Drug Therapy for Anxiety

Overseen By Zeinab A Dastgheib, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: University of Manitoba

Must not be taking: Psychiatric drugs, Anxiolytics, Antibiotics

Disqualifiers: Neurological illness, Substance use disorder, Heart disease, others

Compensation: Varies

Number of Visits: 2

Duration: 2-3 hours

42 Participants Needed

Trial Summary

What is the purpose of this trial?

New technologies are needed to help diagnose anxiety disorders. EVestG has facilitated the identification of numerous possible biomarkers of several psychiatric disorders. Some EVestG features seem to be caused by differences in low-frequency modulation that is consistent (both in frequency and behaviour) with the hippocampal rhythm (theta), which is known to play a role in anxiety. Critically, there is ample support in the literature for an anatomical and functional basis for the modulation of vestibular signals via theta. If anxiety could be measured continuously, perhaps throughout a patient's day, or throughout a task, it might be able to confirm an anxiety disorder. However, current techniques for measuring theta are highly invasive, performed rarely, and only in epilepsy patients. EVestG technology, however, is non-invasive, and could potentially record anxiety levels in any subject for extended periods of time. The proposed study will attempt to identify hippocampal theta in vestibular signals in healthy participants through a double-blind administration of two different drugs that are dissimilar both pharmacologically and in acute clinical effects but which are known to reduce the theta rhythm.

Will I have to stop taking my current medications?

Yes, you will need to stop taking any psychiatric drugs, drugs that interact with the study drugs, or those with anxiety-related effects. Also, avoid antibiotics or natural health products that affect certain enzymes.

What data supports the effectiveness of the treatment measuring hippocampal theta rhythm from the outer ear canal for anxiety?

Research shows that the hippocampal theta rhythm is linked to both anxiety and cognitive functions. Increased theta activity in certain parts of the hippocampus is associated with higher anxiety levels, while changes in theta rhythm can indicate the effectiveness of anxiety treatments. ^{1 2 3 4 5}

Is the drug therapy for anxiety safe for humans?

The research articles do not provide specific safety data for the drug therapy in humans, but they discuss the effects of various drugs on anxiety and brain activity in animal models. ^{1 2 5 6 7}

How does this drug differ from other anxiety treatments?

This drug therapy for anxiety may be unique because it involves the modulation of hippocampal theta rhythms, which are brain wave patterns linked to both cognitive and emotional functions. Unlike traditional anxiolytics that typically reduce theta frequency, this treatment might increase theta frequency, offering a novel approach to managing anxiety. ^{1 3 4 5 8}

Eligibility Criteria

This trial is for men and women aged 18-40 without a history of substance use disorders, neurological illnesses, major hearing loss, or severe allergies. They shouldn't be pregnant, left-handed, colorblind, have had psychological treatment or taken psychiatric drugs in the past year.

Inclusion Criteria

I am between 18 and 40 years old.

Exclusion Criteria

You have a history of drug or alcohol addiction, or someone in your family has a history of addiction.

Major hearing loss, self-reported or as assessed by investigator via audiogram

I have heart, lung disease, or diabetes.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive either triazolam, buspirone, or a placebo and undergo a series of tests and experiments

2-3 hours

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, ensuring drug effects have worn off

1-2 hours

1 visit (in-person)

Treatment Details

Interventions

• Measurement of the Hippocampal Theta Rhythm From the Outer Ear Canal

Trial Overview The study tests if non-invasive EVestG technology can detect anxiety by measuring hippocampal theta rhythms from the ear canal. Participants will receive Buspirone or Triazolam (both known to reduce theta rhythm) versus a placebo in a double-blind setup.

Participant Groups

Group I: Triazolam Experimental Treatment 1 Intervention

Participants will receive triazolam 0.25 mg prior to experiments.

Group II: Buspirone Experimental Treatment 1 Intervention

Participants will receive buspirone 10 mg prior to experiments.

Group III: Placebo Placebo Group 1 Intervention

Participants will receive a placebo prior to experiments.

Who Is Running the Clinical Trial?

University of Manitoba

Lead Sponsor

Trials

628

Recruited

209,000+

Findings from Research

Infusions of histamine into the ventral hippocampus significantly reduced anxiety-like behavior while increasing the evoked theta frequency, challenging the traditional view that anxiolytic effects are associated with theta frequency suppression.

In contrast, dorsal hippocampal histamine infusions did not affect anxiety or theta frequency, and diazepam, a known anxiolytic, successfully decreased theta frequency, indicating that the relationship between theta frequency and anxiety is more complex than previously thought.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ventral hippocampal histamine increases the frequency of evoked theta rhythm but produces anxiolytic-like effects in the elevated plus maze. Yeung, M., Treit, D., Dickson, CT.[2018]

The study tested the construct validity of the hippocampal theta frequency model of anxiety by using three anxiogenic drugs in rats, but found that these drugs did not increase theta frequency despite increasing anxiety behaviors.

This raises questions about the reliability of the hippocampal theta model as a true indicator of anxiety, as proven anxiolytic drugs like diazepam successfully decreased theta frequency, supporting the model's predictive validity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FG7142, yohimbine, and βCCE produce anxiogenic-like effects in the elevated plus-maze but do not affect brainstem activated hippocampal theta. Yeung, M., Lu, L., Hughes, AM., et al.[2016]

Bilateral histamine infusions into the lateral septum of rats reduced anxiety-like behaviors in two anxiety models, indicating potential anxiolytic effects of histamine in this brain region.

Interestingly, while these infusions increased hippocampal theta frequency, the clinically effective anxiolytic buspirone decreased theta frequency, suggesting that theta activity may not directly reflect anxiety levels in rodents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Behavioral anxiolysis without reduction of hippocampal theta frequency after histamine application in the lateral septum of rats. Chee, SS., Menard, JL., Dringenberg, HC.[2014]

Hippocampal damage can lead to cognitive deficits similar to dementia and emotional changes akin to those caused by anxiolytic drugs, highlighting the hippocampus's role in both cognitive and emotional functions.

Restoring theta rhythm in the hippocampus may improve cognitive function, and changes in theta frequency can serve as a reliable indicator for detecting the effects of antianxiety drugs and potentially identifying treatments for memory-related disorders like dementia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elicited hippocampal theta rhythm: a screen for anxiolytic and procognitive drugs through changes in hippocampal function? McNaughton, N., Kocsis, B., Hajós, M.[2009]

In a study with 25 healthy participants, the threat of receiving shocks during navigation tasks increased anxiety levels and improved navigation performance, highlighting the hippocampus's role in both cognition and affect.

MEG analyses showed that enhanced navigation performance was linked to increased theta activity in the left posterior hippocampus, while heightened anxiety was associated with increased theta activity in the left anterior hippocampus, indicating distinct functions within the hippocampus related to spatial cognition and fear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Distinct contributions of human hippocampal theta to spatial cognition and anxiety. Cornwell, BR., Arkin, N., Overstreet, C., et al.[2021]

The P20-N40 potential in rodents is a reliable model for studying auditory gating deficits in schizophrenia, as drug effects observed in this model closely predict similar effects in humans.

The mental state of the subjects, whether anesthetized or alert, does not significantly affect the predictive ability of the P20-N40 recordings, reinforcing its validity as a translational research tool.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Translational utility of rodent hippocampal auditory gating in schizophrenia research: a review and evaluation. Smucny, J., Stevens, KE., Olincy, A., et al.[2021]

Intrahippocampal administration of the Ih blocker ZD7288 at high doses effectively suppressed hippocampal theta rhythm in rats, demonstrating its ability to disrupt theta frequency oscillations.

ZD7288 also exhibited anxiolytic effects in behavioral tests, suggesting that suppression of hippocampal theta may be a valid model for understanding anxiety mechanisms, even for drugs not traditionally associated with anxiolytic action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrahippocampal infusion of the Ih blocker ZD7288 slows evoked theta rhythm and produces anxiolytic-like effects in the elevated plus maze. Yeung, M., Dickson, CT., Treit, D.[2013]

Inhibiting the dorsal lateral septum (dLS) with the GABAA receptor agonist muscimol increased the frequency of hippocampal theta oscillations in urethane-anesthetized rats, suggesting that the dLS plays a crucial role in regulating theta activity.

Interestingly, the increase in theta frequency from dLS inhibition was accompanied by anxiolytic-like effects in anxiety models, challenging the traditional view that anxiolytic treatments slow down theta oscillations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The lateral septum as a regulator of hippocampal theta oscillations and defensive behavior in rats. Chee, SS., Menard, JL., Dringenberg, HC.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Ventral hippocampal histamine increases the frequency of evoked theta rhythm but produces anxiolytic-like effects in the elevated plus maze. [2018]

2. England pubmed.ncbi.nlm.nih.gov

FG7142, yohimbine, and βCCE produce anxiogenic-like effects in the elevated plus-maze but do not affect brainstem activated hippocampal theta. [2016]

3. United States pubmed.ncbi.nlm.nih.gov

Behavioral anxiolysis without reduction of hippocampal theta frequency after histamine application in the lateral septum of rats. [2014]

4. England pubmed.ncbi.nlm.nih.gov

Elicited hippocampal theta rhythm: a screen for anxiolytic and procognitive drugs through changes in hippocampal function? [2009]

5. United States pubmed.ncbi.nlm.nih.gov

Distinct contributions of human hippocampal theta to spatial cognition and anxiety. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Translational utility of rodent hippocampal auditory gating in schizophrenia research: a review and evaluation. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Intrahippocampal infusion of the Ih blocker ZD7288 slows evoked theta rhythm and produces anxiolytic-like effects in the elevated plus maze. [2013]

8. United States pubmed.ncbi.nlm.nih.gov

The lateral septum as a regulator of hippocampal theta oscillations and defensive behavior in rats. [2018]