Clinical trial NCT04181736
Conditions: Major Depressive Disorder
Keywords: guanfacine dorsolateral prefrontal cortex (dLPFC) major depressive disorder (MDD) cognitive control circuit cognitive control behavioral performance
Sponsor: Stanford University
Start date: 2022-09-14; Completion date: 2024-02-12
Enrollment: 28 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Cognitive impairments contribute significantly to psychosocial dysfunction in major depressive disorder (MDD) and respond poorly to conventional antidepressants, yet selective treatments targeted to these impairments are lacking. Our previous research identified a distinct subgroup of depression called "cognitive biotype+" that comprises 27% of depressed patients and is characterized by pre-treatment global cognitive impairments and dysfunction in the cognitive control neural circuit. In this study, we evaluated the medication guanfacine immediate release (GIR), an alpha 2A receptor agonist, as a novel treatment for selectively improving cognitive control circuit function, performance on cognitive testing, and clinical measures the cognitive biotype+ subgroup.

Detailed description:
The flow of procedures and study visits is as follows:

1. Recruitment and screening: Participants experiencing depressive symptoms and not taking any psychiatric medications as determined by a 5 half-life wash out period will be recruited from the community, including students and employees at Stanford. Recruitment will come primarily from Facebook ads, which will use only IRB approved material. A flyer will also be physically posted on boards in public locations in order to include a variety of sources for the study.
2. Individuals will need to participate in 3 screening visits in order to enroll in the study. During the first visit, participants will review informed consent, be administered a clinical interview, and be sent instructions for completing cognitive testing at home.
3. If eligibility after this initial screening visit, the second visit will be a medical screen in order to ensure participants are safe to take GIR and will include standard blood tests, medical history, vitals, and a urine drug test.
4. If the participant meets medical and cognitive criteria, functional magnetic resonance imaging (fMRI) scans will be undertaken at another study visit at The Stanford Center for Cognitive and Neurobiological Imaging (CNI). Using a participant's task-evoked activity in the dorsolateral prefrontal cortex (dLPFC) and performance on objective cognitive testing, we will apply thresholds using established healthy norms to select participants within the cognitive biotype+ group.
5. Participants will receive GIR for a period of 8 weeks sent to their place of residence from Mariner pharmacy.
6. Participants will be seen in-person or virtually by a study clinician at weeks 2, 4, 6, 8, and 10 and an appropriately trained clinical research coordinator at weeks 1, 3, 5, 7, and 9. All subjects will have an fMRI scan after 6-8 weeks of taking GIR. During in-person visits and virtual monitoring, we will assess participants for the following: changes to symptoms, function, and suicidality, adherence to GIR, changes to concomitant medication(s), adverse events (AEs), birth control usage compliance, likelihood of pregnancy (female participants of childbearing potential), and vital signs if appropriate.
7. If participants wish to continue GIR and their psychiatrist or PCP is willing to prescribe this, they will continue with their current dose for weeks 9 and 10. If they prefer to stop taking GIR and/or they do not have a provider who is willing to continue GIR, the participant will be tapered off the medication.

Arms: arm 1: Participants will be prescribed tabs containing guanfacine immediate release (GIR) to be taken for 8 weeks and will be monitored by one of the study psychiatrists/nurse practitioners. Subjects will start with 0.5mg GIR nightly and increase by 0.5mg every 3 days with a goal dose of 2mg.
Interventions: intervention 1: Guanfacine Tablets
Intervention descriptions: intervention 1: Guanfacine immediate release, sold under the brand name Tenex among others, is a medication used to treat high blood pressure and off-label to treat attention deficit hyperactivity disorder (ADHD). It is taken by mouth and will be compounded by a pharmacy to the required doses used in this study.

Protocol documents:
Prot_000.pdf: 
 
Precision Mental Health: Evaluating  
Biotype-guided Interventions for Depression 
NCT04181736 
August 31, 2023 
1. 
PURPOSE OF THE STUDY 
a. 
Brief Summary 
The diagnosis of major depression relies on patient reports, and two patients with the 
same diagnosis might share only one symptom. Thus, a single mechanism is unlikely to 
underlie a broad descriptive diagnosis such as major depression. Our approach is 
anchored by a neural circuit taxonomy that proposes distinct biotypes of depression 
derived from functional magnetic resonance imaging (fMRI)(Williams et al., 2016). In 
this study, we aim to target a putative type of major depression that arises from 
dysfunction in cognitive control neural circuitry with a drug called guanfacine. 
b. 
Objectives 
The proposed study addresses a public health need, generated by the burden of illness 
from depression. Major depressive disorder (MDD) is a prevalent and disabling 
condition; the 1-year prevalence is approximately 17%, and lifetime prevalence is as high 
as 25% globally. Only a subset of individuals with depression reach symptomatic 
remission after adequate treatment with first-line antidepressant medication treatment, 
estimated at approximately 30-40%. Dysfunction in a large-scale neural circuit 
alternatively called the executive or cognitive control circuit is associated with cognitive 
symptoms, including executive dysfunction and difficulty concentrating. These are core 
symptoms of depression and among the most frequently reported untreated symptoms of 
MDD. 
 
Cognition is central to clinical and quality of life outcomes in depression. Research has 
repeatedly shown that cognitive impairments are not effectively treated by antidepressant 
medications. A significant proportion of MDD patients continue to experience 
debilitating cognitive symptoms even after attaining remission of mood symptoms with 
antidepressant treatment. These cognitive impairments are implicated in depression 
relapse and associated morbidity, highlighting the need for novel treatments that improve 
cognitive dysfunction in depression. 
 
Guanfacine immediate release (Brand Name: Tenex) is an FDA-approved medication for 
hypertension and is used off-label for ADHD. The extended-release formulation is FDA-
approved for treating ADHD in children and adolescents. In this study, we aim to 


08/31/2023 
 
Page 2 of 18 
determine whether guanfacine immediate release (referred to hereafter as guanfacine or 
GIR) preferentially increases activation in a key node (dorsolateral prefrontal cortex, 
dLPFC) of the cognitive control circuit in participants with MDD, low baseline activation 
in this node, and cognitive deficits as compared to placebo as well as guanfacine in MDD 
participants with high baseline activation. Furthermore, we aim to determine whether 
change in dLPFC activation is correlated with changes in cognition. If our hypotheses are 
correct, baseline activation in the dLPFC may serve as a mechanistic neural target for 
treatment of symptoms with guanfacine in a subgroup of patients with MDD as well as a 
baseline predictor of response. Thus, this study will move us toward a more personalized 
and brain-based model of depression. 
 
We will use GIR as it has been used more extensively than extended-release guanfacine 
in adult populations with cognitive deficits and has been shown to alter task-evoked 
dLPFC activation. 
 
c. 
Rationale for Research in Humans 
The purpose of the study is to specifically assess how guanfacine affects activation in the 
dLPFC and whether its effects correlate with change in cognitive function, including 
working memory, attention, and executive function in humans. It is difficult to identify a 
proxy for the spectrum of cognitive impairments in depression using animal models. 
Additionally, much of our knowledge of brain connectivity comes from studies in 
nonhuman primates and rodents. The human brain, however, is more complex in its 
architectonics than those of non-human primates or rodents. There is significant 
variability among humans in regard to brain anatomy and connectivity, as ascertained 
with fMRI. As such, understanding neural circuits of the human brain requires its direct 
study. 
 
2. 
STUDY PROCEDURES 
a. 
Procedures 
1. Recruitment and screening: Participants experiencing depressive symptoms and not 
taking any psychiatric medications as determined by a 5 half-life wash out period will be 
recruited from the community, including students and employees at Stanford. 
Recruitment will come primarily from Facebook ads, which will use only IRB approved 
material. A flyer will also be physically posted on boards in public locations in order to 
include a variety of sources for the study. 
2. Individuals will need to participate in 3 screening visits in order to enroll in the study. 
During the first visit, participants will review informed consent, be administered a 
clinical interview, and be sent instructions for completing cognitive testing at home. 
3. If eligibility after this initial screening visit, the second visit will be a medical screen in 
order to ensure participants are safe to take GIR and will include standard blood tests, 
medical history, vitals, and a urine drug test. 
4. If the participant meets medical and cognitive criteria, functional magnetic resonance 
imaging (fMRI) scans will be undertaken at another study visit at The Stanford Center for 
Cognitive and Neurobiological Imaging (CNI). Using a participant's task-evoked activity 


08/31/2023 
 
Page 3 of 18 
in the dorsolateral prefrontal cortex (dLPFC) and performance on objective cognitive 
testing, we will apply thresholds using established healthy norms to select participants 
within the cognitive biotype+ group. 
5. Participants will receive GIR for a period of 8 weeks sent to their place of residence from 
Mariner pharmacy. 
6. Participants will be seen in-person or virtually by a study clinician at weeks 2, 4, 6, 8, and 
10 and an appropriately trained clinical research coordinator at weeks 1, 3, 5, 7, and 9. 
All subjects will have an fMRI scan after 6-8 weeks of taking GIR. During in-person 
visits and virtual monitoring, we will assess participants for the following: changes to 
symptoms, function, and suicidality, adherence to GIR, changes to concomitant 
medication(s), adverse events (AEs), birth control usage compliance, likelihood of 
pregnancy (female participants of childbearing potential), and vital signs if appropriate. 
7. If participants wish to continue GIR and their psychiatrist or PCP is willing to prescribe 
this, they will continue with their current dose for weeks 9 and 10. If they prefer to stop 
taking GIR and/or they do not have a provider who is willing to continue GIR, the 
participant will be tapered off the medication. 
 
b. 
Procedure Risks 
The research procedures outlined in this protocol comply with published protocols for 
clinical trial and functional imaging research, which have been developed to maximize 
subject safety. Following these principles, we will minimize as much as possible the risk, 
consistent with sound research design and good clinical practice, in the following ways: 
1. Screening for Contraindications: 
Participants will be extensively screened for all contraindications of treatments and 
assessments. During screening, participants' eligibility will be established based on a 
full psychiatric (psychiatric and medication history, diagnostic interviews, and self-
report assays to assess all areas that might put participants at risk including history or 
presence of mania, suicidality, and alcohol and drug abuse) and medical screening 
(medical history, physical exam, blood and urine tests to assess all issues that might 
put participants at risk including epilepsy, heart, kidney, and liver function, 
likelihood of drug use, and pregnancy). 
2. Safety Monitoring Plan: 
A data and safety monitoring plan will be established, and the proposed study will be 
registered as a clinical trial on clinicaltrials.gov. 
3. Adherence to Treatment Guidelines: 
The treatment protocol uses parameters described in Butterfield et al. (Psychiatry 
Research, 2016) in adults with ADHD. 
4. Monitoring During the Study: 
Participants will be monitored regularly for treatment side effects and any health 
status changes that might put them at risk. Participants will be monitored every week 
for side effects generally and also specifically (i.e., with quantitative scales) for mood 
changes and suicidality. All significant changes described by participants and/or 
measured in the scales will be recorded in the patients' case report forms, 
immediately reported to prescribing psychiatrists (in case data were collected by 
other research personnel), and all necessary actions will be taken for participants' 
safety and well-being. Participants will be reminded and reassessed for the following: 


08/31/2023 
 
Page 4 of 18 
o 
Use of birth control (females of childbearing potential), 
o 
Alcohol and drug abstinence, and 
o 
Changes to current medications. 
5. Trained Personnel: 
The study will be conducted by experienced lead investigators and appropriately 
trained research personnel. All study research personnel will be adequately and 
appropriately trained with regard to general guidelines for research with human 
subjects. 
Dr. Trisha Suppes, M.D., Ph.D. and Dr. Laura Hack, M.D., Ph.D. has extensive 
experience in clinical trials involving drug treatments for mood disorder patients. All 
study procedures will be detailed in the study's manual of standard operating procedures 
(MOP), and personnel will be required to act according to those. The study's manual will 
include, among others, a safety plan for reporting suicidality during screening and 
monitoring, safety procedures for MRI testing, and recognition and reporting of adverse 
events (AEs) and serious adverse events (SAEs). 
 
c. 
Use of Deception in the Study 
Deception will not be used in this study. 
d. 
Use of Audio and Video Recordings 
No audio or video recordings will occur during the study. 
e. 
Alternative Procedures or Courses of Treatment 
There are currently no standard-of-care medications available that specifically target or 
treat cognitive impairment in depression. Initiation of antidepressant medication, 
particularly serotonin selective reuptake inhibitors (SSRIs), the first-line treatment for 
major depressive disorder, may be advantageous to participants. SSRIs typically take a 
minimum of 6-8 weeks once titrated to therapeutic dose to show therapeutic benefit with 
regard to symptoms. There are risks associated with SSRI treatment including medication 
side effects such as nausea, gastrointestinal side effects, increased anxiety, headaches, 
dizziness, fatigue, and a Black box warning of increasing risk of suicidal ideation in 
adolescence and young adulthood. 
Electing to participate in the current study will delay initiating a trial of SSRI treatment 
by 6 weeks, but participants will then be able to continue with first-line therapy upon 
study completion. This information will be disclosed in the consenting process and form 
as standard-of-care drug. 
f. 
Will it be possible to continue the more (most) appropriate therapy for the 
participant(s) after the conclusion of the study? 
Upon completion of Week 8 of the treatment period, participants will have the choice of 
whether they would prefer to continue on the treatment or be tapered off the drug by the 
study MD during Weeks 9 and 10. To maintain the blind, participants who would like to 
continue treatment will be cross-titrated or down-titrated on their assigned medication 
(placebo or guanfacine) while simultaneously up-titrating on guanfacine. 


08/31/2023 
 
Page 5 of 18 
 
Participants must have a physician willing to prescribe them guanfacine upon termination 
of the study and provide a note from their physician to the study clinician, or they will be 
tapered off the drug over the two-week safety phase. Upon request, a letter will be written 
to notify the physician of the participant's involvement in the study. This would facilitate 
the option for participants' usual care physician to continue treatment with GIR as part of 
their ongoing care of the participant after completion of the study. 
 
g. 
Study Endpoint(s) 
The endpoint for primary and secondary measures will be 8 weeks after initiation of GIR 
or placebo, regardless of the study outcomes. Additional measures will be collected at the 
final endpoint of 10 weeks. If a subject reports a significant adverse event or worsening 
depression, the participant will be removed from the study. The study will not be 
terminated prematurely in the event that participants randomized to GIR have greater 
improvement than participants randomized to placebo. 
 
3. 
BACKGROUND  
a. 
Past Experimental and/or Clinical Findings 
A single mechanism is unlikely to underlie a broad descriptive diagnosis such as 
depression. Thus, our approach is anchored by a neural-circuit taxonomy that proposes 
distinct biotypes of depression derived from functional magnetic resonance imaging 
(fMRI) (Williams, Lancet Psychiatry, 2016; Williams, Depress. Anxiety, 2017). 
One of these circuits is the cognitive control circuit, which has been delineated by the PI 
and others in human neuroimaging work to comprise the dorsolateral prefrontal cortex 
(dLPFC) and its projections to the dorsal parietal cortex and anterior cingulate cortex. 
This circuit is engaged by cognitive control tasks requiring selective attention and 
inhibition, such as the Go-NoGo and Continuous Performance N-back tasks. 
Related neuroimaging indicates that a subset of people with depression is characterized 
by dLPFC hypoactivation and cognitive impairments. These cognitive symptoms result in 
substantial morbidity and disability in individuals struggling with depression and are a 
principal determinant of quality of life and function, including workforce productivity, 
suggested to contribute more than 60% of MDD-related economic burden. 
 
A meta-analysis of 13 studies comparing cognitive function in first-episode MDD 
subjects with healthy control participants found that depressed patients had significant 
impairments in psychomotor speed, attention, and most aspects of executive function 
(including attentional switching, verbal fluency, and cognitive flexibility). A substantial 
subset of these patients (approximately 20%) exhibited cognitive deficits of two standard 
deviations below the mean on two or more cognitive domains. These patients also appear 
to be poor responders to standard antidepressants (Lee et al. Journal of Affective 
Disorders 2012, Gualtieri et al., Journal of Clinical Psychiatry 2008). Thus, there remains 
a critical need to find effective treatments for this subset of MDD patients. 
Cognitive dysfunction greatly contributes to the ongoing burden of disability and 
functional impairment in MDD after mood symptoms attain remission (McIntyre et al., 


08/31/2023 
 
Page 6 of 18 
Journal Anxiety and Depression, 2013). Our research group has previously reported 
results of the International Study to Predict Optimized Treatment in Depression (iSPOT-
D) trial, a randomized controlled study investigating the effects of three different 
antidepressant medications in 1008 depressed patients. These patients demonstrate 
ongoing impairment in five domains of cognitive function – attention, response 
inhibition, verbal memory, decision speed, and information processing – after 8 weeks of 
antidepressant medication treatment, irrespective of the antidepressant treatment group, 
including patients who attained remission based on clinical outcome measures 
(Shilyansky et al., Lancet Psychiatry, 2016). 
 
Guanfacine is an α2A-adrenergic receptor agonist that has been shown to selectively 
facilitate plasticity in frontal norepinephrine pathways. In preclinical studies, guanfacine 
binds more preferentially to postsynaptic α2A-adrenergic receptors than clonidine. 
Preclinical studies and clinical trials indicate that guanfacine acts directly by enhancing 
noradrenaline functioning via α2A-adrenoceptors in the PFC, primarily at postsynaptic 
receptors, through inhibition of cyclic adenosine monophosphate, closing 
hyperpolarization-activated cyclic nucleotide-gated channels, modulating synaptic 
functioning, and strengthening PFC-network connectivity, thereby improving PFC 
cognitive functions. 
b. 
Findings from Past Animal Experiments 
Over three decades of animal research has demonstrated that working memory can be 
improved by alpha-2-adrenoceptor agonists such as guanfacine, while infusions of alpha-
2 antagonists into the PFC impair working memory (Arnsten et al., 1988; Arnsten and 
Goldman-Rakic, 1985; Franowicz and Arnsten, 1998; Rama et al., 1996; Ramos et al., 
2006; Tanila et al., 1996; Wang et al., 2007). Furthermore, animal studies show that 
guanfacine has robust antidepressant effects and can reverse a depression-like state 
induced by cholinergic signaling (Minuer et al., 2015). In particular, both acute and 
chronic guanfacine administration decreased immobility time of mice in the forced swim 
test. 
4. 
RADIOISOTOPES OR RADIATION MACHINES 
a. 
Standard of Care (SOC) Procedures 
Identify Week/Month of Study 
Name of Exam 
Identify if SOC or Research 
NA 
NA 
NA 
b. 
Radioisotopes 
i. 
Radionuclide(s) and chemical form(s) 
NA 
ii. 
Total number of times the radioisotope and activity will be administered (mCi) and 
the route of administration for a typical study participant 
NA 


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Page 7 of 18 
iii. 
If not FDA approved: dosimetry information and source documents (package insert, 
Medical Internal Radiation Dose [MIRD] calculation, and peer reviewed literature) 
NA 
c. 
Radiation Machines – Diagnostic Procedures 
i. 
Examination description (well-established procedures) 
NA 
ii. 
Total number of times each procedure will be performed (typical study participant) 
NA 
iii. 
Setup and techniques to support dose modeling 
NA 
iv. 
FDA status of the machine and information on dose modeling (if procedure is not 
well-established) 
NA 
d. 
Radiation Machines – Therapeutic Procedures 
i. 
Area treated, dose per fraction/number of fractions, performed as part of normal 
clinical management or due to research participation (well-established procedures) 
NA 
ii. 
FDA status of the machine, basis for dosimetry, area treated, dose per fraction and 
number of fractions (if procedure is not well-established) 
NA 
5. 
DEVICES USED IN THE STUDY 
a. 
Investigational Devices (Including Commercial Devices Used Off-Label) 
Investigational Device 1 
Name: 
Sigma MR750 3T scanner 
Description: 
The MR research being conducted requires highly specialized equipment 
and imaging software that does not exist in the clinical MR market, so it is 
designed and manufactured by researchers at the Lucas Center and other 
hardware companies. 
Significant Risk? (Y/N) 
Yes 
Rationale for Non-Significant Risk 
Although some of the imaging software and equipment are not FDA 
approved, they have been tested for safety and are very similar to what is 
used regularly in clinical MR examinations. The MR personnel are 
highly trained in the set-up, utilization, and monitoring of this equipment. 
Investigational Device 2 
Name: 
GE 3 Tesla Ultra-High Performance (UHP) scanner 
Description: 
The MR research being conducted requires highly specialized equipment 
and imaging software that does not exist in the clinical MR market so it is 
designed and manufactured by researchers at the Lucas Center and other 
hardware companies. 
Significant Risk? (Y/N) 
Yes 


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Rationale for Non-Significant Risk 
The 3T UHP scanner from GE is an upgrade to the 3T MR750 which was 
a commercial FDA-approved system. The UHP system utilizes many 
components from GE's 3T Signa Premier, including gradient 
drivers, power supply, transmit and receive system electronics, but uses a 
higher performance gradient coil. The 3T UHP system is not FDA 
approved, and is subject to the 21 CFR 812 investigational device(IDE) 
regulations as well as 21 CFR 50 and 56. The system has been tested by 
GE according to UL606001-1 and also for compliance with IEC 
60601-2-33 (ed 3.1) -- meeting limits and guidelines for peripheral nerve 
stimulation, patient thermal, SAR limit, acoustic noise, 
flammability rating UL94-5VA for safety covers, hydrostatic pressure, 
electrical hazards, dielectric strength and pinch point. The MRI scans in 
this study will also utilize operational parameters within FDA guidelines 
for Nonsignificant Risk thus an Investigational Device Exemption (IDE) 
from FDA should not be necessary. In addition, the MR research being 
conducted requires highly specialized software that does not exist in the 
clinical MR market so it is designed and implemented by researchers at 
the CNI. Any such software will be considered investigational, will 
function as a nonsignificant risk device, and is subject to the 
21 CFR 812 investigational device (IDE) regulations as well as 21 CFR 
50 and 56. The investigational image acquisition software 
will conform to FDA guidelines for MR safety related to heating (SAR), 
peripheral nerve stimulation (dB/dt), and acoustic noise. 
- The scanner is for investigational use only and will not be used in to 
diagnose, cure, treat or prevent the impairment of human 
health. Additionally, the magnet has been tested by GE and meets the 
limits and guidelines for peripheral nerve stimulation, 
patient thermal, SAR limit, acoustic noise, flammability rating UL94-
5VA for safety covers, hydrostatic pressure, electrical 
hazards, dielectric strength and pinch point according to medical 
equipment and flammability standards. 
- The MRI scans in this study will utilize operational parameters within 
FDA guidelines for Nonsignificant Risk, same as before the upgrade. 
 
b. 
IDE-Exempt Devices 
 
IND-Exempt Device 1 
Name: 
NA 
Description: 
NA 
 
6. 
DRUGS, BIOLOGICS, REAGENTS, OR CHEMICALS USED IN THE STUDY 
a. 
Investigational Drugs, Biologics, Reagents, or Chemicals 
Investigational Product 1 
Name: 
NA 
Dosage: 
NA 
Administration Route: 
NA 
b. 
Commercial Drugs, Biologics, Reagents, or Chemicals 
Commercial Product 1 
Name: 
Guanfacine hydrochloride immediate release 
Dosage: 
0.5mg nightly, increase every 3 days until 2mg nightly 
Administration Route 
Oral 
New and different use? (Y/N) 
Y 


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7. 
DISINFECTION PROCEDURES FOR MEDICAL EQUIPMENT USED ON BOTH HUMANS AND 
ANIMALS 
NA 
 
8. 
PARTICIPANT POPULATION 
a. 
Planned Enrollment 
25 
b. 
Age, Gender, and Ethnic Background 
18-69 years old, male and female, all ethnic backgrounds 
c. 
Vulnerable Populations 
Children younger than 18 are not included due to the fact that many of the clinical and 
biological measures that will be used in subsequent research studies in our clinic are 
validated for use in people 18 and older. 
d. 
Rationale for Exclusion of Certain Populations 
NA 
e. 
Stanford Populations 
If any Stanford employees, and/or students qualify and wish to participate, they will be 
treated the same as any other participant. 
f. 
Healthy Volunteers 
NA 
g. 
Recruitment Details 
Dr. Williams' ongoing imaging trials will be leveraged. Recruitment pipelines include 
flyering, online advertisements, Facebook ads, and participants from an IRB-approved 
R01 grant, where approximately one participant per two weeks meets study criteria. 
Psychiatric symptoms are assessed during recruitment. 
We will also use online advertisements through the lab's Facebook platform, where all 
comments are private to prevent inadvertent PHI sharing. Advertisements will be IRB-
approved before launch. 
 
Participants will provide written informed consent, adhering to Stanford IRB guidelines 
and the Declaration of Helsinki 
 
h. 
Eligibility Criteria 
i. 
Inclusion Criteria 
• 
18-69 years of age (inclusive) 


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• 
Go-NoGo fMRI task-evoked dLPFC ≤ - 0.5 SD below the mean of normative 
sample 
• 
Behavioral cognitive control performance ≤ - 0.5 SD below the mean of 
normative sample on a Maze, Digit Span, and/or Verbal Interference (Stroop) 
task administered using WebNeuro 
• 
Score ≥ 14 on the 17-item Hamilton Depression Rating Scale-17 (HDRS-17) 
• 
Meets DSM-5 diagnostic criteria for current, past, or recurrent nonpsychotic 
major depressive disorder established by MINI Plus 
• 
Medication naïve to guanfacine 
• 
Fluent and literate in English, and show non-impaired intellectual abilities to 
ensure adequate comprehension of the task instructions 
• 
Written, informed consent 
• 
fMRI scanning eligibility, including no evidence of any form of metal embedded 
in the body (e.g., metal wires, nuts, bolts, screws, plates, sutures), as these 
produce artifacts when brain imaging. All potential subjects will need to 
successfully complete the screening forms at the Stanford Center for Cognitive 
and Neurobiological Imaging (CNI). 
 
ii. 
Exclusion Criteria 
• 
Presence of suicidal ideations representing imminent risk, defined by a score of > 
8 on the MINI-Plus, or by clinician judgement 
• 
Lifetime history of medical illness or injury that may compromise cognitive 
functioning or interfere with assessments as deemed by the study physician (such 
as neurological disorders such as seizures or stroke, Parkinson's disease, 
dementia, or traumatic brain injury) 
• 
Severe impediment to vision, hearing, and/or hand movement likely to interfere 
with ability to complete the assessments, or are unable and/or unlikely to follow 
the study protocols 
• 
Pregnant, breastfeeding or unwilling or unable to use adequate birth control 
throughout the study 
• 
Loss of consciousness for > 10 minutes during lifetime 
• 
Any contraindication to being scanned in the 3.0T scanner at the CNI such as 
having a pacemaker or implanted device that has not been cleared for scanning at 
3.0 Tesla 
• 
Previous or current DSM-5 bipolar disorder (I, II, not otherwise specified) or 
psychosis 
• 
Meets criteria for DSM-5 alcohol or substance use disorder within the last 12 
months 
• 
Meets criteria for current DSM-5 PTSD, OCD, or eating disorder 
• 
Concurrent participation in other intervention or treatment studies 
• 
Current use of psychotropic medications. If their usual treating physician is 
supportive, participants who are currently on psychotropics that can be safely 
tapered may be tapered off to participate but participant must wait 5 half-lives 
prior to first scan 
• 
Current use of a strong CYP3A4 inhibitor or inducer (macrolide/ketolide 
antibiotics [clarithromycin, telithromycin], azole antifungals [itraconazole, 


08/31/2023 
 
Page 11 of 18 
ketoconazole, posaconazole, voriconazole], protease inhibitors [atazanavir, 
darunavir, indinavir, lopinavir, nelfinavir, ombitasvir, paritaprevir, ritonavir, 
saquinavir], ceritinib, cobicistat, and idealisib), or inducer (apalutamide, 
carbamazepine, enzalutamide, fosphenytoin, lumacaftor, lumacaftor-ivacaftor, 
mitotane, phenobarbital, phenytoin, primidone, rifampin) 
• 
Hypotension as defined by SBP ≤ 90 and/or DBP ≤60 on 2 of 3 separate 
measurements at least 5 minutes apart, bradycardia as defined by HR ≤55 on 2 of 
3 separate measurements at least 5 minutes apart 
• 
General medical condition, disease, or neurological disorder as reported by 
participant or found on in-person screenings that is deemed by the study 
physicians to be unsafe for GIR treatment, including kidney or liver impairment 
that is deemed to be unsafe, EKG abnormalities that are deemed to be unsafe, or 
cardiovascular disease deemed to be unsafe. 
• 
History of sudden cardiac death in first degree relatives 
• 
Positive drug screen for any substance deemed by the study physician to be 
unsafe for use with GIR in combination with other information obtained during 
screening 
 
i. 
Screening Procedures 
Participants will complete an online eligibility survey, provide informed consent, and 
attend two screening visits. Screenings include clinical interviews, medical history, 
cognitive testing, and functional MRI scans to assess dLPFC activation. 
j. 
Participation in Multiple Protocols 
Participants will first be screened via an online REDCap survey in order to determine 
initial eligibility. Once participants have completed the survey and have been determined 
eligible, they will continue to an in-person visit where consenting will take place and 
further screening procedures will be completed. 
Participants will be screened for assessment of inclusion and exclusion criteria at the in-
person baseline visit. We will ensure that consent is obtained and enrollment completed 
before personal health information is collected. 
We also screen using the following physical and laboratory tests: 
a) Physical Exam: 
• 
Participants will be asked to provide additional details of their medical history 
specifically relevant to the treatment contraindications (exclusion criteria). For 
standard monitoring, we will assess height, weight, vital signs, systems assessment, 
and general medical presentation during the physical exam. 
b) Laboratory Testing: 
• 
For standard monitoring, we undertake the following: 
o 
Blood sample: Analyzed for CBC, CMP, LFTs, TSH, and serum pregnancy 
test.  
o 
Urine sample: For urine drug screen. 
o 
Electrocardiogram (EKG): To assess cardiovascular health. 
 
k. 
Payments to Participants 


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Research subjects will be offered 
 for the pretreatment fMRI session, self-report 
questionnaires, and cognitive assessments; and 
 for the subsequent MRI session at 
Week 8 of the treatment phase. Participants who complete the Monetary Incentive Delay 
(MID) task in the three MRI sessions will be offered an additional payment depending on 
their performance on the task, for a maximum total of 
 per session. 
 
Participants will be compensated 
 for each of the 5 phone visits with completed 
questionnaires, 
 for the virtual or in-person physician check-ins at Weeks 2 and 8, and 
 for the physician check-ins at Weeks 4, 6, and 10. 
 
l. 
Costs to Participants 
No protocol-related costs will be charged to participants. 
m. 
Planned Duration of the Study 
The probable duration of the entire study is three years. 
1. Individual Participant Duration: 
o 
Screening: Approximately four hours. 
o 
Active Participation: Approximately 24 hours total over 12 weeks, with 10–
12 days of active engagement. 
o 
Total Study Duration: Participants will spend about 12 weeks enrolled in the 
study, including an 8-week treatment phase and follow-up activities. 
2. Study Completion Timeline: 
o 
The study is planned to be conducted over three years, with data analysis for 
each participant requiring approximately 160 hours. 
9. 
RISKS 
a. 
Potential Risks 
i. 
Investigational devices 
NA 
ii. 
Investigational drugs 
NA 
iii. 
Commercially available drugs, biologics, reagents or chemicals 
Guanfacine Side Effects and Potential Risks in Children and Adolescents with 
ADHD: Drowsiness (28% to 57%), headache (16% to 28%), fatigue (10% to 22%), 
dizziness (4% to 16%), insomnia (2% to 13%), abdominal pain (8% to 19%), 
decreased appetite (5% to 15%), hypotension (4% to 9%), bradycardia (2% to 5%), 
orthostatic hypotension (1% to 5%), first-degree atrioventricular block (≥2%), sinus 
arrhythmia (≥2%), tachycardia (≥2%), syncope (1% to ≥2%), irritability (5% to 8%), 
lethargy (3% to 8%), anxiety (2% to 5%), nightmares (3% to 4%), emotional lability 
(2% to 3%), agitation (≥2%), depression (≥2%), increased blood pressure (≥2%), loss 
of consciousness (children: ≥2%), skin rash (2% to 3%), pruritus, weight gain (2% to 


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3%), xerostomia (3% to 8%), nausea (5% to 7%), vomiting (2% to 7%), diarrhea (2% 
to 6%), constipation (2% to 4%), abdominal distress (≥2%), dyspepsia (≥2%), 
stomach discomfort (≥2%), urinary incontinence (2% to 5%), asthma (≥2%), fever 
(8%; Biederman 2008).  
 
iv. 
Procedures 
Risks Associated with fMRI 
Magnetic fields do not cause harmful effects at the levels used in the MRI machine. 
However, the MR scanner uses a very strong magnet that will attract some metals and 
affect some electronic devices. Participants will be screened for having cardiac 
pacemakers or any other biomedical device in or on their body, including any metal 
objects (especially surgical clips), devices, or implants before entering the magnet 
room. All such objects will be removed (if possible) before entering the magnet 
room. In some cases, having those devices means participants should not have an 
MRI scan performed. Participants will also be screened for history of head or eye 
injury involving metal fragments, having worked in a metal shop, or for being 
pregnant. They will also be asked for any tattoos on their body, including eyeliner 
and other permanent makeup. Tattoos could become warm and irritated during the 
scan and remain so for several days. There is a possibility that participants will 
experience a localized twitching sensation due to the magnetic field changes during 
the scan. This is expected and should not be painful. There is a small risk of heating 
from the cables associated with these devices. Dizziness or nausea may occur if 
participants move their head rapidly within the magnet. The scans performed in this 
study are for specific research purposes and are not optimized to find medical 
abnormalities. The investigators for this project may not be trained to perform 
medical diagnosis. However, on occasion the investigator may notice a finding on an 
MRI scan that seems abnormal. 
Distress During Interviews 
The interviews are time consuming and about personal matters. It is possible that 
participants will feel upset, tired, or anxious. 
Phlebotomy 
There is a minimal risk of infection with blood draw as well as the risk of minor 
discomfort. 
v. 
Radioisotopes/radiation-producing machines 
NA 
vi. 
Physical well-being 
NA 
vii. 
Psychological well-being 
Some participants may experience distress or anxiety related to participating in the 
procedures. Participants will be monitored throughout the procedures and encouraged 
to report any concerns. A psychiatrist will be available to assist the participant if 


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needed, and participants will be removed from the protocol if their distress or anxiety 
becomes intolerable. 
viii. 
Economic well-being 
NA 
ix. 
Social well-being 
NA 
x. 
Overall evaluation of risk 
Low - innocuous procedures such as phlebotomy, urine or stool collection, no 
therapeutic agent, or safe therapeutic agent such as the use of an FDA approved drug 
or device. 
 
b. 
International Research Risk Procedures 
NA 
 
c. 
Procedures to Minimize Risk 
Participants are safeguarded from undue risk by procedures to obtain informed 
consent, ensure confidentiality, and minimize possible risks associated with the 
study. Each is described below. 
Potential risks associated with participation in this study may include the potential for the 
following: 
1. Distress from completing cognitive and psychological questionnaires and from being 
in an fMRI scanner. 
2. Risks associated with blood, saliva, and urine sampling. 
3. Risks associated with GIR administration. 
The risks are reasonable in relation to the anticipated benefits and will be minimized by 
using procedures that are consistent with sound research design, that do not unnecessarily 
expose participants to risk, and that are based on established research and trial protocols. 
Questionnaires: 
The risks associated with the self-report and clinical assessments are minimal. Research 
personnel are trained to manage any distress that is generated by completing these 
assessments, and protocols for managing any distress have been well established in prior 
studies. Some participants might experience discomfort with discussing personal 
information with a person they do not know. 
Behavioral and Cognitive Assays: 
The risks associated with the behavioral and cognitive assessments are also minimal. 
Research personnel are trained to manage any distress that is generated by completing 
these assessments, and protocols for managing any distress have been well established in 
prior studies. 
Brain Imaging Assays: 
The principal piece of equipment used in this protocol is a 3 Tesla GE fMRI scanner. A 
small number of people may feel claustrophobic inside the machines. The study will be 


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immediately stopped via button press if this occurs. Study personnel and technicians will 
be on-site during all acquisitions to address any such discomfort. To minimize fatigue, 
sufficient breaks are provided to participants during the scanning procedure, and the 
experimenter regularly inquires as to whether there is anything that they can do to 
facilitate the participant's comfort. The risks associated with fMRI are minimal. Routine 
contraindications to MRI include the presence of any metal implants (pacemaker, 
aneurysm clips, neurostimulators, cochlear, eyes, tattoos with ink contraindicated for 
fMRI scanning). The scan will be immediately stopped via button press if this occurs. 
Study personnel and MRI technologists will be on-site during all acquisitions to address 
any such discomfort. 
Blood and Urine Sampling: 
Blood and urine samples will be required prior to entry to assess for health problems, 
drug use, and pregnancy (in females). Participants may experience minor discomfort. 
Saliva and Hair Sampling: 
Saliva and hair samples will be collected as optional components of the study. 
Participants may experience minor discomfort. 
Guanfacine: 
GIR studies have reported blood pressure changes in patients with ADHD as well as in 
healthy control participants. Any medical risks from decreased blood pressure will be 
minimized through the careful screening of potential participants. Potential participants 
with baseline hypotension, history of cardiovascular illness, or concerning findings on 
EKG will be excluded. If a participant experiences distressing side effects, GIR will be 
discontinued. Participants will be closely monitored through in-person and bi-weekly 
phone assessments to assess safety and tolerability, specifically asking about known side 
effects detailed above. Bloodwork and physician examination with their PCP will be 
arranged as needed. Participants will be reminded that they can elect to terminate study 
participation at any time, and if experiencing significant distressing side effects, drug 
administration will be discontinued. 
Other Considerations: 
• 
Incidental Findings on MRI: 
Although this study and scans from this study will be used for research purposes, we 
will also collect T1-weighted anatomical images from each participant. We will 
follow the IRB-approved protocol of CNI or the Lucas Center, whereby any 
indications of an incidental finding are sent to a neuroradiologist for a clinical report. 
• 
Emergencies: 
If, during the course of interviewing and assessment procedures, study staff identifies 
a condition that mandates immediate clinical intervention or official reporting, all 
necessary steps will be taken, and the emergency procedures of the institution will be 
followed. In the event that a research participant expresses suicidal ideation during a 
clinical interview or when completing a questionnaire, a suicide risk assessment will 
be performed, and a licensed clinical psychologist or psychiatrist will be consulted in 
order to determine the level and immediacy of risk. If the research subject is deemed 
an imminent danger to self, they will be placed on a 5150 LPS psychiatric hold and 
transferred to Stanford Hospital Emergency Department for comprehensive clinical 
evaluation and assessment. 
 


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Page 16 of 18 
d. 
Study Conclusion 
Emergencies: 
If, during the course of interviewing and assessment procedures, study staff identifies a 
condition that mandates immediate clinical intervention or official reporting (e.g., 
homicidality or suicidality), all necessary steps will be taken, and the emergency 
procedures of the Department of Psychiatry and Behavioral Sciences will be followed. In 
the case that staff determine that the participant is at significant risk for self- or other-
destructive behavior, necessary treatment steps will be taken (e.g., hospitalization, 
referral to a care provider, etc.). All participants will be given numbers to call in the event 
of an emergency during treatment: the primary phone number of the treating clinician and 
the number for the clinic. If the treating clinician is immediately unavailable, participants 
will be instructed to not delay and to go to their nearest Emergency Room. 
Safety Measures Upon Termination: 
After a participant's completion of or early termination from the study, participants will 
be followed up only in the case of an adverse event. If an adverse event occurs, the 
participants will be followed by the study MD until the adverse event is resolved. 
Referrals will be given if needed. 
Termination Due to Loss to Follow-Up: 
Staff will call participants who miss a visit on the same day to inquire about reasons for 
the absence, help problem-solve, and reschedule the missed visit. Staff will be persistent 
in attempting to re-engage noncompliant participants in subsequent follow-ups via phone 
and/or email. Participants are considered lost to follow-up if they miss a scheduled visit 
and are unresponsive to three subsequent attempts to reach them. Staff will encourage 
participants lost to follow-up to contact their standing psychiatrist for ongoing care. 
Additionally, we will email any participants lost to follow-up our mental health resource 
guide to provide them with local and national mental health care resources. 
e. 
Data Safety Monitoring Plan (DSMC) 
The PI will utilize a standardized approach employing contemporary biostatistical, 
medical, and ethical principles to review study design and interim data before trial 
inception and every year thereafter; the PI will also have the ability to ask for more 
frequent reviews at any time during the study if they deem this necessary. The PI, data 
manager, and study statistician will prepare a specific report for the IRB. Specific 
attention will be given to data quality and timeliness, participant recruitment, accrual and 
retention, participant risk versus benefit, adverse events, and other factors that can affect 
study outcome, including scientific developments that may have an impact on the safety 
of the participants or the ethics of the study. The procedures in place for monitoring 
adverse events as well as for site, data and statistical management will enable us to 
generate a timely report to the IRB. The data safety report to the IRB will include: 
1. All serious and unexpected adverse events (for example, inpatient hospitalizations) or 
other unanticipated problems that involve risk to study participants or others at either 
site, and whether these appeared related to the research assessment protocols. Reports 
will not specifically disclose the session/dose arm of the study unless this is required 
for safety reasons; 


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2. Whether participants' safety, privacy, and confidentiality has been consistently 
assured by the investigator; 
3. Whether the PI recommends an interim analysis pertinent to evaluating participants' 
safety; 
4. Judgments as to whether research instruments have been administered in a uniform 
manner and in a way that maintains participants' confidentiality; 
5. A review of the study's progress toward recruitment goals, quality of data (e.g., 
appropriate completion of forms), medication treatment adherence, and participant 
retention/attrition rates; 
6. A review of new scientific literature pertinent to the safety of participants or the 
ethics of research participation (for example, new therapeutic developments). 
These reports will be filed with the PI, who will file them with the Human 
Participants IRBs. The annual reports will also be filed with the IRB. The reports will 
enumerate the dates that the committee met and its procedures for monitoring 
participants' safety and confidentiality and data integrity. There will be regular, 
ongoing communication between the PI and the IRB. IRB protocols and informed 
consent documents will be annually reviewed by the IRB. The PI will take 
responsibility for reporting any serious adverse event (SAE) to the IRB within 24 
hours according to standard regulations. A SAE is defined as follows: death, life-
threatening adverse event, inpatient hospitalization, persistent or significant 
disability/incapacity, and medically significant event. 
 
i. 
Person(s) responsible for Data and Safety Monitoring 
The PI. 
ii. 
Frequency of DSMB meetings 
NA 
iii. 
Specific triggers or stopping rules 
See study endpoints.  
iv. 
DSMB Reporting 
A summary of the report will be submitted to the IRB for review. 
v. 
Will the Protocol Director be the only monitoring entity? (Y/N) 
Yes 
vi. 
Will a board, committee, or safety monitor be responsible for study monitoring? 
(Y/N) 
N 
f. 
Risks to Special Populations 
NA 
10. 
BENEFITS 


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Participants may find that the study drug improves cognitive impairment and depressive 
symptoms, potentially benefiting future participants who struggle with MDD and cognitive 
impairment. 
11. 
PRIVACY AND CONFIDENTIALITY 
All participant information and specimens are handled in compliance with the Health Insurance 
Portability and Accountability Act (HIPAA) and privacy policies of Stanford University, Stanford 
Health Care, and Stanford Children’s Health. 

SAP_001.pdf: 
Precision Mental Health: Evaluating  
Biotype-guided Interventions for Depression 
 
NCT04181736 
 
October 30, 2024 
 
Statistical Analysis Plan 
 
Primary Outcome 
We will evaluate the primary cognitive control circuit measure by testing the effect of 8 weeks of guanfacine 
immediate release (GIR) using a general linear model (GLM). This model will include a within-subjects 
factor for treatment (pre- vs. post-treatment sessions) and a within-subjects repeated measures factor for 
cognitive control circuit function, comprising five measures: task-evoked activation of the dorsal anterior 
cingulate cortex (dACC), left dorsolateral prefrontal cortex (dLPFC), right dLPFC, and connectivity 
between these regions. The analysis will assess the main effect of treatment and, secondarily, the interaction 
between treatment and circuit measure. Planned paired t-tests will evaluate the effect of GIR on changes in 
individual circuit measures. 
 
Secondary Outcomes 
For secondary outcomes, GLMs will include treatment as a within-subjects factor and a repeated measures 
factor for variables with multiple observations. Cognitive behavioral performance will comprise six test 
measures of cognitive control (Maze, Digit Span, Verbal Interference Color and Word, Switching of 
Attention, and GoNoGo), and quality of life, four domains (physical health, psychological health, social 
relationships, and environment) as measured by the by the World Health Organization Quality of Life – 
Brief (WHOQOL-BREF) Scale. Planned paired t-test contrasts will test for the effect of GIR on change in 
each set of individual secondary measures in each general linear model. The secondary measures of 
depression symptom severity (measured by the 17-item Hamilton Depression Rating Scale and Quick 
Inventory of Depressive Symptoms-Self Report), global satisfaction with life (assessed using the 
Satisfaction With Life Scale), and suicidality (measured by the Columbia-Suicide Severity Rating Scale 
Ideation Score) are exceptions that do not have repeated measures. 
 
Significance, Multiple Test Correction, and Handling Missing Data 
A two-sided significance level of 0.05 will be applied to each analysis within each modality for both primary 
and secondary outcomes. Corrections for multiple testing across modalities will not be applied, as each 
outcome targets a distinct hypothesis about the effect of GIR on cognitive, behavioral, symptom, and 
functional measures. Effect sizes (Cohen’s d) will be reported for each outcome, along with 95% confidence 
intervals, to aid interpretation of clinical meaningfulness. Missing data will be handled using listwise 
deletion.