Residual cognitive symptoms


Mood symptoms alone do not account for the extent of disability associated with MDD.12 Cognitive impairment, 1 of the 9 core symptoms of MDD (see Table 1), is significantly associated with impaired daily functioning in individuals with major depression.3,12 Furthermore, cognitive impairment, including changes in attention and executive functioning, is often intractable, even when patients’ mood symptoms are otherwise responsive to therapy. Residual cognitive symptoms have consequences for overall patient functioning and quality of life, increasing relapse and impacting long-term outcomes.3

Despite the fact that cognitive improvement has been shown to correlate with response to antidepressant therapy, a broad range of cognitive symptoms, including apathy, inattentiveness, forgetfulness, word-finding difficulty, and mental slowing, have been reported in more than 30% of patients who have otherwise responded to antidepressant therapy.14-16

McClintock et al reported that among 428 patients with depression who responded to but did not remit after up to 12 weeks of citalopram therapy, 70.6% reported decreased concentration/reasoning as a persistent symptom from baseline to exit.17 Researchers have hypothesized that these symptoms are both a side effect of long-term treatment with antidepressants and residual symptoms of MDD.14

Residual cognitive symptoms are troubling to patients and often impact workplace functioning and overall quality of life. In a post hoc analysis of a double-blind, randomized trial of patients with MDD, 71% of patients self-reported difficulty concentrating among their top 2 most troubling symptoms, after sadness, based on the Patient-Rated Troubling Symptoms of Depression (PaRTS-D).18 A separate study of 260 subjects with MDD found that cognitive symptoms account for more variability in workplace functioning than total depression severity (Figure 2).19 A study by Kurlander et al evaluated cognitive function, disability, and productivity among 564 patients initiating antidepressant therapy for the treatment of MDD. Patients who met criteria for cognitive dysfunction (45%) experienced significantly poorer patient-reported quality of life, as measured by the 12-Item Short Form Health Survey (SF-12), and statistically greater impairment in social life and family life domains, as measured by the Sheehan Disability Scale (SDS).20

Residual symptoms of fatigue


Fatigue is one of the most common residual symptoms of MDD and may present as a core symptom, a residual symptom during or after treatment, or a treatment-emergent side effect.3,21 Fatigue may manifest as sustained fatigue without physical exertion, activities of daily living requiring more time than usual, or even small tasks requiring more energy than the patient feels they have. Table 2 describes patient presentations that may indicate the presence of fatigue or cognitive symptoms in MDD.21

In the Nierenberg study mentioned earlier, among 108 subjects who achieved remission (HAM-D17 score ≤7) with 8 weeks of fluoxetine treatment, 38% reported continued fatigue.10 As previously noted, however, fatigue may be a symptom associated with the treatment, and may potentially be misinterpreted as a residual symptom. 


In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, fatigue was assessed with item 14 on energy level from the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16). A secondary analysis of STAR*D data included 2868 outpatients with MDD.22

At baseline, 94.5% of patients reported some level of fatigue. After ≤14 weeks of citalopram monotherapy, 2.1% had treatment-emergent fatigue, 33.6% reported that fatigue remitted during treatment, and 60.8% had residual fatigue. Higher levels of baseline fatigue were associated with reduced likelihood of remission, decreased overall satisfaction, and reduced mental and physical function at outcome. In addition, subjects with higher baseline fatigue reported higher Work and Social Adjustment Scale (WSAS) scores, indicative of more severe functional impairment. 


Overall, lower baseline fatigue and remission of fatigue during treatment were associated with higher rates of remission of depressive symptoms and improved function and quality of life.22 Study limitations include use of the STAR*D level 1 sample (citalopram as only antidepressant), use of a proxy measure of energy/fatigue (item 14 from the QIDS-SR16), and the secondary post hoc analysis design.22



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