Bereavement, Complicated Grief
Conditions
Keywords
Grief, Bereavement, Psychotherapy, Medication, Treatment study
Brief summary
The major goal of this 4-site, double blind, placebo-controlled intervention trial is to assess the efficacy of medication (Citalopram) alone or with psychotherapy (Complicated Grief Therapy) to treat the symptoms of complicated grief.
Detailed description
Complicated grief (CG) is a debilitating condition that is estimated to affect millions of people in the United States alone. We conducted the first randomized controlled study to address this condition (MH60783) and confirmed efficacy of a targeted psychotherapy, complicated grief treatment (CGT). Participants in our prior study continued stable antidepressant medication while receiving CGT or Interpersonal Psychotherapy (IPT). Individuals taking antidepressants had better outcome in both treatments, though CGT was superior to IPT when administered with (60% responders v. 40%) or without (42% v.19%) antidepressants. Studies of antidepressant medication alone have shown mixed results with SSRIs appearing to be promising. However, there has been no randomized controlled study of SSRIs for CG. Determining the efficacy of SSRI treatment for CG, when administered with and without CGT, is of great public health importance. We assembled 4 groups of investigators with strong track records in bereavement research and extensive experience with intervention studies and multicenter projects, to conduct a study of citalopram (CIT) efficacy. We plan to enroll participants with a primary diagnosis of Complicated Grief and randomly assign them (n=480; 50 at Columbia) to receive treatment with CIT, Placebo (PBO), CIT + CGT or PBO + CGT over a period of approximately 16 weeks. We want to determine whether citalopram shows a better response than placebo, when administered either with or without CGT. We will also address the question of whether CIT performs as well when administered alone as it does when administered with CGT.
Interventions
DRUGCitalopram
16 weeks of medication provided flexibly up to 40 mg/day. Medication will be administered in a double-blind fashion.
BEHAVIORALComplicated Grief Treatment
Complicated Grief Treatment (CGT) is a targeted psychotherapy for complicated grief. The treatment integrates principles, strategies and techniques from interpersonal psychotherapy, trauma-focused cognitive behavioral treatment and motivational interviewing. Treatment includes 16 sessions provided within 20 weeks.
OTHERPlacebo
16 weeks of daily inactive medication. It will be administered in a double-blind fashion.
Sponsors
National Institute of Mental Health (NIMH)
American Foundation for Suicide Prevention
New York State Psychiatric Institute
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 95 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosed with Complicated Grief and this is the patient's most important (primary) problem * Ability to give informed consent * Fluent in English * Willingness to have sessions audiotaped * Willingness to undergo random assignment
Exclusion criteria
* Diagnosis of one or more of the following disorders: Schizophrenia or other psychotic disorder, current (past 6 months) substance abuse, Bipolar Disorder, current manic episode, Dementia * Pregnant or lactating women and women of childbearing potential not using medically accepted forms of contraception * Acute, unstable or severe medical illness such as (but not limited to) stroke, epilepsy, or other neurodegenerative disorders, metastatic or active cancer, hepatic disease, or primary renal disease requiring dialysis * Prior intolerance of citalopram * Pending or active disability claim or lawsuit related to the death
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Responder Status Based on Complicated Grief Clinical Global Impression-Improvement (CGI-I) Scale | Weeks 12 and 20 | Brief rating scale frequently used in clinical trials. For this study, version modified for complicated grief was be used. Response is defined as a score of 1(very much improved) or 2 (much improved) on the scale. The rating was done by an Independent Evaluator. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Inventory of Complicated Grief (ICG) | Baseline and week 12 | The 19-item self-report instrument assesses symptoms of complicated grief. Responses on individual items are added up to a total score, which can range from 0 to 76 with higher scores indicating more intense symptoms. This scale has been utilized previously in treatment studies of CG. Additional times points include weeks 4, 8, 12, 16, 20 and 40. For the pre-specified analyses we compared change in the ICG total score from baseline (calculated as baseline score minus week 12 score) for CIT vs PLA at week 12 (aim 1), based on the intention-to-treat principle including all randomized participants. |
| Change From Baseline in Work and Social Adjustment Scale (WSAS) | Baseline and week 12 | The WSAS is a modification of a scale introduced by Hafner and Marks (1976), consisting of 0-8 point ratings of the extent to which symptoms interfere with five areas of daily functioning: work, home management, private leisure, social leisure, and family relationships. It is a well-validated, widely used self-report measure. Additional time points include weeks 4, 8, 12, 16, and 40. A total score calculated as a sum of all items (possible range 0-40) was used in the analyses with higher scores indicating more impairment. For the pre-specified analyses we compared change in the WSAS total score from baseline (calculated as baseline score minus week 12 score) for CIT vs PLA at week 12 (aim 1), based on the intention-to-treat principle including all randomized participants. |
Countries
United States
Participant flow
Recruitment details
Bereaved individuals age 18-95 were recruited between March 2010 and September 2014 using professional and public outreach, print, broadcast and internet media. Referrals were made by health care professionals, bereavement counselors and patients or family members.
Participants by arm
| Arm | Count |
|---|---|
| Citalopram Citalopram is an Selective Serotonin Reuptake Inhibitor (SSRI) medication. It is combined with grief-focused clinical management.
Citalopram: 16 weeks of medication provided flexibly up to 40 mg/day. Medication is administered in a double-blind fashion. | 101 |
| Placebo (Sugar Pill) Inactive medication. It is combined with grief-focused clinical management.
Placebo: 16 weeks of daily inactive medication. It is administered in a double-blind fashion. | 99 |
| CGT With Citalopram The targeted psychotherapy for complicated grief combined with SSRI medication.
Complicated Grief Treatment: Complicated Grief Treatment (CGT) is a targeted psychotherapy for complicated grief. The treatment integrates principles, strategies and techniques from interpersonal psychotherapy, trauma-focused cognitive behavioral treatment and motivational interviewing. Treatment includes 16 sessions provided within 20 weeks.
Citalopram: 16 weeks of medication provided flexibly up to 40 mg/day. Medication is administered in a double-blind fashion. | 99 |
| CGT With Placebo The targeted psychotherapy for complicated grief combined with inactive medication.
Complicated Grief Treatment: Complicated Grief Treatment (CGT) is a targeted psychotherapy for complicated grief. The treatment integrates principles, strategies and techniques from interpersonal psychotherapy, trauma-focused cognitive behavioral treatment and motivational interviewing. Treatment includes 16 sessions provided within 20 weeks.
Placebo: 16 weeks of daily inactive medication. Medication is administered in a double-blind fashion. | 96 |
| Total | 395 |
Baseline characteristics
| Characteristic | Total | Citalopram | Placebo (Sugar Pill) | CGT With Citalopram | CGT With Placebo |
|---|---|---|---|---|---|
| Age, Continuous | 53.0 years STANDARD_DEVIATION 14.5 | 52.4 years STANDARD_DEVIATION 13.1 | 53.9 years STANDARD_DEVIATION 13.8 | 52.1 years STANDARD_DEVIATION 15.3 | 53.5 years STANDARD_DEVIATION 16 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 45 Participants | 10 Participants | 7 Participants | 8 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 350 Participants | 91 Participants | 92 Participants | 91 Participants | 76 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Gender Female | 308 Participants | 82 Participants | 69 Participants | 78 Participants | 79 Participants |
| Gender Male | 87 Participants | 19 Participants | 30 Participants | 21 Participants | 17 Participants |
| Race/Ethnicity, Customized Black | 39 participants | 10 participants | 8 participants | 11 participants | 10 participants |
| Race/Ethnicity, Customized Others | 31 participants | 6 participants | 11 participants | 7 participants | 7 participants |
| Race/Ethnicity, Customized While | 325 participants | 85 participants | 80 participants | 81 participants | 79 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 101 | 0 / 99 | 0 / 99 | 0 / 96 |
| serious Total, serious adverse events | 0 / 101 | 0 / 99 | 1 / 99 | 0 / 96 |
Outcome results
Primary
Responder Status Based on Complicated Grief Clinical Global Impression-Improvement (CGI-I) Scale
Brief rating scale frequently used in clinical trials. For this study, version modified for complicated grief was be used. Response is defined as a score of 1(very much improved) or 2 (much improved) on the scale. The rating was done by an Independent Evaluator.
Time frame: Weeks 12 and 20
Population: Response rates were compared under the intention-to-treat principle, including all randomized participants in a logistic regression with inverse probability weighting .
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Citalopram (CIT) | Responder Status Based on Complicated Grief Clinical Global Impression-Improvement (CGI-I) Scale | 46 percentage of responders |
| Placebo (PLA; Sugar Pill) | Responder Status Based on Complicated Grief Clinical Global Impression-Improvement (CGI-I) Scale | 38 percentage of responders |
| Complicated Grief Treatment With Citalopram (CGT With CIT) | Responder Status Based on Complicated Grief Clinical Global Impression-Improvement (CGI-I) Scale | 84 percentage of responders |
| Complicated Grief Treatment With Placebo (CGT With PLA) | Responder Status Based on Complicated Grief Clinical Global Impression-Improvement (CGI-I) Scale | 83 percentage of responders |
Comparison: Our prespecified primary analysis was cross-sectional, comparing treatment response rates for CIT vs PLA at week 12 (aim 1), based on the intention-to-treat principle including all randomized participants. With 10% of 440 target enrollment lost to follow-up we had a power of 76-83% to detect predicted between-group difference in response (CGT with PLA, 40%; CGT with CIT, 60%; CIT 40%; and PLA 20%)p-value: <0.0595% CI: [0.82, 1.81]Regression, Logistic
Comparison: Our prespecified primary analysis was cross-sectional, comparing treatment response rates for CIT with CGT vs PLA with CGT at week 20 (aim 2) based on the intention-to-treat principle including all randomized participants.p-value: <0.0595% CI: [0.88, 1.17]Regression, Logistic
Comparison: Our prespecified primary analysis was cross-sectional, comparing treatment response rates for CIT with CGT vs CIT at week 20 (aim 3) based on the intention-to-treat principle including all randomized participants.p-value: <0.0595% CI: [1, 1.46]Regression, Logistic
Secondary
Change From Baseline in Inventory of Complicated Grief (ICG)
The 19-item self-report instrument assesses symptoms of complicated grief. Responses on individual items are added up to a total score, which can range from 0 to 76 with higher scores indicating more intense symptoms. This scale has been utilized previously in treatment studies of CG. Additional times points include weeks 4, 8, 12, 16, 20 and 40. For the pre-specified analyses we compared change in the ICG total score from baseline (calculated as baseline score minus week 12 score) for CIT vs PLA at week 12 (aim 1), based on the intention-to-treat principle including all randomized participants.
Time frame: Baseline and week 12
Population: Prespecified secondary analyses of self-report ratings of CG symptoms (ICG) compared changes in scores using a weighted linear regression with inverse probability weighting to adjust for missing assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Citalopram (CIT) | Change From Baseline in Inventory of Complicated Grief (ICG) | 18 score change from baseline to wk12 | Standard Deviation 11 |
| Placebo (PLA; Sugar Pill) | Change From Baseline in Inventory of Complicated Grief (ICG) | 16 score change from baseline to wk12 | Standard Deviation 12 |
p-value: 0.74Regression, Linear
Secondary
Change From Baseline in Inventory of Complicated Grief (ICG)
The 19-item self-report instrument assesses symptoms of complicated grief. Responses on individual items are added up to a total score, which can range from 0 to 76 with higher scores indicating more intense symptoms. This scale has been utilized previously in treatment studies of CG. Additional times points include weeks 4, 8, 12, 16, 20 and 40. For the pre-specified analyses we compared change in the ICG total score from baseline (calculated as baseline score minus week 20 score) for CIT with CGT vs PLA with CGT (aim 2), and for CIT with CGT vs CIT (aim 3) based on the intention-to-treat principle including all randomized participants.
Time frame: Baseline and week 20
Population: Prespecified secondary analyses of self-report ratings of CG symptoms (ICG) compared changes in scores using a weighted linear regression with inverse probability weighting to adjust for missing assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Citalopram (CIT) | Change From Baseline in Inventory of Complicated Grief (ICG) | 20 score change from baseline to wk20 | Standard Deviation 12 |
| Placebo (PLA; Sugar Pill) | Change From Baseline in Inventory of Complicated Grief (ICG) | 25 score change from baseline to wk20 | Standard Deviation 14 |
| Complicated Grief Treatment With Citalopram (CGT With CIT) | Change From Baseline in Inventory of Complicated Grief (ICG) | 26 score change from baseline to wk20 | Standard Deviation 12 |
p-value: 0.53Regression, Linear
p-value: <0.001Regression, Linear
Secondary
Change From Baseline in Work and Social Adjustment Scale (WSAS)
The WSAS is a modification of a scale introduced by Hafner and Marks (1976), consisting of 0-8 point ratings of the extent to which symptoms interfere with five areas of daily functioning: work, home management, private leisure, social leisure, and family relationships. It is a well-validated, widely used self-report measure. Additional time points include weeks 4, 8, 12, 16, and 40. A total score calculated as a sum of all items (possible range 0-40) was used in the analyses with higher scores indicating more impairment. For the pre-specified analyses we compared change in the WSAS total score from baseline (calculated as baseline score minus week 12 score) for CIT vs PLA at week 12 (aim 1), based on the intention-to-treat principle including all randomized participants.
Time frame: Baseline and week 12
Population: Prespecified secondary analyses of self-report ratings of grief-related functional impairment (WSAS) compared changes in scores using a weighted linear regression with inverse probability weighting to adjust for missing assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Citalopram (CIT) | Change From Baseline in Work and Social Adjustment Scale (WSAS) | 10 score change from baseline to wk12 | Standard Deviation 11 |
| Placebo (PLA; Sugar Pill) | Change From Baseline in Work and Social Adjustment Scale (WSAS) | 8 score change from baseline to wk12 | Standard Deviation 10 |
p-value: 0.59Regression, Linear
Secondary
Change From Baseline in Work and Social Adjustment Scale (WSAS)
The WSAS is a modification of a scale introduced by Hafner and Marks (1976), consisting of 0-8 point ratings of the extent to which symptoms interfere with five areas of daily functioning: work, home management, private leisure, social leisure, and family relationships. It is a well-validated, widely used self-report measure. Additional time points include weeks 4, 8, 12, 16, and 40. A total score calculated as a sum of all items (possible range 0-40) was used in the analyses with higher scores indicating more impairment. For the pre-specified analyses we compared change in the WSAS total score from baseline (calculated as baseline score minus week 20 score) for CIT with CGT vs PLA with CGT (aim 2), and for CIT with CGT vs CIT (aim 3) based on the intention-to-treat principle including all randomized participants.
Time frame: Baseline and week 20
Population: Prespecified secondary analyses of self-report ratings of grief-related functional impairment (WSAS) compared changes in scores using a weighted linear regression with inverse probability weighting to adjust for missing assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Citalopram (CIT) | Change From Baseline in Work and Social Adjustment Scale (WSAS) | 10 score change from baseline to wk20 | Standard Deviation 12 |
| Placebo (PLA; Sugar Pill) | Change From Baseline in Work and Social Adjustment Scale (WSAS) | 14 score change from baseline to wk20 | Standard Deviation 10 |
| Complicated Grief Treatment With Citalopram (CGT With CIT) | Change From Baseline in Work and Social Adjustment Scale (WSAS) | 16 score change from baseline to wk20 | Standard Deviation 11 |
Comparison: Pre-specified secondary analyses compared changes in WSAS scores using a weighted linear regression, controlling for site, baseline MDD, \& race/ethnicity, and with inverse probability weighting to adjust for missing assessments.p-value: 0.4Regression, Linear
Comparison: Pre-specified secondary analyses compared changes in WSAS scores using a weighted linear regression, controlling for site, baseline MDD, \& race/ethnicity, and with inverse probability weighting to adjust for missing assessments.p-value: 0.005Regression, Linear