Evaluation of Individual Items of the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) in Adults with Treatment-Resistant Depression Treated with Esketamine Nasal Spray Combined with a New Oral Antidepressant

Depression is a leading cause of long-term disability worldwide, and around 30% of patients fail to respond to at least two pharmacological treatments, meeting criteria for treatment-resistant depression (TRD). Individuals with TRD experience greater morbidity, poorer quality of life, higher relapse rates and greater healthcare costs than patients with more treatment-responsive major depressive disorder. Prior to esketamine's approval in 2019, few pharmacological options were specifically licensed for TRD, and many augmentation strategies had limited efficacy or tolerability. Clinical outcome assessment instruments such as the Patient Health Questionnaire-9 (PHQ-9; a patient-reported outcome) and the Montgomery–Åsberg Depression Rating Scale (MADRS; a clinician-reported outcome) are commonly used to quantify overall depression severity, but total scores collapse across distinct symptoms and may obscure which specific symptoms drive observed change. Floden and colleagues set out to examine symptom-level change on the PHQ-9 and MADRS using data from the Phase III TRANSFORM-2 randomised trial. The objective was to determine which individual items (symptoms) show greater improvement with esketamine nasal spray plus a newly initiated oral antidepressant (esketamine plus AD) versus intranasal placebo plus a newly initiated oral antidepressant (placebo plus AD) over the 4-week double-blind induction period. By analysing item-level shifts and the likelihood of improvement for each symptom, the study aimed to provide more patient-relevant interpretation of the trial's total-score findings.

The analyses used data from TRANSFORM-2, a Phase III, multicentre, double-blind, active-controlled trial with flexible dosing of esketamine nasal spray (56 mg or 84 mg) administered twice weekly for 4 weeks alongside a newly initiated open-label oral antidepressant. Adults meeting DSM-5 criteria for major depressive disorder without psychotic features and meeting criteria for TRD (non-response to at least two antidepressants in the current episode, and an Inventory of Depressive Symptomatology–Clinician-rated 30-item total score ≥ 34) were randomised 1:1 to receive esketamine plus oral AD or intranasal placebo plus oral AD. The trial excluded patients at serious risk for suicide as determined by other assessments. Patient-reported symptoms were measured with the PHQ-9 (nine items, each scored 0–3, recall 2 weeks, total range 0–27). Clinician-assessed symptoms were measured with the MADRS (ten items, each scored 0–6, total range 0–60); MADRS ratings were collected by independent remote raters who received standardised training. Electronic data capture was used for PROs, and translated versions were deployed where appropriate. The analytic population comprised patients in the intent-to-treat population with at least one clinical outcome assessment. Outcomes were assessed at baseline, day 15 and day 28. Total-score changes were compared by treatment arm using analysis of variance (ANOVA). Item-level improvement was defined using within-patient thresholds: a decrease of ≥ 1 point on a PHQ-9 item (a 25% shift on the 4-point item scale) or ≥ 2 points on a MADRS item (a 29% shift on the 7-point item scale). The analysis also referenced meaningful change thresholds (MCTs) for total scores (PHQ-9 MCT = 6 points; MADRS MCT = 10 points) and noted that the minimal important difference (MID) for MADRS mean differences is commonly considered about 2 points. Proportions of patients achieving item-level improvement at days 15 and 28 were calculated, and generalized estimating equations (GEE) logistic regression models with an autoregressive correlation structure for repeated measures were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the likelihood of improvement, with fixed effects for treatment, time point and their interaction.

Baseline characteristics were similar between arms. The sample was, on average, 46 years old (SD 11.89), predominantly non-Hispanic (93%), White (93%), and female (62%), with a mean duration of TRD of about 12 years (SD 10.2). Baseline PHQ-9 and MADRS scores were comparable across treatment groups. PHQ-9 total scores improved from baseline in both groups at days 15 and 28, but mean reductions were larger with esketamine plus AD. The extracted text reports a greater mean reduction favouring esketamine at day 15 (mean difference −1.8; p = 0.045) and at day 28 (mean difference −2.8; p = 0.006). At the item level, most patients showed improvement on nearly all PHQ-9 items except item 9 (suicidal ideation), where many patients showed no change — likely reflecting low baseline endorsement and trial exclusion criteria for serious suicide risk. The proportion of patients with a ≥ 1-point improvement on each PHQ-9 item was greater in the esketamine plus AD arm at both assessment points. GEE models estimated that the odds of item-level improvement were more than twofold for several PHQ-9 items: item 1 (“Little interest/pleasure in things”) OR 2.252 (95% CI 1.165–4.355); item 2 (“Feeling down, depressed, or hopeless”) OR 2.767 (95% CI 1.400–5.470); and item 4 (“Feeling tired or having little energy”) OR 2.171 (95% CI 1.153–4.087). Item 6 (“Feeling bad about yourself…”) also showed a nominally significant increase in odds: OR 1.878 (95% CI 1.000–3.527). MADRS total scores likewise improved in both arms, with a numerically larger change at day 15 (mean difference −2.0; p = 0.189) and a statistically significant greater reduction at day 28 favouring esketamine plus AD (mean difference −4.4; SE 1.85; p = 0.017; 95% CI −8.10 to −0.80). Item-level MADRS data showed higher proportions of ≥ 2-point improvement across all items in the esketamine arm, especially by day 28. Five MADRS items had statistically significant greater odds of improvement with esketamine plus AD: item 1 (“Reported sadness”) OR 1.844 (95% CI 1.014–3.354); item 2 (“Apparent sadness”) OR 2.007 (95% CI 1.096–3.674); item 3 (“Inner tension”) OR 1.891 (95% CI 1.080–3.313); item 6 (“Concentration difficulties”) OR 1.880 (95% CI 1.054–3.354); and item 8 (“Inability to feel”) OR 2.099 (95% CI 1.180–3.735). Reduced appetite (item 5) was the symptom least likely to improve on both instruments. The extracted text does not provide a full table of absolute responder counts or adverse event rates in these sections.

Floden and colleagues interpret the item-level findings as congruent with the total-score benefits observed for esketamine plus oral antidepressant versus placebo plus oral antidepressant during the 4-week induction. Multiple individual symptoms showed nominally significant greater likelihoods of improvement with esketamine: four PHQ-9 items (including the two cardinal symptoms, low interest/pleasure and feeling down) and five MADRS items (including apparent sadness and inability to feel/anhedonia). The authors emphasise that analysing individual items offers greater specificity about which symptoms are likely to respond, which can aid clinician–patient discussions and shared decision-making about expected benefits versus risks. The discussion notes that the greatest item-level odds ratios (OR > 2.0) were observed for PHQ-9 items assessing anhedonia, depressed mood and low energy, and for MADRS items assessing apparent sadness and anhedonia. The authors also highlight that items reflecting reduced appetite were least responsive. Key limitations acknowledged include the short follow-up (only baseline and two post-baseline time points within a 4-week double-blind period), and the absence of analyses comparing outcomes by the specific oral antidepressant used, despite clinicians prescribing one of four oral ADs. The investigators further note that these are results from a single randomised trial and that replication in other datasets would strengthen confidence in the symptom-level findings.

Analysing single items on the PHQ-9 and MADRS provides a more granular picture of how esketamine plus a newly initiated oral antidepressant affects specific depressive symptoms in adults with TRD. Treatment with esketamine plus AD led to greater improvement in total scores and to higher odds of improvement on several individual patient- and clinician-reported symptoms compared with placebo plus AD, with the largest gains observed for cardinal depressive symptoms and for anhedonia as rated on the MADRS. These item-level results are intended to enhance interpretability of overall score change for patients and clinicians.