Changes in Processing Speed, Cognitive Flexibility, and Selective Attention over a Four-Week Treatment Period in Inpatients with Moderate to Severe Depression
Abstract
Abstract. Cognitive dysfunction among individuals with depression is associated with reduced functional status, and cognitive improvement is often an important treatment goal. We compared changes in cognitive performance over four weeks among 45 inpatients with a unipolar depressive disorder completing inpatient treatment to that of 20 controls on measures of processing speed and set-shifting (Trail Making Test), as well as selective attention (Test d2). In the patients, depressive symptoms improved significantly and with a large effect over the treatment period (d = 1.22–1.81). Among the three cognitive domains examined, the most pronounced reductions among patients compared to controls were observed in cognitive flexibility (Group effect: ηp2 = .04). The effect of Group; however, was not significant. Likewise, there were no significant improvements in cognitive flexibility over time, and changes in cognitive flexibility over the four-week period did not differ between the two groups (Group x Time interaction). Performances in selective attention and processing speed improved over the four-week period, though neither the effect of Group nor the interaction (Group x Time) was significant regarding these performances. Change in cognitive performance was not associated with changes in symptom severity (incl. remission status). Taken together, the significant improvements in selective attention and processing speed were largely attributable to practice effects. Our findings lend further support to the notion that cognitive flexibility, selective attention, and processing speed are independent of improvements in depressive symptoms. This study underscores the importance of including comparison groups to control for practice effects when examining cognitive change, and providing treatments specifically aimed at improving cognitive symptoms.
Zusammenfassung. Kognitive Dysfunktionen werden bei Depressionen mit einem reduzierten Funktionsniveau assoziiert. Daher stellt deren Verbesserung häufig ein wichtiges Behandlungsziel dar. Die Veränderung der kognitiven Leistungsfähigkeit von 45 stationären Patient_innen mit einer unipolaren Depression wurde über einen vierwöchigen Behandlungszeitraum auf Basis der Verarbeitungsgeschwindigkeit und der kognitiven Umstellfähigkeit (Trail Making Test) sowie der selektiven Aufmerksamkeit (Test d2) mit 20 gesunden Kontrollproband_innen verglichen. Bei den Patient_innen verringerte sich die depressive Symptomatik über den Behandlungszeitraum signifikant und mit großer Effektstärke (d = 1.22–1.81). Die kognitive Umstellfähigkeit zeigte sich in der Patienten- im Vergleich zur Kontrollgruppe und relativ zu den anderen kognitiven Maßen numerisch am deutlichsten verringert (Gruppeneffekt: ηp2 = .04). Dieser Gruppeneffekt war jedoch nicht signifikant. Ebenfalls waren die Verbesserung über die Zeit sowie die Veränderungen über die Zeit bezogen auf die verschiedenen Gruppen (Gruppe x Zeit Interaktion) nicht signifikant. Die Testleistungen in selektiver Aufmerksamkeit und Verarbeitungsgeschwindigkeit verbesserten sich über den vierwöchigen Zeitraum. Zwischen den Gruppen und in der Interaktion (Gruppe x Zeit) zeigte sich jedoch auch hinsichtlich dieser Testleistungen kein signifikantes Ergebnis. Die Veränderung der kognitiven Leistungsfähigkeit war nicht mit der Veränderung der Symptomschwere (inkl. Remissionsstatus) assoziiert. Insgesamt waren signifikante Verbesserungen in der selektiven Aufmerksamkeit und der Verarbeitungsgeschwindigkeit damit weitgehend auf Übungseffekte zurückzuführen. Unsere Ergebnisse unterstützen die Annahme, dass Verarbeitungsgeschwindigkeit, selektive Aufmerksamkeit und kognitive Umstellfähigkeit unabhängig von Verbesserungen der depressiven Symptome ist. Zudem unterstreichen sie die Bedeutung der Einbeziehung von Vergleichsgruppen zur Kontrolle von Übungseffekten bei der Untersuchung kognitiver Veränderungen und Behandlungen, die speziell auf die Verbesserung kognitiver Symptome abzielen.
Introduction
Up to two-thirds of individuals presenting for depression treatment report cognitive complaints (Conradi et al., 2011), and difficulties with attention, concentration, and decision-making are core symptoms of major depressive disorder (MDD; World Health Organization, 1992). Improvement in cognitive functioning is a relevant outcome for treatment studies as cognition among individuals with depression mediates impairment in daily functioning and psychosocial deficits (Knight & Baune, 2018). Meta-analyses report significant moderate cognitive deficits among patients with depression (Lee et al., 2012; Rock et al., 2014), though it remains unclear whether and to what extent cognitive functioning may improve over a course of treatment targeting affective symptoms (Douglas & Porter, 2009; Knight & Baune, 2018; Snyder, 2013; Wagner et al., 2012). There has been a call for an improved understanding of whether meaningful improvements in specific cognitive domains and on specific neuropsychological measures occur among patients undergoing treatment (Baune et al., 2018; Shilyansky et al., 2016; Wagner et al., 2012).
Cognitive Change Over the Course of Depression Treatment
Providing support for the potential effects of treatment aimed at affective symptoms on cognitive functioning, impaired cognitive performance may be attributed in part to psychological influences, such as low motivation (Moritz et al., 2017; Scheurich et al., 2008), rumination (Yang et al., 2017), and disengagement from tasks perceived as complex (Bowie et al., 2017). A reduction in such symptoms could lead to improved cognitive functioning. Cognitive bias also plays a central role in the onset and maintenance of depression. Early changes in processes underlying such cognitive bias, namely, information processing and cognitive control, may occur before symptom improvement is observed (Harmer et al., 2009; Roiser et al., 2012; Tranter et al., 2009). Neuroimaging work has identified prefrontal neural predictors of depression recovery (Meyer et al., 2019), and neuropsychobiological mechanisms may be associated with early cognitive improvements (Beblo et al., 2011; Mikoteit et al., 2015).
There are unique associations between affective symptoms and cognitive domains. Across several studies, verbal learning and memory as well as verbal fluency and processing speed were broadly associated with changes in affective symptoms, suggesting these measures may represent state parameters of cognitive functioning within depression (Douglas & Porter, 2009; Lee et al., 2012). In contrast, executive functioning and attention tended to remain impaired across treatment and are, thus, thought to be rather trait markers of depression. However, reflecting the heterogeneity of findings (Knight & Baune, 2018), in a meta-analysis of three studies using the Stroop test, improvements in executive dysfunction were significantly associated with reduced affective symptoms over a course of antidepressant treatment (Wagner et al., 2012).
Such heterogeneity exists for other commonly used neuropsychological measures as well. Among six studies in which the Trail Making Test, Parts A (TMT-A) & B (TMT-B; Reitan, 1992), were administered twice over a short treatment period (i. e., ≤ eight weeks), two (Hinkelmann et al., 2012; Shilyansky et al., 2016) reported nonsignificant improvements among patients with moderate to severe depression compared to controls, whereas three (Clery-Melin & Gorwood, 2016; Sharma et al., 2006; Talarowska et al., 2013) found significant improvements among patients with similar levels of depression receiving antidepressants and/or medication plus a yoga intervention (in the Sharma et al., 2006, study). Among three studies that administered the Test d2 (Brickenkamp, 2002), one found non-significant improvements compared to controls (Hinkelmann et al., 2012), whereas two reported significant improvements within samples of depressed patients (Clery-Melin & Gorwood, 2016; Zobel et al., 2004). All of these studies reported significant improvements in clinician-rated (Hinkelmann et al., 2012; Shilyansky et al., 2016) and/or self-reported symptoms of depression (Shilyansky et al., 2016) among inpatients or outpatients (Clery-Melin & Gorwood, 2016; Sharma et al., 2006; Zobel et al., 2004), suggesting that improvements in mood and cognition can occur over short-term treatment periods.
Douglas and Porter (2009) identified several issues contributing to the heterogeneity of findings among studies examining cognitive change during treatment, including the use of varying neuropsychological measures, a lack of a comparison group to control for practice effects, and different measurement periods. It was also suggested that such studies should examine well-defined patient groups (i. e., excluding patients with bipolar disorders) and report findings on specific neuropsychological measures (Wagner et al., 2012) commonly used in clinical settings.
Cognitive Change Among Patients with Depression and Comorbid Anxiety
The impact of comorbid anxiety on cognitive functioning and cognitive improvement over a treatment period has been understudied. Up to 67 % of individuals with depression have a comorbid anxiety disorder (Baune et al., 2009; Lamers et al., 2011), and comorbidity is associated with poorer treatment outcomes (Kennedy et al., 2007) and increased risk of relapse (Holma et al., 2008). Although relatively more studies have examined cross-sectional differences in cognitive functioning between patients with major depression with (MDDA) and without (MDD) a comorbid anxiety disorder (Airaksinen et al., 2004; Basso et al., 2007; Liu et al., 2020; Lyche et al., 2010; Snyder, 2013), we know of only one study that examined cognitive change over a treatment period. Herrera-Guzmán et al. (2009) reported significant improvements over 24 weeks on a neuropsychological battery, including measures of set-shifting and processing speed; however, improvements did not differ between MDD and MDDA groups. Taken together, it remains unclear to what extent comorbid anxiety may impact cognitive improvement over a treatment period (Herrera-Guzmán et al., 2009; Lyche et al., 2010).
To address the limitations in the current literature and to improve knowledge regarding the possibility of early cognitive improvement during depression treatment, we examined changes on three commonly used neuropsychological measures (i. e., TMT-A, TMT-B, and Test d2) over a four-week period among individuals with moderate to severe depression undergoing intensive inpatient treatment. To control for changes attributable to practice effects, in the first set of analyses we compared cognitive change among patients with depression to change in a control sample without mental disorders. To examine the impact of comorbid anxiety on cognitive change among patients with depression, in a second set of analyses we compared cognitive change among patients with depression and a comorbid anxiety disorder to change in patients with depression but without a comorbid anxiety disorder.
We defined the following three hypotheses: (1) Patients with depression would demonstrate significantly greater improvement in all three cognitive domains over the four-week period compared to the control group. (2) Improvement in cognitive functioning would be significantly associated with improvement in depressive symptoms. (3) Patients with MDD would demonstrate significantly greater improvements in cognitive functioning over the four-week period versus patients with MDDA.
Method
Participants for this study were drawn from two separate studies.
Depressive Sample
Patients with depression were drawn from a randomized controlled trial (RCT) examining the effectiveness of Metacognitive Training for Depression in comparison to an active control group (a modified form of Koppenhöfer’s [2004] euthymic therapy with a focus on activation of pleasant sensory experiences and promotion of everyday positive experiences). Patients from both arms of the RCT were included in the present study. Both interventions were administered as add-on treatments as part of an intensive inpatient program for depression at a university hospital in Germany. The treatment program consisted of individual sessions as well as group therapy and weekly ward rounds. Pharmacotherapy was provided, if indicated, in accordance with the S3 guidelines for depression (DGPPN, 2017). The trial was approved by the Ethics Committee of the German Psychological Association (Hauschildt012015) and was registered at www.clinicaltrials.gov (NWF-15/03, ID NCT02437357). The trial was conducted in concordance with the Declaration of Helsinki as revised 1989.
Patients were consecutively recruited upon admission to inpatient treatment. A psychiatrist screened all patients for inclusion and exclusion criteria. Patients were included if they fulfilled the criteria for a diagnosis of a unipolar depressive disorder (current major depressive episode, recurrent depressive disorder, or dysthymia), as verified by the Mini International Neuropsychiatric Interview (M. I. N. I.; Sheehan et al., 1998) and had adequate German-language abilities. Exclusion criteria included age less than 18 years or greater than 80 years, current or past episode(s) of MDD with psychotic features, current or past psychotic symptoms (e. g., hallucinations, delusions), a psychotic disorder, or current alcohol dependence according to the M. I. N. I., neurological illnesses, a history of head injury or bipolar disorder, aggressiveness, or if the testing had to be terminated due to distress or severe lack of motivation. Comorbid disorders other than psychosis or bipolar disorder were allowed. Twenty-five participants were excluded after the baseline assessment (no unipolar depressive disorder according to the M. I. N. I.: n = 4; psychotic symptoms according to the M. I. N. I.: n = 2; language problems: n = 1; aggressiveness: n = 2; inadequate engagement in testing [e. g., playing with a cell phone despite repeated reminders to focus on testing]: n = 3; assessment terminated due to distress: n = 2; a history of head injury: n = 5; neurological illness: n = 1; current substance or alcohol dependence according to the M. I. N. I.: n = 5).
For the present study, we excluded patients from the index study (clinical trials registration NWF-15/03, ID NCT02437357) who did not complete the second testing session (i. e., lost to follow-up; n = 8). To match the depressive sample to that of controls, patients 65 years of age (n = 3) who participated in the index study were also excluded from the present analyses.
Eligible patients underwent a standardized assessment at baseline and again after four weeks of treatment, which included the TMT and Test d2, as well as the Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory (BDI). Patients gave written informed consent before participation. The assessments were administered by research assistants with bachelor’s degrees in psychology who had received extensive training on all measures before the start of the study. All research assistants received ongoing supervision from licensed psychotherapists and psychotherapists in training. The time of day at which assessments occurred was based on patient preferences and had to be coordinated with treatment appointments (e. g., to allow full participation in therapy groups).
Control Group
Twenty individuals tested as part of another study (Moritz et al., 2018) served as controls. These participants completed two testing sessions by trained researchers, which were also four weeks apart. Participants in the control group completed a range of measures, including the TMT and Test d2. The absence of current mental disorders, including a lifetime history of MDD, (hypo)manic episodes, panic disorder, and/or psychosis was confirmed via the M. I. N. I. Version 5.0.0. Additional exclusion criteria were major neurological disorders (e. g., multiple sclerosis), a history of head injury, and age <18 or >80 years; however, none of the controls tested were over age 65.
Depressive Symptoms
The 17-item Hamilton Depression Rating Scale (HDRS) is a clinician-rated measure of depressive symptoms used to quantify depression severity (Hamilton, 1960). The HDRS has well-documented reliability and validity. In our study, the internal consistency of the scales at baseline and post-assessment were acceptable to good (HDRS baseline: Cronbach’s α = .64; HDRS post: Cronbach’s α = .85). The Beck Depression Inventory (BDI) is a 21-item self-report measure of depressive symptoms (Beck et al., 1961). In our study, internal consistency of the BDI at baseline and post-assessment was good to excellent (BDI baseline: Cronbach’s α = .83; BDI post: Cronbach’s α = .90). Among all patients in our study, change on the BDI was positively associated with change on the HDRS (r = .72, p < .001).
Cognitive Tasks
The Trail Making Test (TMT) is a timed test of processing speed and set-shifting (Reitan, 1992). The reliability coefficients for Part A vary from .60 to .90, whereas the reliability for Part B is .77 (Calamia et al., 2013; Lezak, 1995). Practice effects have been extensively studied. Bornstein et al. (1987) reported a gain of about 3 and 7 seconds, on average, on Parts A and B, respectively, over a 3-week interval. Among controls in our study, correlations for the TMT between the two testing sessions were adequate for TMT-A (r = .73, p < .001) and TMT-B (r = .70, p = .001).
The Test d2 (Brickenkamp, 1978) is a measure of selective attention. In a study examining test-retest effects among 35 university students over three weeks, an average gain of nine points on the concentration subtest was reported with a test-retest correlation of .89 (Gutbert, 2003). Internal consistency is excellent (Bates & Lemay, 2004). Among controls in our study, Test d2 scores at each testing session were highly correlated (r = .90, p < .001).
Strategy of Data Analysis
A logarithmic transformation was performed to correct for significant skew (z-score >2.58 when comparing the skew statistic to its standard deviation; Field, 2013) on the TMT-A and TMT-B total scores at both assessment points.
Chi-square, Mann-Whitney U-tests (patients with depression versus controls), and t-tests (MDD vs. MDDA groups) were used to examine differences in baseline demographic characteristics to ensure that groups were matched by age, education, sex, and testing interval. The association between change in depression (on the HDRS and BDI) and change in cognitive performance was examined using Pearson Product Moment correlations for Test d2 and Spearman correlations for the TMT. Difference scores were calculated as differences in raw scores between baseline and post-assessment.
To examine whether there was a significant difference in cognitive improvement over the four-week treatment period by group, we conducted a repeated measure analysis of covariance (ANCOVA) for each cognitive measure. We conducted these ANCOVAs to analyze differences between patients with depression versus controls as well as patients with (MDDA) and without (MDD) comorbid anxiety. Time was entered as the within-subject variable and Group as the between-subject variable. The dependent variable was the raw score at baseline and the four-week assessment for each of the three neuropsychological measures. Although the groups were matched by age, given the large age range of the sample, age was included as a covariate.
For the comorbidity analyses, based on previous similar studies (Basso, 2007), all individuals with at least one comorbid anxiety disorder according to the Diagnostic and Statistical Manual of Mental Disorders (5th ed., DSM-5; American Psychiatric Association, 2013) were combined into one group. Contrary to previous studies (Basso et al., 2007; Lyche et al., 2010), but in line with evidence that posttraumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD) represent clinical diagnoses distinct from anxiety disorders (Stein et al., 2014), PTSD and OCD were not defined as anxiety disorders.
To account for multiple comparisons, we applied a Bonferroni correction. Given that each hypothesis was tested three times (i. e., once for each measure), significance was determined at the p = .016 level (α = 0.05/3). Effect sizes are expressed as ηp2 (with ηp2 ≈ 0.01, ηp2 ≈ 0.06, and ηp2 ≈ 0.14 corresponding to small, medium, and large effects, respectively). All statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, N. Y., USA).
Results
Patients with depression (n = 45) and controls (n = 20) did not differ regarding age, sex, education or days between testing sessions (all ps >.13; see Table 1).
Description of the Clinical Sample
All 45 patients met the criteria for a current major depressive episode according to the M. I. N. I. Eight (17.8 %) had a single depressive episode, 25 (55.6 %) had recurrent depression, and 12 (26.7 %) had comorbid dysthymia (i. e., double depression). More than half (n = 26, 57.8 %) had at least one comorbid mental disorder (Table 2). The mean clinician-rated and self-reported depression scores at baseline fell in the moderate to severe range. Both self- and clinician-rated depression improved significantly over the four-week treatment period at large effect sizes (Table 2). At post, 48.9 % and 53.3 % of patients were in remission according to the HDRS and BDI, respectively (remission defined as ≤ 7 on the HDRS and ≤ 13 on the BDI). Patients were taking multiple different medications at baseline and post (see Table 2). At post, the medication status for 23 (51.1 %) patients had changed, such that the dosage for an antidepressant medication was adjusted and/or a new medication was added and/or a medication was discontinued (for some patients, multiple adjustments were made).
Cognitive Improvement over Time and Group Differences
The results of the repeated measures ANCOVA (see Table 3) showed that performance on the Test d2 improved in both groups over the four-week period with large effects (F[1, 61] = 23.86, p < .001, ηp2 = .28); after Bonferroni correction, a trend toward significance was found for improvement on the TMT-A (F[1, 62] = 3.06, p = .03, ηp2 = .05). No significant improvement was detected on the TMT-B (F[1, 61] = 2.06, p = .16, ηp2 = .03). The effect of Group was not significant for any measure (Test d2: F[1, 61] = 1.21, p = .28, ηp2 = .02; TMT-A: F[1, 62] = 0.82, p = .37, ηp2 = .01; TMT-B: F[1, 61] = 2.25, p = .14, ηp2 = .04). With regard to our main hypothesis, the Group x Time effects were also not significant (Test d2: F[1, 61] = 0.01, p = .94, ηp2 < .001; TMT-A: F[1, 62] = 0.87, p = .35, ηp2 = .01; TMT-B: F[1, 61] = 1.00, p = .32, ηp2 = .02).
Association Between Change in Cognitive Functioning and Depressive Symptoms
Pearson product-moment (Test d2) and Spearman (TMT) correlations between changes in cognitive performance (based on raw score differences) and change in self- (BDI) and clinician-rated (HDRS) depressive symptoms were small (all r’s < .16) and nonsignificant (all ps >.31).
Cognitive Improvement in Patients with Depression with and without Comorbid Anxiety
Subgroups of patients with (MDDA) and without (MDD) a comorbid anxiety disorder did not differ based on age, sex, education, or days between testing (all ps >.19). In the MDD group, three patients had comorbid OCD (13.0 %) and one had comorbid PTSD (4.3 %). In patients with MDDA, two patients also had comorbid PTSD (9.1 %), three had OCD (13.6 %), and one had anorexia (4.5 %). Depression scores at baseline and post-assessment (see Electronic Supplementary Material [ESM] 1) and rates of remission did not differ between groups (HDRS: nMDD = 12 [52.2 %] vs. nMDDA = 10 [45.5 %]; χ2[1] = .20; p = .65).
With regard to change in cognitive functioning over the treatment period (see ESM 1), repeated measures ANCOVA indicated that performance on the Test d2 improved over the four-week period at a large effect for both groups (F[1, 41] = 14.60, p < .001, ηp2 = .26); however, there was no significant main effect for Group (F[1, 41] = 0.16, p = .70, ηp2 < .001) or the Group x Time interaction (F[1, 41] = 2.99, p = .09, ηp2 = 07). The ANCOVA for the TMT-B indicated nonsignificant effects for Time (F[1, 41] = 0.85, p = .36, ηp2 = .02), Group (F[1, 41] = 0.59, p = .45, ηp2 = .01) and the Group x Time interaction (F[1, 41] = 0.73, p = .40, ηp2 = .02). For the TMT-A, the effects of Group (F[1, 42] = 1.58, p = .22, ηp2 = .04) and Time (F[1, 42] = 0.91, p = .35, ηp2 = .02) were not significant; however, after Bonferroni correction, a trend toward significance with a large effect was found for the Group x Time interaction (F[1,42] = 6.15, p = .017, ηp2 = .13). Post-hoc analyses indicated that TMT-A performance improved significantly over the treatment period only in the MDD group (MDD: F[1, 42] = 23.76, p < .001, ηp2 = .36; MDDA: F[1, 42] = 1.66, p = .21; ηp2 = .04). There were no differences in TMT-A scores between groups at baseline (F[1, 42] = 4.06, p = .05; ηp2 = .09) or post-assessment (F[1, 42] = 0.02, p = .89; ηp2 < .001).
Association Between Change in Cognitive Functioning and Depressive Symptoms by Comorbidity Status
Correlations between change in depressive symptoms and change in cognitive functioning were small and nonsignificant (all rs < 0.26, all ps >.25), indicating that there was no association between cognitive change and symptom change for either the MDD or MDDA group.
Post hoc Power Analysis
According to a post hoc power analysis with G*Power, for an ANCOVA with a total sample size of 65 participants and an alpha of .016, for a Group x Time interaction with a small effect (ηp2 = 0.01), achieved power (1-β) was 0.05. Achieved power for an interaction with moderate effect size (ηp2 = .06) was 0.33. Sample sizes of 1,049 and 168 participants, respectively, would have been needed to identify the effects of these magnitudes.
Discussion
The present study examined change in processing speed, selective attention, and cognitive flexibility among patients with moderate to severe depression completing a four-week course of intensive inpatient treatment. Changes in these domains were examined in three ways. First, we examined changes among patients with depression in comparison to a control group of individuals free of (current) mental disorders. We next assessed whether cognitive improvement was associated with improvement in depressive symptoms. Finally, to determine the impact of comorbid anxiety on cognitive improvement, we also examined whether there were differences in cognitive change between patients with depression with and without comorbid anxiety.
Cognitive Change Among Patients Versus Controls
Patients improved significantly in self- and clinician-rated depressive symptoms with large effect sizes. Both patients and the control group improved in selective attention and processing speed; however, compared to controls, we found no disproportionate improvement in the patient group undergoing intensive inpatient treatment for any neuropsychological measure. This finding is congruent with previous evidence that over a short-term treatment period, the observed improvement in cognitive performance among patients with depression is not significantly greater than practice effects observed in a control group (Hinkelmann et al., 2012; Lin et al., 2014; Shilyansky et al., 2016). Other studies with similar follow-up timeframes which found significant improvements on the TMT (Clery-Melin & Gorwood, 2016; Sharma et al., 2006) and Test d2 (Clery-Melin & Gorwood, 2016; Zobel et al., 2004) among patients with depression failed to include a control group. However, it should be emphasized that controlgroup participants do not represent a perfect proxy. For example, patients may have demonstrated enhanced or diminished practice effects beyond those accounted for by the control group (Shilyansky et al., 2016). Differences between patients and controls in other cognitive domains, such as memory and learning (Rock et al., 2014), also cannot be completely accounted for and likely impacted performances on the domains examined in our study.
In contrast to the findings for selective attention and processing speed, no significant improvements were observed for cognitive flexibility in either group. Although cognitive flexibility did not differ significantly between groups, it is notable that the effect size for this difference was in the moderate range (ηp2 = .04). This effect size is of a similar magnitude to those reported in meta-analyses (Snyder et al., 2013; Lee et al., 2012) as well as a large study in which differences between patients with depression and controls at baseline and post-assessment were significant (Shilyansky et al., 2016). Interpretation of this effect must proceed carefully given the nonsignificant differences as well as the aforementioned limitations of comparisons with a control group; however, this points toward reduced cognitive flexibility among patients in our study. Additionally, the persistently reduced cognitive flexibility over the course of treatment despite improvement in affective symptoms is generally consistent with the proposed trait-like nature of cognitive flexibility (Douglas & Porter, 2009).
Association Between Depressive Symptoms and Cognitive Functioning
In line with several previous studies, cognitive improvement was not associated with improvement in affective symptoms or remission status (Reppermund et al., 2009; Shilyansky et al., 2016; Snyder, 2013, but see also Etkin et al., 2015; McDermott & Ebmeier, 2009; Wagner et al., 2012). In addition to practice effects, it is also possible that changes in cognitive functioning are attributable to factors that went unmeasured in our study, such as emotion regulation strategies (e. g., rumination; Yang et al., 2017), which are not directly measured with the HDRS or BDI, or neurobiological processes, such as increases in brain-derived neurotrophic factor (Mikoteit et al., 2015). It also remains unclear how factors such as performance motivation, attitudes toward cognitive assessment, and momentary symptoms vary between assessments and over the course of depression (Moritz et al., 2017). Measurement of such parameters in clinical studies could help provide more conclusive evidence regarding the extent to which observed changes may be attributable to practice effects.
Our findings suggest that treatments aimed at reducing affective symptoms are alone insufficient for improving cognitive functioning. Therapies directly targeting cognition may be more effective in reducing cognitive impairment associated with depression. Cognitive training programs have demonstrated moderate to large effects in domains of attention, executive functioning, and processing speed among individuals with depression (Motter et al., 2019; Motter et al., 2016). Given accumulating evidence that treatment for affective symptoms does not lead to cognitive improvement as well as the observed persistence of reduced cognitive functioning even after symptom remission (Bora et al., 2013; Lin et al., 2014), cognitive training represents an important treatment option for targeting cognitive impairment in depression.
Cognitive Change Among Patients with Comorbid Anxiety Versus Those Without
Given the relative dearth of research on the impact of comorbidities on cognitive functioning in depression, another aim of this study was to examine whether cognitive improvement among patients with depression differed depending on the presence of comorbid anxiety. Group differences for change on measures of selective attention and cognitive flexibility were nonsignificant, whereas patients in the MDD group demonstrated a relatively greater improvement in processing speed over the treatment period compared to the MDDA group with a large effect. Our conclusions regarding this finding must remain tentative given that the interaction effect did not fully meet the criteria for statistical significance and performance in the MDD group was not compared with that of healthy controls.
We know of only one previous study (Herrera-Guzmán et al., 2009) that examined changes in processing speed over a treatment period among patients with depression with (MDDA) and without (MDD) comorbid anxiety. In that study, there were no significant differences in improvement between MDD and MDDA groups over 24 weeks of pharmacological treatment (Herrera-Guzmán et al., 2009). Given that, in our study, patients in the MDD group demonstrated a slower processing speed at baseline compared to the MDDA group (in line with Mikoteit et al., 2015), it may be that patients with the most impaired performances on measures at baseline also demonstrate the largest improvements. Alternatively, the changes we observed may reflect enhanced practice effects among patients with depression only (Shilyansky et al., 2016) or possibly a state-like nature of processing speed specifically among patients without comorbid anxiety (Douglas & Porter, 2009; Lee et al., 2012). Further work is needed to examine the extent to which greater improvements in processing speed may be observed in patients without comorbid anxiety compared to those with anxiety and a control group. Our study is also limited by the fact that we did not include a measure of the severity of anxiety. Previous studies classified PTSD and OCD as anxiety disorders (Basso et al., 2007; Lyche et al., 2010) or have used measures of anxiety to identify MDDA groups (Airaksinen et al., 2004). Future work should seek to use consistent methods of determining the presence of comorbid anxiety.
Limitations
There are several additional limitations and caveats to our study. According to a post hoc power analysis, our sample size affected our ability to detect effects in the small to moderate range, which have been reported elsewhere in meta-analyses examining cognitive change in depression (Bernhardt et al., 2019). Given that five patients had to be excluded after baseline because of symptoms related to depression, including poor motivation and distress, patients with more severe symptoms may not have been proportionately included in this study. Such patients tend to have greater cognitive impairments (Snyder, 2013) but may also demonstrate more cognitive recovery during an acute treatment period (Mikoteit et al., 2015). Patients in the present study were completing an intensive inpatient psychiatric treatment program but were randomly assigned to differing add-on treatments as part of an RCT. These add-on treatments, and specifically their possibly differing impacts on cognitive performance, were not considered in our analyses. Finally, because of limited study resources for the RCT from which patients with depression were drawn, neuropsychological testing was very brief. The limited spectrum of neuropsychological measures also prohibits a more detailed examination of which cognitive domains may represent state versus trait parameters of neuropsychological functioning in depression (Douglas & Porter, 2009; Kundermann et al., 2015; Snyder, 2013; Wagner et al., 2012). This battery would need to be supplemented by measures tapping into other domains. Future studies would be more informative if measures of verbal learning and memory and verbal fluency are included in addition to measures of executive functioning, attention, and processing speed. In addition to these factors, we also did not control for the time of day at which the assessments occurred (Beblo et al., 2011) or account for the differing effects, including side effects, of antidepressants on cognitive functioning or the differing timeframes in which patients had taken such medications (Hemmeter & Kundermann, 2012).
Nonetheless, strengths include the use of a control group, verified diagnoses, repeated assessments, the use of clinician-rated and self-report measures of depression severity, and a well-defined patient and comparison sample. Given the naturalistic character of this study (e. g., patients with comorbidities, no control of psychotropic medications), our findings reflect cognitive functioning among typical patients seen in inpatient settings rather than highly selected patient groups often recruited for clinical trials.
Conclusions
In summary, no significant improvements in selective attention or processing speed were detected in a sample of inpatients with significant improvements in depressive symptoms at large effects over a four-week treatment period, in comparison to the practice effects demonstrated by a control group. Although, congruent with previous studies, group differences in performance did not reach significance, cognitive flexibility among patients was reduced relative to controls and did not improve significantly over the treatment period. Cognitive improvement was not associated with improvement in depressive symptoms. These findings suggest that interventions treating affective symptoms are alone insufficient for improving cognitive functioning among individuals with depression. Neuropsychological therapies targeting cognitive functioning may more effectively reduce cognitive impairment associated with depression. Finally, although we found evidence of greater improvement in processing speed among patients without comorbid anxiety, interpretation of this finding was limited by several factors. Well-designed studies with large sample sizes are needed to better understand cognitive functioning early in treatment and particularly the impact of comorbid anxiety on cognitive functioning among patients with depression (Beblo et al., 2011; Snyder, 2013).
Electronic Supplementary Material
The electronic supplementary material (ESM) is available with the online version of the article at https://doi.org/10.1024/1016-264X/a000330
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