Acute Stress Reaction
Conditions
Keywords
Stress, amygdala, functional MRI, Hariri paradigm, TSST
Brief summary
The purpose of this study is to explore the effect of Neurexan® on the brain response when participants undergo an emotional stressful condition in verum compared to placebo.
Detailed description
A randomized placebo-controlled, double-blind, two-period crossover study with an explorative design. 40 healthy males aged 31-59 years will be included in the study. Participant allocation to either Neurexan® or Placebo at study start is randomized with a ratio of 1:1, i.e. 20 Neurexan® first to 20 Placebo first individuals. Participants receive totally three tablets of either Neurexan® or Placebo per treatment period orally.
Interventions
DRUGNeurexan
0.6 mg / tablet
DRUGPlacebo
Neurexan-matched Placebo tablet
Sponsors
Biologische Heilmittel Heel GmbH
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
MALE
Age
31 Years to 59 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male 2. Age between ≥31 to ≤59 years 3. Fluent in German language 4. Nonsmoker 5. Able to understand the explanations and instructions given by the study physician 6. Willing to adhere to the prohibitions and restrictions specified in this protocol 7. Healthy on the basis of clinical laboratory tests, physical examination, medical history, vital signs performed at Screening Visit 8. Magnetic Resonance Imaging (MRI) compatible 9. Participants must have signed a written informed consent document prior to any study procedure indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study 10. Screening Scale for Chronic Stress of the Trier Inventory for Chronic Stress (TICS-SSCS) Score ≥ 9 and ≤ 36 11. Perceived Stress Scale (PSS) \> 9
Exclusion criteria
1. Current or past history of psychotic features or a diagnosis of any psychiatric disorder as defined in the Diagnostic and Statistical Manual of Mental Disorder 4th edition (DSM-IV) Axis I (recurrent major depression, panic disorder, social phobia, obsessive-compulsory disorder; alcohol dependency; schizophrenia and mania) 2. History of depressive episodes during the last 3 months prior to Screening Visit 3. Use of any psychotropic medication or suffering from severe psychiatric illness during the last 3 months prior to Screening Visit 4. Intake of prescription drugs for sleeping disorders or nervousness within one month prior to Screening Visit 5. Intake of over the counter (OTC) medication for the treatment of sleeping disorders or nervousness within the last (one) week prior to Screening Visit 6. High chronic stress as verified with the TICS-SSCS (\> 36) 7. Low chronic stress as verified with the TICS-SSCS (\< 9) and PSS ≤ 9 8. Participants with Blood Pressure (BP) ≥ 160/100 on day 0 and at randomization 9. Participants with treated hypertension 10. Known allergies and/or hypersensitivity to ingredients of Neurexan® (Passiflora incarnata, Avena sativa, Coffea arabica, Zincum isovalerianicum, lactose monohydrate, magnesium stearate) or Placebo (Lactose monohydrate, magnesium stearate) 11. Known Lactose intolerance 12. Use of any psychological stress-management intervention within the last 4 weeks prior to Screening Visit 13. History of substance, drug, including nicotine, or alcohol abuse within the preceding 3 months prior to Screening Visit 14. Alcohol, drug, nicotine intake within the last 24 hours before day 0 and at randomization - confirmed by positive screening tests 15. Body Mass Index (BMI) \> 30 kg/m2 16. Works regularly nights shifts 17. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic or hematologic disease as defined by clinical screening interview 18. Any somatic disease or other condition the Investigator or their duly assigned representatives believes could affect the ability of the individual to complete the study or the interpretation of the study results 19. Participants with medical illness that may have influenced brain morphology and/or physiology (e.g. uncontrolled hypertension, diabetes) 20. Participants with a history of one or more seizures without a clear and resolved aetiology 21. Participants with claustrophobia 22. Participants with tinnitus 23. Clinically significant acute illness within 7 days prior to randomization 24. Presence of metallic (ferromagnetic) implants (heart pacemaker, aneurysm clips), tattoos or piercings 25. Have received an experimental drug or used an experimental medical device (participation in any other clinical trial) within the last 30 days before study inclusion 26. Participants whose ability to speak for themselves lacks or can be doubted
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Functional Magnetic Resonance Imaging (fMRI) Task Data: BOLD Activation Changes Within Amygdala During Negative Faces in the Hariri Face Matching Task Between Placebo and Neurexan Treatment | 1 hour after taking a single dose of Neurexan or placebo | The neuronal drug effect was assessed by measuring changes in amygdala activity between placebo and Neurexan using fMRI 1 hour after treatment. The left amygdala was prespecified as region of interest for emotional processing and social stress. Amygdala activation in response to negative emotional faces versus neutral forms in the Hariri task was assessed. Beta values (i.e. parameter estimates) indicate the proportion of activation explained by a variable, here negatives faces or forms. Beta values serve as index of neural activity, the higher the beta value, the higher the activity. A paired t-test analysis of extracted beta values for the left amygdala was performed comparing placebo and Neurexan treatment. Amygdala hypersensitivity to negative stimuli is associated with anxiety disorders and increased stress sensitivity, while a reduction in amygdala activation may indicate a calming or modulating effect of the intervention. |
| Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Change in Global Functional Connectivity Density of the Amygdala at Rest | 1 hour after taking a single dose of Neurexan or placebo | Resting-state fMRI scans were performed before dosing and approximately 1 hour after a single dose of Neurexan or Placebo. Highly connected functional hubs were identified by global functional connectivity density (gFCD) analysis. The number of voxels with a positive rsFC larger than the predefined threshold of r \> 0.6 at a whole brain level was evaluated. gFCD was calculated for each voxel as the total number of significant correlations between this voxel and all voxels in gray matter. The gFCD value in each voxel was divided by the global mean value to improve normality. The larger the number of significant correlations, the greater the gFCD strength. Changes in gFCD strength of the amygdala from pre-dose to 1-hour post-dose were compared between the Neurexan and Placebo conditions using a within-subject repeated-measures ANOVA with main effects of time (pre- vs. post-dose) and drug (placebo vs. Nx4) and their interaction (time x drug). |
| Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Change in Whole-Brain Functional Connectivity of the Amygdala at Rest | 1 hour after taking a single dose of Neurexan or placebo | Resting-state fMRI scans were performed before dosing and approximately 1 hour after a single dose of Neurexan or Placebo. Left centromedial amygdala (CeMA) was defined as the seed based on probabilistic cytoarchitectonic maps. The time course of the average BOLD signal within the seed was correlated with the signals in each voxel in the whole brain. The Pearson correlation coefficients were transformed to Z values (Fisher's Z), resulting in a map representing voxel-wise strength of rsFC to the seed region. Changes in left CeMA rsFC from pre-dose to post-dose, evaluated as binary connectivity coefficients, were compared between the Neurexan and Placebo conditions. |
| Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Baseline Activity of the Amygdala at Rest as Measured by Amplitude of Low-Frequency Fluctuations (ALFF) | 1 hour after taking a single dose of Neurexan or placebo | The time series in each voxel of the rs-fMRI data were converted to the frequency domain using a Fast Fourier Transform (FFT), and the power spectrum was obtained. The square root of the power spectrum was computed and then averaged across each predefined frequency band. This averaged square root was taken as amplitude of low frequency fluctuation (ALFF). A ratio of the power spectrum of low-frequency range to that of the entire frequency range, i.e. the fractional ALFF (fALFF), was computed. High fALFF in the amygdala may reflect hyperactivity and could serve as a marker for heightened stress sensitivity. To examine the effect of drug on rs-metrics (RS1) while taking baseline rs-metrics before drug administration (RS0) as control variable, mean fALFF values of the amygdala were compared between placebo and Neurexan. |
| Functional Magnetic Resonance Imaging (fMRI) Task Data: Stress Network Activation in Response to Psychosocial Stress Induction. | 1.5 hours after taking a single dose of Neurexan or placebo | The neuronal drug effect was assessed by measuring activity changes within a predefined stress network, comprising the anterior cingulate cortex, medial orbitofrontal cortex, hippocampus, amygdala, and hypothalamus, between placebo and Neurexan using fMRI. Stress network activation in response to psychosocial stress induced by the ScanSTRESS paradigm was assessed. Beta values (i.e. parameter estimates) indicate the proportion of activation that is explained by a variable, in this case mental rotation or simple matching of figures. Beta-estimates serve as an index of neural activity, the higher the beta value, the higher the activity. The paradigm contrast (stress-control) for each participant was taken to a second level analysis of all voxels comprised by an ACC mask. A voxelwise paired t-test, controlled for multiple comparison, compared placebo and verum conditions. The endpoint was assessed approximately 1.5 hours post-dose after a single dose of Neurexan or placebo. |
Countries
Germany
Participant flow
Recruitment details
Out of 53 screened subjects, 40 met all eligibility criteria and were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Neurexan First, Then Placebo Participants received a single dose of three Neurexan tablets on trial Day 1. Following a washout period of 7 to 35 days, they received a single dose of three placebo tablets on trial Day 2. | 20 |
| Placebo First, Then Neurexan Participants received a single dose of three placebo tablets on trial Day 1. Following a washout period of 7 to 35 days, they received a single dose of three Neurexan tablets on trial Day 2. | 19 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Day 1 | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Neurexan First, Then Placebo | Placebo First, Then Neurexan | Total |
|---|---|---|---|
| Age, Continuous Age | 43.2 years STANDARD_DEVIATION 10 | 43.7 years STANDARD_DEVIATION 9.6 | 43.7 years STANDARD_DEVIATION 9.8 |
| Region of Enrollment Germany | 20 Participants | 19 Participants | 39 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 20 Participants | 19 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 39 | 0 / 39 |
| other Total, other adverse events | 0 / 39 | 0 / 39 |
| serious Total, serious adverse events | 0 / 39 | 0 / 39 |
Outcome results
Primary
Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Baseline Activity of the Amygdala at Rest as Measured by Amplitude of Low-Frequency Fluctuations (ALFF)
The time series in each voxel of the rs-fMRI data were converted to the frequency domain using a Fast Fourier Transform (FFT), and the power spectrum was obtained. The square root of the power spectrum was computed and then averaged across each predefined frequency band. This averaged square root was taken as amplitude of low frequency fluctuation (ALFF). A ratio of the power spectrum of low-frequency range to that of the entire frequency range, i.e. the fractional ALFF (fALFF), was computed. High fALFF in the amygdala may reflect hyperactivity and could serve as a marker for heightened stress sensitivity. To examine the effect of drug on rs-metrics (RS1) while taking baseline rs-metrics before drug administration (RS0) as control variable, mean fALFF values of the amygdala were compared between placebo and Neurexan.
Time frame: 1 hour after taking a single dose of Neurexan or placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neurexan | Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Baseline Activity of the Amygdala at Rest as Measured by Amplitude of Low-Frequency Fluctuations (ALFF) | -0.0120 fractional ALFF | Standard Deviation 0.02534 |
| Placebo | Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Baseline Activity of the Amygdala at Rest as Measured by Amplitude of Low-Frequency Fluctuations (ALFF) | 0.0007 fractional ALFF | Standard Deviation 0.0359 |
p-value: >0.05Paired t-test
Primary
Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Change in Global Functional Connectivity Density of the Amygdala at Rest
Resting-state fMRI scans were performed before dosing and approximately 1 hour after a single dose of Neurexan or Placebo. Highly connected functional hubs were identified by global functional connectivity density (gFCD) analysis. The number of voxels with a positive rsFC larger than the predefined threshold of r \> 0.6 at a whole brain level was evaluated. gFCD was calculated for each voxel as the total number of significant correlations between this voxel and all voxels in gray matter. The gFCD value in each voxel was divided by the global mean value to improve normality. The larger the number of significant correlations, the greater the gFCD strength. Changes in gFCD strength of the amygdala from pre-dose to 1-hour post-dose were compared between the Neurexan and Placebo conditions using a within-subject repeated-measures ANOVA with main effects of time (pre- vs. post-dose) and drug (placebo vs. Nx4) and their interaction (time x drug).
Time frame: 1 hour after taking a single dose of Neurexan or placebo
Population: Of the 39 participants, 3 were excluded due to excessive micromovement artifacts, and 1 was excluded due to data corruption.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neurexan | Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Change in Global Functional Connectivity Density of the Amygdala at Rest | 0.0139 normalized FCD strength | Standard Deviation 0.1338 |
| Placebo | Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Change in Global Functional Connectivity Density of the Amygdala at Rest | -0.0073 normalized FCD strength | Standard Deviation 0.0855 |
p-value: >0.05Paired t-test
Primary
Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Change in Whole-Brain Functional Connectivity of the Amygdala at Rest
Resting-state fMRI scans were performed before dosing and approximately 1 hour after a single dose of Neurexan or Placebo. Left centromedial amygdala (CeMA) was defined as the seed based on probabilistic cytoarchitectonic maps. The time course of the average BOLD signal within the seed was correlated with the signals in each voxel in the whole brain. The Pearson correlation coefficients were transformed to Z values (Fisher's Z), resulting in a map representing voxel-wise strength of rsFC to the seed region. Changes in left CeMA rsFC from pre-dose to post-dose, evaluated as binary connectivity coefficients, were compared between the Neurexan and Placebo conditions.
Time frame: 1 hour after taking a single dose of Neurexan or placebo
Population: Of the 39 participants, 3 were excluded due to excessive micromovement artifacts, and 1 was excluded due to data corruption.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neurexan | Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Change in Whole-Brain Functional Connectivity of the Amygdala at Rest | -0.0127 Binary connectivity coefficient | Standard Deviation 0.0328 |
| Placebo | Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Change in Whole-Brain Functional Connectivity of the Amygdala at Rest | 0.0239 Binary connectivity coefficient | Standard Deviation 0.0346 |
p-value: <0.001Paired t-test
Primary
Functional Magnetic Resonance Imaging (fMRI) Task Data: BOLD Activation Changes Within Amygdala During Negative Faces in the Hariri Face Matching Task Between Placebo and Neurexan Treatment
The neuronal drug effect was assessed by measuring changes in amygdala activity between placebo and Neurexan using fMRI 1 hour after treatment. The left amygdala was prespecified as region of interest for emotional processing and social stress. Amygdala activation in response to negative emotional faces versus neutral forms in the Hariri task was assessed. Beta values (i.e. parameter estimates) indicate the proportion of activation explained by a variable, here negatives faces or forms. Beta values serve as index of neural activity, the higher the beta value, the higher the activity. A paired t-test analysis of extracted beta values for the left amygdala was performed comparing placebo and Neurexan treatment. Amygdala hypersensitivity to negative stimuli is associated with anxiety disorders and increased stress sensitivity, while a reduction in amygdala activation may indicate a calming or modulating effect of the intervention.
Time frame: 1 hour after taking a single dose of Neurexan or placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neurexan | Functional Magnetic Resonance Imaging (fMRI) Task Data: BOLD Activation Changes Within Amygdala During Negative Faces in the Hariri Face Matching Task Between Placebo and Neurexan Treatment | 0.196 Beta value | Standard Deviation 0.045 |
| Placebo | Functional Magnetic Resonance Imaging (fMRI) Task Data: BOLD Activation Changes Within Amygdala During Negative Faces in the Hariri Face Matching Task Between Placebo and Neurexan Treatment | 0.361 Beta value | Standard Deviation 0.04 |
p-value: 0.004Paired t-test
Primary
Functional Magnetic Resonance Imaging (fMRI) Task Data: Stress Network Activation in Response to Psychosocial Stress Induction.
The neuronal drug effect was assessed by measuring activity changes within a predefined stress network, comprising the anterior cingulate cortex, medial orbitofrontal cortex, hippocampus, amygdala, and hypothalamus, between placebo and Neurexan using fMRI. Stress network activation in response to psychosocial stress induced by the ScanSTRESS paradigm was assessed. Beta values (i.e. parameter estimates) indicate the proportion of activation that is explained by a variable, in this case mental rotation or simple matching of figures. Beta-estimates serve as an index of neural activity, the higher the beta value, the higher the activity. The paradigm contrast (stress-control) for each participant was taken to a second level analysis of all voxels comprised by an ACC mask. A voxelwise paired t-test, controlled for multiple comparison, compared placebo and verum conditions. The endpoint was assessed approximately 1.5 hours post-dose after a single dose of Neurexan or placebo.
Time frame: 1.5 hours after taking a single dose of Neurexan or placebo
Population: Of the 39 participants, 3 were excluded due to excessive micromovement artifacts.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neurexan | Functional Magnetic Resonance Imaging (fMRI) Task Data: Stress Network Activation in Response to Psychosocial Stress Induction. | 0.02 Beta Estimate | Standard Deviation 0.14 |
| Placebo | Functional Magnetic Resonance Imaging (fMRI) Task Data: Stress Network Activation in Response to Psychosocial Stress Induction. | 0.41 Beta Estimate | Standard Deviation 0.14 |
p-value: <0.05Paired t-test