatric illness, confirmed by MINI assessment and a Licensed Clinical Psychologist

Participants must have a level of understanding of the English language sufficient to provide informed consent and to agree to all tests and procedures, as well as the capacity and willingness to attend all study related visits and to comply with the study protocol

Exclusion Criteria

Tobacco use (including electronic cigarettes)

I have used hormone replacement therapy in the past or am currently using it.

Serious and imminent active suicidal/homicidal ideation with intent, plans, or behaviors

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Testing Cycle

Multiple dynamic aspects of affective regulation and daily stress processes are assessed during routine everyday life

14 days

Daily assessments via mobile app

Physiological Assessment

Mechanistic regulation of microvascular endothelial function is assessed using physiological and pharmacological approaches

2 days

In-person assessments immediately before and after the testing cycle

Follow-up

Participants are monitored for safety and effectiveness after the testing cycle

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• NG-nitro-L-arginine methyl ester (L-NAME)

Trial Overview

The study tests if a drug called L-NAME, which affects nitric oxide in the body, can influence how blood vessels dilate in response to stress, especially when someone has heightened negative emotions.

How Is the Trial Designed?

Group I: adults with major depressive disorder Experimental Treatment 1 Intervention

adults with major depressive disorder (unmedicated)

Group II: healthy adults Active Control 1 Intervention

non-depressed healthy adults

Who Is Running the Clinical Trial?

University of Delaware

Lead Sponsor

Trials

167

Recruited

25,700+

National Institute of General Medical Sciences (NIGMS)

Collaborator

Trials

315

Recruited

251,000+

Published Research Related to This Trial

In a study of 11 patients undergoing cardiac catheterization, mental stress was found to increase coronary blood flow by 34%, indicating that stress can significantly affect heart function.

The study revealed that neuronal nitric oxide synthase (nNOS) plays a crucial role in mediating this stress-induced vasodilation in the coronary microvasculature, suggesting a potential target for improving heart health in patients with coronary artery disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The human coronary vasodilatory response to acute mental stress is mediated by neuronal nitric oxide synthase. Khan, SG., Melikian, N., Shabeeh, H., et al.[2021]

In a study of male and female mice subjected to 8 weeks of unpredictable chronic mild stress, females exhibited more severe depressive symptoms but showed a reduced impact on vascular function compared to males, indicating a sex-based difference in response to chronic stress.

While males experienced significant impairment in blood vessel dilation due to increased inflammation and oxidative stress, females maintained better vascular reactivity, suggesting they may have a protective mechanism against the development of cardiovascular disease despite higher depressive symptom severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protective effect of sex on chronic stress- and depressive behavior-induced vascular dysfunction in BALB/cJ mice. Stanley, SC., Brooks, SD., Butcher, JT., et al.[2021]

Chronic stress in rats led to a significant decrease in cerebral blood flow responses, indicating impaired hemodynamic function, which could contribute to cerebrovascular diseases like stroke and vascular dementia.

The study found that chronic stress downregulated important vasomodulator enzymes (nNOS and HO-2) and altered cellular expressions in the brain, including decreased GABAergic interneuron activity and increased microglial activation, suggesting a complex interplay between stress and brain vascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic Stress Decreases Cerebrovascular Responses During Rat Hindlimb Electrical Stimulation. Lee, S., Kang, BM., Shin, MK., et al.[2020]

In a study of 50 young adults with a first episode of major depression, plasma levels of nitric oxide metabolites were significantly lower compared to 50 healthy controls, suggesting reduced nitric oxide production in depressed individuals.

Despite the lower nitric oxide levels, there was no significant difference in vascular endothelial function between the depressed and control groups, indicating that decreased nitric oxide production may not directly lead to vascular dysfunction in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma nitrate levels and flow-mediated vasodilation in untreated major depression. García, RG., Zarruk, JG., Barrera, C., et al.[2011]

In a study involving 24 young adults with major depressive disorder (MDD) and 20 healthy controls, it was found that oxidative stress leads to reduced nitric oxide (NO) availability, causing impaired endothelial function, which is crucial for blood vessel dilation.

Targeting oxidative stress through scavenging superoxide or inhibiting NADPH oxidase improved endothelial function in individuals with MDD, suggesting that therapies aimed at reducing oxidative stress could help improve vascular health and lower cardiovascular risks associated with depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxidative Stress Contributes to Microvascular Endothelial Dysfunction in Men and Women With Major Depressive Disorder. Greaney, JL., Saunders, EFH., Santhanam, L., et al.[2020]

Chronic administration of L-NAME in rats led to increased mean arterial pressure and elevated plasma IL-1β levels, indicating significant vascular dysfunction due to nitric oxide deficiency.

The study found that while L-NAME inhibited endothelial nitric oxide synthase (eNOS), the increase in inducible NOS (iNOS) and decrease in dimethylarginine dimethylaminohydrolase (DDAH) activity also contributed to the vascular pathology, suggesting multiple mechanisms are involved in the progression of endothelial dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Involvement of inducible nitric oxide synthase and dimethyl arginine dimethylaminohydrolase in Nω-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Leo, MD., Kandasamy, K., Subramani, J., et al.[2014]

Chronic inhibition of nitric oxide synthesis using L-NAME in pigs led to increased microvascular hyperreactivity to 5-HT, indicating a significant alteration in vascular response after 4 weeks of treatment.

The study found that the enhanced decrease in coronary blood flow (CBF) due to 5-HT in L-NAME treated pigs was only partially blocked by a 5-HT2 antagonist, suggesting that changes in receptor affinity or new expression of 5-HT1 receptors may play a role in this hyperreactivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Altered serotonin receptor subtypes mediate coronary microvascular hyperreactivity in pigs with chronic inhibition of nitric oxide synthesis. Kadokami, T., Egashira, K., Kuwata, K., et al.[2019]

Long-term treatment with l-NAME in both wild-type and eNOS-KO mice led to significant vascular changes, including medial thickening and perivascular fibrosis in coronary microvessels, indicating that these effects are not solely due to the inhibition of endothelial NO synthesis.

The study suggests that l-NAME's long-term vascular effects are mediated through NO-independent mechanisms, such as the upregulation of vascular ACE and increased oxidative stress, which can be mitigated by ACE inhibitors or angiotensin II receptor antagonists.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term treatment with N(omega)-nitro-L-arginine methyl ester causes arteriosclerotic coronary lesions in endothelial nitric oxide synthase-deficient mice. Suda, O., Tsutsui, M., Morishita, T., et al.[2019]

L-NG-Nitro arginine methyl ester (L-NAME) not only acts as a nitric oxide synthase (NOS) inhibitor but also slowly releases nitric oxide (NO), which can enhance vasodilation effects when combined with nitrodilators like nitroglycerin.

The release of NO from L-NAME is influenced by factors such as inflammation and the presence of transition metals, suggesting that its effects may complicate its use as a straightforward NOS inhibitor in research and clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

L-NAME releases nitric oxide and potentiates subsequent nitroglycerin-mediated vasodilation. Liu, T., Zhang, M., Mukosera, GT., et al.[2020]

Chronic stress in mice led to significant impairments in endothelium-dependent vascular dilation, indicating that stress can negatively affect blood vessel function, even without prior vascular disease.

While insulin resistance and inflammation were observed in stressed mice, they were not strong predictors of vascular dysfunction, suggesting that other unknown mechanisms may play a more critical role in vascular health under chronic stress conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Depressive behavior and vascular dysfunction: a link between clinical depression and vascular disease? d'Audiffret, AC., Frisbee, SJ., Stapleton, PA., et al.[2021]

Short-term treatment with the NF-κB inhibitor salsalate improved nitric oxide (NO)-mediated dilation in young adults with major depressive disorder (MDD), suggesting a potential therapeutic approach for endothelial dysfunction associated with depression.

The study provides evidence that increased reactive oxygen species (ROS) production, linked to NF-κB activation, contributes to impaired NO-dependent dilation in MDD, highlighting a mechanistic role of vascular inflammation in depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term salicylate treatment improves microvascular endothelium-dependent dilation in young adults with major depressive disorder. Greaney, JL., Saunders, EFH., Alexander, LM.[2023]

An 8-week low-dose treatment of L-NAME in borderline hypertensive rats led to increased blood pressure and left ventricular hypertrophy, indicating that this treatment may negatively affect nitric oxide synthesis regulation in prehypertensive conditions.

In contrast, the same treatment improved nitric oxide synthase activity and vascular function in normotensive Wistar rats, highlighting a significant difference in how nitric oxide regulation works in healthy versus borderline hypertensive states.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic low-dose L-NAME treatment effect on cardiovascular system of borderline hypertensive rats: feedback regulation? Kopincova, J., Puzserova, A., Bernatova, I.[2013]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10699357/

Perinatal N(G)-Nitro-L-arginine methyl ester administration ...

The results of L-NAME administration are controversial, including a reduction or elevation of anxiety-like behaviors in different experimental protocols.

2.

ahajournals.org

ahajournals.org/doi/pdf/10.1161/CIRCRESAHA.118.313764

Oxidative Stress Contributes to Microvascular Endothelial ...

Given the afore- mentioned preclinical data indicating a role for superoxide in mediating endothelial dysfunction in depression, we further.

3.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0091305713001330

Inhibition of the l-arginine–nitric oxide pathway mediates ...

In conclusion, the results of the present study suggest that the l-arginine–NO pathway is deeply involved in ketamine's antidepressant actions and that the ...

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC9018008/

Short-term salicylate treatment improves microvascular ...

Our data indicate that short-term treatment with therapeutic doses of the nuclear factor-κB (NF-κB) inhibitor salsalate improved nitric oxide (NO)-mediated ...

5.

researchgate.net

researchgate.net/publication/277536731_13_Anti-inflammatory_role_of_L-NG-Nitroarginine_Methyl_Ester_in_a_chronic_model_of_depression

13. Anti-inflammatory role of L-NG-Nitroarginine Methyl ...

13. Anti-inflammatory role of L-NG-Nitroarginine Methyl Ester in a chronic model of depression. September 2013; Brain Behavior and Immunity 32.

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC6303682/

Neuronal nitric oxide synthase and affective disorders - PMC

In line with this finding, studies found that NG-nitro-L-arginine (L-NA or L-NNA), another type of non-preferential NOS inhibitor, resulted in antidepressant- ...

7.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0304394015004085

Antidepressant action via the nitric oxide system: A pilot ...

However, its role in MDD is not yet known. The purpose of our study was to determine if antidepressants improve depression via the NO pathway ...

8.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/27082990/

Neuroprotective Role of L-NG-Nitroarginine Methyl Ester ...

Further, we evaluated the ameliorative effect of L-NG-Nitroarginine Methyl Ester (L-NAME) to reverse the stress induced depressive mood state.

9.

journals.physiology.org

journals.physiology.org/doi/pdf/10.1152/ajpheart.00643.2021

dependent dilation in young adults with major depressive ...

These data suggest that NF-κB activation, via increased vascular ROS production, contributes to blunted NO-dependent dilation in young adults ...

10.

mdpi.com

mdpi.com/1424-8247/3/1/273

Nitric Oxide Synthase Inhibitors as Antidepressants

The present paper will review general aspects of the NO system, as well as focus on inhibitors of NO production as putative therapeutic agents towards anxiety ...