PET Imaging for Depression

Overseen By Tara N Turon, C.R.N.P.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Mental Health (NIMH)

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

Disqualifiers: Psychotic disorders, Substance use, Pregnancy, others

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

Compensation: Varies

Number of Visits: Unknown

64 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if certain brain enzymes show increased activity in people with depression compared to those without. Researchers will use PET imaging, a special tool, to examine the brains of individuals experiencing a major depressive episode. Suitable participants include those diagnosed with major depressive disorder who are currently experiencing a depressive episode lasting at least four weeks. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

If you are unmedicated, you must be medication-free for at least two weeks (or five weeks for certain drugs like aripiprazole, brexpiprazole, and fluoxetine) before the first screening visit. If you are already on medication and in Group B, you may continue your current therapy.

What prior data suggests that this radioligand is safe for use in PET imaging?

Previous studies lack clear safety information specifically for 11C-MC1 in humans, making it difficult to determine its tolerability. As a Phase 1 study, the treatment is being tested in humans for the first time. The main goal is to assess safety and determine the optimal dose.

For 11C-PS13, research has shown it has been tested in humans before. Studies found that it binds well to a protein called COX-1 in the body. However, like 11C-MC1, limited safety information is available specifically for humans.

In general, Phase 1 treatments are closely monitored to detect any side effects early. Participants are usually observed carefully to ensure safety. If questions or concerns arise about joining a trial, discussing them with the trial team or a doctor is important. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about these treatments, 11C-MCI and 11CPS13, because they offer a new approach to understanding and potentially treating depression through PET imaging. Unlike standard treatments such as SSRIs, SNRIs, and psychotherapy, these treatments focus on imaging the brain's biochemical activity to provide a clearer picture of how depression affects brain function. This could lead to more personalized and effective treatment strategies in the future, as it allows clinicians to see the specific areas of the brain impacted by depression and tailor treatments accordingly.

What evidence suggests that this trial's treatments could be effective for depression?

Research has shown that PET imaging can detect brain inflammation associated with psychiatric disorders like major depressive disorder (MDD). A study on the compound \[11C\]PS13 found that it effectively targets COX-1, an enzyme linked to inflammation, in major organs. This suggests that \[11C\]PS13 might help identify brain inflammation in MDD. Although specific safety data for \[11C\]MC1 and \[11C\]PS13 in humans is not yet available, early animal tests have shown promising results. These initial findings suggest that PET imaging with these compounds could provide valuable insights into brain inflammation related to mood disorders. ^{3 6 7 8 9}

Who Is on the Research Team?

Robert B Innis, M.D.

Principal Investigator

National Institute of Mental Health (NIMH)

Are You a Good Fit for This Trial?

This trial is for adults aged 18-70 with Major Depressive Disorder (MDD) currently having a depressive episode, and healthy volunteers of the same age range. Participants should be in good health overall, understand the study requirements, and agree to them by signing consent forms. Women who can have children must use birth control. People on certain medications must be off them for specific periods before starting.

Inclusion Criteria

You have been diagnosed with major depression by a mental health professional using the DSM-5 criteria and a structured interview.

I have been feeling depressed for at least four weeks.

I am in good health overall, as confirmed by my doctor.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Imaging and Treatment

Participants undergo PET imaging with [11C]MC1 and [11C]PS13 to measure COX-1 and COX-2 levels. Group A participants receive celecoxib.

36 months

Follow-up

Participants are monitored for safety and effectiveness after imaging and treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• 11C-MCI
• 11CPS13

Trial Overview [11C]MC1 and [11C]PS13 are being tested to detect COX-1 and COX-2 enzymes in the brain during depression. Group A will receive [11C]MC1 before/after celecoxib without randomization or placebo control; Group B's MDD patients (medicated/unmedicated) will be compared with healthy volunteers using [11C]PS13.

How Is the Trial Designed?

Group I: One Arm Experimental Treatment 2 Interventions

All subject receive the same tests

Who Is Running the Clinical Trial?

National Institute of Mental Health (NIMH)

Lead Sponsor

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

The synthesized compound [N-methyl-11C]LY257327 showed high brain uptake and localized in serotonergic areas, indicating potential for studying serotonin-related functions.

However, its accumulation was largely nonspecific and not significantly affected by the selective serotonin reuptake inhibitor citalopram, suggesting it is not suitable for measuring serotonin reuptake sites in vivo using PET imaging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiosynthesis and PET imaging of [N-methyl-11C]LY257327 as a tracer for 5-HT transporters. Zea-Ponce, Y., Baldwin, RM., Stratton, MD., et al.[2022]

A new method for producing N'-(4-[11C]methyl)-imipramine allows for high yields, achieving a radiochemical yield of 60% in just 40 minutes, which is efficient for medical applications.

The process minimizes unwanted reactions by using excess desipramine and results in about 60 mCi of the labeled product, with a specific activity of 50 mCi/mumole, making it suitable for further research or clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The production in high yield of N'-(4-[11C]methyl)-imipramine. Denutte, H., Goethals, P., Cattoir, H., et al.[2013]

Preclinical PET imaging studies in animal models of depression have revealed important insights into brain physiology, focusing on glucose metabolism, neuroreceptor availability, and inflammatory responses associated with depression.

These findings suggest that PET imaging can enhance our understanding of depression's mechanisms, potentially aiding in the development of new therapies by providing a more detailed characterization of clinical depressive phenotypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PET imaging of animal models with depressive-like phenotypes. Vazquez-Matias, DA., de Vries, EFJ., Dierckx, RAJO., et al.[2023]

Patients with major depressive disorder who have larger pretreatment hippocampus volumes are more likely to respond positively to treatment, suggesting that MRI findings can help predict treatment outcomes.

Functional imaging studies indicate that different brain activity patterns can distinguish between patients likely to respond to medication versus those likely to benefit from psychotherapy, highlighting the potential of imaging in tailoring treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Magnetic resonance imaging and prediction of outcome in patients with major depressive disorder. MacQueen, GM.[2021]

Positron emission tomography (PET) using fluorine-18-labeled fluorodeoxyglucose can effectively measure brain metabolism in patients with affective disorders, revealing potential metabolic subgroups based on their conditions.

Pharmacological interventions, like methylphenidate, can alter brain metabolism patterns in patients with mood disorders, indicating that mood changes are linked to biochemical changes in the brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Positron emission tomographic study of affective disorders: problems and strategies. Phelps, ME., Mazziotta, JC., Baxter, L., et al.[2019]

Neuroimaging techniques reveal significant structural and functional differences in brain regions related to emotion and mood regulation in individuals with major depression, which can aid in diagnosis and treatment.

Recent advancements in machine learning applied to neuroimaging data show promise for categorizing patients and predicting their response to treatments, suggesting that these methods could enhance personalized treatment strategies in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diagnostic and therapeutic utility of neuroimaging in depression: an overview. Wise, T., Cleare, AJ., Herane, A., et al.[2022]

Molecular imaging techniques like PET have the potential to enhance our understanding of mental disorders by exploring new targets and processes beyond the traditional focus on monoaminergic neurotransmission, which has not significantly changed clinical practice.

To improve research outcomes, there is a need for methodological advancements, including the development of new radioligands, multimodal imaging approaches, and longitudinal study designs that include severely ill patients and promote data sharing for larger sample sizes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Application of positron emission tomography in psychiatry-methodological developments and future directions. Cervenka, S., Frick, A., Bodén, R., et al.[2022]

SPECT and PET imaging studies indicate that clinical depression is linked to dysfunction in specific brain regions, particularly the frontal and temporal lobes, suggesting that depression is fundamentally a brain disorder.

Frontal lobe hypometabolism is a common feature across various types of depression, with its severity correlating to the severity of depressive symptoms; treatment appears to normalize this hypometabolism alongside mood improvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SPECT and PET imaging in mood disorders. George, MS., Ketter, TA., Post, RM.[2016]

The safety assessment of [11C]Cimbi-36, a radioligand for imaging serotonin 2A receptors, showed low radiation dosimetry in both rats and pigs, with effective doses of 7.67 and 4.88 μSv/MBq, respectively, indicating it is safe for clinical use.

In vivo pharmacological testing demonstrated that while a higher dose of Cimbi-36 (0.5 mg/kg) caused significant effects on behavior (head-twitch response), lower doses (0.05 mg/kg) did not, suggesting that tracer doses used in PET scans are unlikely to cause adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical safety assessment of the 5-HT2A receptor agonist PET radioligand [ 11C]Cimbi-36. Ettrup, A., Holm, S., Hansen, M., et al.[2021]

Recent PET studies have shown mixed results regarding neurotransmission in depression, with some studies reporting lower binding potentials in depressed individuals compared to healthy controls, while others found no significant differences or even higher binding potentials in depressed subjects.

Current PET radioligands have not definitively established a causal relationship between neuromolecular processes and depressive disorders, suggesting that new molecular tools are needed to better understand the underlying mechanisms of depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular tools for assessing human depression by positron emission tomography. Smith, DF., Jakobsen, S.[2016]

In a study involving 24 participants (8 with late-life depression, 8 with probable Alzheimer's disease, and 8 healthy controls), those with late-life depression exhibited significant reductions in glucose metabolism across various brain regions, similar to patterns observed in Alzheimer's disease.

The findings suggest that late-life depression may involve widespread brain metabolic decline, indicating potential shared pathophysiological mechanisms between major depressive disorder and Alzheimer's disease in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regional cerebral glucose metabolism in late-life depression and Alzheimer disease: a preliminary positron emission tomography study. Kumar, A., Newberg, A., Alavi, A., et al.[2019]

[11C]Cyanoimipramine, a radiolabeled compound, was successfully synthesized with high specific activity and showed significant accumulation in the brain and lungs of mice after intravenous administration, indicating its potential for studying brain activity.

The study found that [3H]cyanoimipramine exhibited specific binding in the cerebral cortex, with about 40-50% of total radioactivity attributed to this binding, suggesting its usefulness in understanding receptor distribution and activity in the brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and evaluation of [11C]cyanoimipramine. Hashimoto, K., Inoue, O., Suzuki, K., et al.[2019]

The study assessed the radiation dosimetry of the radioligand 11C-UCB-J in four healthy adults, finding that it is safe for use in both adults and adolescents to measure synaptic density, which is important for understanding neuropsychiatric disorders.

The urinary bladder was identified as the dose-limiting organ for adult males, while the liver was the limit for adult females, and the large intestine for adolescents, indicating specific safety considerations for different demographics when using this imaging technique.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human adult and adolescent biodistribution and dosimetry of the synaptic vesicle glycoprotein 2A radioligand 11C-UCB-J. Bini, J., Holden, D., Fontaine, K., et al.[2023]

Positron emission tomography (PET) can help differentiate between unipolar and bipolar depression and Alzheimer's disease by measuring glucose metabolism in specific brain regions, such as the parahippocampal gyrus-hippocampus and dorsolateral prefrontal cortex.

The study found significant differences in glucose metabolism between patients with depression and those with Alzheimer's dementia, suggesting that PET could be a valuable tool for accurate diagnosis in these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in glucose metabolism in dementia of the Alzheimer type compared with depression: a preliminary report. Guze, BH., Baxter, LR., Schwartz, JM., et al.[2019]

Citations

1. withpower.com withpower.com/trial/phase-1-depressive-disorder-major-6-2021-6b821

PET Imaging for Depression Is PET imaging with 11C-MCI or 11CPS13 safe for humans? The research articles provided do not contain specific safety data for 11C-MCI or 11CPS13 in humans.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7893630/

Neuroinflammation in psychiatric disorders: PET imaging and ... This Review critically evaluates PET imaging results of inflammation in psychiatric disorders, including major depressive disorder, schizophrenia and psychosis ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32399622/

First-in-human evaluation of [ 11 C]PS13, a novel PET ... This study assessed whether the newly developed PET radioligand [ 11 C]PS13, which has shown excellent in vivo selectivity in previous animal studies, could be ...

4. researchgate.net researchgate.net/publication/361854494_Whole-body_PET_imaging_in_humans_shows_that_11_C-PS13_is_selective_for_cyclooxygenase-1_and_can_measure_the_in_vivo_potency_of_nonsteroidal_anti-inflammatory_drugs

(PDF) Whole-Body PET Imaging in Humans Shows That 11 ... Results: High 11C-PS13 uptake was observed in major organs with high COX-1 density, including the spleen, lungs, kidneys, and gastrointestinal ...

5. thelancet.com thelancet.com/journals/lanpsy/article/PIIS2215-0366(20)30255-8/abstract

Neuroinflammation in psychiatric disorders: PET imaging ... This Review critically evaluates PET imaging results of inflammation in psychiatric disorders, including major depressive disorder, schizophrenia and psychosis ...

6. mdpi.com mdpi.com/1424-8247/15/5/583

Future Prospects of Positron Emission Tomography ... In this study, 16 MDD patients and 14 healthy controls were scanned using [11C]raclopride PET and functional MRI. Hamilton et al. found an increase in the D ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11070570/

The utility of PET imaging in depression - PMC This educational review article aims to discuss growing evidence from PET studies in the diagnosis and treatment of depression.

8. cms.gov cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=N&NCAId=104

NCA - Positron Emission Tomography (FDG) and Other ... 2) The evidence is not adequate to conclude that FDG-PET is reasonable and necessary for the diagnosis of patients with mild cognitive impairment (MCI) or early ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7541680/

A Randomized Controlled Trial (RCT) of Amyloid Positron ... Recent studies suggest that AD biomarker disclosure has no discernable psychological impact on cognitively healthy persons.