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

Trial Summary

What is the purpose of this trial?

Background: Researchers developed \[11C\]MC1, a radioligand for cyclooxygenase-2 (COX-2). COX-2 is an enzyme induced in the brain during inflammation. Researchers want to see the levels of COX-1 (measured as distribution volume VT) are elevated in the brain of two groups of mood disorders patients undergoing MDE relative to the control group. Objective: To determine whether COX-1 and COX-2 are detectable in the brains of individuals with MDD experiencing a major depressive episode (MDE). Eligibility: People aged 18-70 years with MDD and Healthy Volunteers aged 18 70 years. Design: Group A: MDD participants will be studied with the same dose of \[11C\]MC1 before and after administration of 600 mg celecoxib; the study is neither randomized nor placebo-controlled. Group B: MDD participants, both medicated and unmedicated, will be studied with \[11C\]PS13 and compared to healthy volunteers.. https://nimhcontent.nimh.nih.gov/start/surveys/?s=TJW4RA4WN3LDD988

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 evidence supports the effectiveness of the drug 11C-MCI, 11CPS13 for depression?

While there is no direct evidence for the effectiveness of 11C-MCI, 11CPS13 in treating depression, PET imaging studies have shown that changes in brain activity patterns can predict treatment response in depression. These imaging techniques have been useful in understanding brain function changes with treatment, suggesting potential for similar drugs to impact depression. ^{1 2 3 4 5}

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. However, similar PET imaging agents have been evaluated for safety, including radiation dosimetry (measurement of radiation exposure) and in vivo pharmacology (how the drug behaves in the body), which are important for assessing safety in clinical use. ^{6 7 8 9 10}

How does PET imaging differ from other treatments for depression?

PET imaging is unique because it allows doctors to see how different areas of the brain are functioning in people with depression, which can help in understanding the disorder and tailoring treatments. Unlike medications or talk therapy, PET imaging is a diagnostic tool that provides a visual map of brain activity, potentially identifying specific brain regions involved in depression. ^{5 11 12 13 14}

Research Team

Robert B Innis, M.D.

Principal Investigator

National Institute of Mental Health (NIMH)

Eligibility Criteria

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

I am between 18 and 70 years old.

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.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

[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]

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]

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]

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]

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]

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]

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]

References

1. Canada pubmed.ncbi.nlm.nih.gov

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

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

Positron emission tomographic study of affective disorders: problems and strategies. [2019]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Diagnostic and therapeutic utility of neuroimaging in depression: an overview. [2022]

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

Application of positron emission tomography in psychiatry-methodological developments and future directions. [2022]

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

SPECT and PET imaging in mood disorders. [2016]

6. England pubmed.ncbi.nlm.nih.gov

Synthesis and evaluation of [11C]cyanoimipramine. [2019]

7. Germany pubmed.ncbi.nlm.nih.gov

Human adult and adolescent biodistribution and dosimetry of the synaptic vesicle glycoprotein 2A radioligand 11C-UCB-J. [2023]

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

Radiosynthesis and PET imaging of [N-methyl-11C]LY257327 as a tracer for 5-HT transporters. [2022]

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

The production in high yield of N'-(4-[11C]methyl)-imipramine. [2013]

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

Preclinical safety assessment of the 5-HT2A receptor agonist PET radioligand [ 11C]Cimbi-36. [2021]

11. Germany pubmed.ncbi.nlm.nih.gov

PET imaging of animal models with depressive-like phenotypes. [2023]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Molecular tools for assessing human depression by positron emission tomography. [2016]

13. Ireland pubmed.ncbi.nlm.nih.gov

Changes in glucose metabolism in dementia of the Alzheimer type compared with depression: a preliminary report. [2019]

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

Regional cerebral glucose metabolism in late-life depression and Alzheimer disease: a preliminary positron emission tomography study. [2019]