Therapies for Treatment-Resistant Panic Disorder Symptoms

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00118417
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 46
• Location: 1
• Arms: 2
• Duration (Months): 103
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This study will determine the effectiveness of different treatments for panic disorder symptoms in individuals who still have symptoms after initial treatment with medication.

Condition or Disease	Intervention/Treatment	Phase
Panic Disorder	Drug: Clonazepam; Drug: Sertraline; Behavioral: Cognitive behavioral therapy	Phase 2/Phase 3

Detailed Description

Panic disorder is a serious condition that may cause significant psychological and physical distress. Many patients with panic disorder remain symptomatic despite initial intervention. Unfortunately, little data is available to guide health care providers in "next-step" treatment approaches. This study will evaluate the effectiveness of treatments for individuals with panic disorder that is resistant to initial treatment with selective serotonin reuptake inhibitors (SSRIs).

This study will last 24 weeks and will comprise three phases. In Phase 1, participants will receive the SSRI sertraline for 6 weeks. Phase 1 will be used to determine participants' resistance to treatment. During Phase 1, participants will begin a medication schedule and symptom diary and will have weekly study visits to assess regimen adherence and any side effects they may be experiencing. In Phase 2, participants will be randomly assigned to 6 weeks of one of two treatments: sertraline at an elevated dose from that given in Phase 1 or a sertraline and placebo regimen. During Phase 2, participants will have 3 study visits. Self-report scales and diary entries will be used to assess panic disorder symptoms and medication side effects. In Phase 3, participants will be randomly assigned to receive either cognitive behavioral therapy (CBT) or sertraline and clonazepam for 12 weeks. All participants will have weekly study visits during Phase 3. Questionnaires and self-report scales will be used to assess participants at the end of Phase 3.

Study hypothesis: Combined selective serotonin reuptake inhibitors (SSRIs) and benzodiazepine treatment, increasing the dose of SSRI, and the addition of cognitive behavioral therapy (CBT) each may have benefits for patients with panic disorder who remain symptomatic after initial treatment with SSRIs.

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Treatment Refractory Panic Disorder
• Study Start Date: Mar 1, 1999
• Actual Primary Completion Date: Oct 1, 2007
• Actual Study Completion Date: Oct 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Participants in phase II will receive sertraline, or an equivalent medication, up to 100 mg plus a placebo pill. Participants in phase III will receive the same medication with cognitive behavioral therapy.	Drug: Sertraline; Participants will receive sertraline.; Behavioral: Cognitive behavioral therapy; Participants will receive cognitive behavioral therapy
Experimental: 2 Participants in phase II will receive sertraline, or equivalent medication, up to 200 mg. Participants in phase III they will receive the same medication with flexible clonazepam augmentation.	Drug: Clonazepam; Participants will receive clonazepam.; Drug: Sertraline; Participants will receive sertraline.

Outcome Measures

Primary Outcome Measures

1. Change in Panic Disorder Symptoms, Phase 1 (Week 0 - Week 6) [Measured at baseline and after Phase 1 (6 weeks)]

   This measure is the change in points between baseline and endpoint scores on the Panic Disorder Severity Scale (PDSS). The PDSS is a 7-item scale with each item rated from 0 (none) to 4 (extreme), for a total score range of 0 to 28 points, and an established interrater reliability of 0.87.

2. Change in Panic Disorder Symptoms, Phase 2 (Week 6 - Week 12) [Measured after Phase 1 (Week 6) and Phase 2 (Week 12)]

   This measure is the change in points between baseline and endpoint scores on the Panic Disorder Severity Scale (PDSS). The PDSS is a 7-item scale with each item rated from 0 (none) to 4 (extreme), for a total score range of 0 to 28 points, and an established interrater reliability of 0.87.

3. Change in Panic Disorder Symptoms, Phase 3 (Week 12 - Week 24) [Measured after Phase 2 (Week 12) and Phase 3 (Week 24)]

   This measure is the change in points between baseline and endpoint scores on the Panic Disorder Severity Scale (PDSS). The PDSS is a 7-item scale with each item rated from 0 (none) to 4 (extreme), for a total score range of 0 to 28 points, and an established interrater reliability of 0.87.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of panic disorder

Exclusion Criteria:

• History of bipolar disorder, schizophrenia, psychosis, or delusional disorders

• Post-traumatic stress disorder diagnosis within 6 months prior to study entry

• Current use of psychotropic medications

• Current use of cognitive behavioral therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114

Sponsors and Collaborators

• Massachusetts General Hospital
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Naomi M. Simon, MD, MSc, Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Naomi M. Simon, Director, Center for Anxiety and Traumatic Stress Disorders, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00118417
• Other Study ID Numbers: K23MH001831; K23MH001831; DSIR AT-CD
• First Posted: Jul 11, 2005
• Last Update Posted: Jun 11, 2014
• Last Verified: Jun 1, 2014

• Keywords provided by Naomi M. Simon, Director, Center for Anxiety and Traumatic Stress Disorders, Massachusetts General Hospital: Selective serotonin reuptake inhibitor; Anxiety; Pharmacotherapy; Cognitive behavioral therapy; CBT
• Additional relevant MeSH terms: Panic Disorder; Clonazepam; Sertraline

Study Results

Participant Flow

Recruitment Details	Participants were recruited by advertisement and referral to research at the Center for Anxiety and Traumatic Stress Related Disorders at Massachusetts General Hospital.
Pre-assignment Detail	46 participants enrolled, but four participants were lost prior to Phase 1, two due to alcohol abuse and two due to follow-up. Participants were not randomized until the start of Phase 2.

Arm/Group Title	Sertraline / Increased Dose / Medication Optimization	Sertraline / + Placebo / Cognitive Behavior Therapy Augment.
Arm/Group Description	In Phase 1, this group will receive a moderate dose of sertraline (or escitalopram, an equivalent SSRI); In Phase 2, this group will receive an increased dosage of their SSRI; In Phase 3, this group will receive medication optimization, which includes an SSRI and clonazepam	In Phase 1, this group will receive a moderate dose of sertraline (or escitalopram, an equivalent SSRI); In Phase 2, this group will receive their SSRI plus a placebo; In Phase 3, this group will receive their SSRI plus cognitive behavioral therapy (CBT)
Period Title: Phase I (Weeks 0 to 6)
STARTED	39	0
COMPLETED	21	0
NOT COMPLETED	18	0
Period Title: Phase I (Weeks 0 to 6)
STARTED	11	13
COMPLETED	9	10
NOT COMPLETED	2	3
Period Title: Phase I (Weeks 0 to 6)
STARTED	9	10
COMPLETED	8	9
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description
Overall Participants	42
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	42 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.7 (11.2)
Sex: Female, Male (Count of Participants)
Female	24 57.1%
Male	18 42.9%
Region of Enrollment (participants) [Number]
United States	42 100%

Outcome Measures

1. Primary Outcome

Title	Change in Panic Disorder Symptoms, Phase 1 (Week 0 - Week 6)
Description	This measure is the change in points between baseline and endpoint scores on the Panic Disorder Severity Scale (PDSS). The PDSS is a 7-item scale with each item rated from 0 (none) to 4 (extreme), for a total score range of 0 to 28 points, and an established interrater reliability of 0.87.
Time Frame	Measured at baseline and after Phase 1 (6 weeks)

Outcome Measure Data

Analysis Population Description

Analyses in each study phase were for a modified intent to treat (ITT) sample, defined as all participants who had at least one on-treatment assessment during that phase.

Arm/Group Title	Moderate Sertraline Treatment
Arm/Group Description	This group will receive moderate sertraline or escitalopram treatment
Measure Participants	39
Mean (Standard Deviation) [Points on a scale]	4.3 (4.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate Sertraline Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0000
	Comments	Paired t-test between endpoint and baseline PDSS
	Method	t-test, 2 sided
	Comments	Degrees of Freedom = 38

2. Primary Outcome

Title	Change in Panic Disorder Symptoms, Phase 2 (Week 6 - Week 12)
Description	This measure is the change in points between baseline and endpoint scores on the Panic Disorder Severity Scale (PDSS). The PDSS is a 7-item scale with each item rated from 0 (none) to 4 (extreme), for a total score range of 0 to 28 points, and an established interrater reliability of 0.87.
Time Frame	Measured after Phase 1 (Week 6) and Phase 2 (Week 12)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Increased Sertraline	Sertraline Plus Placebo
Arm/Group Description	This group will receive an increased dosage of sertraline or escitalopram	This group will receive sertraline or escitalopram with a placebo
Measure Participants	11	13
Mean (Standard Deviation) [Points on a scale]	2.36 (3.44)	2.31 (4.29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate Sertraline Treatment, Sertraline Plus Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.97
	Comments	T-test of PDSS change score
	Method	t-test, 2 sided
	Comments	Degrees of Freedom = 22

3. Primary Outcome

Title	Change in Panic Disorder Symptoms, Phase 3 (Week 12 - Week 24)
Description	This measure is the change in points between baseline and endpoint scores on the Panic Disorder Severity Scale (PDSS). The PDSS is a 7-item scale with each item rated from 0 (none) to 4 (extreme), for a total score range of 0 to 28 points, and an established interrater reliability of 0.87.
Time Frame	Measured after Phase 2 (Week 12) and Phase 3 (Week 24)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Medication Optimization	Augmented Cognitive Behavior Therapy
Arm/Group Description	This group will receive medication optimization, which includes sertraline or escitalopram with clonazepam	This group will receive sertraline or escitalopram with cognitive behavioral therapy (CBT)
Measure Participants	9	10
Mean (Standard Deviation) [Points on a scale]	3.78 (3.80)	2.9 (3.63)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate Sertraline Treatment, Sertraline Plus Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.061
	Comments	T-test of PDSS change between baseline and endpoint of Phase 3
	Method	t-test, 2 sided
	Comments	Degrees of Freedom = 17

Adverse Events

Arm/Group Title	Phase I: Sertraline		Phase II: Cont. SSRI Plus Placebo OR Increased Dose SSRI Alone		Phase III: Cont. Medication Plus CBT OR SSRI and Clonazepam
Arm/Group Description	In Phase 1, this group will receive a moderate dose of sertraline (or escitalopram, an equivalent SSRI).
All Cause Mortality
	Phase I: Sertraline		Phase II: Cont. SSRI Plus Placebo OR Increased Dose SSRI Alone		Phase III: Cont. Medication Plus CBT OR SSRI and Clonazepam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Phase I: Sertraline		Phase II: Cont. SSRI Plus Placebo OR Increased Dose SSRI Alone		Phase III: Cont. Medication Plus CBT OR SSRI and Clonazepam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/39 (5.1%)		0/24 (0%)		3/19 (15.8%)
General disorders
Patient admitted to inpatient rehabiliation center for alcohol abuse	0/39 (0%)	0	0/24 (0%)	0	2/19 (10.5%)	2
Patient admitted to the hospital after experiencing symptoms similar to panic attacks.	1/39 (2.6%)	1	0/24 (0%)	0	0/19 (0%)	0
Patient was in a motorcycle accident of unknown etiology	0/39 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1
Patient was found to have blockage of one cardiac vessel	1/39 (2.6%)	1	0/24 (0%)	0	0/19 (0%)	0
Other (Not Including Serious) Adverse Events
	Phase I: Sertraline		Phase II: Cont. SSRI Plus Placebo OR Increased Dose SSRI Alone		Phase III: Cont. Medication Plus CBT OR SSRI and Clonazepam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/39 (84.6%)		21/24 (87.5%)		15/19 (78.9%)
Gastrointestinal disorders
Gastrointestinal distress	19/39 (48.7%)	19	7/24 (29.2%)	7	6/19 (31.6%)	6
General disorders
Headache	16/39 (41%)	16	7/24 (29.2%)	7	6/19 (31.6%)	6
Nausea or Vomiting	15/39 (38.5%)	15	0/24 (0%)	0	0/19 (0%)	0
Jitteriness or Restlesness	12/39 (30.8%)	12	4/24 (16.7%)	4	0/19 (0%)	0
Insomnia	11/39 (28.2%)	11	4/24 (16.7%)	4	0/19 (0%)	0
Sedation	0/39 (0%)	0	6/24 (25%)	6	4/19 (21.1%)	4
Dizziness	0/39 (0%)	0	0/24 (0%)	0	3/19 (15.8%)	3

Limitations/Caveats

Power in Phase 2 limited detection to a large effect size. High drop-out for increased SSRI dose may indicate poor tolerability. Effectiveness of adding an SSRI to initial CBT was unexamined, limiting generalization to community treatment decisions.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.