Cognitive function after clinical remission in patients with melancholic and non-melancholic depression: A 6 month follow-up study

Journal of Affective Disorders 171 (2015) 85–92

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Research report

Cognitive function after clinical remission in patients with melancholic and non-melancholic depression: A 6 month follow-up study Miquel Roca a,b,n, Saray Monzón a, Margalida Vives a,b, Emilio López-Navarro a,b, Mauro Garcia-Toro a,b, Caterina Vicens b,c, Javier Garcia-Campayo b,d, John Harrison e, Margalida Gili a,b a

Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), University of Balearic Islands, Palma de Mallorca, Spain Red de Actividades Preventivas y Promoción de la Salud en Atención Primaria (RediAPP), Institute Carlos III, Spain c Centro de Salud Son Serra-La Vileta, Ib-Salut., Baleares, Spain d Department of Psychiatry, Miguel Servet Hospital, University of Zaragoza, Zaragoza, Spain e Department of Medicine, Imperial College, London, UK b

art ic l e i nf o

a b s t r a c t

Article history: Received 26 March 2014 Received in revised form 2 September 2014 Accepted 4 September 2014 Available online 28 September 2014

Background: Cognitive symptoms are core symptoms with an impact on functioning in depression. Remission is considered as the main objective of the management and treatment of depression. This study was aimed to compare cognitive performance between melancholic (MelD) and non-melancholic depression (NMelD) and to determine whether these cognitive alterations remain after clinical remission. Methods: We performed a 6 month follow-up study of 88 melancholic and non-melancholic depressive patients. Sociodemographic and clinical characteristics were recorded. Depression was examined using the Hamilton Depression Rating Scale and the CORE Index for Melancholia. Cognitive performance was assessed with the Trail Making Test (TMT), the Digit Span subtest of the WAIS-III, Stroop Colour Word Test (SCWT), the Tower of London (TOL DX), the Controlled Oral Word Association Test (FAS), Semantic Verbal Fluency and Finger Tapping Test (FTT). Results: MelD patients show worse performance than N-MelD at baseline, with significant differences at Digit Span subtest of WAIS Part I and Part II, SCWT Part I and Part II, TOL DX, Total Problem Solving, Total Execution Time and FTT- Preferred hand. Cognitive impairment remains at six months follow-up after clinical remission in MelD. In the comparison between remitted and non-remitted patients, cognitive impairment in Trail Making Test Part B and Verbal and Semantic Fluency (Animals) remains after clinical remission in MelD group but not in non-melancholic patients. Limitations: The use of psychopharmacological treatment and the small sample of melancholic patients. Conclusions: Patients with MelD do not improve cognitive performance despite clinical remission compared with remitted NMelD patients. The persistence of some cognitive dysfunctions in MelD remitted patients could represent a trait marker of a different depressive subtype and not be secondary to disease severity. & 2014 Elsevier B.V. All rights reserved.

Keywords: Cognition Depressive disorder Remission Melancholic depression

1. Introduction Cognitive symptoms are “core” symptoms of depressive disorders with clear impact on social and occupational functioning in these patients (McCall and Dunn, 2003; McIntyre et al., 2013; Jaeger et al., 2006). Cognitive impairment, including on executive functions,

Abbreviations: MelD, melancholic depression; NMelD, non-melancholic depression n Corresponding author at: Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), University of Balearic Islands, 07122 Palma, Ctra. Valldemossa, km 7.5, Spain. Tel.: þ 34 971173081; fax: þ 34 971259935. E-mail address: [email protected] (M. Roca). http://dx.doi.org/10.1016/j.jad.2014.09.018 0165-0327/& 2014 Elsevier B.V. All rights reserved.

information processing speed, episodic and semantic memory, has been reported in different groups of patients during acute episodes of major depression (Ravnkilde et al., 2002; Porter et al., 2003). Remission is now considered as the main objective of the management and treatment of depression. The published studies on cognitive performance on remitted patients offer controversial results: cognitive dysfunctions remain during remitted states (Neu et al., 2005; Paelecke-Habermann et al., 2005; Nakano et al., 2008; Preiss et al., 2009; Bhardwaj et al., 2010; Hasselbalch et al., 2011). Nonspecific deficits have also been found in recovered depressive patients (Reppermund et al., 2009). In a recent study of patients with at least two previous episodes, the presence of mild cognitive impairment during remission failed to predict future relapses

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within two years. There was no significant association between neuropsychological performance and prior course of the disease (Wekking et al., 2012). Inconsistent findings have been also published with regard to severity of depression or depressive subtypes (Hasselbalch et al., 2011; McDermott and Ebmeier, 2009; Herrmann et al., 2007). The clinical subtypes of atypical depression, melancholic depression or psychotic depression are typically regarded as qualitatively different, or just as a more severe form of the disease (Leventhal and Rehm, 2005; Shorter, 2007; Porter et al., 2007). However, in melancholic depression, clinical episodes are characterized by lack of reactivity, psychomotor retardation, agitation, weight loss and inappropriate guilt (American Psychiatric Association, 2013). The results of one study (Marcos et al., 1994) suggested that cognitive dysfunctions in recovered melancholic patients unlikely to be state-dependent. The first and only study comparing cognitive performance of 34 patients with and without melancholic depression from hospital admission to recovery, found a distinctly different with greater cognitive impairment in the melancholic group on memory acquisition, mental flexibility, selective attention, concept-formation and multi-tasking (Withall et al., 2010). Follow-up studies comparing samples of melancholic and non melancholic depressive outpatients during an acute episode and after clinical remission are still rare and it remains unclear with current data if cognitive disturbances are state or trait factors. A key issue is to determine whether cognitive impairment predates a first episode of depression and whether cognition continues to decline as a function of disease progression. The aim of the present study was to analyze cognitive performance between melancholic depression and non-melancholic depression and to compare cognitive dysfunction in both groups of outpatients, determining whether these alterations remain after clinical remission or not. We hypothesize a greater cognitive difficulty in the MelD group by comparison with the NMelD group analyzed.

2. Methods 2.1. Subjects, settings and procedure A total of 88 outpatients with a DSM-IV-TR diagnosis of acute episode of major depressive disorder (MDD) were followed up after 6 months. Consecutive patients were recruited by clinical psychiatrists from 4 health care units during the period between January 2011 and June 2011. Any outpatient who might fulfil all the inclusion criteria was invited to participate in the study. Male and female outpatients who were eligible and signed the written informed consent were entered into the study. All neuropsychological assessments were performed by two trained psychologists (SM, MV). Inclusion criteria were: a diagnosis of DSM-IV-TR MDD, to be under treatment with antidepressant agents or to initiate this treatment, age between 18 and 55 years, a total 17-item Hamilton Depression Rating Scale (Hamilton, 1960) score Z17, a total score greater or equal to 8 in the CORE Index for Melancholia (Parker et al., 1994) and DSM-IV-TR criteria (American Psychiatric Association, 2000) for the Melancholic Depression patients and less than 8 for the non-melancholic depression individuals and enough capacity for understanding and signing the written informed consent form. Exclusion criteria were: history of medical conditions that could entail cognitive deterioration, history of head injury or neurological disorder, current psychotic symptoms, current treatment with antipsychotic or mood stabilizer agents, electroconvulsive therapy in the 6 months prior to the study; a Mini-Mental State Examination (Folstein et al., 1975) score lower or equal to 25; a diagnosis of

intellectual disability or inability to understand or complete the cognitive assessment. Clinical interview was performed both at baseline and followup assessments. The structured clinical interview addressed sociodemographic characteristics, medical history and current medication prescription. Clinical scales and questionnaires were also administered. The cognitive assessment followed the clinical interview. The follow-up assessment took place after 6 months of inclusion in the study and included all patients, irrespective of their clinical state (i.e. acute phase, clinical remission or recovery). Clinical remission was defined as having a HAM-D total score r7 at the 6-month follow-up assessment. All assessments were carried out in the morning in order to avoid the confounding effects of diurnal fluctuation in mood and cortisol levels. The study protocol received the approval of the Ethics and Clinical Research Committee of the Balearic Islands (Palma de Mallorca, Spain). 2.2. Measurements A socio-demographic and clinical questionnaire was designed specifically for this study. Relevant socio-demographic information including gender, date of birth and age, marital status, education level and occupational status, as well as clinical data regarding age of disorder onset, number of previous episodes and current pharmacological treatment (type of drug, mean dose and time of administration) was collected. 2.3. Clinical assessment – DSM-IV criteria for Melancholic features Checklist. Required features include anhedonia and or a lack of reactivity plus three of the following symptoms: distinctly depressed mood, early insomnia, psychomotor retardation or agitation, marked weight loss and unwarranted or disproportionate guilt. – 17-item Hamilton Depression Rating Scale. The HAM-D is the most commonly used scale in clinical practice and research in mood disorders to rate the symptom severity. – The CORE Index for Melancholia is an 18-item scale which assesses retardation, agitation and non-interactivity by behavioural observation. The instrument was validated by comparison with clinical and neuroendocrine measures. The CORE Index appears able to distinguish melancholia from other residual depressive disorders with respect to neurobiological variables and treatment-specific responses. – Mini-Mental State Examination. The MMSE is a brief 30-point questionnaire of a broad array of cognitive functions including orientation, memory and language. MMSE is employed as a screening tool to identify and exclude potential patients with early onset dementia. 2.4. Cognitive assessments Neuropsychological assessment was administered in this fixed order and conducted at inclusion and follow-up: 1. Trail Making Test-Parts A and B (TMT) (Army Individual Test Battery, 1964). It measures visual attention and task-switching. The subject has to connect consecutively numbered circles (Trials A) and then has to connect numbers and letters in alternating sequence (Trails B). The difference score B A would minimize visuoperceptual and working memory demands, providing a relatively pure indicator of executive control abilities. 2. Digit Span subtest of the Weschler Adult Intelligence Scale, 3rd edition (WAIS-III) (Weschler, 1997). Digit span forward is used to measure attention and phonological storage in working

M. Roca et al. / Journal of Affective Disorders 171 (2015) 85–92

memory. Digit span backwards also is used to measure executive function (Lezak, 1995). 3. Stroop Colour Word Test (SCWT) (Golder, 1978). This is a measure of selective attention, freedom from distractibility and response inhibition. First, the subject has to read out three colour names printed in black as fast as possible. Then, is presented with the same words printed in a colour different from the colour which it names and the subject has to name the colour of the ink in which word is printed as fast as possible. The time used to complete the task increases significantly in the third trial, it is called “interference effect”. The interference score is calculated by subtracting Trial 1 (naming words) from Trial 3 (naming the colour in which the word is printed). A higher score indicates greater interference. 4. Tower of London, 2nd Edition (TOL-DX) (Culberston and Zillmer, 2006). This is an instrument of planning that taxes central executive function. The subjects have to rearrange a set of spheres to match a given target arrangement in a specified number of moves. Accuracy and latency are recorded (Gallagher et al., 2007). 5. The Controlled Oral Word Association Test (FAS) (Borkowski et al., 1967). This task involves development of a strategy to produce the words. In this instrument the subject has to

87

generate words starting with letters F, A and S as fast as possible during 1 min. A mean of 12 words beginning with a specific letter in 1 min is a standard score. 6. Semantic Verbal Fluency (ANIMALS) (Ardila and Ostrosky-Solls, 2006). The subject has to generate words corresponding to a specific semantic category (animals in this case). The number of correct words in one minute is counted and a mean of 16 words is a standard score. 7. Finger Tapping Test (FTT) (Western Psychological Services, 1994). The Finger Tapping Test is a measure of motor speed and motor control. Speed, coordination and pacing requirements can be influenced by alertness levels, impaired ability to focus attention or slowing of responses. More specific details on methodological issues of the present study have been described elsewhere (Monzón et al., 2010). 2.5. Data analysis Descriptive statistics were reported as frequencies, means and standard deviations. In addition to raw scores, standard scores (controlled by gender and age) were used to compute neuropsychological performance. Before proceeding to conduct comparisons

Table 1 Sociodemographic and clinical characteristics. Variable

Gender n (%) Male Female Age, years mean (SD) Civil status n (%) Single Married Widowed Separated Education n (%) Incomplete primary Complete primary Secondary University Employment status n (%) Employed Unemployed Housework Student Retired Lives n(%) Living alone Living accompanied Length from first episode (Months) mean (SD) Previous episodes n (%) Single Recurrent 1–2 previous episodes Z 3 previous episodes HRSD mean (SD) Pharmacological treatment n(%) No treatment Antidepressant SSRIa SNRIb TCAc Other Benzodiazepines Antidepressantþ Benzodiazepines a b c

Selective Serotonin Reuptake Inhibitors. Serotonin Norepinephrine Reuptake Inhibitors. Tricyclic antidepressants.

Total

Melancholic

Non-melancholic

n¼ 88

n¼ 25

n¼63

21 (23.9) 67 (76.1) 48.17 (8.95)

10 (40) 15 (60) 49.56 (7.21)

11 56 3 18

(12.5) (63.6) (3.4) (20.5)

6 16 1 2

6 50 19 12

(6.9) (57.4) (21.8) (13.8)

1 9 6 8

50 8 1 2 6

(57.5) (9.2) (1.1) (2.3) (6.9)

11 (17.5) 52 (82.5) 47.62 (9.55)

p-Value

0.025 0.496

(24) (64) (4) (8)

5 40 2 16

(7.9) (63.5) (3.2) (25.4)

0.095

(4.2) (37.5) (25) (33.3)

5 41 13 4

(7.9) (65) (20.6) (6.3)

0.017

12 (50) 3 (12.5) 2 (8.3)

38 5 1 2 4

(60.3) (7.9) (1.6) (3.2) (6.3)

0.756

10 (11.4) 76 (86.4) 111.35 (137.8) 29 53 29 24 23.68

(35.4) (64.6) (54.7) (45.3) (4.44)

5 80 39 33 2 20 43 40

(5.7) (90.9) (44.3) (37.5) (2.3) (22.7) (48.9) (45.5)

6 (24) 19 (76) 181.96 (172.5) 7 17 6 13 24.16

(29.2) (70.8) (35.3) (64.7) (5.53)

– 24 (96) 11 (44) 13 (52) 2 (8) 6 (24) 14 (56) 13 (52)

4 (6.3) 57 (90.5) 83.33 (111.07) 22 36 23 13 23.49

(37.9) (62.1) (63.9) (36.1) (3.97)

5 (7.9) 56 (88.9) 28 (44.4) 20 (31.8) 14 (21.9) 29 (46) 27 (42.9)

0.057 0.058 0.450 0.051

0.527 0.314

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M. Roca et al. / Journal of Affective Disorders 171 (2015) 85–92

between groups, the assumption of sample normality was checked. When statistical assumptions of the parametric tests were not adequate, Mann–Whitney U-test was performed. To identify possible differences between the course of cognitive functions in MelD patients and NMelD patients as a function of remission (time group  remission) repeated-measures multivariate analysis of covariance (MANCOVA) was conducted with education level as covariate. If parametric assumptions were not met a bootstrapped MANCOVA was performed at 2000 iterations with education level as covariate. Interaction analysis was performed using Bonferroni correction to control Type I error across comparisons. Statistical significance was set at 0.05.

3. Results From a total of 88 participants, 63 patients (71.6%) receive diagnoses of non-melancholic depression (NMelD) and 25 patients (28.4%) were diagnosed as having melancholic depression (MelD). The total sample had a mean age of 48.17 years (SD ¼8.95) and they were mainly women (76.1%), married (63.3%) or living accompanied (86.4%), employed (57.5%), with at least primary education studies (57.4%). 35.4% were patients in their first episode and the remaining 64.6% were recurrent depressive patients. The mean length from first depressive episode was 9.28 years (SD ¼11.48). The mean HRSD total score for the whole sample was 23.68 (SD ¼4.44) and most of the participants were treated with antidepressant (90.9%). In the comparison of MelD versus NMelD, statistically significant differences were found by gender (p ¼0.025) and level of education (p¼ 0.017). More detailed information on sociodemographic and clinical characteristics of the sample is included in Table 1. Information regarding cognitive dysfunction collected at baseline assessment is shown in Table 2. Attention, speed of information processing, psychomotor speed, mental flexibility and verbal and semantic fluency were impaired during acute phase. At baseline melancholic patients demonstrated worse performance in TMT-Part B (standard score¼  3.29, SD¼3.60) and SCWT (Part I: standard score¼  1.66, SD¼1.45; Part II: standard score¼ 1.45, SD¼1.29; Part III: standard score¼  1.41, SD¼ 1.34). Non-melancholic patients obtained worse results in TMT (Part A: standard score¼ 2.39, SD¼ 4.54; Part B: standard score¼ 3.09, SD¼3.21) and Controlled Oral Word Association Test (standard score¼  1.57, SD¼0.99). Comparison of the two groups indicated that MelD patients exhibited worse results than NMelD in most of the neuropsychological tests. Significant differences were found between MelD and NMelD in Digit Span subtest of WAIS-Part I (mean¼ 6.29, SD¼2.35 vs. mean¼6.57, SD¼ 1.57; p¼ 0.027), Digit Span subtest of WAIS-Part II (mean¼ 3.96, SD¼ 1.85 vs. mean¼4.24, SD¼1.49; p¼0.049), SCWT-Part I (mean¼85.58, SD¼29.67 vs. mean¼92.43, SD¼ 15.48; p¼0.031), SCWT- Part II (mean¼55.5, SD¼ 17.44 vs. mean¼ 62.1, SD¼11.19; p¼0.005), TOL DX Total Problem-Solving (mean¼ 410.96, SD¼182.3 vs. mean¼342.65, SD¼150.39; p¼ 0.018), TOL DX Total Execution Time (mean¼320.52, SD¼167.56 vs. mean¼ 265.22, SD¼141.283; p¼0.043), and FTT- Preferred hand (mean¼46.56, SD¼11.92 vs. mean¼ 52.25, SD¼12.99; p¼0.034). Comparison between depressive subtypes at baseline and 6-moths is show in Table 3. No significant association was found. Six month follow-up assessment results allowed evaluating clinical remission and non-remission (Table 4). In the comparison between remitted and non-remitted depressed patients, cognitive impairment remains after clinical remission in MelD group. In contrast, these disturbances improved in non-melancholic patients. Significant differences were found between MelD remitted and nonremitted patients in TMT-Part B (mean¼90.22, SD¼41.59 vs. mean¼ 157.17, SD¼76.86; p¼0.016) and Semantic Verbal Fluency

Table 2 Baseline cognitive assessment. Melancholic n¼ 25 mean (SD)

Attention TMT-Aa 62.50(42) TMT-Bb 150.74(80.04) c WAIS-I 6.29(2.35) Speed of information processing TMT-A 62.50(42) TMT-B 150.74(80.04) d SCWT I 85.58(29.67) SCWT IIe 55.5 (17.44) Psychomotor speed TMT-A 62.50(42) TMT-B 150.74(80.04) 46.56(11.92) FTT-If FTT- IIg 41.75(14.26) Response inhibition h SCWT III 1.69(9.47) TOL DX Total Movei 39.96(19.41) Planning and problema solving TOL DX Total Move 39.96(19.41) TOL DX Total 410.96(182.3) j Problem-Solving 93.30 (93.5) TOL DX Total Initiation Timek 320.52(167.56) TOL DX Total Execution Timel TMT-A 62.50(42) TMT-B 150.74(80.04) Mental flexibility TMT-A 62.50(42) TMT-B 150.74(80.04) SCWT III 1.69(9.47) TOL DX Total Move 39.96(19.41) Working memory WAIS-I 6.29(2.35) WAIS-IIm 3.96(1.85) TOL DX Total Move 39.96(19.41) Verbal and semantic fluency FASn 28.88(13.31) Animalso 15.25(5.73)

Non-melancholic n¼ 63 mean (SD)

pValue

57.73 (50.74) 138.9(74.87) 6.57(1.57)

0.121 0.050 0.027

57.73 (50.74) 138.9(74.87) 92.43(15.48) 62.1(11.19)

0.121 0.050 0.031 0.005

57.73 (50.74) 138.9(74.87) 52.25(12.99) 47.33(14.1)

0.121 0.050 0.034 0.083

 0.3(11.03) 36.24(17.12)

0.723 0.127

36.24(17.12) 342.65(150.39)

0.127 0.018

71.56(69.96)

0.156

265.22(141.283)

0.043

57.73 (50.74) 138.9(74.87)

0.121 0.050

57.73 (50.74) 138.9(74.87) -0.3(11.03) 36.24(17.12)

0.121 0.050 0.723 0.127

6.57(1.57) 4.24(1.49) 36.24(17.12)

0.027 0.049 0.127

24(10.07) 15.22(4.94)

0.551 0.260

a

Trail Making Test-Part A (TMT-A). Trail Making Test-Part B (TMT-B). Digit Span subtest of the Weschler Adult Intelligence Scale (WAIS)- Part I (WAIS-I). d Stroop Colour Word Test- Part I (SCWT I). e Stroop Colour Word Test- Part II (SCWT II). f Finger Tapping Test- Preferred hand (FTT-I). g Finger Tapping Test- Non preferred hand (FTT-II). h Stroop Colour Word Test- Part III (SCWT III). i Tower of London Total Move (TOL DX Total Move). j Tower of London Total Problem-Solving (TOL DX Total Problem-Solving). k Tower of London Total Initiation Time (TOL DX Total Initiation Time). l Tower of London (TOL DX Total Execution Time). m Digit Span subtest of the Weschler Adult Intelligence Scale (WAIS)- Part II (WAIS-II). n Controlled Oral Word Association Test (FAS). o Semantic Verbal Fluency (Animals). b c

(Animals) (mean¼17.5, p¼0.002).

SD¼4.43

vs.

mean¼13.39,

SD¼3.7;

4. Discussion The main finding of our study is that cognitive impairment remains after clinical remission in patients with melancholic depression compared with non-melancholic patients. Patients with

M. Roca et al. / Journal of Affective Disorders 171 (2015) 85–92

89

Table 3 Comparison between depressive subtypes and time. Mean (SD) TMT-Aa Baseline 6 months TMT-Bb Baseline 6 months WAIS-Ic Baseline 6 months WAIS-IId Baseline 6 months SCWT-Ie Baseline 6 months SCWT-IIf Baseline 6 months SCWT-IIIg Baseline 6 months TOL DX Total Baseline 6 months TOL DX Total Baseline 6 months TOL DX Total Baseline 6 months TOL DX Total Baseline 6 months FASl Baseline 6 months Animalsm Baseline 6 months FTT-In Baseline 6 months FTT- IIo Baseline 6 months

MELANCHOLIC

NON-MELANCHOLIC

F

p-Value

55.55 (24.49) 52.75 (33.06)

55.06 (43.47) 46.94 (31.54)

0.535

0.467

147.40 (81.37) 140.50 (72.44)

143.66 (80.39) 131.53 (72.92)

0.028

0.867

6.45 (2.37) 7.15 (2.13)

6.64 (1.62) 7.23 (1.95)

0.181

0.6727

4.05 (1.76) 4.65 (1.81)

4.23 (1.52) 4.65 (1.507)

0.702

0.405

88.40 (27.26) 94.50 (26.35)

92.43 (15.58) 96.16 (18.97)

1.058

0.307

56.30 (13.80) 59.05 (14.38)

62.12 (11.13) 63.67 (13.77)

0.014

0.908

2.05 (10.24) 2.87 (7.40)

-0.30 (10.14) -0.38 (8.14)

0.033

0.856

37.25 (11.39) 37.40 (20.56)

35.09 (17.17) 32.77 (22.11)

0.105

0.747

407.10 (164.05) 345.90 (211.29)

340.21 (159.66) 298.36 (146.44)

0.111

0.740

100.80 (98.22) 81.95 (81.59)

70.60 (69.25) 70.19 (65.28)

0.118

0.732

309.60 (144.02) 263.70 (182.60)

263.70 (145.59) 230.92 (135.91)

0.138

0.711

28.40 (9.35) 29.60 (11.24)

23.96 (10.05) 26.98 (11)

1.145

0.288

15.90 (4.89) 15.20 (3.74)

15.30 (5.02) 14.94 (4.43)

0.043

0.835

50.20 (14.02) 58.40 (10.41)

49.35 (13.71) 54.12 (9.81)

0.651

0.431

48.40 (18.47) 58.20 (10.16)

44.47 (16.51) 50.18 (12.72)

0.447

0.513

Moveh

Problem-Solving

i

Initiation Timej

Execution Timek

a

Trail Making Test-Part A (TMT-A). Trail Making Test-Part B (TMT-B). c Digit Span subtest of the Weschler Adult Intelligence Scale (WAIS)- Part I (WAIS-I). d Digit Span subtest of the Weschler Adult Intelligence Scale (WAIS)- Part II (WAIS-II). e Stroop Colour Word Test- Part I (SCWT I). f Stroop Colour Word Test- Part II (SCWT II). g Stroop Colour Word Test- Part III (SCWT III). h Tower of London Total Move (TOL DX Total Move). i Tower of London Total Problem-Solving (TOL DX Total Problem-Solving). j Tower of London Total Initiation Time (TOL DX Total Initiation Time). k Tower of London (TOL DX Total Execution Time). l Controlled Oral Word Association Test (FAS). m Semantic Verbal Fluency (Animals). n Finger Tapping Test- Preferred hand (FTT-I). o Finger Tapping Test- Non preferred hand (FTT-II). b

melancholic depression present with a distinct profile of more impaired cognitive performance. At baseline both groups also shows significant differences. The NMelD patient group exhibited superior performances on tests of working memory and speed of information processing. Our results are in line with the only longitudinal study of cognitive function in these depressive subtypes published before our paper but in an inpatient sample (Withall et al., 2010). Another similar study also showed significant cognitive impairment in young adult outpatients compared with a matched control groups. However, an important caveat is

that only five patients who fulfilled the DSM-IV criteria of melancholia were included in the sample (Porter et al., 2003). Some authors have been suggested that melancholic depression is likely to constitute a more severe form of the disease. Austin et al. (2001) comment that correlating cognitive performance with depression severity measured by the HAM-D may be problematic due to the fact that HAM-D scores rated as severe may be confounded with ‘endogenous depression’ or melancholia. However, this might be an artefact of patient selection in that the findings are related to depressive subtypes, rather than linear

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Table 4 Six month follow-up cognitive assessment. p-Value

Melancholic mean (SD) Remitted n¼ 9 Attention TMT-Aa TMT-Bb WAIS-Ic Speed of information processing TMT-A TMT-B Stroop Id Stroop IIe Psychomotor speed TMT-A TMT-B FTT-If FTT- IIg Response inhibition Stroop IIIh TOL DX Total Movei Planning and problema solving TOL DX Total Move TOL DX Total Problem-Solvingj TOL DX Total Initiation Timek TOL DX Total Execution Timel TMT-A TMT-B Mental flexibility TMT-A TMT-B Stroop PC TOL DX Total Move Working Memory WAIS-I WAIS-IIm TOL DX Total Move Verbal and semantic fluency FASn Animalso

Non-remitted n¼ 12

p-Value

Non-melancholic mean (SD) Remitted n ¼20

Non-remittedn¼ 33

 1.04 (1.71)  1.77 (1.86) 1.73 (1.86)

 2.29 (3.95)  3.69 (3.72) 0.75 (1.6)

0.776 0.286 0.204

 0.13 (1.18)  1.23 (1.73) 1.48 (1.39)

 2.21 (3.11)  4.17 (4.1) 0.87 (1.38)

0.001 0.002 0.079

 1.04  1.77  1.08  1.15

(1.71) (1.86) (1.03) (0.97)

 2.29  3.69  1.51  1.10

(3.95) (3.72) (1.51) (1.87)

0.776 0.286 0.437 0.545

 0.13  1.23  0.78  0.73

(1.18) (1.73) (0.93) (0.81)

 2.21  4.17  1.53  1.41

(3.11) (4.1) (1.19) (1.01)

0.001 0.002 0.030 0.017

 1.04  1.77 0.27 0.62

(1.71) (1.86) (2.03) (0.04)

 2.29  3.69  1.11  0.38

(3.95) (3.72) (3.37) (2.51)

0.776 0.286 0.724 0.696

 0.13  1.23  0.54  0.13

(1.18) (1.73) (1.05) (0.98)

 2.21  4.17  0.65  1.18

(3.11) (4.1) (2.49) (1.40)

0.001 0.002 0.947 0.803

 1.09 (1.26)  0.5 (1.46)

0.749 0.545

 0.93 (1.02) 0.34 (0.69)

 1.45 (0.86)  0.39 (1.39)

0.092 0.036

 0.95 (0.91) 0.04 (0.66) 0.04  0.003  0.1 0.08  1.04  1.77

(0.66) (0.6) (1.01) (0.55) (1.71) (1.86)

 0.5  1.03  1.33  0.67  2.29  3.69

(1.46) (2) (2.25) (1.99) (3.95) (3.72)

0.545 0.302 0.201 0.414 0.776 0.286

0.34 0.19  0.28 0.35  0.13  1.23

(0.69) (0.6) (1.05) (0.6) (1.18) (1.73)

 0.39  0.51  0.58  0.39  2.21  4.17

(1.39) (1.3) (1.75) (1.33) (3.11) (4.1)

0.036 0.041 0.755 0.030 0.001 0.002

 1.04  1.77  0.95 0.04

(1.71) (1.86) (0.91) (0.66)

 2.29  3.69  1.09  0.5

(3.95) (3.72) (1.26) (1.46)

0.776 0.286 0.749 0.545

 0.13  1.23  0.93 0.34

(1.18) (1.73) (1.02) (0.69)

 2.21  4.17  1.45  0.39

(3.11) (4.1) (0.86) (1.39)

0.001 0.002 0.092 0.036

1.73 (1.86) 0.73 (2.03) 0.04 (0.66)

0.75 (1.6) 0.10 (1.26)  0.5 (1.46)

0.204 0.942 0.545

1.48 (1.39) 0.27 (1.16) 0.34 (0.69)

0.87 (1.38) 0.11 (1.15)  0.39 (1.39)

0.079 0.651 0.036

 0.99 (0.92)  0.87 (0.63)

 1.12 (1.01)  1.12 (0.91)

0.943 0.392

 1.17 (1.03)  0.59 (0.96)

 1.58 (1.06)  1.46 (0.81)

0.071 0.001

a

Trail Making Test-Part A (TMT-A). Trail Making Test-Part B (TMT-B). Digit Span subtest of the Weschler Adult Intelligence Scale (WAIS)- Part I (WAIS-I). d Stroop Colour Word Test- Part I (Stroop I). e Stroop Colour Word Test- Part I (Stroop II). f Finger Tapping Test- Preferred hand (FTT-I). g Finger Tapping Test- Non preferred hand (FTT-II). h Stroop Colour Word Test- Part III (Stroop III). i Tower of London Total Move (TOL DX Total Move). j Tower of London Total Problem-Solving (TOL DX Total Problem-Solving). k Tower of London Total Initiation Time (TOL DX Total Initiation Time). l Tower of London (TOL DX Total Execution Time). m Digit Span subtest of the Weschler Adult Intelligence Scale (WAIS)- Part II (WAIS-II). n Controlled Oral Word Association Test (FAS). o Semantic Verbal Fluency (Animals). b c

depression severity. Different levels and patterns of cognitive impairment reported across studies have been attributed to different mean depression scores of patient's samples (Austin et al., 2001). The relationship between severity of depression and cognitive impairment may differ across individual cognitive domains. The severity of depression was associated with impaired performance in executive functioning, episodic memory and processing speed, but not with impaired semantic memory (McDermott and Ebmeier, 2009). A promising way of analyzing the relationship between change in depressive symptomatology and change in cognitive function has been the comparison between remitters and non-remitters, or responders and non-responders, at the end of the treatment period. Herrera-Guzmán et al. (2010) conducted a comparison of 36 patients treated with a SSRI and 37 patients treated with an SNRI 24 weeks after study start when patients were unmedicated and in

a recovery phase. Cognitive performance was compared with 37 healthy subjects. These control subjects showed a broader better cognitive performance than depressive patients and patients treated with SNRI performed better in some domains than SSRI treated patients in remission phase and during the recovery phase. Other studies have shown that major depressive patients in recovery can present with a memory deficit which persists 3 years after the initial evaluation (Airaksinen et al., 2006). None of these studies includes melancholic patients. In a systematic review Hasselbalch et al. (2011) analyzed nine of the 11 strictly selected studies with 500 remitted depressive patients and 471 healthy controls. Cognitive impairments in different domains were found in individuals at the remitted state. In other systematic review and meta-analysis of 24 studies using the Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess cognitive function in 784 currently depressed patients (and 727 controls) and 6 studies including 168

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remitted patients (and 128 controls), significant moderate deficits in executive function and attention were found to persist in patients whose depressive symptoms had remitted (Rock et al., 2013). An additional meta-analysis, comparing euthymic adults with MDD patients (n¼ 895) and healthy participants (n¼997), indicated that euthymic patients were characterized by significantly poorer cognitive functions, especially poor response inhibition. Cognitive deficits appear to be more common among patients with lateonset depression (Bora et al., 2013). Patients with a first-episode of MDD have been found to perform significantly worse than healthy controls in a range of cognitive domains (Kikuchi et al., 2013; Schmid and Hammar, 2013; Lee et al., 2012). A very recent meta-analysis to evaluate the literature (Lee et al., 2012) on first episode MDD to determine whether cognition may be a feasible target for early identification and intervention. The authors identified 15 small studies, with a total of 644 patients and a mean age of 39.36 years. Significant cognitive deficits were identified for psychomotor speed, attention, visual learning and memory. It is not entirely clear whether MDD recurrence is systematically associated with cognitive dysfunction. Follow-up studies in executive functioning/attention tasks are usually conducted within 6 months after baseline assessment (Biringer et al., 2007) and find significant improvement of attention/executive functioning for euthymic or fully recovered MDD patients, although performance never completely returned to standardized values. The impairment on executive functioning/attention tasks persists even when performance on other neuropsychological tasks is comparable to healthy controls (Weiland-Fiedler et al., 2004). Methodological issues are likely to be a major contributor in the variability of findings in neuropsychological studies of major depression. Reduced sample size, age and gender differences, hospitalized patients and combining patients with unipolar and bipolar depression are common limitations, as well as factors such as depressive subtypes and the remission state. When focusing on young adults with MDD, executive functioning seems to be impaired among these patients since most of the studies have found deficits in several subcomponents of this function (Smith et al., 2006). The instruments used to measure these functions have considerable overlap, with studies showing combined findings from these cognitive domains (Lim et al., 2013). Short-term studies suggest that attention and executive function remain impaired during treatment and recovery from MDD (Reischies and Neu, 2000; Mandelli et al., 2006). Trichard et al. (1995) found no correlation between improvement in MDD and performance on the SCWT task after 4 weeks. Gallagher et al. (2007) found no differences in executive functioning/ attention between responders and no responders—using the Tower of London task. Verbal fluency is one of the measures within the domain of executive functioning for which there is evidence of an association with changes in depression severity symptoms. Two studies support this hypothesis: improvement in both verbal and design fluency was the only cognitive measure that was significantly different between responders and non-responders (Stordal et al., 2004). A second study showed a significant correlation between improvement in mood and improvement in verbal fluency, despite the SCWT task remaining impaired (Trichard et al., 1995). In summary, executive functioning/attention has generally been shown to remain impaired during and following treatment compared with healthy controls. Several studies have shown a decrease of psychomotor activity in depressed patients (Parker, 2007). Psychomotor retardation has been showed as a crucial symptom of melancholic-depression (Parker et al., 2009). Psychomotor speed is sensitive to clinical state in younger depressed population. The majority of depressed patients report decreased speed of thought and a high incidence of psychomotor retardation. Cognitive and psychomotor activity

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includes three components: reaction time, speech and psychomotor speed. Depressed patients tend to show slower reaction times when compared to healthy subjects. However, slowed reaction time is not specific to depression and is probably more likely to reflect the severity of illness, though remitters showed a significant improvement in reaction time when compared to with nonremitters (Reppermund et al., 2009). The first limitation of our study is the use of psychopharmacological treatment. Our sample was starting antidepressant treatment for a first episode or continuing drug treatment. Some research suggests that cognitive impairment is not solely due to the effects of antidepressant medication (Kikuchi et al., 2013), though might have an impact on performance. Some types of antidepressants may impair cognitive functioning through a central muscarinic blockade (Constant et al., 2005). Antidepressant use has also been associated with better cognitive flexibility (Gualtieri et al., 2006). A futher limitation of our study is the relatively small sample of melancholic patients. However, our study compares favourably with other studies of depressive subtypes, which have tended to feature relatively small samples. A major strength of our study is that we recruited two highly homogeneous groups of melancholic and non-melancholic patients using DSM-IV-TR criteria, as well as the CORE Index for Melancholia. A major advantage of this approach is that melancholic depression defined by the CORE measure is differentiated from nonmelancholic depression with respect to symptom severity, suicidal ideation and comorbidities (Caldieraro et al., 2013). In conclusion, we found a different cognitive impairment profile between melancholic and non-melancholic depressive patients during clinical remission. Cognitive impairment may have a long term impact on a deteriorating course of the disease and persistent cognitive deficits during remission states could represent an important focus in the rehabilitation process of depressive patients. The persistence of some cognitive dysfunction in remission of depressive episodes, particularly in some functions of melancholic-patients of our sample may not be secondary to the severity in depression but could represent a trait marker of a distinct depressive subtype.

Role of the funding source The sponsor had no role in the design and development of the study, analysis, writing of the report or in the decision to submit the paper for publication. The authors declare no conflict of interest.

Conflict of interest Dr. Roca, Ms. Monzón, Ms. Vives, Dr. García-Toro and Dr. Gili report grants from the Instituto de Salud Carlos III (Institute of Health Carlos III) of the Ministry of Economy and Competitiveness (Spain) and the European Union ERDF funds, during the conduct of the study; Dr. Roca reports personal fees from Eli Lilly, Servier and Pfizer; and grants and personal fees from Lundbeck and Jannsen, outside the submitted work. Dr. García-Campayo reports personal fees from Pfizer, Eli Lilly, Rovi and GSK, outside the submitted work. Dr. Harrison reports personal fees from Abbvie, Anavex, AstraZeneca, Avraham, Axon, Boehringer Ingelheim, Catenion, CRF Health, DeNDRoN, EnVivo Pharma, ePharmaSolutions, Eisai, Eli Lilly, Heptares, Janssen AI, Kyowa Hakko Kirin, Lundbeck, MedAvante, Merck, Mind Agilis, MyCognition, Neurocog, Neuroscios, Novartis, Nutricia, Orion Pharma, Pharmanet / i3, Pfizer, Prana Biotech, PriceSpective, Prophase, Prostrakan, Roche, Reviva, Servier, Shire, TCG, TransTech Pharma, Velacor, outside the submitted work. Dr. Vicens reports no conflict of interest.

Contributors M Roca, S Monzón and M Gili designed the study and wrote the protocol. M Roca, C Vicens, M Vives and M Gili managed the literature searches and analyses. E López-Navarro, S Monzón and M Vives undertook the statistical analysis, and M Roca, M García-Toro, J

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Garcia-Campayo and J Harrison wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript. Acknowledgements This project has been funded by a Grant from the Instituto de Salud Carlos III (Institute of Health Carlos III) ( FIS n° PI08 1270) of the Ministry of Economy and Competitiveness (Spain), and co-financed with European Union ERDF funds.

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