Antidepressants for Anxious Depression

(DOTS-AD Trial)

Overseen By Heidi K Schroeder

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of two medications, duloxetine and escitalopram, for individuals with anxiety disorders, such as generalized or social anxiety, who also experience depression. If the initial treatment does not improve symptoms, participants may receive additional medication, either clonazepam or pregabalin, to address persistent anxiety. The trial seeks individuals fluent in English who have experienced anxiety or panic disorders and have been on specific anxiety medications for at least six weeks. As a Phase 4 trial, this research involves FDA-approved treatments and aims to understand how they can benefit more patients.

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 is the safety track record for these treatments?

Research has shown that both duloxetine and escitalopram are generally well-tolerated for treating depression and anxiety. Duloxetine is often prescribed for these conditions, and studies indicate that most side effects, such as nausea, dry mouth, and tiredness, are mild to moderate. However, safety for doses exceeding 120 mg per day has not been fully studied.

Escitalopram is approved for treating depression and generalized anxiety disorder and is also well-tolerated. Common side effects include trouble sleeping, nausea, and dizziness. Long-term use has not revealed major safety issues.

Both medications are widely used and have been tested in numerous studies, providing a good understanding of their safety. However, individual experiences can vary, so discussing any concerns with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments for anxious depression because they offer new combinations and adaptability. Duloxetine and escitalopram are being combined with adjunctive medications like clonazepam or pregabalin for patients who don’t initially respond, providing a tailored approach. This adaptability could lead to more personalized and effective treatment plans compared to traditional antidepressants alone. Unlike the usual single-drug therapies, this trial explores how different combinations might better target the complex symptoms of anxious depression.

What is the effectiveness track record for duloxetine and escitalopram in treating anxious depression?

Research has shown that duloxetine, one of the treatments in this trial, effectively treats both mood and anxiety symptoms related to depression. A review of studies found that most demonstrated significant improvements in these symptoms with duloxetine. Additionally, duloxetine consistently reduces depressed mood, regardless of initial symptom severity.

Studies have also shown that escitalopram, another treatment option in this trial, effectively treats major depressive disorder (MDD) with anxiety symptoms. Patients tolerated it well over long-term use, experiencing fewer side effects. The FDA has approved escitalopram for treating depression in adults and teenagers, highlighting its reliability. Both medications show promise in effectively managing symptoms of anxious depression. ^{2 6 7 8 9}

Who Is on the Research Team?

Jeffrey R Strawn, MD, FAACAP

Principal Investigator

University of Cincinnati

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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 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 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]

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 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]

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