Antidepressants for Anxious Depression

(DOTS-AD Trial)

Overseen By Zoe N Neptune, BS

Age: 18 - 65

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Cincinnati

Must be taking: Escitalopram, Duloxetine

Disqualifiers: Intellectual disability, Suicide risk, Alcohol use, others

Stay on Your Current Meds You can continue your current medications while participating

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: Unknown

84 Participants Needed

Trial Summary

What is the purpose of this trial?

Acute, double-blind, adaptively randomized treatment with duloxetine or escitalopram, followed by double-blind, randomized adjunctive treatment with clonazepam or pregabalin for persistent symptoms.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop your current medications, but it excludes those taking medications that require a taper or washout period longer than 5 days.

What data supports the effectiveness of the drug for anxious depression?

Research shows that escitalopram, one of the drugs in the treatment, is effective in treating depression and anxiety symptoms. Additionally, escitalopram has shown significant effects in reducing anxiety in conditions like social anxiety disorder and generalized anxiety disorder. ^{1 2 3 4 5}

Is citalopram or escitalopram safe for humans?

Citalopram and escitalopram are generally considered safe, but they have important safety considerations, such as potential heart-related side effects, especially in people with a history of fainting or poisoning. It's recommended to perform an electrocardiogram (a test that checks for heart problems) on elderly patients before starting these medications. ^{2 6 7 8 9}

How do the drugs Duloxetine and Escitalopram differ from other treatments for anxious depression?

Duloxetine and Escitalopram are unique because they target both depression and anxiety symptoms, with Escitalopram showing rapid improvement in anxiety symptoms within the first week. Unlike some other antidepressants, they have fewer sedative effects, making them a preferred choice for treating anxiety symptoms in depression. ^{1 5 10 11 12}

Research Team

Jeffrey R Strawn, MD, FAACAP

Principal Investigator

University of Cincinnati

Eligibility Criteria

This trial is for English-speaking adults aged 18-50 with anxiety and depression, confirmed by specific criteria and tests. They must have a certain score on the HAM-A scale, no significant health issues or drug use, not be pregnant or breastfeeding, and agree to reliable contraception.

Inclusion Criteria

You must use both a diaphragm and a condom during the study.

I use a vaginal ring or contraceptive implant for birth control.

Patients must be fluent in English

Exclusion Criteria

I am on medication that cannot be stopped immediately and requires more than 5 days to safely stop.

You are allergic or have had bad reactions to escitalopram, duloxetine, pregabalin, or clonazepam.

You have a history of having difficulty with learning or understanding things.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Adaptively randomized, double-blind treatment with escitalopram or duloxetine for 11 weeks

11 weeks

Weekly visits (in-person)

Phase 2 Treatment

Non-remitting patients receive adjunctive treatment with clonazepam or pregabalin for 8 weeks

8 weeks

Bi-weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Duloxetine
• Escitalopram

Trial Overview The study compares two antidepressants: Escitalopram and Duloxetine. It starts with one of these drugs chosen randomly. If symptoms persist, participants are then given either Clonazepam or Pregabalin in addition to their initial treatment.

Participant Groups

Group I: Escitalopram Active Control 1 Intervention

Adaptively randomized, double-blind treatment with escitalopram for 11 weeks in Phase 1. Non-remitting patients will be randomized in Phase 2 to adjunctive clonazepam or pregabalin for 8 weeks. Additionally, adults who are already treated with escitalopram or citalopram for at least 6 weeks prior to screening, may enter Phase 2 and be randomized to adjunctive clonazepam or pregabalin for 8 weeks.

Group II: Duloxetine Active Control 1 Intervention

Adaptively randomized, double-blind treatment with duloxetine for 11 weeks in Phase 1. Non-remitting patients will be randomized in Phase 2 to adjunctive clonazepam or pregabalin for 8 weeks. Additionally, adults who are already treated with duloxetine for at least 6 weeks prior to screening, may enter Phase 2 and be randomized to adjunctive clonazepam or pregabalin for 8 weeks.

Duloxetine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Cymbalta for:

• Major Depressive Disorder
• Generalized Anxiety Disorder
• Fibromyalgia
• Neuropathic Pain
• Chronic Musculoskeletal Pain

Approved in European Union as Cymbalta / Yentreve for:

• Major Depressive Disorder
• Generalized Anxiety Disorder
• Diabetic Peripheral Neuropathic Pain
• Fibromyalgia
• Stress Urinary Incontinence

Approved in Canada as Cymbalta for:

• Major Depressive Disorder
• Generalized Anxiety Disorder
• Fibromyalgia
• Neuropathic Pain
• Chronic Musculoskeletal Pain

Who Is Running the Clinical Trial?

University of Cincinnati

Lead Sponsor

Trials

442

Recruited

639,000+

Findings from Research

In a study of 2,841 patients with major depressive disorder, duloxetine was found to be significantly more effective than placebo in improving depression symptoms for both anxious and nonanxious patients, with a greater change in Hamilton Depression Rating Scale (HAMD) scores.

The level of anxiety did not influence the effectiveness of duloxetine, as both anxious and nonanxious patients showed similar response and remission rates, indicating that duloxetine is a viable treatment option regardless of anxiety levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anxiety does not predict response to duloxetine in major depression: results of a pooled analysis of individual patient data from 11 placebo-controlled trials. Nelson, JC.[2015]

In a study of 366 outpatients with panic disorder, escitalopram significantly reduced the frequency of panic attacks compared to placebo, demonstrating its efficacy in treating this condition.

Escitalopram was found to be safe and well tolerated, with a low rate of discontinuation due to adverse events, similar to that of the placebo group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Escitalopram in the treatment of panic disorder: a randomized, double-blind, placebo-controlled trial. Stahl, SM., Gergel, I., Li, D.[2022]

Patients with anxious depression experience a more chronic illness, higher rates of suicidal thoughts, and poorer treatment responses compared to those with major depressive disorder alone.

Treatment for anxious depression may require tailored approaches, including lower starting doses and longer treatment durations, alongside nonpharmacologic options like targeted psychotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anxious depression: clinical features and treatment. Rao, S., Zisook, S.[2021]

Escitalopram, a more active isomer of citalopram, showed a faster onset of action and greater overall effectiveness in treating major depressive disorder compared to citalopram, with significant improvements in depression and anxiety symptoms observed as early as one week into treatment.

Both escitalopram and citalopram were effective in reducing symptoms of depression and anxiety compared to placebo, but escitalopram demonstrated statistically significant advantages over citalopram at multiple time points during the treatment period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder: pooled analysis of placebo-controlled trials. Gorman, JM., Korotzer, A., Su, G.[2019]

In a study involving 124 patients with major depressive disorder and high anxiety, escitalopram, desvenlafaxine, and vortioxetine showed similar overall efficacy and tolerability in treating anxious depression over a 6-week period.

Desvenlafaxine was particularly effective in reducing specific anxiety-related symptoms, such as somatic and hypochondriasis scores, compared to escitalopram, indicating it may have unique benefits for certain anxiety symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Escitalopram, Desvenlafaxine, and Vortioxetine in the Acute Treatment of Anxious Depression: A Randomized Rater-blinded 6-week Clinical Trial. Shin, C., Jeon, SW., Lee, SH., et al.[2023]

In a study of 175 patients with alcohol dependence and depressive disorders, fluvoxamine showed the fastest efficacy in relieving depressive symptoms by the 7th day, while other SSRIs like sertraline and paroxetine took 14 days, and fluoxetine took 30 days.

Fluvoxamine also demonstrated the best safety profile among the SSRIs, with fewer adverse reactions compared to fluoxetine, citalopram, and sertraline, making it a favorable option for treating depression in patients with alcohol dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Fluvoxamine in the treatment of depressive disorders in alcohol dependence: results of randomized open-label comparative study]. Vinnikova, MA., Severtsev, VV., Komarov, SD., et al.[2022]

A study evaluated the adherence to prescribing guidelines for citalopram and found that implementing an EMIS safety prompt and providing prescriber training led to a significant reduction in incorrect prescriptions for patients over 65, from 8 to 1.

The interventions also decreased dangerous drug interactions involving citalopram from 44 to 8 and overall unsafe prescribing from 47 to 9, highlighting improved patient safety and resource use that could be applied to other medications with safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safer citalopram use in primary care: Can staff education and prescribing prompts improve adherence to national guidance? A closed loop clinical audit, service evaluation and quality improvement study. Waller, M.[2023]

In a double-blind trial with 60 patients suffering from endogenous depression, citalopram showed a significantly greater reduction in depression scores compared to mianserin after just 1 and 2 weeks of treatment.

Citalopram was found to be safe, with only mild to moderate side effects reported in six patients, while no cardiovascular side effects were observed, suggesting it may be a preferable option over mianserin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Citalopram versus mianserin. A controlled, double-blind trial in depressed patients. de Wilde, J., Mertens, C., Overø, KF., et al.[2019]

Regulatory alerts regarding the cardiac toxicity of citalopram and escitalopram primarily concern patients with a history of syncope or poisoning, suggesting that the risk may not be as widespread as initially thought.

It is recommended that elderly patients undergo an electrocardiogram as a precaution before starting treatment with these medications to monitor for potential cardiac issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Citalopram, escitalopram and prolonged QT: warning or alarm?]. Alvarez, E., Vieira, S., Garcia-Moll, X.[2022]

In a study of 61 patients with anxious depression, both Zoloft (sertraline) and Coaxil (tianeptine) were found to be equally effective as monotherapy treatments.

The research highlighted differences in the dynamics of clinical parameters between the two medications, suggesting that while they are similarly effective, their effects may manifest differently over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The dynamics of anxious depression under the treatment with antidepressants with different mechanisms of action]. Maksimova, NM., Vertogradova, OP.[2022]

Selective serotonin reuptake inhibitors (SSRIs), particularly escitalopram, are effective in treating anxiety symptoms associated with depression, showing significant improvement compared to placebo as early as the first week of treatment.

Escitalopram not only demonstrates rapid efficacy but also has a favorable tolerability profile, making it a preferred choice over traditional anxiolytics like benzodiazepines, which have more adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effects of escitalopram on anxiety symptoms in depression]. Spadone, C.[2022]

In a study of 43 subjects with Generalized Anxiety Disorder, both escitalopram and duloxetine showed significant improvements in anxiety and depression scores over 6 months, with similar dropout rates.

Duloxetine demonstrated higher remission and response rates compared to escitalopram after the first month, particularly in the somatic symptoms of anxiety, suggesting it may be a more effective initial treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An open, non-randomised comparison of escitalopram and duloxetine for the treatment of subjects with Generalized Anxiety Disorder. Pierò, A., Locati, E.[2022]

References

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

Anxiety does not predict response to duloxetine in major depression: results of a pooled analysis of individual patient data from 11 placebo-controlled trials. [2015]

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

Escitalopram in the treatment of panic disorder: a randomized, double-blind, placebo-controlled trial. [2022]

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

Anxious depression: clinical features and treatment. [2021]

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

Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder: pooled analysis of placebo-controlled trials. [2019]

5. Korea (South) pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Escitalopram, Desvenlafaxine, and Vortioxetine in the Acute Treatment of Anxious Depression: A Randomized Rater-blinded 6-week Clinical Trial. [2023]

6. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Fluvoxamine in the treatment of depressive disorders in alcohol dependence: results of randomized open-label comparative study]. [2022]

7. India pubmed.ncbi.nlm.nih.gov

Safer citalopram use in primary care: Can staff education and prescribing prompts improve adherence to national guidance? A closed loop clinical audit, service evaluation and quality improvement study. [2023]

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

Citalopram versus mianserin. A controlled, double-blind trial in depressed patients. [2019]

9. Spain pubmed.ncbi.nlm.nih.gov

[Citalopram, escitalopram and prolonged QT: warning or alarm?]. [2022]

10. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[The dynamics of anxious depression under the treatment with antidepressants with different mechanisms of action]. [2022]

11. France pubmed.ncbi.nlm.nih.gov

[Effects of escitalopram on anxiety symptoms in depression]. [2022]

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

An open, non-randomised comparison of escitalopram and duloxetine for the treatment of subjects with Generalized Anxiety Disorder. [2022]