SSRI Therapy for Depression

(CAN-D Trial)

Overseen By Tiffany Chinn, BS

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: University of California, San Francisco

Must not be taking: Statins, Hormonal medications

Disqualifiers: Neurological disorders, Substance use, others

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

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how antidepressant treatment affects the gut microbiome and whether certain blood compounds and genetic markers link to memory, mood, and brain function in people with depression. Participants with depression will receive one of several serotonin-specific reuptake inhibitors (SSRIs) for eight weeks, while researchers compare their progress to that of healthy individuals. Those diagnosed with major depressive disorder (lasting over six weeks) and without recent substance use issues might be a good fit.

As an unphased trial, this study offers a unique opportunity to contribute to groundbreaking research that could enhance understanding and treatment of depression.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that SSRIs, or selective serotonin reuptake inhibitors, are generally safe for treating depression. Medications like fluoxetine (Prozac®) and sertraline (Zoloft®) are commonly prescribed and well-tolerated by most people. Surveys indicate that about 38% of SSRI users report experiencing one or more side effects, often mild, such as nausea or headaches. SSRIs rank among the most frequently prescribed antidepressants, underscoring their established safety. Although some studies suggest a slight risk of birth defects with certain SSRIs during pregnancy, this concern does not apply to most users. Overall, SSRIs provide a safe option for many dealing with depression. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about these treatments because serotonin-specific reuptake inhibitors (SSRIs) like fluoxetine, sertraline, citalopram, and escitalopram are tailored to boost serotonin levels, a key neurotransmitter linked to mood regulation. Unlike some traditional antidepressants that can affect multiple neurotransmitters, SSRIs specifically target serotonin reuptake, potentially leading to fewer side effects and improved tolerability for patients. Additionally, the personalized selection of the specific SSRI based on clinical interviews and patient preferences helps optimize individual responses and overall treatment effectiveness.

What is the effectiveness track record for SSRIs in treating depression?

Research has shown that SSRIs, a type of antidepressant, effectively treat depression. A review of studies found that these medications work better than a placebo, which contains no active ingredients. In this trial, participants will receive treatment with one of the following SSRIs: sertraline, fluoxetine, citalopram, or escitalopram. Studies have demonstrated that SSRIs like sertraline, fluoxetine, and escitalopram help about 92% of patients feel better. Specifically, escitalopram proved more effective than other antidepressants. This evidence suggests that SSRIs can significantly improve mood and reduce depression symptoms. ^{5 6 7 8 9}

Who Is on the Research Team?

Owen Wolkowitz, MD

Principal Investigator

University of California, San Francisco

Ryan Rampersaud, MD, PhD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

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.

I am generally healthy with no major uncontrolled illnesses.

Exclusion Criteria

No history of DSM-5 Axis I diagnoses

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• Standard Clinical Care with an SRRI

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.

How Is the Trial Designed?

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 European Union, United States, Canada, Japan for the following indications:

Approved in European Union as SSRIs for:

• Major depressive disorder
• Anxiety disorders
• Obsessive-compulsive disorder
• Panic disorder
• Post-traumatic stress disorder

Approved in United States as SSRIs for:

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

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+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8633963/

Effectiveness of common antidepressants: a post market ... This study summarizes the experiences of patients, who have multiple comorbidities, with 15 mono-treated antidepressants.

2. thelancet.com thelancet.com/article/S0140-6736(17)32802-7/fulltext

a systematic review and network meta-analysis In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89–2·41) ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10001334/

Impact of Sertraline, Fluoxetine, and Escitalopram on ... The overall improvement rate of 92.48% among the study sample indicates only that selective serotonin reuptake inhibitor medication effectively ...

4. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.ajp.20230356

Real-World Evidence on Clinical Outcomes of Commonly ... This real-world evidence suggests that clinical outcomes may vary among initiators of commonly used antidepressants in older adults.

5. bmcpsychiatry.biomedcentral.com bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-023-05382-8

Escitalopram versus other antidepressive agents for major ... Escitalopram was superior to other ADs for the acute phase treatment of MDD in terms of efficacy, acceptability and tolerability.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8395812/

Selective Serotonin Reuptake Inhibitors and Adverse Effects More recent data report an association between SSRIs (mainly paroxetine and fluoxetine) and a slightly increased risk of congenital defects, ...

7. npr.org npr.org/sections/shots-health-news/2025/10/23/nx-s1-5582787/antidepressant-side-effects-mental-health

Antidepressant side effects vary depending on the drug The findings are based on existing data, mostly from 8-week drug studies, that altogether represent more than 58,000 patients. The most ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2719451/

Real-World Data on SSRI Antidepressant Side Effects - PMC Thirty-eight percent of the approximately 700 patients surveyed reported experiencing one or more side effects as a result of taking an SSRI antidepressant.

9. mayoclinic.org mayoclinic.org/diseases-conditions/depression/in-depth/ssris/art-20044825

Selective serotonin reuptake inhibitors (SSRIs) SSRIs are the type of antidepressant prescribed most often. They can ease symptoms of moderate to severe depression. They are relatively safe.