SSRI Therapy for Depression

(CAN-D Trial)

Overseen by Ryan Rampersaud, MD, PhD

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: University of California, San Francisco

Must not be taking: Statins, Hormonal medications

Disqualifiers: Neurological disorders, Substance use, others

No Placebo Group

Approved in 5 Jurisdictions

Trial Summary

What is the purpose of this trial?

We are conducting an eight week longitudinal study to learn if blood levels of certain naturally occurring compounds and genetic markers differ between patients with depression and healthy adults who are not depressed, and if any such differences relate to memory performance, mood, and neurobiology. We are also interested in how the gut microbiome is affected by antidepressant treatment. We will do this by comparing the unmedicated depressed patients with matched healthy controls at baseline and then following the depressed patients over the course of eight weeks of standardized antidepressant treatment to gauge which baseline abnormalities normalize over the course of treatment.

Will I have to stop taking my current medications?

Yes, you will need to stop taking any psychotropic medications (including antidepressants) for at least 6 weeks before the study, except for occasional short-acting benzodiazepines or sedative-hypnotics. You also cannot take medications that might interfere with the study, like statins or hormonal medications.

What data supports the effectiveness of this drug for depression?

Research shows that SSRIs are effective for treating mild to moderate depression and are better tolerated than older antidepressants. They are also found to be as effective as older drugs for severe depression, making them a good choice for many patients. ^{1 2 3 4 5}

Is SSRI therapy generally safe for humans?

SSRIs are generally considered safe for treating depression and other conditions, but they can cause side effects like nausea, headaches, and anxiety. Some studies have noted digestive issues as common side effects, and there is ongoing research about their link to suicidal risk. ^{6 7 8 9 10}

How is SSRI therapy for depression different from other drugs?

SSRI therapy for depression is unique because it is generally better tolerated than older antidepressants like tricyclic antidepressants (TCAs), making it a preferred choice for many patients. While SSRIs are effective for mild to moderate depression, they are also used for severe depression, although their effectiveness in severe cases may be less than older therapies. Additionally, SSRIs are used for other conditions like obsessive-compulsive disorder and panic disorders, highlighting their versatility. ^{1 2 8 11 12}

Research Team

Owen Wolkowitz, MD

Principal Investigator

University of California, San Francisco

Ryan Rampersaud, MD, PhD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This study is for adults aged 21-60 with a current diagnosis of Major Depressive Disorder, experiencing a depressive episode lasting over 6 weeks. Participants must be in good health, not using drugs or certain medications, and women must use non-hormonal birth control. People with neurological disorders, recent concussions, substance abuse issues, or those who are needle-phobic cannot join.

Inclusion Criteria

I am not pregnant and use non-hormonal birth control methods.

I am between 21 and 60 years old and can legally consent.

English-speaking to allow accurate use of behavioral rating scales and verbal cognitive tests

Exclusion Criteria

No history of DSM-5 Axis I diagnoses

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline

Baseline visit for initial assessments including urine and blood tests, cognitive tests, and meeting with the study psychiatrist

1 day

1 visit (in-person)

Treatment

Participants receive 8 weeks of treatment with an SSRI, with monitoring and follow-up visits

8 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including blood draw and cognitive tests

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Standard Clinical Care with an SRRI (SSRI)

Trial Overview The trial examines how blood compounds and genetic markers related to depression may change after eight weeks of treatment with an SSRI (a type of antidepressant). It also looks at the impact on memory performance, mood changes, and gut microbiome compared to healthy individuals without depression.

Participant Groups

Group I: Treatment with SSRI Experimental Treatment 1 Intervention

Depressed participants will receive 8 weeks of treatment with one of the following serotonin-specific reuptake inhibitors: fluoxetine (Prozac®), sertraline (Zoloft®), citalopram (Celexa®), escitalopram (Lexapro®) The specific drug used for treatment will be selected by the study clinician based on clinical interviews and the participants preferences. Participants will be monitored for response and side effects by study clinician and will return after 8 weeks for a follow up study visit.

Standard Clinical Care with an SRRI is already approved in Canada, Japan for the following indications:

Approved in Canada as SSRIs for:

• Major depressive disorder
• Generalized anxiety disorder
• Social anxiety disorder
• Obsessive-compulsive disorder
• Panic disorder
• Post-traumatic stress disorder

Approved in Japan as SSRIs for:

• Major depressive disorder
• Anxiety disorders
• Obsessive-compulsive disorder
• Panic disorder

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Suresh Gunasekaran

University of California, San Francisco

Chief Executive Officer since 2022

MBA from Southern Methodist University

Dr. Lukejohn Day

University of California, San Francisco

Chief Medical Officer

MD from Stanford University School of Medicine

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Dr. Jeanne Marrazzo

National Institutes of Health (NIH)

Chief Medical Officer

MD from University of California, Los Angeles

Dr. Jay Bhattacharya

National Institutes of Health (NIH)

Chief Executive Officer

MD, PhD from Stanford University

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Dr. Joshua A. Gordon

National Institute of Mental Health (NIMH)

Chief Executive Officer since 2016

MD, PhD

Dr. Shelli Avenevoli

National Institute of Mental Health (NIMH)

Chief Medical Officer

PhD

Findings from Research

Selective serotonin reuptake inhibitors (SSRIs) are considered first-line treatments for certain disorders, such as compulsive disorders and seasonal depression, due to their positive efficacy.

SSRIs are also recommended for their favorable side-effect profile, making them a preferred choice for various conditions, although further research is needed to confirm their effectiveness for some indications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Therapy with selective serotonin reuptake inhibitors (SSRI). Indications, uses and risks]. Ebert, D.[2022]

A review of 16 controlled studies indicates that SSRIs are more effective than placebo and have similar efficacy to tricyclic antidepressants (TCAs) in treating severe depression, while being better tolerated.

Despite some clinical impressions that SSRIs may be less effective in severely depressed patients, the majority of studies support their use, suggesting they remain a viable treatment option for this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of severe depression with the selective serotonin reuptake inhibitors. Schatzberg, AF.[2022]

In a study of 88,755 patients in Italy, 41% of those new to antidepressants (SSRIs and SNRIs) had a treatment duration of 3 months or less, indicating a trend of short-term use, especially among naïve patients.

Adherence to antidepressant therapy was low (MPR < 60%) in 63% of naïve patients, while those already on treatment showed better adherence (58% with MPR ≥ 80%), suggesting that ongoing treatment may improve adherence rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patterns of antidepressant use in Italy: therapy duration, adherence and switching. Degli Esposti, L., Piccinni, C., Sangiorgi, D., et al.[2022]

In a study of 2,876 outpatients with major depressive disorder treated with citalopram for up to 14 weeks, remission rates were found to be 28% using the Hamilton Depression Rating Scale and 33% using the Quick Inventory of Depressive Symptomatology, indicating that citalopram is effective in real-world settings.

Factors such as being Caucasian, female, employed, and having higher education or income were associated with higher remission rates, while longer episodes of depression and more comorbid conditions were linked to lower remission rates, highlighting the complexity of treating depression in diverse patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Trivedi, MH., Rush, AJ., Wisniewski, SR., et al.[2022]

Selective serotonin reuptake inhibitors (SSRIs) are effective for treating pediatric affective disorders, showing modest effects in major depressive disorder, intermediate effects in obsessive-compulsive disorder, and stronger effects in anxiety disorders.

Despite a modest increase in the risk of suicidal thoughts and behaviors, SSRIs are associated with a significant decrease in suicide rates among children and adolescents, likely due to their efficacy, good compliance, and low toxicity in overdose situations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Antidepressant use in children and adolescents]. Bailly, D.[2009]

A study of adverse drug reactions (ADRs) for SSRIs in Belgium and the Netherlands found that 30% of reported reactions were well-established, while 60% were poorly documented or not serious, indicating a need for better reporting and documentation.

Serious ADRs, such as movement disorders and convulsions, were reported in less than 1% of cases in Belgium and about 13% in the Netherlands, suggesting that while SSRIs have a known safety profile, some serious reactions may not be adequately represented in product information.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Reports of suspected side effects of selective serotonin reuptake inhibitors in Belgium and The Netherlands]. Van Ermen, AM., Ottervanger, JP., Roisin, T., et al.[2022]

A review of Health Canada's database from 1986 to 1996 found that intentional overdoses were the leading cause of death among patients taking SSRIs, with benzodiazepines and other drugs commonly involved in these overdoses.

Patients taking SSRIs alongside two or more other medications, especially those metabolized by CYP-450, faced a higher risk of severe adverse drug reactions (ADRs), including serious cardiovascular issues, highlighting the need for careful monitoring by physicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Who develops severe or fatal adverse drug reactions to selective serotonin reuptake inhibitors? Dalfen, AK., Stewart, DE.[2022]

Selective serotonin reuptake inhibitors (SSRIs) are considered safe and effective for treating depression and other disorders, with only fluvoxamine and paroxetine approved for use in Japan.

The therapeutic effects of SSRIs are primarily linked to the desensitization of serotonin 1A autoreceptors, although other neurotransmitters and mechanisms may also play a role, highlighting the complexity of their action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Selective serotonin reuptake inhibitor(SSRI)]. Motohashi, N.[2022]

Fluoxetine is associated with the lowest risk of digestive side effects among the SSRIs studied, making it a preferable option for patients concerned about gastrointestinal issues.

Sertraline has the highest likelihood of causing digestive system side effects, which may affect patient compliance with treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risks of Digestive System Side-Effects of Selective Serotonin Reuptake Inhibitors in Patients with Depression: A Network Meta-Analysis. Wang, Z., Li, H., Kang, Y., et al.[2022]

In a study of 48,277 depressed patients from randomized controlled trials, the suicide rates were similar across those treated with SSRIs (0.59%), other antidepressants (0.76%), and placebo (0.45%).

The results indicate that there is no significant difference in suicide risk between patients treated with SSRIs, other antidepressants, or placebo, suggesting that SSRIs do not increase the risk of completed suicides compared to these alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. Khan, A., Khan, S., Kolts, R., et al.[2022]

A nationwide study in Sweden involving 5,866 suicides found that initiating treatment with selective serotonin reuptake inhibitors (SSRIs) is associated with a significantly increased short-term suicide risk, with odds ratios of 2.7 for women and 4.3 for men.

The highest risk was observed 8-11 days after starting SSRIs, suggesting that healthcare providers should closely monitor patients during this initial period for any signs of increased suicidal thoughts or behaviors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An association between initiation of selective serotonin reuptake inhibitors and suicide - a nationwide register-based case-crossover study. Björkenstam, C., Möller, J., Ringbäck, G., et al.[2022]

Selective serotonin reuptake inhibitors (SSRIs) are commonly regarded as the best treatment for depression, but they are not all the same and can have different pharmacological properties due to their varied chemical structures.

Understanding the differences in pharmacokinetics, efficacy, safety, and tolerability among SSRIs can help clinicians choose the most suitable medication for individual patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing SSRIs: From chemistry to clinical choice. Van den Berg, SJ.[2019]

References

1. Germany pubmed.ncbi.nlm.nih.gov

[Therapy with selective serotonin reuptake inhibitors (SSRI). Indications, uses and risks]. [2022]

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

Treatment of severe depression with the selective serotonin reuptake inhibitors. [2022]

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

Patterns of antidepressant use in Italy: therapy duration, adherence and switching. [2022]

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

Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. [2022]

5. France pubmed.ncbi.nlm.nih.gov

[Antidepressant use in children and adolescents]. [2009]

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

[Reports of suspected side effects of selective serotonin reuptake inhibitors in Belgium and The Netherlands]. [2022]

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

Who develops severe or fatal adverse drug reactions to selective serotonin reuptake inhibitors? [2022]

8. Japan pubmed.ncbi.nlm.nih.gov

[Selective serotonin reuptake inhibitor(SSRI)]. [2022]

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

Risks of Digestive System Side-Effects of Selective Serotonin Reuptake Inhibitors in Patients with Depression: A Network Meta-Analysis. [2022]

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

Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. [2022]

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

An association between initiation of selective serotonin reuptake inhibitors and suicide - a nationwide register-based case-crossover study. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Comparing SSRIs: From chemistry to clinical choice. [2019]