Cortical Excitability, Psychiatric Disorder
Conditions
Keywords
L-theanine, Cortical Excitability, NMDA, GABA, Paired-Pulse TMS
Brief summary
Major depressive disorder (MDD) is a serious mental illness and the leading cause of disability worldwide. New pharmacotherapeutic agents with complementary neurobiological mechanism and better side effect profile are of great needs. In addition to the monoamine system, the glutamatergic system plays a crucial role in MDD. L-theanine (N5-ethyl-L-glutamine) is the primary psychoactive component uniquely in green tea. Preclinical studies have demonstrated anti-depressant effect of L-theanine in rodents and provided evidences for its pharmacological properties of N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA) agonism. Yet these effects have not been proven in humans. Only one open-label clinical trial has studied and supported antidepressant effects of L-theanine in MDD patients. We propose using pair-pulse transcranial magnetic stimulation (ppTMS) to probe how L-theanine may manipulate the glutamatergic and GABA systems in the frontal region by changing cortical excitability first in healthy subjects. We plan to investigate the neurobiological effects of L-theanine in healthy subjects first. Granted that the first phase pilot trial provides neurophysiological evidence of L-theanine on motor cortex excitability in human subjects, next phases of studies on L-theanine in MDD patients cortical excitability could be justified.
Detailed description
Background and Significance: Major depressive disorder (MDD) is a serious mental illness and the leading cause of disability worldwide. Although many antidepressants acting on synaptic monoamine levels have been used as the first-line drug treatment for MDD, around one third of MDD are pharmacologically resistant. Side effects of these medications impose additional hardship on adherence and further affect treatment outcome. New pharmacotherapeutic agents with complementary neurobiological mechanism and better side effect profile are of great needs. In addition to the monoamine system, the glutamatergic system plays a crucial role in MDD. L-theanine (N5-ethyl-L-glutamine) is the primary psychoactive component uniquely in green tea. Epidemiological studies support that green tea consumption is an independent factor associated with lower prevalence of depression. Preclinical studies have demonstrated anti- depressant effect of L-theanine in rodents and provided evidences for its pharmacological properties of N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA) agonism. Yet these effects have not been proven in humans. Only one open-label clinical trial has studied and supported antidepressant effects of L-theanine in MDD patients. We propose using pair-pulse transcranial magnetic stimulation (ppTMS) to probe how L-theanine may manipulate the glutamatergic and GABA systems in the frontal region by changing cortical excitability first in healthy subjects. ppTMS is a well-established technique to investigate frontal motor cortical excitability mediated by the inter-neuron NMDA and GABA receptors. Specific changes of ppTMS measures, including impaired short-term and long-term intracortical inhibition (SICI, mediated by GABA-A receptor; LICI, mediated by GABA-B receptor) and intracortical facilitation (ICF, mediated by NMDA receptor), have been demonstrated in MDD. Using this technique, we plan to investigate the neurobiological effects of L-theanine in healthy subjects first. Granted that the first phase pilot trial provides neurophysiological evidence of L-theanine on motor cortex excitability in human subjects, next phases of studies on L-theanine in MDD patients cortical excitability could be justified. This will lay foundation for further exploration of L-theanine's potential as an augmenting agent for MDD in a placebo- controlled design. Aims and Hypothesis: Given the potential NMDA and GABA agonistic effects of L-theanine, we hypothesize that it increases intracortical inhibition and facilitation through enhancement of NMDA- and GABA-receptor mediated neurotransmission, in healthy subjects (N=10 to complete study). Study Procedures: Double-blinded, Randomized-order, Cross-over placebo-controlled to evaluate acute effect of single-dose L-theanine on motor cortex excitability by ppTMS in 10 healthy subjects. Dose of L-theanine or placebo is 400mg. At baseline, subjects will be randomized to L- theanine or placebo group, then receive ppTMS protocol before drug administration. The ppTMS protocol is repeated after 30min of administration. Then subjects will return to clinic after 1 week free of any medications and repeat the above protocol with the second drug condition. Visual analog scale will be used to evaluate psychosomatic symptoms and wellbeing of the subjects pre- and post-each drug administration. Data Analytic Plan: Wilcoxon test will be used to compare the baseline-to-post-drug means of SICI, LICI and ICF measures. Prespecified covariates include age, sex, handedness, level of fatigue will be analyzed in linear regression model. The time-condition relationship with continuous dependent variables of ICI and ICF values will be evaluated by Mixed Effect Model. Two- sided P value \< 0.05 is considered statistically significant.
Interventions
DRUGL-theanine
The subject will receive paired-pulse TMS (ppTMS) procedure before and 30min after taking the drug orally, to assess motor cortex excitability, measured by surface electromyogram (EMG). The ppTMS procedure is administered by a TMS stimulator controlled a program software named Signal. The coil of the stimulator is placed above the scalp where the stimulation would activate the left primary motor cortex region that controls the right thumb. When a pulse stimulation is delivered by the coil, the EMG over a thumb muscle (abductor pollicis brevis) will record a motor-evoked potential on the tracing. Cross-over with placebo in two separate sessions at least 72 hours apart.
DRUGPlacebo
The subject will receive paired-pulse TMS (ppTMS) procedure before and 30min after taking the drug orally, to assess motor cortex excitability, measured by surface electromyogram (EMG). The ppTMS procedure is administered by a TMS stimulator controlled a program software named Signal. The coil of the stimulator is placed above the scalp where the stimulation would activate the left primary motor cortex region that controls the right thumb. When a pulse stimulation is delivered by the coil, the EMG over a thumb muscle (abductor pollicis brevis) will record a motor-evoked potential on the tracing. Cross-over with L-theanine in two separate sessions at least 72 hours apart.
Sponsors
Butler Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Intervention model description
This is a pilot study, investigating the effects of single dose L-theanine in Healthy subjects, to further assess the validity and feasibility to study this compound in patient population.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Adult, aged between 18 and 65 years old; 2. Able to read/speak English and give informed consent 3. No current or history of Axis I psychiatric disorders by DSM-5. 4. Free of psychotropic medication use
Exclusion criteria
1. History of significant acute or chronic neurological or medical disorder or condition that increases risk for seizure with TMS; 2. History of alcohol use disorder, nicotine dependence, adjustment disorder; 3. History of allergic reactions to L-theanine or green tea; 4. Pregnancy; 5. Unable/unwilling to abstain from nutraceutical supplements and psychotropic agents during participation in the study 6. Unable/ unwillingness to refrain from recreational substance use (e.g. alcohol or marijuana) during participation in the study; 7. Meet criteria for exclusion from TMS or MRI procedures, including intracranial metal implants or nonremovable ferromagnetic items in the head/neck.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Change of Motor Cortex Excitability Measures by ppTMS | Before and 30 minutes after each drug administration (no long-term follow up as this is a study on acute effect of a single-dose agent). | The changes of Short-interval Intracortical Inhibition (SICI), Intracortical Facilitation (ICF), and Long-interval Intracortical Inhibition (LICI) before and 30 minutes after each drug administration. SICI, ICF and LICI are paired-pulse TMS (ppTMS)-EMG outcome measures that assess the activity of motor cortex GABA-A, NMDA and GABA-B interneurons, respectively. They are measured by the ratio between the peak-to-peak amplitude of motor-evoked potential (MEP) elicited by a testing TMS pulse (120% of the intensity of the resting motor threshold, following a conditioning pulse at different inter-stimuli interval, 2-5 milliseconds for SICI, 10-20 milliseconds for ICF, 100-200 milliseconds for LICI) and the peak-to-peak MEP amplitude elicited by a single pulse (120% of the intensity of the resting motor threshold). The baseline-to-post-drug change of SICI, ICF and LICI elicited by L-theanine will be compared to that elicited by placebo within each subject. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Change of Visual Analog Scale (VAS) | Throughout each session; each session lasts up to 3 hours; 2 sessions for each subject. The 2 sessions are 3-7 days apart. | VAS is a quick scale to assess and track how the participant subjectively feels through out each study session, e.g. anxiety, depression, excitement, etc. The score for each word ranges from 0 being the least in your life and 100 being the most in your life. It takes 3-4 minutes to complete each VAS, and there are 4 takes of VAS during each session. The outcome measure is the change of VAS throughout the 4 time points: 1) before the baseline ppTMS procedure; 2) before drug administration; 3) 30 minutes after drug administration; 4) before discharge from the session, during the session. |
Countries
United States
Participant flow
Pre-assignment details
We screened and enrolled 11 subjects altogether. 10 subjects in total completed the study. As this is a cross-over study, so each arm has 10 subjects.
Participants by arm
| Arm | Count |
|---|---|
| L-Theanine and Placebo Cross-over in All Subjects Subject will receive 400mg single dose of L-theanine or Placebo, by oral ingestion with water. After 72 hours washout period, the same subject will then receive 400mg single dose of Placebo or L-theanine (opposite condition from the first dose). The capsules are prepared and dispensed by hospital pharmacy, with the investigator and participant both blinded. All subjects receive both conditions of drugs. | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | L-Theanine and Placebo Cross-over in All Subjects |
|---|---|
| Age, Continuous | 29.5 years STANDARD_DEVIATION 3.2 |
| Average Sleep Hours | 7.4 Hours STANDARD_DEVIATION 0.6 |
| Body Mass Index (BMI) | 23.7 kg/m^2 STANDARD_DEVIATION 3.1 |
| Daily Coffee Drinker | 6 Participants |
| Handedness (Right) | 10 Participants |
| Multilingual | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 5 Participants |
| Years of Education | 20.8 years STANDARD_DEVIATION 2.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 11 |
| other Total, other adverse events | 1 / 11 | 1 / 11 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 |
Outcome results
Primary
The Change of Motor Cortex Excitability Measures by ppTMS
The changes of Short-interval Intracortical Inhibition (SICI), Intracortical Facilitation (ICF), and Long-interval Intracortical Inhibition (LICI) before and 30 minutes after each drug administration. SICI, ICF and LICI are paired-pulse TMS (ppTMS)-EMG outcome measures that assess the activity of motor cortex GABA-A, NMDA and GABA-B interneurons, respectively. They are measured by the ratio between the peak-to-peak amplitude of motor-evoked potential (MEP) elicited by a testing TMS pulse (120% of the intensity of the resting motor threshold, following a conditioning pulse at different inter-stimuli interval, 2-5 milliseconds for SICI, 10-20 milliseconds for ICF, 100-200 milliseconds for LICI) and the peak-to-peak MEP amplitude elicited by a single pulse (120% of the intensity of the resting motor threshold). The baseline-to-post-drug change of SICI, ICF and LICI elicited by L-theanine will be compared to that elicited by placebo within each subject.
Time frame: Before and 30 minutes after each drug administration (no long-term follow up as this is a study on acute effect of a single-dose agent).
Population: This is a cross-over study, therefore each subject will receive the drug conditions in both arms. The outcomes will be compared using Wilcoxon Signed-rank test to see if L-theanine elicits different changes of SICI, ICF or LICI within each individual than placebo does.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-Theanine | The Change of Motor Cortex Excitability Measures by ppTMS | SICI | 0.059 Ratio | Standard Error 0.028 |
| L-Theanine | The Change of Motor Cortex Excitability Measures by ppTMS | ICF | 0.073 Ratio | Standard Error 0.073 |
| L-Theanine | The Change of Motor Cortex Excitability Measures by ppTMS | LICI | 0.145 Ratio | Standard Error 0.1 |
| Placebo | The Change of Motor Cortex Excitability Measures by ppTMS | SICI | 0.005 Ratio | Standard Error 0.06 |
| Placebo | The Change of Motor Cortex Excitability Measures by ppTMS | ICF | -0.341 Ratio | Standard Error 0.176 |
| Placebo | The Change of Motor Cortex Excitability Measures by ppTMS | LICI | -0.068 Ratio | Standard Error 0.053 |
Secondary
The Change of Visual Analog Scale (VAS)
VAS is a quick scale to assess and track how the participant subjectively feels through out each study session, e.g. anxiety, depression, excitement, etc. The score for each word ranges from 0 being the least in your life and 100 being the most in your life. It takes 3-4 minutes to complete each VAS, and there are 4 takes of VAS during each session. The outcome measure is the change of VAS throughout the 4 time points: 1) before the baseline ppTMS procedure; 2) before drug administration; 3) 30 minutes after drug administration; 4) before discharge from the session, during the session.
Time frame: Throughout each session; each session lasts up to 3 hours; 2 sessions for each subject. The 2 sessions are 3-7 days apart.