Do side effects of antidepressants impact efficacy estimates based on the Hamilton Depression Rating Scale? A pooled patient-level analysis

Abstract

The Hamilton Depression Rating Scale (HDRS-17) measures symptoms that may overlap with common antidepressant side effects (e.g., sexual dysfunction), thus making it possible that side effects of antidepressant treatment are erroneously rated as symptoms of depression, and vice versa. This study uses patient-level data from previously conducted antidepressant treatment trials to assess whether side effect ratings co-vary with HDRS-17 ratings. Data from all HDRS-17-rated, industry-sponsored pre- and post-marketing trials (n = 4647) comparing the serotonin and noradrenaline reuptake inhibitor, duloxetine, to placebo and/or to a selective serotonin reuptake inhibitor were pooled; three studies, which utilised sub-therapeutic doses, did not have symptom-level ratings available and could not be included. Severity was assessed for side effects related to sleep, somatic anxiety, gastrointestinal function, and sexual dysfunction. Analysis of covariance was used to assess the relation between these side effects and ratings of relevant HDRS-17-derived outcome parameters. Side effects related to sleep, somatic anxiety and sexual dysfunction significantly and exclusively associated with higher scores on HDRS-17 items measuring the corresponding domains. Side effects related to gastrointestinal function associated with higher HDRS-17 item scores on all assessed domains. Treatment outcome was significantly related to side effect severity when assessed using HDRS-17-sum (beta 0.32 (0.074), p < 0.001), but not when the HDRS-6-sum-score (beta 0.035 (0.043), p = 0.415) or the depressed mood item (beta 0.007 (0.012), p = .527) were used as effect parameters. That some HDRS-17 items co-vary with common antidepressant side effects suggests some of these adverse events are counted twice, potentially leading to an underestimation of antidepressant efficacy.

Impact of chosen cutoff on response rate differences between selective serotonin reuptake inhibitors and placebo

“…Of note is that the separation between active drug and placebo with respect to the proportion of subjects displaying very low remaining endpoint scores as well as proportions of baseline scores was substantial when assessed using the shorter and unidimensional HDRS-6 subscale but less so when using HDRS-17-sum. Since healthy volunteers on average score about three points on the HDRS [ 20 ], since particularly some of the items not included in the HDRS-6 subscale may capture side effects of active treatment [ 4 , 19 ], and since residual symptoms of depression usually remain after only 6 weeks of treatment also in responders [ 21 , 22 ], it is not surprising that only a few subjects displayed very low HDRS-17-sum scores also in the actively treated group.…”

“…Indeed, if, for example, all antidepressant-treated patients improve by 50% and all those treated with placebo by 49%, the resultant 100% difference in response rates would be statistically highly significant but clinically unimportant. Conversely, it has been argued that using HDRS-17-sum as an effect parameter may underestimate the actual antidepressant effects of SSRIs, one reason being that several items included in this scale may capture common side effects of these drugs [ 2 – 4 ].…”

Efficacy and safety of Gyejibokryeong-hwan (GBH) in major depressive disorder: study protocol for multicentre randomised controlled trial

“…Also, most previous clinical trials of herbal medicine for depression used HDRS-17 total score [ 47 , 54 , 55 ]. However, few critics suggest that HDRS is a multidimensional rating scale and the cumulative 17-item HDRS score has a limited role in reflecting the core symptoms of depression [ 33 , 34 , 56 ]. The 17 items of HDRS also include multiple components like insomnia and gastrointestinal and genital symptoms.…”

“…The HDRS-6 subscale consists of 6 items in HDRS, including depressed mood, feelings of guilt, work and activities, psychomotor retardation, psychic anxiety, and general somatic symptoms [ 32 ]. It can be used as a unidimensional measure of depressive severity, excluding insomnia and gastrointestinal symptoms [ 33 , 34 ]. BDI-II, ISI, STAI, STAXI, and EQ-5D-3L are all validated self-reporting questionnaires.…”

Effects of CYP2D6*4 polymorphism on the steady-state concentration of paroxetine in patients diagnosed with depressive episode and comorbid alcohol use disorder

“…Since HAMD includes three items pertaining to insomnia (items 4-6), one for gastrointestinal symptoms (item 12), one for genital symptoms (item 14), and one for weight loss (item 16), there is potential for the adverse drug reactions (ADRs) of SSRIs to be erroneously accounted for as symptoms of depression. Similarly, the somatic anxiety item of the HAMD scale (item 11), which includes complaints such as dry mouth, micturition difficulties, and palpitations, may also reflect common antidepressant ADRs (Hieronymus et al, 2021).…”