Anhedonia Therapies for Depression

(ADEPT Trial)

Overseen By Ashley Pogue, BA

Age: < 65

Sex: Any

Trial Phase: Phase 4

Sponsor: Erika Forbes

Must be taking: Antidepressants

Must not be taking: SNRIs, Bupropion, Antipsychotics, Stimulants

Disqualifiers: Psychosis, Bipolar, Substance use, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 5

123 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that participants stop taking certain medications, such as SNRIs, bupropion, antipsychotics, or stimulants, before participating in Phase 2 activities like TMS and ketamine administration.

What data supports the effectiveness of the treatment Continuous theta burst stimulation (cTBS) for depression?

Research shows that theta-burst stimulation, a type of transcranial magnetic stimulation, can help improve symptoms in people with major depressive disorder, especially those who have not responded well to other treatments. Studies indicate that combining different forms of theta-burst stimulation may lead to better outcomes. ^{1 2 3 4 5}

Is continuous theta burst stimulation (cTBS) safe for humans?

Research on continuous theta burst stimulation (cTBS) for depression shows it is generally safe, with studies reporting only mild side effects and no serious issues like seizures or mania. ^{2 5 6 7 8}

How does the treatment for anhedonia in depression differ from other treatments?

The treatment uses intermittent theta-burst stimulation (iTBS), a form of transcranial magnetic stimulation that targets brain areas involved in reward processing, potentially offering a unique approach by modulating the brain's reward system, which is often impaired in anhedonia. ^{1 2 3 6 9}

What is the purpose of this trial?

The goal of the ADEPT Study is to understand anhedonia in young people and how it changes based on treatments targeting the brain circuit underlying it. Anhedonia is a challenging mental health symptom that involves difficulty with motivation to experience pleasant events. This study could help develop treatments for people whose depression does not improve with traditional treatments. The ADEPT Study includes two phases. In Phase 1, participants are asked to go through a series of activities to measure anhedonia, including MRI scans, blood draws, behavioral tasks, clinical interviews, questionnaires, and app-based assessments of experiences and behaviors. Phase 2 involves therapeutic activities, such as transcranial magnetic stimulation (TMS), positive affect training, and, for some people, ketamine administration. If the participant qualifies and is interested, they may choose to do Phase 2 activities in addition to Phase 1.

Research Team

Erika E Forbes, PhD

Principal Investigator

University of Pittsburgh

Eligibility Criteria

This trial is for young people with depression and anhedonia, who have not improved after at least one antidepressant treatment. Participants must show moderate to severe symptoms of anhedonia and a certain level of depression severity. They cannot join if they've had brain injuries causing unconsciousness, use daily nicotine or certain medications, have metal in their body, are pregnant, or have specific psychiatric or neurological conditions.

Inclusion Criteria

You have been diagnosed with current depressive disorder according to the DSM-5.

You have a depression score of 12 or higher on the MADRS scale.

I have tried at least one antidepressant for 6 weeks without improvement.

Exclusion Criteria

You have used ketamine or PCP for fun at any time in your life.

I haven't taken MAOI antidepressants in the last 2 weeks.

Before the study, you drank a lot of alcohol in a short period of time or had more than three drinks per day recently.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-3 hours

1 visit (in-person)

Phenotyping

Participants undergo activities to measure anhedonia, including MRI scans, blood draws, behavioral tasks, clinical interviews, questionnaires, and app-based assessments

Approximately 1 year

4 visits (in-person), ongoing app-based assessments

Therapeutic Activities

Participants receive therapeutic interventions such as transcranial magnetic stimulation (TMS), Positive Affect Training, and potentially ketamine administration

2 weeks

Multiple visits (in-person)

Follow-up

Participants are monitored for changes in anhedonia and depression severity over time

Approximately 1 year

Treatment Details

Interventions

• Continuous theta burst stimulation (cTBS)
• Ketamine Injectable Solution
• Positive Affect Training

Trial Overview The ADEPT Study aims to understand and treat anhedonia by using MRI scans, blood tests, interviews, and app-based assessments (Phase 1). In Phase 2, treatments like transcranial magnetic stimulation (TMS), positive affect training exercises, and ketamine injections are tested for therapeutic effects on the brain circuits associated with pleasure and motivation.

Participant Groups

Group I: TMS and PAT, then Ketamine Experimental Treatment 3 Interventions

All open label with no randomization to placebo

Group II: TMS and PAT Experimental Treatment 2 Interventions

All open label with no randomization to placebo

Who Is Running the Clinical Trial?

Erika Forbes

Lead Sponsor

Trials

3

Recruited

180+

Findings from Research

In a study of 60 treatment-refractory patients with major depressive disorder, both intermittent and combined theta-burst stimulation showed significantly better antidepressant responses compared to continuous theta-burst stimulation and sham treatment after 2 weeks.

Theta-burst stimulation is well-tolerated and effective, especially in patients with lower levels of treatment refractoriness, indicating that the severity of refractoriness can influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study. Li, CT., Chen, MH., Juan, CH., et al.[2022]

In a study involving 72 patients with major depressive disorder, two daily sessions of prolonged intermittent theta-burst stimulation (piTBS) over two weeks showed significantly more responders compared to a sham treatment, indicating its efficacy as an antidepressant option.

However, the study found no evidence that longer piTBS sessions led to greater improvements in depression scores compared to other treatments, suggesting that while piTBS is effective, increasing treatment duration does not enhance its antidepressant effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The longer, the better ? Longer left-sided prolonged intermittent theta burst stimulation in patients with major depressive disorder: A randomized sham-controlled study. Li, CT., Cheng, CM., Lin, HC., et al.[2023]

In a study involving 50 patients with major depressive disorder (MDD), accelerated intermittent theta-burst stimulation (aiTBS) did not significantly affect reward responsiveness during a learning task, regardless of the patients' levels of anhedonia.

However, brain imaging revealed that aiTBS treatment altered neural activity in the reward system differently based on anhedonia severity, with low anhedonic patients showing decreased activity and high anhedonic patients showing increased activity after one week of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated iTBS treatment in depressed patients differentially modulates reward system activity based on anhedonia. Duprat, R., Wu, GR., De Raedt, R., et al.[2019]

In a randomized controlled trial involving 56 patients with moderate to severe depression, bilateral theta-burst stimulation (TBS) and repetitive transcranial magnetic stimulation (rTMS) did not show significant improvements in depression scores compared to sham treatment.

However, there was a noted tendency for both active treatments to increase the responder rate, particularly for the TBS group, suggesting that further research may be needed to explore its potential benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bilateral prefrontal rTMS and theta burst TMS as an add-on treatment for depression: a randomized placebo controlled trial. Prasser, J., Schecklmann, M., Poeppl, TB., et al.[2015]

In a study of 27 participants, a prolonged intermittent theta burst stimulation (piTBS) protocol using 1,800 pulses showed limited effectiveness for major depressive disorder, with only 18.2% of participants achieving a response and 9.1% reaching remission.

Safety and tolerability were concerns, as 18.5% of participants experienced issues, suggesting that while piTBS is a promising approach, further research is needed to optimize its parameters and improve outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged intermittent theta burst stimulation in the treatment of major depressive disorder: a case series. Richard, M., Noiseux, C., Desbeaumes Jodoin, V., et al.[2022]

Continuous theta burst stimulation (cTBS) was found to be safe and well-tolerated in patients with major depressive disorder (MDD) or bipolar depression (BD), with no significant differences in adverse events compared to sham treatment.

However, the meta-analysis of three randomized controlled trials involving 78 participants showed no significant improvement in depression scores or response rates with cTBS compared to sham, indicating that cTBS may not provide a therapeutic advantage for treating major depressive episodes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive continuous theta burst stimulation for major depressive disorder or bipolar depression: A meta-analysis of randomized controlled studies. Cai, DB., Qin, XD., Qin, ZJ., et al.[2023]

In a study involving 29 patients with major depression, continuous theta-burst transcranial magnetic stimulation (cTBS) did not show a significant overall improvement compared to sham treatment, indicating modest efficacy.

However, patients who were either medication-free or had unchanged medication status experienced a greater reduction in depression scores with active cTBS, suggesting it may be beneficial for those not responding to traditional pharmacological treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary assessment of the therapeutic efficacy of continuous theta-burst magnetic stimulation (cTBS) in major depression: a double-blind sham-controlled study. Chistyakov, AV., Kreinin, B., Marmor, S., et al.[2018]

Theta-burst stimulation (TBS) shows promise as a rapid and effective treatment for psychiatric disorders, particularly treatment-resistant depression and auditory hallucinations, with studies indicating mild adverse effects but no severe complications like seizures or mania.

The current research on TBS is varied in design and outcomes, highlighting the need for more rigorous sham-controlled studies to better assess its long-term safety and efficacy in treating various psychiatric conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Theta-Burst Stimulation in the Treatment of Psychiatric Disorders: A Review of the Literature. Rachid, F.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

The longer, the better ? Longer left-sided prolonged intermittent theta burst stimulation in patients with major depressive disorder: A randomized sham-controlled study. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Accelerated iTBS treatment in depressed patients differentially modulates reward system activity based on anhedonia. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Bilateral prefrontal rTMS and theta burst TMS as an add-on treatment for depression: a randomized placebo controlled trial. [2015]

5. Ireland pubmed.ncbi.nlm.nih.gov

Prolonged intermittent theta burst stimulation in the treatment of major depressive disorder: a case series. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Adjunctive continuous theta burst stimulation for major depressive disorder or bipolar depression: A meta-analysis of randomized controlled studies. [2023]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Preliminary assessment of the therapeutic efficacy of continuous theta-burst magnetic stimulation (cTBS) in major depression: a double-blind sham-controlled study. [2018]

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

Safety and Efficacy of Theta-Burst Stimulation in the Treatment of Psychiatric Disorders: A Review of the Literature. [2019]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Intermittent Theta-Burst Stimulation Transcranial Magnetic Stimulation Increases GABA in the Medial Prefrontal Cortex: A Preliminary Sham-Controlled Magnetic Resonance Spectroscopy Study in Acute Bipolar Depression. [2021]