1. RESPONSE TO ANTIDEPRESSANT MEDICATION, COGNITIVE BEHAVIOR THERAPY AND PLACEBO IN CHRONIC TENSION-TYPE HEADACHE VARIES WITH PSYCHIATRIC COMORBIDITY & HEADACHE SEVERITY Kenneth A. Holroyd 1, Ph.D. and Jennifer Labus, Ph.D. 2 1 Ohio University, Athens, OH, 2 UCLA Center of Neurovisceral Sciences/Women’s Health Objectives: To determine if patients with more severe headache problems or with psychiatric comorbidity differentially responded to antidepressant medication, stress-management therapy, or their combination. Background: Tricyclic antidepressant therapy (AM) and cognitive-behavioral stress-management therapy (SM) are each moderately effective in treating chronic tension-type headaches (CTTH). However, information about patient characteristics that might moderate treatment response is unavailable. (1) Headache Severity (but not Psychiatric Comorbidity) moderated headaches improvement (Headache Index). For High & Moderate Headache Severity participants all three active treatments were more effective than placebo. For Low Headache Severity y participants only the combined treatment was more effective than placebo. (2) Psychiatric Comorbidity (but not Headache Severity) moderated improvements in Headache Disability ( Headache Disability Inventory) For participants with Psychiatric comorbidity all three active treatments were more effective than placebo. For participants with no psychiatric comorbidity only the combined treatment was more effective than placebo. (3)Treatment effects reflected that placebo responses varied with headache severity and psychiatric comorbidity. Methods: Trial Design Data are from 169 participants in the Treatment of Chronic Tension-type Headache (TCTH) trial 1. of 203 randomized who completed the treatment/dose adjustment phase. Participants had been randomized to treatment with: (1) Tricyclic antidepressant (AM; amitriptyline HCL to 100mg./day; nortriptyline HCL to 75 mg./day), (2) Placebos (PL), (3) CBT Stress-Management Therapy + PL (SMT) or SMT + AM in a parallel groups trial. Participants were predominately female (75%) and Caucasian (96%) with a mean age of 38.1 years (range 18-65), experiencing a mean of 26 headache days/mo. Primary outcome measures were the Headache Index (average daily pain rating taken 4 times per day) and the Headache Disability Inventory (HDI) that assesses the impact of headaches on psychosocial and affective functioning. Measures - Primary outcome measures (and measures of headache severity) were the Headache Index (average daily pain rating taken 4 times per day) 1 and the Headache Disability Inventory (HDI)2 which assesses the impact of headaches on psychosocial and affective functioning. The Prime MD Interview3, a validated brief psychiatric diagnostic interview was used to diagnose DSMIV anxiety and mood disorders. Outcomes were evaluated at Baseline ( M 0 ), Treatment/Dose Adjustment Phase (Tx; M 1-2 ) and Evaluation (M 3, M 8 ). M 8 was the primary endpoint. Analysis – Mixed-effects analyses. Moderator effects are presented graphically by displaying treatment effects for high (> 1 SD above the Mean), medium (± 1 SD of the Mean) and low (> 1 SD below the Mean) baseline values of the continuous moderator variables. Figure 1: Model values and 95% confidence intervals for High, Medium & Low Baseline Headache Severity (Headache Index) with Headache Index as Outcome Figure 2: Model values and 95% confidence intervals for PrimeMD Diagnosis (Mood or Anxiety Disorder) or No Diagnosis with Quality of Life (Headache Disability Inventory Scores) as Outcome. 1 Holroyd et al. (2001). Management of chronic tension-type Headache with trycyclic antidepressant medication, stress management therapy and their combination. JAMA, 285, 2208 – 2215; 2 Jacobson GP et al. (1994). The Henry Ford Hospital Headache Disability Inventory (HDI). Neurology, 44:837-842; 3 Spitzer RL, et al. (1994) Utility of a new procedure for diagnosing mental disorders in primary care: The PRIME MD 1000 study. JAMA;272:1749-1756. Headache Index PLAMSMTAM + SMT Low Severityvs. PL -----.12-.15-.43 vs. BL -.53-.37-.66-.89 Moderate Severityvs. PL ------1.1-.91-1.3 vs. BL -.30-1.3 -1.6 High Severityvs. PL ------1.7-1.2-1.4 vs. BL.07-1.7-1.2-1.4 Treatment Effect Sizes (Cohen’s d ) Relative to Placebo & Relative to Baseline Psychiatric Comorbidity PLAMSMTAM + SMT Absentvs. PL ------.03-.15-.45 vs. BL -.38-.44-.58-.88 Presentvs. PL ------.53-.79-.66 vs. BL -.02-.79-.85 CONCLUSIONS