Combined Treatment for Generalized Anxiety Disorder (GAD)

• Sponsor: University of Pennsylvania (Other)
• Overall Status: Completed
• CT.gov ID: NCT00620776
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 69
• Location: 1
• Arms: 2
• Duration (Months): 17
• Patients Per Site Per Month: 4.1

Study Details

Study Description

Brief Summary

The purpose of this study is to conduct a preliminary evaluation of the efficacy of combined medication and psychotherapy for generalized anxiety disorder (GAD). The general goals of the current study are to conduct a late stage treatment development study. The goal of this stage of research is to provide a preliminary answer to the question and to gather data to estimate intervention parameters (e.g., effect size, attrition rates, response rates) that would assist in planning further research.

Condition or Disease	Intervention/Treatment	Phase
Generalized Anxiety Disorder	Behavioral: Cognitive Behavioral Therapy; Drug: Venlafaxine XR	Phase 2

Detailed Description

The specific aims of this study are to collect preliminary data relevant to the following hypotheses:

1. Primary Hypothesis: Acute phase improvement for combined cognitive behavioral therapy (CBT) plus medication will be superior to medication alone.

2. Secondary Hypotheses: Combined CBT plus medication will be superior to medication alone on a number of secondary outcome measures, including the core feature of GAD (worry), depressive symptoms, functional impairment, and quality of life.

3. Additional Exploratory Aim: We will explore the comparative relapse rates for the combined CBT plus medication treatment and the medication alone treatment condition at 6-month follow-up.

Study Design

• Study Type: Interventional
• Actual Enrollment: 69 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Combined Treatment for Generalized Anxiety Disorder (GAD)
• Study Start Date: Oct 1, 2006
• Actual Primary Completion Date: Mar 1, 2008
• Actual Study Completion Date: Mar 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Combined Treatment Patients who receive combined cognitive behavioral therapy (CBT) plus medication (venlafaxine XR, flexibly dosed between 75-225 mg/day) treatment for GAD. CBT was once/week sessions for 12 weeks. Medication continued for the full 6 months.	Behavioral: Cognitive Behavioral Therapy; This cognitive behavioral therapy for GAD has a cognitive restructuring component and an applied relaxation component. Patients will be educated about the nature of anxiety and be trained in the recognition and monitoring of situational, physiological, cognitive, and behavioral cues associated with anxious responding. They will be guided through copings skill rehearsals in addition to imaginal and in vivo exposure to anxiety cues. This cognitive behavioral treatment will consist of 1 to 1.5 hour sessions of psychotherapy, which will be held once weekly over a period of 12 weeks.; Drug: Venlafaxine XR; Venlafaxine XR, 75-225 mg/d, oral administration. 14 days at 75 mg/d, 150 mg/d for the remaining 6 months, 225 mg/3 for patients unimproved at week 6, tapered at 75 mg/week (this intervention is provided by protocol 709012).; Other Names: Effexor extended release
Active Comparator: Venlafaxine XR 75-225 mg alone These patients receive only medication treatment for GAD. Patients take venlafaxine (flexibly dosed from 75-225 mg/day) as part of NCT00183274 and are assessed over a 6 month period. Medication continued for the full 6 months.	Drug: Venlafaxine XR; Venlafaxine XR, 75-225 mg/d, oral administration. 14 days at 75 mg/d, 150 mg/d for the remaining 6 months, 225 mg/3 for patients unimproved at week 6, tapered at 75 mg/week (this intervention is provided by protocol 709012).; Other Names: Effexor extended release

Outcome Measures

Primary Outcome Measures

1. Hamilton Anxiety Rating Scale (HAM-A) [Data collected as part of protocol 709012 at baseline, week 2, 4, 6, 8, 12, 16, 20, and 24]

   The HAM-A was used to measure the severity of anxiety symptoms. The scale consists of 14 items; each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where <17 indicates mild severity, 18-24 mild to moderate and 25-30 moderate to severe anxiety. This measure was conducted by research psychiatrists trained and highly experienced in the use of these scales. The evaluators were blind to group assignment.

Secondary Outcome Measures

1. Hospital Anxiety Depression Scale (HAD)-Anxiety Score [Data collected as part of protocol 709012 at baseline, week 2, 4, 6, 8, 12, 16, 20, and 24]

   The HAD was used to assess patients' report of anxiety and depressive symptoms. Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for either anxiety or depression. A higher score indicates greater anxiety.

2. Hospital Anxiety Depression Scale (HAD)-Depression Score [Data collected as part of protocol 709012 at baseline, week 2, 4, 6, 8, 12, 16, 20, and 24]

   The HAD was used to assess patients' report of anxiety and depressive symptoms. Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for either anxiety or depression. A higher score indicates greater depression.

3. Hamilton Rating Scale for Depression (HAM-D)-17-item Score [Data collected as part of protocol 709012 at baseline, week 12, and week 24]

   The 17-item version of the HAM-D was used to assess severity of depressive symptoms. Eight items are scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine are scored from 0-2.The total score is the sum of the 17 items, with a range from 0 to 50. A higher scores indicates greater depression. The ratings were conducted by research psychiatrists trained and highly experienced in the use of these scales. The evaluators were blind to group assignment.

4. Clinical Global Impression (CGI)-Severity Score [Data collected as part of protocol 709012 at baseline, week 2, 4, 6, 8, 12, 16, 20, and 24]

   The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale (1=normal; 7 = extremely ill) that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. The ratings were conducted by research psychiatrists trained and highly experienced in the use of these scales. Evaluators were blind to group assignment.

5. Clinical Global Impression (CGI)-Improvement Score [Data collected as part of protocol 709012 at baseline, week 2, 4, 6, 8, 12, 16, 20, and 24]

   The Clinical Global Impression - Improvement scale (CGI-I) is a 7 point scale (1= very much improved; 7 = very much worse) that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. The ratings were conducted by research psychiatrists trained and highly experienced in the use of these scales. Evaluators were blind to group assignment.

6. Quality of Life Subscale of the General Health Questionnaire (GHQ) [Data collected as part of protocol 709012 at baseline, week 12, and week 24]

   The General Health Questionnaire (GHQ) is a psychometric screening tool to identify common psychiatric conditions. Patients completed the 12 quality of life questions (each on a 0 to 3 scale) on this questionnaire. Scores on the 12 items were added up to create summary score (range = 0 to 36). Higher scores indicate worse health.

7. Penn State Worry Questionnaire (PSWQ) [Data collected as part of protocol 709012 at baseline, week 12, and week 24]

   The Penn State Worry Questionaire is a 16-item inventory that aims to measure the trait of worry, using Likert rating from 1 (not at all typical of me) to 5 (very typical of me). A total score is calculated (range = 16 to 80), with higher scores indicating greater worry.

8. Physical Component Score of the 12-Item Short Form Survey (SF-12) [Data collected as part of protocol 709012 at baseline, week 12, and week 24]

   The Short Form (12) Health Survey is a 12-item, patient-reported survey of patient health. Physical and Mental Health Component Scores (PCS & MCS) are computed using the scores of twelve questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health.

9. Mental Component Score of the 12-item Short Form Survey (SF-12) [Data collected as part of protocol 709012 at baseline, week 12, and week 24]

   The Short Form (12) Health Survey is a 12-item, patient-reported survey of patient health. Physical and Mental Health Component Scores (PCS & MCS) are computed using the scores of twelve questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health.

10. Clinical Response Rate [Data collected as part of protocol 709012 at baseline, week 2, 4, 6, 8, 12, 16, 20, and 24]

    Clinical response on the HAM-A was defined as a 50% or greater reduction from baseline to last value with the 24-week open label medication phase.

11. 50 Percent or Greater Reduction in PSWQ Score [Data collected as part of protocol 709012 at baseline, week 12, and week 24]

    Clinically significant change was defined on the PSWQ as an estimated (based on linear mixed effects model) endpoint score of less than 50.9. This score was calculated using the PSWQ normative data provided by Gillis, Haaga, and Ford (1995) and the baseline PSWQ mean and standard deviation (SD) from the current sample. The PSWQ mean and SD from the normative and current GAD samples were entered into the Jacobson et al. (1984) formula "c" for clinically significant change. This method provides a cutoff indicating whether or not the level of functioning by a patient is statistically more likely to be in the functional rather than the dysfunctional population.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• GAD diagnosis by structured interview

• Hamilton Anxiety Scale score of 18 or less

• Clinical Global Impressions Scale score of at least 4

• Hamilton Depression Scale score of 18 or less

• Hamilton Depression Scale suicide item score less than 2

• Use of an effective form of contraception throughout the s

Exclusion Criteria:

• Hypersensitivity to venlafaxine XR

• History of seizures

• Episode of major depressive disorder in the previous 6 months

• History of any psychotic illness, bipolar disorder, or dementia

• Substance abuse and dependence during the past 6 months

• Other anxiety disorders with the exception of social phobia as long as GAD is primary

• Regular use of anxiolytics or antidepressants within 7 days of study onset

• Use of fluoxetine or monoamine oxidase inhibitors within 28 days of study onset (low dose usage of benzodiazepines will not prevent participation)

• Use of other psychotic medication besides benzodiazepines

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pennsylvania, 3535 Market Street, Suite 650	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• University of Pennsylvania
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Paul Crits-Christoph, PhD, University of Pennsylvania

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Paul Crits-Christoph, Professor of Psychology in Psychiatry, University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT00620776
• Other Study ID Numbers: 802307; 5R34MH072678-02
• First Posted: Feb 21, 2008
• Last Update Posted: Feb 16, 2017
• Last Verified: Dec 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Paul Crits-Christoph, Professor of Psychology in Psychiatry, University of Pennsylvania: Generalized Anxiety Disorder; Cognitive Behavioral Therapy; Psychotherapy plus medication; Combined treatment
• Additional relevant MeSH terms: Disease; Anxiety Disorders; Venlafaxine Hydrochloride

Study Results

Participant Flow

Recruitment Details	Three hundred thirty four patients enrolled in the first phase (6-month open-label) of a parent medication trial for GAD (NCT00183274) were recruited and seen in one of four primary care practices or a psychopharmacology clinic in a university setting from 2005 to 2009. The current study was conducted from October, 2006 to March, 2008.
Pre-assignment Detail	Of 334 patients who consented to the parent trial, 66 did not receive study drug (64 withdrew consent and 2 were protocol violators), leaving 268 who received at least one dose of open-label venlafaxine XR. For this study, 77 patients were randomly assigned to be offered CBT and 40 patients to not be offered CBT.

Arm/Group Title	Combined Treatment	Medication Alone
Arm/Group Description	Patients received Venlafaxine XR (75-225 mg/d) plus 12 weeks of CBT (one 1 to 1.5 hour session per week) for GAD over a period of 6 months.	Patients received Venlafaxine XR (75-225 mg/d) alone as treatment for GAD over a period of 6 months.
Period Title: Overall Study
STARTED	29	40
Received at Least One Session/Dose	26	35
COMPLETED	17	24
NOT COMPLETED	12	16

Baseline Characteristics

Arm/Group Title	Combined Treatment	Medication Alone	Total
Arm/Group Description	Patients received Venlafaxine XR (75-225 mg/d) plus 12 weeks of CBT (one 1 to 1.5 hour session per week) for GAD over a period of 6 months.	Patients received Venlafaxine XR (75-225 mg/d) alone as treatment for GAD over a period of 6 months.	Total of all reporting groups
Overall Participants	26	35	61
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.5 (16.0)	46.6 (19.8)	47.0 (18.3)
Gender (Count of Participants)
Female	17 65.4%	18 51.4%	35 57.4%
Male	9 34.6%	17 48.6%	26 42.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 7.7%	0 0%	2 3.3%
Not Hispanic or Latino	24 92.3%	35 100%	59 96.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 3.8%	0 0%	1 1.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	8 30.8%	10 28.6%	18 29.5%
White	17 65.4%	25 71.4%	42 68.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	26 100%	35 100%	61 100%

Outcome Measures

1. Primary Outcome

Title	Hamilton Anxiety Rating Scale (HAM-A)
Description	The HAM-A was used to measure the severity of anxiety symptoms. The scale consists of 14 items; each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where <17 indicates mild severity, 18-24 mild to moderate and 25-30 moderate to severe anxiety. This measure was conducted by research psychiatrists trained and highly experienced in the use of these scales. The evaluators were blind to group assignment.
Time Frame	Data collected as part of protocol 709012 at baseline, week 2, 4, 6, 8, 12, 16, 20, and 24

Outcome Measure Data

Analysis Population Description

Number analyzed at various time points differ due to patient dropout.

Arm/Group Title	Combined Treatment	Medication Alone
Arm/Group Description	Patients received Venlafaxine XR (75-225 mg/d) plus 12 weeks of CBT (one 1 to 1.5 hour session per week) for GAD over a period of 6 months.	Patients received Venlafaxine XR (75-225 mg/d) alone as treatment for GAD over a period of 6 months.
Measure Participants	26	35
Baseline	25.9 (2.6)	23.8 (2.7)
Week 2	20.9 (5.0)	19.4 (5.1)
Week 4	17.3 (5.6)	14.7 (5.6)
Week 6	13.5 (6.5)	10.9 (5.5)
Week 8	12.7 (7.5)	7.8 (6.0)
Week 12	10.8 (7.2)	5.9 (4.3)
Week 16	8.1 (6.9)	4.3 (3.1)
Week 20	6.2 (5.5)	4.3 (3.2)
Week 24	6.5 (5.4)	3.4 (1.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Treatment, Medication Alone
	Comments	Mixed model analysis (differential slopes over time) comparing the 26 patients who received combined treatment with at least one CBT session to the 35 patients randomized to venlafaxine XR alone (and received at least one dose) on HAM-A total scores. Only available scores were used (no imputation for missing data). Because the HAM-A demonstrated a relatively rapid improvement early in treatment and then a leveling off, a shifted log-transformation of time of assessment was implemented.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.17
	Comments
	Method	Mixed Models Analysis
	Comments

2. Secondary Outcome

Title	Hospital Anxiety Depression Scale (HAD)-Anxiety Score
Description	The HAD was used to assess patients' report of anxiety and depressive symptoms. Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for either anxiety or depression. A higher score indicates greater anxiety.
Time Frame	Data collected as part of protocol 709012 at baseline, week 2, 4, 6, 8, 12, 16, 20, and 24

Outcome Measure Data

Analysis Population Description

Numbers analyzed at various time points differ due to patient dropout.

Arm/Group Title	Combined Treatment	Medication Alone
Arm/Group Description	Patients received Venlafaxine XR (75-225 mg/d) plus 12 weeks of CBT (one 1 to 1.5 hour session per week) for GAD over a period of 6 months.	Patients received Venlafaxine XR (75-225 mg/d) alone as treatment for GAD over a period of 6 months.
Measure Participants	26	35
Baseline	13.6 (3.4)	13.0 (4.2)
Week 2	11.7 (4.8)	10.9 (5.1)
Week 4	10.9 (4.5)	8.3 (5.0)
Week 6	9.2 (4.7)	7.1 (4.6)
Week 8	9.0 (4.7)	5.7 (4.1)
Week 12	6.9 (4.3)	4.1 (3.4)
Week 16	6.9 (5.2)	4.6 (3.4)
Week 20	6.2 (4.6)	4.9 (3.6)
Week 24	6.2 (3.3)	4.7 (4.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Treatment, Medication Alone
	Comments	Analyses were conducted using mixed effects models that tested for differential slopes over time between the CBT plus venlafaxine XR and venlafaxine XR alone groups using only available scores (no imputation for missing data).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.54
	Comments
	Method	Mixed Models Analysis
	Comments

3. Secondary Outcome

Title	Hospital Anxiety Depression Scale (HAD)-Depression Score
Description	The HAD was used to assess patients' report of anxiety and depressive symptoms. Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for either anxiety or depression. A higher score indicates greater depression.
Time Frame	Data collected as part of protocol 709012 at baseline, week 2, 4, 6, 8, 12, 16, 20, and 24

Outcome Measure Data

Analysis Population Description

Numbers analyzed at various time points differ due to patient dropout.

Arm/Group Title	Combined Treatment	Medication Alone
Arm/Group Description	Patients received Venlafaxine XR (75-225 mg/d) plus 12 weeks of CBT (one 1 to 1.5 hour session per week) for GAD over a period of 6 months.	Patients received Venlafaxine XR (75-225 mg/d) alone as treatment for GAD over a period of 6 months.
Measure Participants	26	35
Baseline	9.8 (5.7)	7.3 (3.4)
Week 2	8.5 (5.1)	6.8 (3.9)
Week 4	7.9 (5.1)	5.3 (3.8)
Week 6	6.3 (5.0)	4.5 (3.3)
Week 8	7.0 (5.3)	3.4 (3.3)
Week 12	5.5 (4.6)	2.9 (2.7)
Week 16	5.6 (4.9)	2.0 (2.3)
Week 20	4.3 (4.3)	2.1 (2.3)
Week 24	4.7 (3.9)	2.9 (3.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Treatment, Medication Alone
	Comments	Analyses were conducted using mixed effects models that tested for differential slopes over time between the CBT plus venlafaxine XR and venlafaxine XR alone groups using only available scores (no imputation for missing data).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.86
	Comments
	Method	Mixed Models Analysis
	Comments

4. Secondary Outcome

Title	Hamilton Rating Scale for Depression (HAM-D)-17-item Score
Description	The 17-item version of the HAM-D was used to assess severity of depressive symptoms. Eight items are scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine are scored from 0-2.The total score is the sum of the 17 items, with a range from 0 to 50. A higher scores indicates greater depression. The ratings were conducted by research psychiatrists trained and highly experienced in the use of these scales. The evaluators were blind to group assignment.
Time Frame	Data collected as part of protocol 709012 at baseline, week 12, and week 24

Outcome Measure Data

Analysis Population Description

Numbers analyzed at various time points differ due to patient dropout.

Arm/Group Title	Combined Treatment	Medication Alone
Arm/Group Description	Patients received Venlafaxine XR (75-225 mg/d) plus 12 weeks of CBT (one 1 to 1.5 hour session per week) for GAD over a period of 6 months.	Patients received Venlafaxine XR (75-225 mg/d) alone as treatment for GAD over a period of 6 months.
Measure Participants	26	35
Baseline	13.1 (2.2)	12.3 (2.8)
Week 12	7.0 (3.4)	3.9 (2.6)
Week 24	5.1 (4.0)	3.0 (1.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Treatment, Medication Alone
	Comments	Data collected at week 24 were analyzed using analysis of covariance (ANCOVA) with the baseline score as the covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.051
	Comments
	Method	ANCOVA
	Comments

5. Secondary Outcome

Title	Clinical Global Impression (CGI)-Severity Score
Description	The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale (1=normal; 7 = extremely ill) that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. The ratings were conducted by research psychiatrists trained and highly experienced in the use of these scales. Evaluators were blind to group assignment.
Time Frame	Data collected as part of protocol 709012 at baseline, week 2, 4, 6, 8, 12, 16, 20, and 24

Outcome Measure Data

Analysis Population Description

Number analyzed at each time point differs due to patient dropout.

Arm/Group Title	Combined Treatment	Medication Alone
Arm/Group Description	Patients received Venlafaxine XR (75-225 mg/d) plus 12 weeks of CBT (one 1 to 1.5 hour session per week) for GAD over a period of 6 months.	Patients received Venlafaxine XR (75-225 mg/d) alone as treatment for GAD over a period of 6 months.
Measure Participants	26	35
Baseline	4.7 (0.6)	4.7 (0.5)
Week 2	4.1 (0.6)	3.9 (0.7)
Week 4	3.6 (0.8)	3.2 (1.0)
Week 6	3.0 (1.0)	2.6 (1.0)
Week 8	2.9 (1.3)	1.9 (1.0)
Week 12	2.4 (1.1)	1.6 (0.7)
Week 16	2.1 (1.1)	1.4 (0.6)
Week 20	1.7 (0.9)	1.4 (0.6)
Week 24	1.8 (1.1)	1.2 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Treatment, Medication Alone
	Comments	Analyses were conducted using mixed effects models that tested for differential slopes over time between the CBT plus venlafaxine XR and venlafaxine XR alone groups using only available scores (no imputation for missing data).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.06
	Comments
	Method	ANCOVA
	Comments

6. Secondary Outcome

Title	Clinical Global Impression (CGI)-Improvement Score
Description	The Clinical Global Impression - Improvement scale (CGI-I) is a 7 point scale (1= very much improved; 7 = very much worse) that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. The ratings were conducted by research psychiatrists trained and highly experienced in the use of these scales. Evaluators were blind to group assignment.
Time Frame	Data collected as part of protocol 709012 at baseline, week 2, 4, 6, 8, 12, 16, 20, and 24

Outcome Measure Data

Analysis Population Description

Number analyzed at different time points varies due to patient dropout.

Arm/Group Title	Combined Treatment	Medication Alone
Arm/Group Description	Patients received Venlafaxine XR (75-225 mg/d) plus 12 weeks of CBT (one 1 to 1.5 hour session per week) for GAD over a period of 6 months.	Patients received Venlafaxine XR (75-225 mg/d) alone as treatment for GAD over a period of 6 months.
Measure Participants	26	35
Baseline	2.6 (1.9)	3.1 (1.7)
Week 2	3.3 (0.7)	3.2 (1.0)
Week 4	2.7 (0.9)	2.4 (0.8)
Week 6	2.4 (0.9)	2.0 (0.8)
Week 8	2.3 (1.2)	1.5 (0.8)
Week 12	1.9 (1.0)	1.4 (0.6)
Week 16	1.6 (0.8)	1.2 (0.4)
Week 20	1.4 (0.7)	1.2 (0.4)
Week 24	1.4 (0.6)	1.1 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Treatment, Medication Alone
	Comments	Analyses were conducted using mixed effects models that tested for differential slopes over time between the CBT plus venlafaxine XR and venlafaxine XR alone groups using only available scores (no imputation for missing data).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.95
	Comments
	Method	Mixed Models Analysis
	Comments

7. Secondary Outcome

Title	Quality of Life Subscale of the General Health Questionnaire (GHQ)
Description	The General Health Questionnaire (GHQ) is a psychometric screening tool to identify common psychiatric conditions. Patients completed the 12 quality of life questions (each on a 0 to 3 scale) on this questionnaire. Scores on the 12 items were added up to create summary score (range = 0 to 36). Higher scores indicate worse health.
Time Frame	Data collected as part of protocol 709012 at baseline, week 12, and week 24

Outcome Measure Data

Analysis Population Description

Number analyzed at different time points varies due to patient dropout.

Arm/Group Title	Combined Treatment	Medication Alone
Arm/Group Description	Patients received Venlafaxine XR (75-225 mg/d) plus 12 weeks of CBT (one 1 to 1.5 hour session per week) for GAD over a period of 6 months.	Patients received Venlafaxine XR (75-225 mg/d) alone as treatment for GAD over a period of 6 months.
Measure Participants	26	35
Baseline	34.5 (7.0)	32.2 (6.4)
Week 12	24.8 (7.3)	20.4 (5.2)
Week 24	23.8 (6.6)	22.9 (5.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Treatment, Medication Alone
	Comments	Data collected at week 24 were analyzed using ANCOVA with the baseline score as the covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.17
	Comments
	Method	ANCOVA
	Comments

8. Secondary Outcome

Title	Penn State Worry Questionnaire (PSWQ)
Description	The Penn State Worry Questionaire is a 16-item inventory that aims to measure the trait of worry, using Likert rating from 1 (not at all typical of me) to 5 (very typical of me). A total score is calculated (range = 16 to 80), with higher scores indicating greater worry.
Time Frame	Data collected as part of protocol 709012 at baseline, week 12, and week 24

Outcome Measure Data

Analysis Population Description

Number analyzed at different time points varies due to patient dropout.

Arm/Group Title	Combined Treatment	Medication Alone
Arm/Group Description	Patients received Venlafaxine XR (75-225 mg/d) plus 12 weeks of CBT (one 1 to 1.5 hour session per week) for GAD over a period of 6 months.	Patients received Venlafaxine XR (75-225 mg/d) alone as treatment for GAD over a period of 6 months.
Measure Participants	26	35
Baseline	61.8 (9.5)	57.9 (12.7)
Week 12	48.6 (11.8)	42.3 (13.0)
Week 24	46.4 (11.1)	45.1 (14.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Treatment, Medication Alone
	Comments	Data collected at week 24 were analyzed using ANCOVA with the baseline score as the covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.53
	Comments
	Method	ANCOVA
	Comments

9. Secondary Outcome

Title	Physical Component Score of the 12-Item Short Form Survey (SF-12)
Description	The Short Form (12) Health Survey is a 12-item, patient-reported survey of patient health. Physical and Mental Health Component Scores (PCS & MCS) are computed using the scores of twelve questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health.
Time Frame	Data collected as part of protocol 709012 at baseline, week 12, and week 24

Outcome Measure Data

Analysis Population Description

Number analyzed at different time points varies due to patient dropout.

Arm/Group Title	Combined Treatment	Medication Alone
Arm/Group Description	Patients received Venlafaxine XR (75-225 mg/d) plus 12 weeks of CBT (one 1 to 1.5 hour session per week) for GAD over a period of 6 months.	Patients received Venlafaxine XR (75-225 mg/d) alone as treatment for GAD over a period of 6 months.
Measure Participants	26	35
Baseline	46.1 (13.6)	52.7 (10.7)
Week 12	46.2 (12.5)	51.9 (6.9)
Week 24	45.5 (12.7)	49.7 (7.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Treatment, Medication Alone
	Comments	Data collected at week 24 were analyzed with ANCOVA with baseline data as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.23
	Comments
	Method	ANCOVA
	Comments

10. Secondary Outcome

Title	Mental Component Score of the 12-item Short Form Survey (SF-12)
Description	The Short Form (12) Health Survey is a 12-item, patient-reported survey of patient health. Physical and Mental Health Component Scores (PCS & MCS) are computed using the scores of twelve questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health.
Time Frame	Data collected as part of protocol 709012 at baseline, week 12, and week 24

Outcome Measure Data

Analysis Population Description

Number analyzed at different time points varies due to patient dropout.

Arm/Group Title	Combined Treatment	Medication Alone
Arm/Group Description	Patients received Venlafaxine XR (75-225 mg/d) plus 12 weeks of CBT (one 1 to 1.5 hour session per week) for GAD over a period of 6 months.	Patients received Venlafaxine XR (75-225 mg/d) alone as treatment for GAD over a period of 6 months.
Measure Participants	26	35
Baseline	28.5 (9.8)	31.4 (10.9)
Week 12	46.2 (12.6)	48.3 (9.5)
Week 24	45.5 (12.7)	49.8 (10.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Treatment, Medication Alone
	Comments	Data collected at week 24 were analyzed with ANCOVA including baseline data as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.07
	Comments
	Method	ANCOVA
	Comments

11. Secondary Outcome

Title	Clinical Response Rate
Description	Clinical response on the HAM-A was defined as a 50% or greater reduction from baseline to last value with the 24-week open label medication phase.
Time Frame	Data collected as part of protocol 709012 at baseline, week 2, 4, 6, 8, 12, 16, 20, and 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combined Treatment	Medication Alone
Arm/Group Description	Patients received Venlafaxine XR (75-225 mg/d) plus 12 weeks of CBT (one 1 to 1.5 hour session per week) for GAD over a period of 6 months.	Patients received Venlafaxine XR (75-225 mg/d) alone as treatment for GAD over a period of 6 months.
Measure Participants	26	35
Count of Participants [Participants]	17 65.4%	25 71.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Treatment, Medication Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.63
	Comments
	Method	Chi-squared
	Comments

12. Secondary Outcome

Title	50 Percent or Greater Reduction in PSWQ Score
Description	Clinically significant change was defined on the PSWQ as an estimated (based on linear mixed effects model) endpoint score of less than 50.9. This score was calculated using the PSWQ normative data provided by Gillis, Haaga, and Ford (1995) and the baseline PSWQ mean and standard deviation (SD) from the current sample. The PSWQ mean and SD from the normative and current GAD samples were entered into the Jacobson et al. (1984) formula "c" for clinically significant change. This method provides a cutoff indicating whether or not the level of functioning by a patient is statistically more likely to be in the functional rather than the dysfunctional population.
Time Frame	Data collected as part of protocol 709012 at baseline, week 12, and week 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combined Treatment	Medication Alone
Arm/Group Description	Patients received Venlafaxine XR (75-225 mg/d) plus 12 weeks of CBT (one 1 to 1.5 hour session per week) for GAD over a period of 6 months.	Patients received Venlafaxine XR (75-225 mg/d) alone as treatment for GAD over a period of 6 months.
Measure Participants	26	35
Count of Participants [Participants]	19 73.1%	28 80%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Treatment, Medication Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.52
	Comments
	Method	Chi-squared
	Comments

Adverse Events

Time Frame	Over the 6-month study period, adverse events were assessed at each visit (from week 2 up to week 24) using an open-ended approach, which was facilitated by the use of a physician-completed medication problem checklist.
Arm/Group Title	Combined Treatment		Medication Alone
Arm/Group Description	Patients received Venlafaxine XR (75-225 mg/d) plus 12 weeks of CBT (one 1 to 1.5 hour session per week) for GAD over a period of 6 months.		Patients received Venlafaxine XR (75-225 mg/d) alone as treatment for GAD over a period of 6 months.
All Cause Mortality
	Combined Treatment		Medication Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Combined Treatment		Medication Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/26 (15.4%)		4/35 (11.4%)
Eye disorders
Severe Vision Impairment	1/26 (3.8%)		0/35 (0%)
Gastrointestinal disorders
Severe Constipation	0/26 (0%)		1/35 (2.9%)
General disorders
Severe Fatigue	2/26 (7.7%)		0/35 (0%)
Severe Migraine	0/26 (0%)		1/35 (2.9%)
Severe Impact on Libido	0/26 (0%)		1/35 (2.9%)
Infections and infestations
Pneumonia	1/26 (3.8%)		0/35 (0%)
Skin and subcutaneous tissue disorders
Severe Rash	0/26 (0%)		1/35 (2.9%)
Other (Not Including Serious) Adverse Events
	Combined Treatment		Medication Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/26 (84.6%)		27/35 (77.1%)
Endocrine disorders
Increased Sweating	8/26 (30.8%)		8/35 (22.9%)
Eye disorders
Blurred Vision	2/26 (7.7%)		1/35 (2.9%)
Gastrointestinal disorders
Nausea	7/26 (26.9%)		6/35 (17.1%)
Diarrhea	3/26 (11.5%)		3/35 (8.6%)
Abdominal Pain	2/26 (7.7%)		5/35 (14.3%)
Flatulence	5/26 (19.2%)		7/35 (20%)
Constipation	4/26 (15.4%)		6/35 (17.1%)
Gas	4/26 (15.4%)		1/35 (2.9%)
General disorders
Lightheadedness	6/26 (23.1%)		9/35 (25.7%)
Muscle Aches	5/26 (19.2%)		4/35 (11.4%)
Headache	9/26 (34.6%)		8/35 (22.9%)
Faintness	2/26 (7.7%)		3/35 (8.6%)
Fatigue	2/26 (7.7%)		3/35 (8.6%)
Decreased Orgasm	3/26 (11.5%)		5/35 (14.3%)
Jittery	5/26 (19.2%)		9/35 (25.7%)
Nightmares/Vivid Dreams	6/26 (23.1%)		4/35 (11.4%)
Anxiety	0/26 (0%)		2/35 (5.7%)
Decreased Appetite	2/26 (7.7%)		1/35 (2.9%)
Decreased Sex Drive	5/26 (19.2%)		5/35 (14.3%)
Delayed Orgasm	2/26 (7.7%)		1/35 (2.9%)
Drowsiness	9/26 (34.6%)		13/35 (37.1%)
Dry Mouth	8/26 (30.8%)		13/35 (37.1%)
Tremors	1/26 (3.8%)		2/35 (5.7%)
Psychiatric disorders
Insomnia	10/26 (38.5%)		6/35 (17.1%)
Anorexia	1/26 (3.8%)		2/35 (5.7%)

Limitations/Caveats

Only one-third of those approached to add on CBT were interested in this option. Strict exclusion criteria reduces the generalizability of the study results. Possible that other forms of CBT treatment may produce different results.

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.