Can onset and recovery in depression be predicted by temperament? A systematic review and meta-analysis

Journal of Affective Disorders 135 (2011) 20–27

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Journal of Affective Disorders j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d

Review

Can onset and recovery in depression be predicted by temperament? A systematic review and meta-analysis Olli Kampman a,c,⁎, Outi Poutanen a,b a b c

University of Tampere, Medical School, Tampere, Finland Tampere University Hospital, Department of Psychiatry, Tampere, Finland Seinäjoki Hospital District, Department of Psychiatry, Seinäjoki, Finland

a r t i c l e

i n f o

Article history: Received 24 September 2010 Received in revised form 23 December 2010 Accepted 23 December 2010 Available online 22 January 2011 Keywords: Temperament TCI Harm avoidance Depressive disorder Meta-analysis Review

a b s t r a c t Background: Behavioural inhibition and more specifically harm avoidance temperament dimension (HA) has been found to be associated with depression. Temperament and Character Inventory (TCI) by Cloninger et al. is the most widely used instrument in the assessment of temperament. The aims of the present study were to explore 1) if current or future depressive symptoms in non-clinical adult sample can be explained by TCI temperament dimensions, and 2) if recovery from major depression (MDD) during the acute phase of treatment is predictable by TCI temperament dimensions. Method: Literature search from eight databases. Systematic review and meta-analysis. Results: High HA was associated with current depressive symptoms in 11/12 studies and with depressive trait in 3/4 studies. In MDD studies, a consistent negative change in HA was found during treatment and this change was even more clearly associated with treatment response. Limitations: The studies with general population samples were heterogeneous in methodology. Most of the intervention studies were of case–control design. Conclusions: HA is indisputably associated with the risk and treatment response in depression. © 2011 Elsevier B.V. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Stress and behavioural inhibition . . . . . . . . . . . . . . . . 1.2. Cloninger's model of temperament . . . . . . . . . . . . . . 1.3. Biological processes behind temperament development . . . . . 1.4. Temperament findings and depression . . . . . . . . . . . . . 1.5. Aims of the study . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Systematic literature review . . . . . . . . . . . . . . . . . . 2.2. Statistical methods. . . . . . . . . . . . . . . . . . . . . . . Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Normative data and temperament dimensions . . . . . . . . . . 3.2. Temperament dimensions during depressive episode and recovery

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⁎ Corresponding author. University of Tampere, Medical School, FI-33014 Tampere, Finland. Tel.: + 358 44 4155547 (mobile); fax: + 358 3 35516164. E-mail address: olli.kampman@uta.fi (O. Kampman). 0165-0327/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2010.12.021

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O. Kampman, O. Poutanen / Journal of Affective Disorders 135 (2011) 20–27

4. Discussion. . . . Role of funding source Conflict of interest . . References . . . . . .

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1. Introduction 1.1. Stress and behavioural inhibition Exposure to stress in early life has been associated with hyperactivity in hypothalamic–pituitary–adrenal (HPA) axis and further with susceptibility to depression and anxiety disorders (Essex et al., 2010; Heim and Nemeroff, 2001; Zobel et al., 2004). Behavioural inhibition reflects sensitivity to stress on a behavioural level (Tyrka et al., 2008) and in the context of social behaviour this may be expressed as lack of social support. The individual's ability to secure social support also has a moderate genetic component according to a twin study with women presenting with depressive symptomatology (Yuh et al., 2008). 1.2. Cloninger's model of temperament Behavioural inhibition and other temperament dimensions can be assessed by specific temperament inventories, of which the Temperament and Character Inventory (TCI) is probably the most widely used among adult samples (Cloninger et al., 1993). The TCI includes four dimensions of temperament, namely novelty seeking (NS), harm avoidance (HA), reward dependence (RD), and persistence (P), and three dimensions of character, namely self-directedness (SD), cooperativeness (CO), and self-transcendence (ST) (Cloninger et al., 1993). HA is the temperament dimension that corresponds to behavioural inhibition in the TCI. The structure of temperament in this model has been inferred largely from genetic studies of personality in humans and neurobiological studies with rodents. According to these findings, the temperament dimensions have been hypothesized to be related to neurotransmitter systems of the brain (HA relates to serotonergic function, RD to noradrenergic function, and NS to dopaminergic function) (Cloninger et al., 1993). However, later studies have reported some contradictory findings (Serretti et al., 2006). Some cultural differences between dimensions of temperament have been found, e.g. between North American or European and Asian samples (Miettunen et al., 2006). 1.3. Biological processes behind temperament development Such serotonergic and dopaminergic genes as serotonin transporter (5-HTTLPR), dopamine D4 receptor (DRD4) and monoamine oxidase A (MAO-A) have been connected with NS, HA and P scores respectively (Serretti et al., 2006). The 5HTTLPR ll genotype was associated with higher P and more optimal decision-making in depression (Must et al., 2007). Two brain-derived neurotrophic factor (BDNF) polymorphisms (–281 CNA and Val66Met) have been associated with the risk for anxiety and depression, –281 A-allele being connected with lower HA and 66Met allele with higher HA

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(Jiang et al., 2005). Behavioural inhibition in early childhood is associated with parental depressive disorders (Olino et al., 2010), and further with social anxiety in adolescence (Essex et al., 2010). In several studies, the 5-HTTLPR and DRD4 polymorphisms or their interaction have been connected either with parenting and attachment problems, or elevated anxiety and behavioural inhibition during early childhood (Ivorra et al., 2010). The effects of BDNF Val66Met polymorphism in transgenic mice have comprised depression- and anxiety-prone behavioural patterns associated specifically with impaired hippocampal learning (Bath and Lee, 2006), which may constitute an important heritable mechanism for vulnerability in depression (Hankin et al., 2009; Oler et al., 2010). 1.4. Temperament findings and depression In their review Pelissolo and Corruble concluded that HA seems to be a vulnerability factor or at least an associated factor in depressive disorders (Pelissolo and Corruble, 2002). There are also more sceptical views on the association between temperament and depression. According to a review by Enns and Cox (1997) several personality dimensions are significantly associated with depressive illness, but the evidence that unequivocally demonstrates a true personality predisposition for depression is modest. Five large studies on depressive symptoms and temperament profiles in general population samples including 804, 850, 1576, 631 and 591 individuals (Cloninger et al., 2006; Elovainio et al., 2004; Farmer and Seeley, 2009; Grucza et al., 2003; Richter et al., 2003) have all shown a positive association between high HA and depressive symptoms. On the other hand the findings with RD have been contradictory in part, as in the study by Elovainio et al. (2004) depressive symptoms and one facet of RD score (sentimentality) were positively associated, whereas in the study by Farmer (Farmer and Seeley, 2009) the association was negative, but this finding was in contrast with the change in depressive symptoms. In the study by Cloninger et al. (2006) the P score was positively associated with the occurrence of depressive symptoms and in the study by Elovainio et al. (2004) with the future risk for depression. High HA may be associated with a family history of mental disorder (Jylha and Isometsa, 2006; Smith et al., 2005). A comparison of HA scores between depressed patients and their siblings showed stable trait-like characteristics that were likely related to the genetic susceptibility to depression (Farmer et al., 2003). In three case–control studies using TCI (Hirano et al., 2002; Richter et al., 2000; Sato et al., 2001) with patient samples of 126, 121 and 108 with follow-up periods of 9, 26 and 16 weeks respectively, the change in HA score was positively correlated with recovery from depression.

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O. Kampman, O. Poutanen / Journal of Affective Disorders 135 (2011) 20–27

1.5. Aims of the study The study focused on the following two questions. 1) Can current or future depressive symptoms in non-clinical adult sample be explained by TCI temperament dimensions? 2) Is recovery from major depression (MDD) during the acute phase of treatment predictable by TCI temperament dimensions? 2. Methods 2.1. Systematic literature review We conducted a literature search from the databases below in June 21st, 2010 using the terms “temperament” and (“depression” or “depressive disorder”) and limiting the search to peer-reviewed journal articles published in English during the period 1991–2010. The starting year was determined according to the introduction date of the term “temperament” in Medical Subject Headings. The databases comprised EBM Reviews (Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effectiveness), Genetics Abstracts (CSA), Neurosciences Abstracts (CSA), PubMed (MEDLINE), Web of Science (ISI), Psycinfo and PsycArticles The initial search resulted in total of 4022 articles. The inclusion criteria for the selected papers were: using TCI for temperament assessment and focusing either on 1) the occurrence of current or future depressive symptoms and temperament in non-clinical adult sample (aged 18 and over), or 2) the association of acute treatment response and temperament in major depression (MDD) in adults. The exclusion criteria were: 1) duplicates and 2) reports on studies with identical samples (of which all reported results were used, but different reports were considered as a single study in the analyses), 3) papers reporting temperament profiles in different clinical samples. We also searched publications with similar focus according to reference lists of selected papers. Fifty-one papers were screened. The final selection agreed by both investigators comprised 22 papers. In cases of initial disagreement a final consensus was reached after discussion. All papers included described prospective studies. Twelve of the papers selected focused on general population samples (Table 1) and ten on treatment response in MDD (Table 2). The quality of the evidence in individual studies focusing on study question 2 was graded according to the GRADE workgroup recommendation (Atkins et al., 2004). 2.2. Statistical methods The selected papers of the systematic literature review were analysed according to the results reported in each paper. The twelve papers on general population samples were heterogeneous in design, including sample selections and symptom assessments. For this reason it was not possible to perform a meta-analysis on this focus. We classified the associations between temperament dimensions and depression into state and trait-dependent findings in these studies (Table 1). The state-dependent findings refer to current depressive symptoms and trait-dependent findings to future symptoms of depression. Six of the ten papers on patient samples with clinical depression presented results for

baseline and endpoint (after anti-depressive medication) temperament dimension scores. Four of these ten studies also presented the corresponding results for the responders' group separately. We performed meta-analyses for each temperament dimension (NS, HA, RD, and P) for total samples by comparing baseline and endpoint scores and the corresponding analyses for responders' groups (except for Persistence scores). The meta-analyses were calculated with MIX software (version 1.7; Bax et al., 2006) using the fixed effects model and inverse variance as a weighting method. The results of meta-analyses are presented as mean differences (MD) from baseline to endpoint scores for each temperament dimension (positive values indicate higher endpoint scores compared to baseline) with 95% confidence intervals (95% CI).

3. Results 3.1. Normative data and temperament dimensions Five of the twelve studies used Center for Epidemiologic Studies Depression Scale (CES-D) (Cloninger et al., 2006; Farmer and Seeley, 2009; Grucza et al., 2003; Jurado et al., 2005; Yuh et al., 2008), four Beck Depression Inventory (BDI) (Elovainio et al., 2004; Jylha and Isometsa, 2006; Peirson and Heuchert, 2001; Richter et al., 2003), one Hospital Anxiety and Depression Scale (HADS-D) (Matsudaira and Kitamura, 2006), and two Self-rating Depression Scale (SDS) (Naito et al., 2000; Tanaka et al., 1997) as measures for depressive symptoms. Six of the studies represented general population samples (Cloninger et al., 2006; Elovainio et al., 2004; Farmer and Seeley, 2009; Grucza et al., 2003; Jylha and Isometsa, 2006; Richter et al., 2003), four of the studies young adult student samples (Matsudaira and Kitamura, 2006; Naito et al., 2000; Peirson and Heuchert, 2001; Tanaka et al., 1997), one study a certain profession (teachers; Jurado et al., 2005), and one study female twins (Yuh et al., 2008). Four of the studies reported follow-up results (range from 3 months to 4 years) of depressive symptoms (Cloninger et al., 2006; Elovainio et al., 2004; Farmer and Seeley, 2009; Naito et al., 2000). Eight of the studies were cross-sectional (Table 1). All twelve studies reported associations between temperament dimensions and depressive state. In all other studies except the study by Matsudaira and Kitamura (2006) there was a positive association between depressive state and high HA score. Four studies reported an association between depressive symptoms and low RD score (Grucza et al., 2003; Matsudaira and Kitamura, 2006; Naito et al., 2000; Peirson and Heuchert, 2001). One study reported an association between high NS score and depression (Jurado et al., 2005) and one study an association between low NS and depression (Jylha and Isometsa, 2006). Low P score was associated with depression in two studies (Matsudaira and Kitamura, 2006; Peirson and Heuchert, 2001) and high P score in two studies (Cloninger et al., 2006; Elovainio et al., 2004). In four studies analysing the association between depressive trait and temperament three of them reported a definitive or indicative positive association between HA and depressive trait (Cloninger et al., 2006; Elovainio et al., 2004; Farmer and Seeley, 2009), and one study reported no association (Naito et al., 2000).

Table 1 Studies focusing on relationship between TCI temperament dimensions and depression or prediction of depression by temperament in general populations. Later depressive symptoms (depressive trait) associated with

4 years

High HA (all subscales)

CES-D, NR

4 years

631

CES-D, NR

1 year

21

167

SDS, 41.8/80

3 months

German general population U.S. general population, 18–88 years Japanese undergraduates

35.6 45

850 804

BDI, 5.8/63 CES-D 11.9/60

CS CS

19.6

541

HADS-D 5.2/21

CS

Spanish primary or secondary school teachers South African psychology undergraduates

45.0

498

CES-D, 13.8/60

CS

19.2

472

BDI, 10.7/63

CS

Finnish general population, 20–70 years Swedish female twins Japanese students

45.0

347

BDI, 6.0/63

CS

High HA (anticipatory worry, fatigability) High HA High P High HA Low RD High HA High HA Low RD Low RD Low P High HA High NS High HA Low RD Low P High HA

High HA (shyness, fatigability) high RD (sentimentality) low RD (attachment) high P High HA

44 19.2

326 306

CES-D, NR SDS, 41.5/80

CS CS

Sample

Age mean, years

N

Measure of depression, severity of symptoms (mean/max)

Follow-up

Elovainio et al. (2004)

Finnish general population, 20–35 years

31.4

1576

BDI, 2.1/63

Farmer and Seeley (2009)

U.S. community sample (home owners) U.S. general population, N 18 years Japanese college students

51

591

46

Cloninger et al. (2006) Naito et al. (2000) Richter et al. (2003) Grucza et al. (2003) Matsudaira and Kitamura (2006) Jurado et al. (2005) Peirson and Heuchert (2001) Jylha and Isometsa (2006) Yuh et al. (2008) Tanaka et al. (1997)

Study limitations

Selected population, small sample

Selected population

Selected population

Female twin population Selected population

High HA High HA

High HA None N/A N/A N/A N/A N/A

N/A N/A N/A

O. Kampman, O. Poutanen / Journal of Affective Disorders 135 (2011) 20–27

Current depressive symptoms (depressive state) associated with

Study

SDS = Self-rating Depression Scale. CES-D = Center for Epidemiological Studies depression scale. BDI = Beck Depression Interview. HADS-D = Hospital Anxiety and Depression Scale, the depression subscale. CS = crosssectional study, NR = not reported, N/A = not applicable.

23

24

Table 2 Studies focusing on relationship between TCI temperament dimensions and recovery from major depressive episode in clinical populations.

Joyce et al., 2007, RCT, TCI-R Agosti and McGrath, 2002, RCT Kronstrom et al., 2011, RCT

177 35.2

MADRS, 23.8/60

19.0 a

24.6 a

21.9 a

19.6 a

154 41.6

HDRS-28, NR

21.0

24.2

11.1

4.7

35 42.7

HDRS-17, 18.8/54

NR

NR

NR

NR

86 40

MADRS, 30/60

17.7

25.4

14.5

4.8

HDRS-17, 23.4/54

17.5 (4.8)

27.0 (5.0)

14.7 (3.5)

4.2 (1.8)

BDI-21, 19/63

15.2 (5.6)

24.0 (5.4)

16.6 (3.3)

3.5 (1.6)

HDRS-17, 23.5/54

NR

NR

NR

NR

HDRS-21, 20.8/ 63MADRS, 25.8/60 HDRS-17, 18.2/54

16.8 (6.0)

24.3 (6.7)

15.3 (3.4)

4.6 (1.8)

NR

24.3

NR

NR

MADRS, 32.2/60

18.9

24.4

15.6

4.5

108 46.4

Richter et al., 2000, 126 44.5 case–control Sato et al., 2001, 121 43.6 case–control Marijnissen et al., 35 51.3 2002, case–control Abrams et al., 2004, 39 32.2 case–control Corruble et al., 57 42.3 2002, open label

NR = not reported. a TCI-R-temperament dimension score.

Temperament dimensions related to recovery

Quality of evidence and limitations

HA in IPT

High

HA

Moderate Moderate; small groups, temperament scores not reported

2 years

High RD and depression at 16 weeks in Flx group HA

16 weeks

HA

Moderate

8.8 (± 5.4) weeks 26 weeks

HA

Low

HA

Low; temperament scores not reported Very low; small sample, short follow-up Very low; small sample, females only Very low; small sample, malesb 20%

Follow-up

Interpersonal psychotherapy/ 16 weeks cognitive-behavioural-therapy Fluoxetine ad. 60 mg/d or 10 weeks imipramine ad. 300 mg/d 16 weeks Fluoxetine 20–40 mg/d or weekly psychodynamic psychotherapy Standardized medication protocol, in- and outpatients Maprotiline starting mean 84 mg/d, at 8 weeks mean 146 mg/d Clinical decision in hospital setting Clinical decision in outpatient setting Clinical decision in hospital setting Clinical decision in outpatient setting Clinical decision in hospital setting

6 weeks 12 weeks

HA

1 year

HA in 1st month

Moderate

O. Kampman, O. Poutanen / Journal of Affective Disorders 135 (2011) 20–27

N

de Winter et al., 2007 case–control Hirano et al., 2002, case–control

Age years Measure and severity (mean) of depression (mean/max)

NS mean (SD), HA mean (SD), RD mean (SD), P mean (SD), Treatment and medication baseline baseline baseline baseline dosage

Study and design

O. Kampman, O. Poutanen / Journal of Affective Disorders 135 (2011) 20–27

25

Weight (%)

Association measure with 95% CI

Study

Baseline N HA mean/ SD

Endpoint N HA mean/ SD

Richter 2000

126/24/5.4

126/20.8/6.2

26.06 % ||||||||

3,2 (1.76 to 4.64)

Hirano 2002

108/27/5

108/25.3/6

24.75 % ||||||||

1.7 (0,23 to 3.17)

Marijnissen 2002

35/24.3/6.7

35/23.9/5.6

6.42 % |

0.4 (-2.49 to 3.29)

deWinter 2007

70/25.4/5.3

58/23.2/6.1

13.40 % ||||

2.2 (0.20 to 4.20)

Corruble 2002

57/24.4/5.9

57/22/6.8

9.83 % |

2.4 (0.06 to 4.74)

Agosti 2002

117/24.2/3.5

65/22.6/6.3

19.54 % ||||

1.6 (-0.06 to 3.26)

100%

2.12 (1.39 to 2.86)

META -ANALYSIS: -4

-2

0

2

4

|||||||||||||||||||||||||||||

6

mean difference

Fig. 1. Meta-analysis of baseline and endpoint harm avoidance scores in six studies. Statistics: N = 449, mean difference 2.12 (95% CI 1.39–2.86), z-score 5.68, p b 0.0001.

95% CI= −0.80–1.40; z = 0.53, p = 0.59). In RD scores there was a small overall positive change from baseline to endpoint (MD = 0.89, 95% CI = 0.21–1.58; z = 2.55, p = 0.01), but marked heterogeneity in the results between individual studies (I2 = 85.1%, 95% CI= 63.1%–94.0%). In HA scores, there was a clear negative change from baseline to endpoint (MD = −3.13, 95% CI= −4.38–1.88; z = 4.89, p b 0.0001; Fig. 2).

3.2. Temperament dimensions during depressive episode and recovery Six of the ten papers on patient samples with clinical depression (Table 2) presented results for baseline and endpoint (after antidepressive medication) temperament dimension scores (total N = 449; Agosti and McGrath, 2002; Corruble et al., 2002; de Winter et al., 2007; Hirano et al., 2002; Marijnissen et al., 2002; Richter et al., 2000). There were no differences between baseline and endpoint scores in NS (MD = 0.29, 95% CI = −0.42–1.00; z = 0.80, p = 0.42) and P (MD = 0.13, 95% CI = − 0.10–0.36; z = 1.10, p = 0.27). In RD scores there was a small overall positive change from baseline to endpoint scores (MD = 0.59, 95% CI = 0.16–1.02; z = 2.68, p = 0.008), but there was also marked heterogeneity with the results between studies (I2 = 88.9%, 95% CI = 78.6%–94.3%). In HA scores there was a marked negative change from baseline to endpoint (MD = −2.12, 95% CI = − 2.86–1.39; z = 5.68, p b 0.0001; Fig. 1). In four out of the ten studies also presenting data for responders' group separately (total N = 181; Agosti and McGrath, 2002; Corruble et al., 2002; de Winter et al., 2007; Hirano et al., 2002) there were no significant differences between baseline and endpoint scores in NS scores (MD = 0.33,

Study

Baseline, responders N HA mean/ SD

4. Discussion The purpose of this review and meta-analysis is to ascertain the impact of temperament dimensions on susceptibility to depressive symptoms and on the course of and recovery from major clinical depression. We would like to add to the knowledge about biological risk factors for depression, especially considering the genetic influence. For the focus of this review we selected firstly the association between current symptoms of depression and the risk for future onset of depression and temperament dimensions in general population samples, and secondly the association between recovery from clinical major depression and temperament. The two main findings within the review from studies including general population samples were 1) a definite and undisputable association between HA temperament

Endpoint, responders N HA mean/ SD

Weight (%)

Association measure with 95% CI

Hirano 2002

77/26.2/5.5

77/23.6/6.9

40.48 % ||||||||||||||||

2.6 (0.63 to 4.57)

deWinter 2007

41/25.7/5

41/21.7/7

22.68 % ||||||||

4 (1.37 to 6.63)

Corruble 2002

26/22.5/6.8

26/17.9/8.3

9.24 % |

4.6 (0.48 to 8.72)

Agosti 2002

37/22.4/2.7

37/19.7/6.9

27.59 % ||||||||

2.7 (0.31 to 5.09)

META -ANALYSIS:

100% 0

2

4

6

8

||||||||||||||||||||||||||||| 3.13 (1.88 to 4.38)

10

MD

Fig. 2. Meta-analysis of responders' baseline and endpoint harm avoidance scores in four studies. Statistics: N = 181, mean difference (baseline–endpoint) 3.13 (95% CI 1.88–4.38), z-score 4.89, p b 0.0001.

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dimension and occurrence or severity of current depressive symptoms (11/12 studies) and 2) a similar, but more diffuse association between HA and depressive trait. In addition, the low RD was associated with current symptoms of depression, but in the minority of studies reviewed (4/12). All non-clinical sample studies analysed here were observational in design. According to the GRADE guidelines, the evidence of the findings within individual studies should be considered low in such cases (Atkins et al., 2004). However, as the GRADE system was created for evaluating treatment effects, it is not directly applicable to these studies. When assessing the quality of these studies, we focused on the criteria of sample selection, assessment methods, follow-up time and rates of missing data. The studies had heterogeneous designs, samples and measures of depression. The limitations and weaknesses of such studies included small samples size (nb 200) in one study, and selection of sample according to sociodemographic factors, age or gender in five studies. Measures of depression were considered valid in all twelve studies. Due to the marked methodological heterogeneity in general population sample studies, we decided not to perform a meta-analysis of this group, but only of the studies with patient samples. Instead, we concluded the essential findings within the non-clinical sample studies. There was little heterogeneity in the results, especially given the association of high HA temperament score and depressive state. The level of evidence for this finding can thus be considered high (Atkins et al., 2004). There was less evidence for an association between low RD score and depressive state. In longitudinal studies the association between temperament dimensions and later depression was found in three of the four studies. All three studies reporting a positive association for temperament and depressive trait were large community studies high in quality. In one smaller study with a relatively short follow-up time no such association was found (Naito et al., 2000). The level of evidence even for this finding can thus be considered high. Altogether it seems that in studies with non-clinical samples HA is both trait- and state-dependent in depressive-spectrum disorders. Low score on RD might be state-dependent in depression, but this finding is less consistent, and the level of evidence can be considered low. The studies with major depression samples and treatment interventions comprised three randomized controlled studies (RCTs), six case–control studies and one open-label study. The study limitations included small sample size (b50 patients) in three studies, short follow-up time (b8 weeks) in one study and lack of standardized treatment intervention in five studies. Within the studies with major depression samples and focusing on treatment response, high HA was almost consistently associated with treatment response in the studies reviewed (Abrams et al., 2004; Agosti and McGrath, 2002; Corruble et al., 2002; de Winter et al., 2007; Hirano et al., 2002; Joyce et al., 2007; Richter et al., 2000). The two exceptions from this were the studies by Marijnissen et al. (2002), and by Kronstrom et al. (2011) which found no change in HA score during treatment. The association between HA level and recovery from depression was found in two large RCTs, and the level of evidence for this finding can thus be considered high (Atkins et al., 2004). We also performed a meta-analysis on the associations of depression recovery and HA score in total samples and

separately for responders' groups. In both analyses the findings supported the result from general population sample studies showing positive associations between levels of HA and recovery from MDD. Compared with the studies on general population samples, the studies with patient samples showed less heterogeneity in their methodology. The most marked differences included variations in follow-up time, or in antidepressive medication procedures. The limitations and weaknesses of such studies included small samples, short follow-up periods and lack of standardized treatment interventions. There was some heterogeneity among the age distributions in the patient samples. Age has been found to have no marked effect on temperament, except for NS (Brandstrom et al., 2001; Miettunen et al., 2007). In studies with either non-clinical or clinical samples the severity of depressive symptoms had no significant effect on the associations with HA scores, in spite of wide variation in severity of depression, especially in the non-clinical samples. Theoretically, the current findings are in line with earlier hypotheses presented by Pelissolo and Corruble (2002). The results from general population sample studies clearly indicate the influence of state on trait measure both in general population and in patients with major depression. In addition, these results of longitudinal general population sample studies supported the hypothesis about HA as a susceptibility factor for depression. In conclusion, HA temperament dimension is indisputably associated with both the occurrence of depressive symptoms and recovery from major depression. There is also some evidence to suggest that high HA indicates susceptibility to depression, but more longitudinal studies are needed to confirm this finding. Role of funding source None declared. Conflict of interest Dr. Kampman has consulted for Pfizer, Janssen-Cilag and Lundbeck and participated in international scientific meetings as a guest of Bristol-MeyersSquibb and Janssen-Cilag. Dr. Poutanen has participated in international scientific meetings as a guest of Lundbeck and Janssen-Cilag.

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