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ORLANDO, FL — Mark Zimmerman, MD, professor of psychiatry at Brown Medical School in Providence, Rhode Island, presented a review on controversies related to both categorizing disease severity and treatment of depression at the US Psych Congress 2018, held October 25 to 28.1
According to Dr Zimmerman, “there is no clear consensus on how to conceptualize severity and there [are] no data in the literature as to how clinicians think about severity.” Determination of severity of depression affects an individual’s decision to seek treatment, the type and intensity of treatment, and whether to continue or stop treatment. Disease severity affects daily life activities, determines whether a patient qualifies for disability, and is used to monitor the efficacy of treatment.
Severity of depression as outlined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) is determined by the number of symptoms, distress due to symptoms, and impairment due to symptoms. However, Dr Zimmerman notes that there is no mention in the DSM-5 of self-injury, suicidality, or the need for hospitalization. Mild depression is associated with few, if any, symptoms in excess of those required to make the diagnosis and symptom intensity is distressing but manageable; mild depression is associated with no more than minor impairment in social or occupational functioning. Severe depression is associated with a substantial number of symptoms required to make the diagnosis and symptom intensity is unmanageable and distressing. Depression that is determined to be moderate falls between mild and severe and is currently undefined.
Although depression symptom scales exist, they differ in content and rating instructions for characterizing and classifying severity. In addition, cutoff values that indicate whether someone has mild, moderate, or severe depression are inconsistent or lacking. For example, marked differences in severity assessment were seen in a study of 245 outpatients with major depressive disorder who were evaluated using the Hamilton Depression Rating Scale (HAM-D) and the CUDOS, PHQ-9, and QIDS self-report tools.2 Marked differences in severity were found when patients were classified into severity groups according to the developers’ recommended cutoff values. Approximately 70% of patients were classified as having severe depression according to the PHQ-9, while the HAM-D classified slightly more than 20% as having severe depression.
Dr Zimmerman further explained that researchers do not consistently use the same cutoff values to indicate the severity groups. For example, 2 studies classified severe depression as HAM-D ≥ 20; 1 study compared cognitive behavioral therapy to medication and another assessed the use of fluoxetine and venlafaxine.3-4 A third meta-analysis uses a HAM-D score ≥ 28 to indicate severe depression.5 The American Psychiatric Association (APA) Handbook of Psychiatric Measures defines severity of depression as follows: mild to moderate, HAM-D < 18; severe, 19 to 22; very severe, > 23. Dr Zimmerman questioned whether severity of illness should be based only on symptom scores or if impairment, duration, frequency, persistence, coping ability, suicidality should also be considered.
Treatment for Depression Based on Severity
Both the APA and the British Association for Psychopharmacology recommend medication or psychotherapy for mild major depressive disorder, medication or psychotherapy for moderate major depressive disorder, and medication for severe major depressive disorder. The National Institute for Health and Clinical Excellence (NICE) guidelines recommend psychotherapy only for mild major depressive disorder and both medication and psychotherapy for moderate and severe major depressive disorder .
Numerous analysis were conducted that assessed the efficacy of antidepressants for severe depression. Khan and colleagues5 concluded that antidepressant effects were better and placebo was less effective in patients with severe depression. Results of analysis by Kirsch and collegues6 were similar; however, the conclusion of their study triggered a controversy regarding the use of antidepressants. In the context of the NICE criteria, their outcomes were not felt to be clinically meaningful and there was insufficient evidence to support the use of antidepressant medication in patients who were not severely depressed, unless other treatments failed to improve symptoms.
Both studies were limited in that conclusions were based on mean values and individual data were not considered. Both analyses examined the mean change in HAM-D score instead of the percentage of patients who improved. In addition, there was inconsistent use of HAM-D cutoff scores in the analyses compared with guidelines, such as the APA Handbook of Psychiatric Measures. Dr Zimmerman noted that the generalizability of these studies may present another limitation because very few patients seen in clinical practice would qualify for antidepressant efficacy trials due to the restrictive inclusion/exclusion criteria.
A pooled analysis of 6 studies (N = 700) was published in JAMA in 2010; this study included individual patient data that could categorize patients into the correct categories.7 The investigators concluded that when the HAM-D was ≤ 18 or HAM-D was 19 to 22, there was minimal effect for antidepressants compared with placebo. A moderate effect size was seen for HAM-D scores ≥ 23.
Gibbons and colleagues examined 41 company-sponsored studies (N < 9000) of fluoxetine and venlafaxine.4 The researchers compared participants with HAM-D scores ≤ 19 vs those with scores ≥ 20 and found little difference between active drug and placebo in mean change, response rate, and remission rates. Mosca and colleagues examined 9 company-sponsored studies (N = 4271) of desvenlafaxine vs placebo in 3 severity cohorts; patients were required to have a minimum HAM-D score of 20, which included 3% of participants in the mild group.8 They established that a HAM-D score ≤ 18 was reflective of mild depression, 19 to 24 indicated moderate, and ≥ 25 indicated severe depression. The investigators concluded that low baseline severity should not preclude using an antidepressant.
Another assessment of 34 company-sponsored studies (N = 10, 737) of citalopram, escitalopram, duloxetine, sertraline, or quetiapine vs placebo in 3 severity cohorts defined mild as HAM-D ≤ 21, moderate as HAM-D from 22 to 25, and severe as HAM-D ≥ 26.9 The researchers concluded that the effect size was the same across all groups, meaning active drug was more effective than placebo. A second analysis of the data in the same study revealed findings similar to those of Khan et al5 and Kirsh et al.6
The conclusion of these analyses is that antidepressants are effective across a range of severities and their use should not be limited to only severely depressed patients, noted Dr Zimmerman.
Medication vs Psychotherapy
The National Institute of Mental Health (NIMH) collaborative study for the treatment of depression compared the efficacy of imipramine, cognitive behavioral therapy, interpersonal therapy, and placebo for severe depression.10 Severity was defined as less severe (<20 on HAM-D) and more severe (≥ 20 on HAM-D). The investigators concluded that in the less-severe group, there was no difference from pretreatment to posttreatment in the 4 groups. In the more-severe group, only imipramine significantly differed from placebo; cognitive behavioral therapy did not differ from placebo. The authors concluded that more severe depression should be treated with pharmacology vs psychotherapy.
Another meta-analysis of psychotherapy vs medication by Cuijpers and colleagues concluded that differential treatment outcomes were not associated with mean baseline scores, and there was no differential treatment response between psychotherapy and medication with HAM-D scores <20 vs >20.11 A pooled analysis by Weitz and colleagues concluded that psychotherapy was as effective as medication for individuals with severe depression.12 A meta-analysis of psychotherapy studies by Driessen and colleagues concluded that mean baseline symptom severity did not predict poor response to treatment.13 Dr Zimmerman noted that many psychotherapy studies exclude patients scoring above a certain symptom severity threshold while pharmacotherapy studies exclude participants based on low scores on severity scales.
Dr Zimmerman concluded that antidepressant efficacy is not limited to severely depressed patients and psychotherapy efficacy is not limited to patients with mild to moderate depression. There is a paucity of evidence to support treatment guidelines that recommend medication as the first-line treatment for patients with severe depression. A major limiting factor to determining the effect of treatment on severity of depression is the exclusion of patients with high or low scores on a severity scale.
- Zimmerman M. Severity and the treatment of depression: a review of two controversies. Presented at: US Psych Congress 2018; October 25-28, 2018; Orlando, FL.
- Zimmerman M, Martinez JH, Friedman M, Boerescu DA, Attiullah N, Toba C. How can we use depression severity to guide treatment selection when measures of depression categorize patients differently? J Clin Psychiatry. 2012;73(10):1287-1291.
- DeRubeis RJ, Gelfand LA, Tang TZ, Simons AD. Medications versus cognitive behavior therapy for severely depressed outpatients: mega-analysis of four randomized comparisons. Am J Psychiatry. 1999;156(7):1007-1013.
- Gibbons RD, Hur K, Brown CH, Davis JM, Mann JJ. Benefits from antidepressants: synthesis of 6-week patient-level outcomes from double-blind placebo-controlled randomized trials of fluoxetine and venlafaxine. Arch Gen Psychiatry. 2012;69(6):572-579.
- Khan A, Leventhal RM, Khan SR, Brown WA. Severity of depression and response to antidepressants and placebo: an analysis of the Food and Drug Administration database. J Clin Psychopharmacol. 2002;22(1):40-45.
- Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 2008;5(2):e45.
- Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA. 2010;303(1):47-53.
- Mosca D, Zhang M, Prieto R, Boucher M. Efficacy of desvenlafaxine compared with placebo in major depressive disorder patients by age group and severity of depression at baseline. J Clin Psychopharmacol. 2017;37(2):182-192.
- Rabinowitz J, Werbeloff N, Mandel FS, Menard F, Marangell L, Kapur S. Initial depression severity and response to antidepressants v. placebo: patient-level data analysis from 34 randomised controlled trials. Br J Psychiatry. 2016;209(5):427-428.
- Elkin I, Shea MT, Watkins JT, et al. National Institute of Mental Health Treatment of Depression Collaborative Research Program. General effectiveness of treatments. Arch Gen Psychiatry. 1989;46(11):971-982.
- Cuijpers P, van Straten A, van Oppen P, Andersson G. Are psychological and pharmacologic interventions equally effective in the treatment of adult depressive disorders? A meta-analysis of comparative studies. J Clin Psychiatry. 2008;69(11):1675-1685.
- Weitz ES, Hollon SD, Twisk J, et al. Baseline depression severity as moderator of depression outcomes between cognitive behavioral therapy vs pharmacotherapy: An individual patient data meta-analysis. JAMA Psychiatry. 2015;72(11):1102-1109.
- Driessen E, Cuijpers P, Hollon SD, Dekker JJ. Does pretreatment severity moderate the efficacy of psychological treatment of adult outpatient depression? A meta-analysis. J Consult Clin Psychol. 2010;78(5):668-680.