Relationship Between Residual Symptoms of Depression and Self-reported Cognitive Impairment

Paola Pedrelli, PhD
Instructor of Psychology, Harvard Medical School; Assistant in Psychology, Massachusetts General Hospital

Lee Baer, PhD
Professor of Psychology, Department of Psychiatry, Harvard Medical School; Associate Chief of Psychology, Massachusetts General Hospital

Dan V. Iosifescu, MD, MSc
Associate Professor of Psychiatry, Harvard Medical School

Maurizio Fava, MD
Professor of Psychiatry, Harvard Medical School

First published in Psychiatry Weekly, Volume 5, Issue 3, on February 8, 2010

Introduction

Despite the availability of numerous antidepressants, many patients with major depressive disorder (MDD) receiving optimal pharmacological treatment do not remit while still experiencing residual symptoms.^1,2 Fava and Davidson¹ observed that between 29% and 46% of depressed patients fail to fully respond to antidepressant treatment of adequate dose and duration. Further, it has been estimated that 30% to 50% of patients who remitted from depression continue to have residual symptoms.^1-3

The presence of residual symptoms in remitted MDD patients has been associated with greater risk of relapse, higher rates of suicidal attempts and ideation, and impaired functioning.^2,4,5 In a longitudinal study of 64 patients with MDD, 75% of patients with partial response experienced residual symptoms, such as fatigue, psychic anxiety, somatic anxiety, genital symptoms, depressed mood, insomnia, or guilt.⁴ The most prevalent residual symptoms among adult individuals with MDD who remitted after fluoxetine treatment were sleep disturbances and fatigue.³

Deficits in a range of cognitive domains are prevalent in patients remitted from MDD who continue to experience residual symptoms and may play an important role in the course and phenomenology of depression. Fava and colleagues⁶ observed that out of 117 patients with MDD meeting criteria for response after receiving antidepressants, over 30% reported cognitive symptoms such as apathy, inattentiveness, forgetfulness, word finding difficulty, and mental slowing. Cognitive impairment is not only prevalent in patients who remitted from MDD, but it also appears that some persistent cognitive deficits (eg, impaired attention) are associated with relapse.⁷

Methods

The current study aimed at investigating the relationship between specific depressive symptoms and reported cognitive symptoms in patients with remitted, or partially remitted, MDD. Inclusion criteria for the study were: >18 years of age and being considered with MDD in partial or full remission (responders) after having received antidepressants for at least 3 months for the treatment of MDD. Subjects were 117 patients with MDD, mean age 43.4+12.6 (median age=43), of which the majority were women (66.7%).

Approximately two thirds of the participants were on one antidepressant (75.9%), and the rest were on two (16.2%) or three (7.8%). Overall, ~50% of the participants were on at least one adjunct medication in combination with an antidepressant. Less than one in five participants were taking two adjunct medications (17.9%) and one participant was on three medications in conjunction with an antidepressant (0.9%). With regard to medications with sedative side effects, 9.4% of patients were on tricyclic antidepressants (TCAs), 30.8% were on benzodiazepines, and 0.9% were on mirtazapine.

Discussion

Upon examining the relationships between specific items of the Cognitive and Physical Functioning Questionnaire (CPFQ) and of the Harvard Department of Psychiatry National Depression Screening Day Questionnaire (HANDS) among depressed outpatients who had responded to antidepressant therapy, we observed several novel associations between residual depressive symptoms and reported cognitive impairment. Our findings add to the current knowledge by suggesting that fatigue is associated with impairment in specific cognitive domains (focusing and sustained attention). This enhances previous reports describing fatigue as a frequent residual symptom in remitted MDD patients^3,6 and associated with increased risk of MDD relapse.⁸

Apathy has been defined as a symptom indicating loss of interest or emotions distinct from anhedonia,⁹ and it has been observed not only among remitted MDD patients^6,10 but in other illnesses with different etiologies. We found an association between apathy and difficulty with concentration among MDD remitted patients; this suggests that apathy is associated with cognitive deficits in several cognitive domains in a range of illnesses. Furthermore, the associations among feeling “blue,” difficulty with concentration, and apathy underline the need to further examine the presence of common subcortical neurocircuits underlying these symptoms.

As anticipated, difficulty with concentration, as measured by the HANDS, was associated with inability to focus and with mental acuity reported on the CPFQ. Moreover, fatigue was associated with reported problems of low energy. Predictably, lack of interest was associated with lower motivation and apathy. Given that the CPFQ was developed to measure cognitive and physical dysfunctions common in mood disorders, these associations provide further support for the convergent validity of the CPFQ. Patients who reported residual difficulty with appetite, sleep, self-blaming, worthlessness, hopelessness, and suicidal thoughts did not endorse cognitive symptoms.

The current study has several limitations. Cognitive symptoms were assessed only by a self-report measure, which asked for the subjective experience of the participants. The CPFQ has demonstrated to be correlated with a validated neuropsychological objective measure of cognitive impairment,¹¹ however further studies are needed to examine whether our findings are replicated when using standardized measures of cognitive deficits. Results have to be interpreted with caution; we cannot determine whether the physical and cognitive symptoms were residual symptoms of MDD or side effects of antidepressant medications. We examined possible differences in CPFQ total score due to medications and we did not find any statistically significant differences.

Conclusion

Our findings underline the importance of assessing cognitive deficits in remitted MDD patients reporting residual depressive symptoms such as fatigue, feeling “blue”, and low motivation. Furthermore, given the significant psychosocial impairment found even with subthreshold symptoms of depression, and the call by Judd and colleagues⁵ for treating MDD even when at a deceptively mild level of severity, these findings further underscore the importance of treating fatigue and feeling “blue” among MDD remitted patients. Lastly, our findings suggest the need for further studies of common clinical and neurobiological substrates among co-occurring symptoms in remitted MDD patients.

Disclosure: Dr. Iosifescu is on the speaker’s bureau of Eli Lilly, Forest Laboratories, Pfizer, and Reed Medical Education; and has received grant/research support from Aspect Medical Systems, Forest Laboratories, Janssen, the National Alliance for Research on Schizophrenia and Depression, and the National Institutes of Health. Dr. Fava is a consultant to Abbott, Amarin, Aspect Medical Systems, AstraZeneca, Auspex, Bayer AG, Best Practice Project Management, Biovail, BrainCells, Bristol-Myers Squibb, Cephalon, Clinical Trials Solutions, CNS Response, Compellis, Cypress, Dov, Eli Lilly, EPIX, Fabre-Kramer, Forest Pharmaceuticals, GlaxoSmithKline, Grunenthal GmBH, Janssen, Jazz, Johnson & Johnson, Knoll, Labopharm, Lorex, Lundbeck, MedAvante, Merck, Methylation Sciences, Neuronetics, Novartis, Nutrition 21, Organon, PamLab, Pfizer, PharmaStar, Pharmavite, Precision Human Biolaboratory, Roche, Sanofi-Aventis, Sepracor, Schering-Plough, Solvay, Somaxon, Somerset, Synthelabo, Takeda, Tetragenex, Transcept, Vanda, and Wyeth; is on the speaker’s bureau of AstraZeneca, Belvoir, Boehringer-Ingelheim, Bristol-Myers Squibb, Cephalon, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, Imedex, Novartis, Organon, Pfizer, PharmaStar, UBC, and Wyeth; has received grant/research support from Abbott, Alkermes, Aspect Medical Systems, AstraZeneca, Bio Research, BrainCells, Bristol-Myers Squibb, Cephalon, Clinical Trial Solutions, Eli Lilly, Forest Pharmaceuticals, Ganeden, GlaxoSmithKline, Johnson & Johnson, Lichtwer Pharma GmbH, Lorex, NARSAD, the National Center for Complementary and Alternative Medicine, the National Institute on Drug Abuse, the National Institutes of Mental Health, Novartis, Organon, PamLab, Pfizer, Pharmavite, Roche, Sanofi-Aventis, Shire, Solvay, Synthelabo, and Wyeth; and owns stock in Compellis. Dr. Pedrelli and Dr. Baer report no affiliation with or financial interest in any organization that may pose a conflict of interest.

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