Combination Therapy for Anxiety Disorders

(PCAY Trial)

Recruiting at 2 trial locations

Overseen By John Lavigne, Ph.D.

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Ann & Robert H Lurie Children's Hospital of Chicago

Must not be taking: Fluoxetine, Sertraline, Citalopram, others

Disqualifiers: Autism, Bipolar, Schizophrenia, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 21

Duration: 6 months

468 Participants Needed

Trial Summary

What is the purpose of this trial?

Pediatric onset anxiety disorders (generalized anxiety, social anxiety, separation anxiety) are highly prevalent, and if untreated, are impairing into adolescence and adulthood. In the largest comparative efficacy study remission occurred in about 65% of children and adolescents treated with a combination of a selective serotonin reuptake inhibitors (SSRI) and cognitive behavioral therapy (CBT). In contrast, CBT without an SSRI achieved remission in 35% of children at 3 months and 45% at 6 months-a 30% and 20% difference, respectively. Despite the difference in remission rates, CBT alone is the preferred treatment of most patients and families. Lack of awareness of the significant difference in remission rates and concerns about medication side effects may drive patient and family preference even though SSRIs have a positive safety profile. Critiques of CBT in the above study suggest that CBT was not as effective as it could be due to short treatment duration, restricted family involvement and limited exposure sessions. Would the combination of CBT and an SSRI still be superior to CBT only, if CBT was of longer duration, and included more family involvement and exposure sessions? In the Partners in Care for Anxious Youth (PCAY) study, children and adolescents with an anxiety disorder ages 7-17 years followed in pediatric primary care clinics affiliated with three institution: Lurie Children's Hospital of Chicago, University of California Los Angeles and University of Cincinnati will be randomized to one of two treatment arms; either CBT only or CBT combined with an SSRI (either fluoxetine, sertraline, or escitalopram). CBT in PCAY will be 6 months in duration and include more family involvement, and more exposure opportunities than past trials. The 6-month acute treatment phase will be followed by 6 months of followup. The primary outcome will be anxiety symptom remission and reduction in impairment over 6 and 12-months.

Do I have to stop taking my current medications to join the trial?

The trial protocol does not specify if you must stop taking your current medications. However, if you have experienced minimal or no change on an adequate dose of certain medications for anxiety, you may be excluded from the trial. It's best to discuss your specific situation with the trial coordinators.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you have been on certain medications like fluoxetine, sertraline, citalopram, or escitalopram at specific doses for at least 6 of the last 10 weeks, you may not be eligible to participate.

What data supports the idea that Combination Therapy for Anxiety Disorders is an effective treatment?

The available research shows that combining Cognitive Behavioral Therapy (CBT) with medication, like SSRIs (a type of drug), can be effective for treating anxiety disorders. One study found that this combination is more effective for panic disorder than using either CBT or the drug alone. Another study suggests that CBT is as effective as drugs for treating various anxiety disorders, and combining them might offer additional benefits, although more research is needed to confirm this. ^{1 2 3 4 5}

What data supports the effectiveness of the combination therapy for anxiety disorders?

Research shows that Cognitive Behavioral Therapy (CBT) is effective for treating various anxiety disorders, and combining it with medication like SSRIs (a type of drug that helps balance brain chemicals) may enhance treatment, although more research is needed to confirm this. ^{1 2 3 4 5}

What safety data exists for combination therapy for anxiety disorders?

The safety data for combination therapy involving Cognitive Behavioral Therapy (CBT) and medications like sertraline, citalopram, and escitalopram includes findings from various studies. A pilot study on Cambodian refugees with PTSD showed that combining CBT with sertraline provided additional benefits compared to sertraline alone. Another study highlighted the potential cardiac toxicity of citalopram and escitalopram, suggesting caution in patients with a history of syncope or poisoning, and recommending ECGs for elderly patients. Overall, these treatments have demonstrated efficacy and safety in treating anxiety-related disorders, but specific precautions may be necessary for certain populations. ^{6 7 8 9 10}

Is combination therapy for anxiety disorders safe?

Combination therapy involving medications like sertraline, citalopram, and escitalopram, often used with cognitive behavioral therapy (CBT), is generally considered safe for humans. However, there are concerns about potential heart-related side effects with citalopram and escitalopram, especially in people with a history of fainting or poisoning, so an electrocardiogram (a heart test) is recommended for older patients. ^{6 7 8 9 10}

Is the combination of Cognitive Behavioral Therapy (CBT) and drugs like Zoloft, Lexapro, and Prozac a promising treatment for anxiety disorders?

Yes, combining Cognitive Behavioral Therapy (CBT) with drugs like Zoloft, Lexapro, and Prozac can be promising for treating anxiety disorders. This combination may offer more benefits than using drugs alone, especially for panic disorder, by improving symptoms more effectively. ^{1 11 12 13 14}

How does the combination treatment for anxiety disorders differ from other treatments?

The combination treatment for anxiety disorders, which includes Cognitive Behavioral Therapy (CBT) and medications like SSRIs (such as Escitalopram, Fluoxetine, and Sertraline), is unique because it aims to maximize benefits by addressing both psychological and biological aspects of anxiety. While CBT focuses on changing thought patterns, SSRIs help balance brain chemicals, and together they may offer more comprehensive relief than either treatment alone, especially for conditions like panic disorder. ^{1 11 12 13 14}

Research Team

John Walkup, MD

Principal Investigator

Chair, Pritzker Department of Psychiatry and Behavioral Health

Eligibility Criteria

This trial is for children and teens aged 7-17 with separation anxiety, generalized anxiety, or social anxiety. They must be medically cleared and have a primary caretaker involved. It's not for those with certain severe psychiatric disorders, major medical illnesses that could interfere, or if they're pregnant without using birth control.

Inclusion Criteria

I am between 7 and 17 years old.

I have been diagnosed with anxiety disorder (SAD, GAD, or SocAD) confirmed by an interview.

An available primary caretaker with ongoing patient contact who can legally provide consent

Exclusion Criteria

Patients with lifetime psychiatric disorders: moderate to severe autism, bipolar disorder, schizophrenia, or schizoaffective disorder, history of intellectual disability

Patients with major medical illness that would interfere with study participation

Patients posing significant and imminent risk to self or others

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive either CBT only or CBT combined with an SSRI for 6 months

6 months

Up to 20 therapy sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Regular follow-up visits

Treatment Details

Interventions

• Cognitive Behavioral Therapy (CBT)
• Combination therapy (COMB)
• Escitalopram
• Fluoxetine
• Sertraline

Trial Overview The study tests whether Cognitive Behavioral Therapy (CBT) alone or combined with an SSRI (fluoxetine, sertraline, escitalopram) is more effective in treating pediatric anxiety. The CBT will last 6 months with increased family involvement and exposure sessions followed by a 6-month follow-up.

Participant Groups

Group I: Combination therapy (COMB) Active Control 2 Interventions

Participants randomized to this arm will receive cognitive behavioral therapy and one of three study medications (fluoxetine, sertraline, or escitalopram).

Group II: Cognitive behavioral therapy (CBT) Active Control 1 Intervention

Participants randomized to this arm will receive cognitive behavioral therapy (CBT) only

Cognitive Behavioral Therapy (CBT) is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Cognitive Behavioral Therapy for:

• Chronic pain
• Anxiety disorders
• Depressive disorders
• Trauma-related disorders

Approved in European Union as Cognitive Behavioural Therapy for:

• Chronic pain
• Anxiety disorders
• Depressive disorders
• Trauma-related disorders

Approved in Canada as Cognitive Behavioral Therapy for:

• Chronic pain
• Anxiety disorders
• Depressive disorders
• Trauma-related disorders

Who Is Running the Clinical Trial?

Ann & Robert H Lurie Children's Hospital of Chicago

Lead Sponsor

Trials

275

Recruited

5,182,000+

University of Cincinnati

Collaborator

Trials

442

Recruited

639,000+

University of California, Los Angeles

Collaborator

Trials

1,594

Recruited

10,430,000+

Findings from Research

Patients with panic disorder showed a significant reduction in panic attack frequency with all treatment options (Cognitive Behavioral Therapy, SSRIs, and combined CBT+SSRI) over a year-long study involving randomized treatment groups.

The combination of CBT and SSRIs led to a faster rate of improvement in panic frequency, especially for patients with moderate to severe agoraphobia, while SSRIs alone were effective for those with mild symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rate of improvement during and across three treatments for panic disorder with or without agoraphobia: cognitive behavioral therapy, selective serotonin reuptake inhibitor or both combined. Van Apeldoorn, FJ., Van Hout, WJ., Timmerman, ME., et al.[2022]

Cognitive Behavioral Therapy (CBT) is highly effective for treating various mood and anxiety disorders in adults, showing equal or superior efficacy compared to medication for conditions like major depressive disorder and generalized anxiety disorder.

While CBT demonstrates good long-term effectiveness, access to this therapy is limited, and research on the benefits of combining CBT with medication is still in early stages, making it difficult to draw definitive conclusions about combined treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of cognitive behavioral therapy in the treatment of mood and anxiety disorders in adults]. Sighvatsson, MB., Kristjánsdottir, H., Sigurdsson, E., et al.[2020]

In a study of 150 patients with panic disorder, all treatment groups (CBT, SSRI, and CBT + SSRI) showed significant improvements in anxiety and coping levels, with these gains maintained even after treatment ended.

While CBT + SSRI and SSRI showed slightly better initial results compared to CBT alone, by the follow-up periods, all treatments had similar long-term effectiveness, indicating that CBT is a viable standalone option despite slower initial progress.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized trial of cognitive-behavioral therapy or selective serotonin reuptake inhibitor or both combined for panic disorder with or without agoraphobia: treatment results through 1-year follow-up. van Apeldoorn, FJ., Timmerman, ME., Mersch, PP., et al.[2022]

In a study involving 24 female children and adolescents aged 10 to 17, both groups receiving trauma-focused cognitive-behavioral therapy (TF-CBT) showed significant improvements in PTSD symptoms after 12 weeks, regardless of whether they also received the selective serotonin reuptake inhibitor sertraline or a placebo.

The addition of sertraline provided minimal additional benefits over TF-CBT alone, suggesting that psychotherapy should be the first line of treatment for children with PTSD before considering medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot randomized controlled trial of combined trauma-focused CBT and sertraline for childhood PTSD symptoms. Cohen, JA., Mannarino, AP., Perel, JM., et al.[2022]

In a study of 150 patients with panic disorder, the combination of cognitive-behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRI) was found to be more effective than CBT alone after 9 months of treatment.

While both CBT and SSRI were effective on their own, the differences in effectiveness between the combined treatment (CBT + SSRI) and SSRI alone were minimal, indicating that both approaches can be beneficial for treating panic disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is a combined therapy more effective than either CBT or SSRI alone? Results of a multicenter trial on panic disorder with or without agoraphobia. van Apeldoorn, FJ., van Hout, WJ., Mersch, PP., et al.[2022]

In a pilot study involving ten Khmer-speaking women with PTSD, combining sertraline (an antidepressant) with cognitive-behavior therapy (CBT) showed medium to large effect sizes in improving PTSD symptoms compared to sertraline alone.

The study suggests that integrating CBT, which includes information, exposure, and cognitive restructuring, can be effectively adapted for Cambodian refugees, leading to significant treatment benefits for those who have not responded to medication alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of pharmacotherapy-refractory posttraumatic stress disorder among Cambodian refugees: a pilot study of combination treatment with cognitive-behavior therapy vs sertraline alone. Otto, MW., Hinton, D., Korbly, NB., et al.[2019]

In a study of 36 adults with PTSD, combining sertraline (an SSRI) with mirtazapine resulted in a significantly higher remission rate and greater improvement in depressive symptoms compared to sertraline plus placebo over 24 weeks.

Both treatment options were well-tolerated, with the combined treatment showing some increased appetite but no significant weight gain, suggesting it may be a viable option for improving symptoms in PTSD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

COMBINED MIRTAZAPINE AND SSRI TREATMENT OF PTSD: A PLACEBO-CONTROLLED TRIAL. Schneier, FR., Campeas, R., Carcamo, J., et al.[2022]

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 176 veterans, changes in negative posttraumatic thoughts were linked to reductions in PTSD symptoms when participants received sertraline, indicating that medication can influence the relationship between thoughts and symptoms.

The findings suggest a bidirectional relationship between PTSD symptoms and negative thoughts when treated with sertraline, but this association was not present when prolonged exposure therapy was combined with a placebo, highlighting the potential impact of medication on treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Change in posttraumatic stress disorder-related thoughts during treatment: Do thoughts drive change when pills are involved? Rauch, SAM., Kim, HM., Venners, MR., et al.[2023]

Citalopram is an effective selective serotonin re-uptake inhibitor (SSRI) that has shown antidepressant efficacy in multiple controlled clinical trials, making it a reliable treatment for depression.

Beyond depression, citalopram also benefits patients with various conditions related to serotonergic dysfunction, such as anxiety, panic disorder, and obsessive-compulsive disorder, indicating its broad therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Citalopram: a comprehensive review. Pollock, BG.[2022]

Combining cognitive-behavioral therapy (CBT) with pharmacotherapy did not show a clear advantage over CBT alone for treating obsessive-compulsive disorder, social phobia, and generalized anxiety disorder, based on a review of ten randomized trials.

For panic disorder, combined treatment showed some benefits over CBT alone immediately after treatment, but it was linked to a higher risk of relapse once treatment stopped, indicating that the effectiveness of combined therapies may differ depending on the specific anxiety disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Context in the clinic: how well do cognitive-behavioral therapies and medications work in combination? Foa, EB., Franklin, ME., Moser, J.[2019]

Comorbidity of anxiety and depression is very common, and patients with both conditions often experience poorer treatment outcomes and increased healthcare utilization, highlighting the need for effective management strategies.

Combination treatment with benzodiazepines and SSRIs/SNRIs may enhance treatment outcomes for patients with comorbid anxiety and depression, particularly by improving the speed and overall response to therapy, despite limited controlled research on this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination treatment with benzodiazepines and SSRIs for comorbid anxiety and depression: a review. Dunlop, BW., Davis, PG.[2021]

The combination of pharmacotherapy and behavior therapy led to significant improvement in two patients with panic disorder, agoraphobia, depressive disorder, and alcohol abuse, highlighting the potential effectiveness of integrated treatment approaches.

These case histories suggest that understanding both the theoretical and practical aspects of panic disorders can enhance treatment outcomes, indicating a need for comprehensive care strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Integrated treatment strategies in panic disorder with agoraphobia and depressive disorder]. Boerner, RJ.[2013]

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]

References

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[Efficacy of cognitive behavioral therapy in the treatment of mood and anxiety disorders in adults]. [2020]

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A randomized trial of cognitive-behavioral therapy or selective serotonin reuptake inhibitor or both combined for panic disorder with or without agoraphobia: treatment results through 1-year follow-up. [2022]

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A pilot randomized controlled trial of combined trauma-focused CBT and sertraline for childhood PTSD symptoms. [2022]

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Is a combined therapy more effective than either CBT or SSRI alone? Results of a multicenter trial on panic disorder with or without agoraphobia. [2022]

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Treatment of pharmacotherapy-refractory posttraumatic stress disorder among Cambodian refugees: a pilot study of combination treatment with cognitive-behavior therapy vs sertraline alone. [2019]

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COMBINED MIRTAZAPINE AND SSRI TREATMENT OF PTSD: A PLACEBO-CONTROLLED TRIAL. [2022]

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

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Change in posttraumatic stress disorder-related thoughts during treatment: Do thoughts drive change when pills are involved? [2023]

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Citalopram: a comprehensive review. [2022]

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Context in the clinic: how well do cognitive-behavioral therapies and medications work in combination? [2019]

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Combination treatment with benzodiazepines and SSRIs for comorbid anxiety and depression: a review. [2021]

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