BACKGROUND: Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown. METHODS: This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. Percent of symptom improvement, response rate and remission rate from baseline to week 8 were evaluated using both scales. Analyses were performed for the full cohort and for the subset of patients who at baseline were taking medications predicted by the test to have moderate or significant gene-drug interactions. A Mokken scale analysis was conducted to compare the homogeneity of HAM-D17 with that of HAM-D6. RESULTS: At week 8, the guided-care arm demonstrated statistically significant benefit over TAU when the HAM-D6 ( = 4.4%, p = 0.023) was used as the continuous measure of symptom improvement, but not when using the HAM-D17 ( = 3.2%, p = 0.069). Response rates increased significantly for guided-care compared with TAU when evaluated using both HAM-D6 ( = 7.0%, p = 0.004) and HAM-D17 ( = 6.3%, p = 0.007). Remission rates also were significantly greater for guided-care versus TAU using both measures (HAM-D6 = 4.6%, p = 0.031; HAM-D17 = 5.5%, p = 0.005). Patients in the guided-care arm who at baseline were taking medications predicted to have gene-drug interactions showed further increased benefit over TAU at week 8 for symptom improvement ( = 7.3%, p = 0.004) response ( = 10.0%, p = 0.001) and remission ( = 7.9%, p = 0.005) using HAM-D6. All outcomes showed continued improvement through week 24. Mokken scale analysis demonstrated the homogeneity and unidimensionality of HAM-D6, but not of HAM-D17, across treatment arms. CONCLUSIONS: The HAM-D6 scale identified a statistically significant difference in symptom improvement between combinatorial pharmacogenomics-guided care and TAU, whereas the HAM-D17 did not. The demonstrated utility of pharmacogenomics-guided treatment over TAU as detected by the HAM-D6 highlights its value for future biomarker-guided trials comparing active treatment arms. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02109939. Registered 10 April 2014.

OBJECTIVE: The objective of the Genomics Used to Improve DEpression Decisions (GUIDED) trial was to evaluate the utility of pharmacogenomic testing to improve outcomes among patients with major depressive disorder (MDD) who had not responded to at least 1 prior medication trial. The objective of the present analysis was to assess outcomes for the subset of patients expected to benefit from combinatorial pharmacogenomic testing because they were taking medications with predicted gene-drug interactions. METHODS: Participants (enrolled from April 14, 2014, to February 10, 2017) had an inadequate response to at least 1 psychotropic medication in the current episode of MDD. Patients were randomized to treatment as usual (TAU) or the guided-care arm, in which clinicians had access to a combinatorial pharmacogenomic test report to inform medication selection. Patients and raters were blinded to study arm through week 8. The following outcomes were assessed using the 17-item Hamilton Depression Rating Scale (HDRS-17): symptom improvement (percent change in HDRS-17 score), response ( > /= 50% decrease in HDRS-17 score), and remission (HDRS-17 score < /= 7). In the GUIDED trial, the primary endpoint of symptom improvement did not reach significance in the intent-to-treat cohort (P = .069). Here, a post hoc analysis of patients who were taking medications subject to gene-drug interactions at baseline as predicted by combinatorial pharmacogenomic testing (N = 912) is presented. RESULTS: Among participants taking medications subject to gene-drug interactions at baseline, outcomes at week 8 were significantly improved for those in the guided-care arm compared to TAU (symptom improvement: 27.1% versus 22.1%, P = .029; response: 27.0% versus 19.0%, P = .008; remission: 18.2% versus 10.7%, P = .003). When patients who switched medications were assessed, all outcomes were significantly improved in the guided-care arm compared to TAU (P = .011 for symptom improvement, P = .011 for response, P = .008 for remission). CONCLUSIONS: By identifying and focusing on the patients with predicted gene-drug interactions, use of a combinatorial pharmacogenomic test significantly improved outcomes among patients with MDD who had at least 1 prior medication failure. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02109939.

We conducted a secondary analysis of data from the Prevention of Recurrent Episodes of Depression With Venlafaxine Extended Release (ER) for Two Years (PREVENT) trial to evaluate whether discrepancies between clinician and patient ratings of depression severity were predictive of response, remission, and recurrence during treatment for a depressive episode. Patients who self-rated depression severity in concordance with the clinician ("concordant patients") were defined as having a standardized patient-rated Inventory of Depressive Symptoms-Self Report (IDS-SR) score minus standardized clinician-rated Hamilton Rating Scale for Depression (HAM-D) score <1 SD from mean. Non-concordant patients>("underrating patients" [-1 SD], "overrating patients" [+1 SD]) were identified. Cohorts were compared for remission and response on the HAM-D, Clinician Global Impression--Severity (CGI-S), and IDS-SR during acute and continuation therapy and time to recurrence during maintenance therapy. During acute treatment female patients were more likely to overrate their depression severity compared to the clinician; older age predicted overrating during continuation treatment. Overrating patients had a slower onset of response on the HAM-D during acute treatment (P=0.004). There were no differences between cohorts for remission or response on the HAM-D or CGI-S. Overrating patients at week 10 had lower remission and response rates on the IDS-SR during continuation therapy (32% and 50%, respectively; P

BACKGROUND: The degree of agreement between patient- and clinician-rated scales of depressive severity varies widely. This study analyzed agreement between commonly used depression rating scales in the Prevention of Recurrent Episodes of Depression with Venlafaxine Extended Release (ER) for Two Years (PREVENT) trial. METHODS: The PREVENT trial was a multiphase, randomized, double-blind study of patients with recurrent major depressive disorder. This secondary analysis evaluated acute (10weeks) and continuation phase (6months) data. Pearson correlation coefficients at each acute-phase (weekly) and continuation-phase (monthly) visit were calculated for patient-rated (30-item Inventory of Depressive Symptomatology-Self-Rated [IDS-SR30] and clinician-rated (17-item Hamilton Rating Scale for Depression [HAM-D17] and Clinical Global Impressions-Severity [CGI-S]) measures and for response and remission. RESULTS: Data from 1,047 patients were analyzed. The respective correlation coefficients at baseline, week 10, and month 6 were: IDS-SR30: HAM-D17: 0.46, 0.75, 0.70; and for IDS-SR30: CGI-S 0.28, 0.67, 0.65. Agreement between IDS-SR30- and HAM-D17-defined remission and response was relatively poor: week 10, 0.52 and 0.34, respectively; month 6, 0.45 and 0.32, respectively. CONCLUSIONS: These findings suggest that patient-rated measures of depression severity do not correspond strongly with clinician ratings, and are particularly poor prior to the initiation of treatment.

Background: Antidepressant tachyphylaxis describes the return of apathetic depressive symptoms, such as fatigue and decreased motivation, despite continued use of a previously effective treatment. Methods: Data were collected from a multiphase, doubleblind, placebo-controlled study that assessed the efficacy of venlafaxine extended release (ER) during 2 sequential 1-year maintenance phases (A and B) in patients with recurrent major depressive disorder (MDD). The primary outcome was the cumulative probability of tachyphylaxis in patients receiving venlafaxine ER, fluoxetine, or placebo. Tachyphylaxis was defined as Rothschild Scale for Antidepressant Tachyphylaxis (RSAT) score Results: The maintenance phase A population was comprised of 337 patients (venlafaxine ER [n = 129], fluoxetine [n = 79], placebo [n = 129]), whereas 128 patients (venlafaxine ER [n = 43], fluoxetine [n = 45], placebo [n = 40]) were treated during maintenance phase B. No difference in the probability of experiencing tachyphylaxis were observed between the active treatment groups during either maintenance phase; however, a significant difference between venlafaxine ER and placebo was observed at the completion of maintenance phase A. A significant relationship between tachyphylaxis and recurrence was observed. Limitations: Despite demonstrating psychometric validity and reliability, the current definition of tachyphylaxis has not been widely studied. Conclusions: Although no significant differences were observed in the probability of tachyphylaxis among patients receiving active treatment, the relationship between tachyphylaxis and recurrence suggests that tachyphylaxis may be a prodrome of recurrence.

BACKGROUND: We evaluated the comparative efficacy and safety of venlafaxine extended release (ER) and fluoxetine in the acute and continuation phases of treatment. METHODS: In this multicenter, double-blind study, outpatients with recurrent unipolar major depression were randomly assigned to receive venlafaxine ER (75-300 mg/day; n = 821) or fluoxetine (20-60 mg/day; n = 275). After a 10-week acute treatment phase, responders entered a 6-month continuation phase of ongoing therapy with double-blind venlafaxine ER (n = 530) or fluoxetine (n = 185). In the acute phase, the primary outcome was response, defined as a 17-item Hamilton Depression Rating Scale (HDRS) score < or =12 or > or =50% decrease from baseline; the secondary outcome was remission, defined as a HDRS score < or =7. In the continuation phase, the primary outcome was the proportion of patients who sustained response or remission. Secondary measures included time to onset of sustained response or remission (i.e., meeting criteria at two or more consecutive visits), relapse rates, and quality-of-life measures. RESULTS: At the acute treatment phase end point, response rates were 79% for both venlafaxine ER and fluoxetine; remission rates were 49% and 50% for venlafaxine ER and fluoxetine, respectively. In the continuation phase, response rates were 90% and 92%, and remission rates were 72% and 69% for venlafaxine ER and fluoxetine, respectively. Rates of sustained remission at the end of the continuation phase were 52% and 58% for venlafaxine ER and fluoxetine, respectively. CONCLUSION: Venlafaxine ER and fluoxetine were comparably effective during both acute and continuation phase therapy.