Structural brain abnormalities in major depressive disorder: A selective review of recent MRI studies

Journal of Affective Disorders 117 (2009) 1–17

Contents lists available at ScienceDirect

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

Structural brain abnormalities in major depressive disorder: A selective review of recent MRI studies Valentina Lorenzetti a,b,c,e, Nicholas B. Allen b,c,d, Alex Fornito a, Murat Yücel a,b,c,⁎ a b c d e

Melbourne Neuropsychiatry Centre, Department of Psychiatry, Australia ORYGEN Research Centre, Melbourne, VIC, Australia The University of Melbourne and Melbourne Health, VIC, Australia Department of Psychology, University of Melbourne, VIC, Australia Department of Psychology, University of Bologna, Viale Berti Pichat 5, 40126, Bologna, Italy

a r t i c l e

i n f o

a b s t r a c t Background: While there is evidence to suggest that major depressive disorder (MDD) is associated with structural brain abnormalities, the precise nature of these abnormalities remains unclear. Aims: To review recent structural magnetic resonance imaging (MRI) research findings in MDD while considering the potential influence of key clinical and demographic variables. Method: A selective review of all T1-weighted structural MRI studies published between 2000 and 2007 in adult samples of MDD patients. Results: Volumetric reductions of the hippocampus, basal ganglia and OFC and SGPFC are consistently found in MDD patients, with more persistent forms of MDD (e.g., multiple episodes or repeated relapses, longer illness duration) being associated with greater impact on regional brain volumes. Gender, medication, stage of illness, and family history all affect the nature of the findings in a regionally specific manner. Limitations: Overall, differences between the samples in factors such as illness severity, medication, gender and family history of mental illness makes difficult to identify their confounding effects on the observed neuroanatomical changes. Also, the tracing protocols used for particular brain regions were different amongst the reviewed studies, making difficult to compare their findings. Conclusions: The data support the notion that MDD involves pathological alterations of limbic and cortical structures, and that they are generally more apparent in patients with more severe or persistent forms of the illness. © 2009 Published by Elsevier B.V.

Article history: Received 13 June 2008 Received in revised form 26 November 2008 Accepted 26 November 2008 Available online 23 February 2009 Keywords: Depression Imaging Brain Morphology Hippocampus Amygdala Cingulate

Contents 1. 2. 3.

Introduction . . . . . . . . . . Methods . . . . . . . . . . . Results . . . . . . . . . . . . 3.1. Method . . . . . . . . . 3.2. Temporal lobes . . . . . 3.3. Hippocampus . . . . . . 3.4. Amygdala . . . . . . . 3.5. Frontal lobes . . . . . . 3.6. Anterior cingulate cortex

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⁎ Corresponding author. Melbourne Neuropsychiatry Centre, c/o AG Building, 161 Barry St Carlton South Victoria, 3053, Australia. Tel.: +613 8344 1877; fax: +613 9348 0469. E-mail address: [email protected] (M. Yücel). 0165-0327/$ – see front matter © 2009 Published by Elsevier B.V. doi:10.1016/j.jad.2008.11.021

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V. Lorenzetti et al. / Journal of Affective Disorders 117 (2009) 1–17

3.7. Basal ganglia . . . . . . . . Discussion . . . . . . . . . . . . . 4.1. Mechanisms of neurobiological 4.2. Limitations of research to date 5. Conclusions . . . . . . . . . . . . Role of the funding source . . . . . . . . Conflict of interest . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . References . . . . . . . . . . . . . . . 4.

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1. Introduction Major Depressive Disorder (MDD) has been identified as a leading cause of disability worldwide, and will represent an increasing health, social and economic problem in the forthcoming years (Murray and Lopez, 1996, 1997). For these reasons, it is critical to understand the relevant causal mechanisms in order to develop effective intervention strategies to prevent these illnesses and/or ameliorate their effects. From a neurobiological perspective, we are only beginning to understand the critical processes and brain regions that are associated with MDD. Nonetheless, the application of Magnetic Resonance Imaging (MRI) has fuelled increasingly sophisticated efforts to identify the disorder's pathophysiological mechanisms. A large body of neuroimaging research in MDD has now been published, identifying several neuroanatomical changes in affected patients. However, findings can vary significantly across studies. Given the heterogeneity of depression, it is likely that one important issue is investigating the influence of key clinical and demographic characteristics (e.g., treatment status, stage of illness, gender) on the findings across different brain regions. Most neuroimaging studies still lack the power to examine the influence of these clinical and demographic differences on structural brain abnormalities within depressive samples, therefore systematic reviews of the literature can play a critical role in examining these effects across studies, and thus can direct future research efforts. To date, several reviews of this work have already been published (Beyer and Krishnan, 2002; Brambilla et al., 2002a; Campbell and Mac Queen, 2006; Drevets et al., 1998; Soares and Mann, 1997; Steffens and Krishnan, 1998; Videbeck and Ravnkilde, 2004), but they have often been quite broad. Indeed, several reviews focussed on how brain changes in MDD relate to those seen in other disorders, thus preventing detailed consideration of how the findings relate to the pathophysiology of MDD specifically. Also, other reviews have considered studies of adolescent or elderly samples in addition to adult patient groups, which may be limited in what their observations cannot disentangle disease-related changes from neurodevelopmental and/or age-related effects (Raz et al., 2005, 2007, 2004; Resnick et al., 2003). Alternatively, various reviews have maintained a narrow focus, restricting their discussion to one or a few specific brain regions. In fact, since 2000, only one systematic review of imaging research in MDD has been reported (Campbell and Mac Queen, 2006), but it only considered research published between 2004 and 2005. As such, the studies and findings were restricted to a very specific time period.

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12 14 14 14 15 15 15 15 15

This paper presents a selective review of studies that investigated the more “trait like” neurobiological underpinning of MDD by using T1-weighted structural MRI, in contrast to other MRI measures such as functional Magnetic Resonance Imaging or even Magnetic Resonance Spectroscopy, as it provides a relatively stable brain measure that minimizes state related processes associated with the stage of illness, recovery and outcome. We selected the studies which have been published between 2000 and 2007, that investigated adult samples of patients (age 19–50 years) with a diagnosis of MDD, with specific attention being paid to the influence of clinical and demographic factors on the putative neuroanatomical phenotype of the disorder. 2. Methods We followed the QUORUM (Moher et al., 1999) and AMSTAR (Shea et al., 2007) guidelines to perform the review. First, we searched the databases PubMed, MEDLINE, and PsycINFO using the terms “unipolar depression AND MRI”. We then restricted the search criteria in order to include only studies conducted on adult human beings, published between 2000 and 2007 and other criteria (i.e., described in Fig. 1). All the studies that investigated psychopathology/medical conditions other than MDD were excluded, as were studies that non-T1-weighted protocols for the assessment of regional brain anatomy. We also excluded studies that investigated patients with co-morbid psychopathology/medical conditions or MDD secondary to other disorders; studies with samples with a mean age not between 19–50 years or those that did not use a healthy control group; studies that were not published between 2000/01/01–2007/01/23; or studies that were not research articles. We further excluded studies on the corpus callosum, pituitary gland, thalamus and posterior cingulate cortex since there were few in number, indicating the results may not be as reliable as studies addressing other brain regions. Studies retained using this procedure are described in detail in Fig. 1, for further consideration. 3. Results 3.1. Method In accordance with the QUORUM and AMSTAR guidelines there are a few study characteristics that should be noted. Firstly, most of the reviewed studies have matched the clinical and the control groups on cognitive and socio-demographical variables. A few studies did not explicitly match their groups (Brambilla et al., 2002b; Monkul et al., 2007; Saylam et al., 2006; Vythilingam et al., 2002, 2004) but did not differ in

V. Lorenzetti et al. / Journal of Affective Disorders 117 (2009) 1–17

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Fig. 1. Method used for the study selection. ⁎9 studies (1–7) were a priori; T.L. = temporal lobe; Hippoc. = hippocampus; F.L. = frontal lobe; ACC = anterior cingulate cortex; B.G. = basal ganglia; PCC = posterior cingulate cortex, PG = pituitary gland, CC = corpus callosum; 1inclusive: several studies have been excluded by multiple exclusion criteria; 2exclusive: no study has been excluded by more than 1 exclusion criteria.

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Table 1 Temporal lobe. Study

Caetano et al. (2004)

Patients

Controls

Group size (males)/diagn.

Age (M) MDD duration

21 (6) cMDD 10 (1) rMDD

37.6 42.7

Vythilingam 21 (0) cMDD et al. (2002) childhood abuse inp. 11 (0) cMDD inp. Shah et al. 20 (13) mel. TRD (2002) endogenous symptoms inp. and outp. 20 (13) Recov. mel. MDD outp. Bremner et al. 16 (10) MDD in (2000) rem. outp.

Method Voxel/slice size (mm)

Findings

Curr. (M)

Tot (M) Age onset (M)

– –

11.0 y 12.3 y

26.7 30.5

5.2 4.9

31(7)

36.7

I.5 T

13 m

1201 d

25

2

33(12)

34

I.5 T

7.9 y

37.1 –

40(21)

41.7

I.5 T

No difference in tot T.L. vol between patients and controls, or between rem. MDD and cMDD; no diff. in STG vol between patients and controls; I.C. between: MDD length and right STG vol; STG vol and No. ep. 0.93×1.25×1.5 (c.) No diff. in right T.L. vol between MDD and controls; MDD had bleft T.L. than controls; T.L. vol did not change before and after antidepressant treatment. 0.4 × 0.4 × 1.5 No relation between T.L. vol and MDD.

27.7 m (cum.)

0.93 × 1.25 × 1.5

–

–

–

–

16

39.3

0.5 T

–

33

–

–

–

–

14(0)

27

I.5 T

1.5 (c.)

48.9

– 197 w (longest MDE)

– 263 w

– – 38.9 (last MDE = 45.8) 2.2

20(13)

49.3

1.0 T

1.875 (c.)

47.7

46 w (longest MDE)

76 w

38.2 (last MDE = 44.8) 2.5

43

31w, r = 6–120 w (rem.) –

16

45

I.5 T

3

–

2 (prev)

Patients had a bilaterally Ntemporal horn of the lateral ventricle than controls; Sign. diff. between the left and right side of the ventricle horn for both depressed and controls; no effect of MDD on STG and BTA vol; ROIs vol differed between left and right hemispheres in control, but not in MDD group. No diff. in T.L. vol.

TRD patients had bGM density in the left STG and MTG (no associated CSF changes) than healthy controls and recov. patients; no diff. between recov. patients and healthy controls; Corr. between: increasing cum. no. of ECT and bilateral MTG and STG. No diff. vol in T.L. between patients and controls.

Diagn. = diagnosis; M = mean; no. ep. = number of episodes; cMDD = current Major Depressive Disorder; rMDD = recurrent MDD; MDD = Major Depressive Disorder; outp. = outpatients; FE = first episode; rem. = remission; mel. = melancholic; inp. = inpatients; TRD = Treatment Resistant Depression; recov. = recovered; cum = cumulative; MDE = Major Depressive Episode; r = range; w = weeks; m = months; y = years; prev. = previous; c. = contiguous; T.L. = temporal lobe; diff. = differences; vol = volume, volumes, volumetric; STG = superior temporal gyrus; I.C. = inverse correlation; corr. = correlation; no. = number; MTG = medial temporal gyrus; BTA = basolateral temporal area; ROI = region of interest; CSF = cerebral spinal fluid; ECT = electro convulsive therapy; GM = grey matter; b = smaller; N = larger; – = not available.

V. Lorenzetti et al. / Journal of Affective Disorders 117 (2009) 1–17

Vythilingam 38 (15) MDD outp.: 41 et al. (2004) (7) FE, (31) MDD in rem. (11) mel. and (6) atypical Frodl et al. 40 (21) cMDD inp. 44.4 (2004) Morys et al. 10 (0) cMDD 39.8 (2003)

No. ep (M) Group size Age (M) (males)

V. Lorenzetti et al. / Journal of Affective Disorders 117 (2009) 1–17

these variables (e.g., IQ, education, gender, handedness or age). Only three studies did not report any group matching (Lacerda et al., 2003; Morys et al., 2003; Neumeister et al., 2005). Therefore, the reported findings are unlikely to be due to cognitive or socio-demographical variables. Second, we have found difficulty in clearly categorizing the reviewed studies as a priori vs exploratory. While a few studies are clearly hypothesis driven (Brambilla et al., 2002b; Caetano et al., 2006; Frodl et al., 2003; Lacerda et al., 2004, 2003; Monkul et al., 2007; Saylam et al., 2006), most tend to describe only broad aims or very general hypotheses, wherein both a priori and exploratory analyses are reduced. This may be due to the fact that neuroimaging research in psychiatric disorders is still in its infancy and lacks well developed models and theories. Finally, most of the studies have explicitly acknowledged the funding agency (exceptions being: (Morys et al., 2003; Neumeister et al., 2005; Saylam et al., 2006) and had national or independent funding support (exceptions being: (Caetano et al., 2006; Vythilingam et al., 2004). It is unlikely that conflict of interests (Shea et al., 2007) have affected the reviewed literature. 3.2. Temporal lobes Table 1 lists all the identified studies examining temporal lobe regions in patients with MDD. None of the studies investigating total temporal lobe volume (collapsed across hemispheres) reported any significant changes in unipolar depressed patients compared with healthy controls (Bremner et al., 2000; Caetano et al., 2004; Frodl et al., 2004; Shah et al., 2002; Vythilingam et al., 2002, 2004). While several of these studies assessed left and right temporal volumes separately (Bremner et al., 2000; Caetano et al., 2004; Vythilingam et al., 2004), only Vythilingam et al. (2004) found evidence for a lateralization effect, reporting smaller left temporal lobe volume in patients. Notably, the patient sample studied by these authors had the longest illness duration compared to the other studies (Vythilingam et al., 2004). In this regard, left-lateralized temporal lobe changes may reflect progression of the disease over time, or a distinct pathophysiological process that affects risk of relapse. Consistent with studies examining total temporal lobe volume, studies examining specific structures such as the superior temporal gyrus (STG) and basolateral temporal area (BTA) have yielded conflicting findings. For example, the study of Shah et al. (2002) found volumetric changes in the STG of patients with MDD, while Morys et al. (2003) failed to find such evidence. Other studies have identified STG volume to be inversely correlated with number of depressive episodes and total length of illness (Caetano et al., 2004; Shah et al., 2002), suggesting that the volumetric differences may only become apparent in chronically ill patients with recurrent episodes. The evidence to date provides no evidence for sexually dimorphic changes (Caetano et al., 2004), nor do they support any effects of medication (Bremner et al., 2000; Caetano et al., 2004; Shah et al., 2002; Vythilingam et al., 2004) or family history (Caetano et al., 2004; Vythilingam et al., 2004), although only a handful of studies have examined these effects in detail.

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3.3. Hippocampus The hippocampus is the most extensively studied region in MDD, and the resulting findings, albeit not homogeneous, seem to suggest that hippocampal volumetric reductions are associated with MDD. While reduced hippocampal volume differences have been the most frequent finding (Bremner et al., 2000; Caetano et al., 2004; Frodl et al., 2002b, 2004, 2006; Lange and Irle, 2004; MacQueen et al., 2003; Neumeister et al., 2005; Saylam et al., 2006; Shah et al., 2002; Sheline et al., 2003; Weniger et al., 2006), others have reported no difference between patients and controls (Hastings et al., 2004; Monkul et al., 2007; Morys et al., 2003; Posner et al., 2003; Rusch et al., 2001; Vythilingam et al., 2002, 2004) and tendencies toward volumetric enlargements (Frodl et al., 2002b; Vakili et al., 2000; Vythilingam et al., 2004) have also been reported. It should be reported that while Posener et al. (2003) found no hippocampal volumetric alteration they did observe significant shape changes (Table 2), which may suggest that more subtle subregional changes occurring within the hippocampus could be relevant in the neurobiology of MDD. Notably, illness severity, gender and medication effects each appear to have an influence on the reported findings. Regarding the effects of illness severity, smaller hippocampal volumes have been more commonly found in patients suffering multiple depressive episodes rather than patients in remission or those experiencing their first episode (Caetano et al., 2004; Frodl et al., 2004, 2006; MacQueen et al., 2003; Neumeister et al., 2005; Videbeck and Ravnkilde, 2004), suggesting that volumetric reduction of the hippocampus may be associated with repeated depressive episodes (Frodl et al., 2006; MacQueen et al., 2003). Accordingly, several studies have reported negative correlations between hippocampal volumes and length of illness and/or measures of depressive symptom severity in unipolar patients (Caetano et al., 2004; MacQueen et al., 2003; Vakili et al., 2000). This apparent relationship between hippocampal reductions and illness chronicity may explain negative findings reported in the literature, given that half of such studies examined outpatients, suggesting that the chronicity of disorder in these samples may have been insufficient to result in a volumetric change in this region (Hastings et al., 2004; Posner et al., 2003; Rusch et al., 2001; Vythilingam et al., 2004). Interestingly, gender may moderate the relationship between hippocampal volume and illness duration. For example, while failing to reach statistical significance, Frodl et al. (2002b) found a trend for hippocampal volume to be enlarged in female first episode patients but decreased in males, relative to healthy controls. It has been previously demonstrated that hippocampal size decreases with age in men more than in women, and men normally have larger hippocampal volume than women (Frodl et al., 2002b; Videbeck and Ravnkilde, 2004). As such, it is possible that MDD in males may exacerbate normal age-related reductions in hippocampal volumes, whereas hippocampal changes in female patients may be caused by a different mechanism. Further longitudinal work is required to examine these possibilities. However, it must be noted that the mean age of onset in Frodl et al's. (2002b) sample was 40 years. As such, the findings may not be generalizable to a population of

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Table 2 Hippocampus. Study Result direction (=, ±, ↑, ↓)

↓

Patients Group size (males)/diagn.

Controls

Age onset (M)

34 (19) inp.: 13 FE MDD and 20 rMDD Saylam et al. 24 (6) outp.: (2006)

45.5 –

6.8 y

33.4 22.6 w

Weniger 21 (0) Recent et al. (2006) onset MDD inp. Neumeister 31 (8) rMDD et al. (2005)

34 40.1

Frodl et al. (2004)

40 (21) cMDD inp.

44.4 27.7 m(cum.)

Lange and Irle (2004) Caetano et al. (2004)

17 (0) cMDD inp. 10 (1) MDD in rem. 21 (6) cMDD

34

Frodl et al. (2006)

MacQueen 20 (7) FE MDD et al. (2003) 7 (6) ME MDD

Sheline et al. 38 (0) rMDD (2003) in rem. outp.

Shah et al. (2002)

20 (13) mel. TRD inp. and outp. 20 (13) recov. mel. MDD outp.

Method Voxel/slice size(mm)

Medication (no. Of patients)

Findings

I.5 T

(31) antidep., (4) also on neurol., (3) off. (6) FE MDD off. (18) MDD off for M = 33.6 d E.C.: antidep. ⁎⁎⁎, fluox. ⁎⁎⁎⁎. All antidep.: TCA or SSRI for M = 13 w All off for M = 30 m (8) näive. (23) past use of SSRI, SNRI, TCA, BDP, and comb. (4) off. (36) SSRI, TCA, or new antidep. Tot prev. durat. Of antidep. use M = 25.5 m

Patients had b hippo GM and WM vol than controls; no corr. between: hippo vol and MDD severity. Patients had b left (but not diff. right) hippo than controls; Corr. right hippo and HAM-D scores; trend for I.C. left hippo and tot MDD duration. Patients had b hippo than controls.

No. ep (M)

Group size

Age (M)

38.8

–

34(19)

43.6

54.4 w

–

1.7, but6 were FE

24(6)

30.16 1.5 T

2 (c.)

17 w

5y

28

1.4

23(0)

32

I.5 T

–

30.5 w (rem.)

24.6

3.2

57(21)

38.0

3T

1.0 × 1.0 × 1.33 (c.) 224 × 224 voxels

7.9 y

37.1

–

40(21)

41.7

I.5 T

0.4 × 0.4 × 1.5

5y

29

17(0)

32

I.5 T

1.0 × 1.0 × 1.3

42.7 –

12.3 y

30.5

2(n = 6 FE) 4.9

31(7)

36.7

I.5 T

37.6

11.0 y

26.7

5.2

28.4 –

–

26.3

Curr.

20(7)

28.4

I.5 T

35.9

10 y

24.9

6.0

17(6)

36.2

50.8 –

1341 d

–

5.4 38(0) (r = 1–20)

–

48.9 197 w 263 w (longest MDE)

38.9 (last 2.2 MDE = 45.8)

47.7

38.2 (last 2.5 MDE = 44.8)

46 w 76 w (longest MDE)

20(13)

–

I.5 T

49.3

I.0 T

0.4 × 0.4 × 1.5

All antidep.: TCA or SSRI. 0.93 × 1.25 × 1.5 All off ⁎⁎. 5 (3 cMDD and 2 rem. MDD) past antipsych. use. 0.44 × 0.66 × 1.2 All naïve. Some on antidep. before scan. All serot. antidep. Some on serot., TCA, novel agents, MAOIs. 1 × 1 × 1.25 (c.) Antidep. treatm. outcome: d. “treated” (M = 517) and d. “untreated” (M = 824). 1.875 (c.) All stable ⁎⁎ neurol., lithium or BDP. (11) Off. (9) stable ⁎⁎ antidep., neurol., or lithium.

No diff. between drug näive and prev. medicated patients; rMDD patients had b total and posterior (not anterior) hippo vol than controls. Patients had b hippo GM and WM vol than controls; L/L homozygous genotype patients had a sign. diagnosis and genotype interaction for hippo WM vol; No corr. hippo vol and MDD duration or severity. Patients had b hippo vol (more right than left) than controls. cMDD patients had bbilateral hippo vol than rem. MDD patients; I.C. between: length of illness and left hippo vol ME MDD patients had bhippo vol than healthy controls and FE MDD patients; trend toward a logarithmic association between MDD length and hippo vol

Patients had b hippo vol than controls; I.C. between: untreated MDD (but not treated) duration with antidep. and hippo reductions. TRD patients had reciprocal vol reductions with overlapping WM increases in bilateral hippo areas, particularly anteriorly and on the left, using VBA (but not volumetric) analysis.

V. Lorenzetti et al. / Journal of Affective Disorders 117 (2009) 1–17

A g e MDD duration (M) Curr. (M) Tot (M)

Vythilingam 21 (0) cMDD et al. (2002) childhood abuse inp. 11 (0) cMDD inp.

=

Bremner et al. (2000) Monkul et al. (2007)

↓↑

–

–

–

34

–

–

–

–

31 w, r = 6– 120 w (rem.) –

–

–

15.6 y

–

–

14(0)

27

I.5 T

1.5 (c.)

2 (prev.)

16(0)

45

I.5 T

16.0

18.6

17(0)

31.3

I.5 T

All parox., fluox., or desipr. 0.93 × 1.25 × 1.5 All off⁎⁎.

9.7 y

26.9

3.9

38.9 –

–

23

4.7

18(8)

34.8

I.5 T

39.8 –

–

–

–

16(−)

39.3

98.8 m –

0.8

42(19)

–

–

1201 d 25

27 (12) cMDD outp. 33.0 59.4 m

33.2 – 13 (6) mel. and 12 (5) non-mel. MDD outp. Vythilingam 38 (15): 7 FE MDD 41 13 m et al. (2004) and 31 rMDD outp.

–

3

E.C.

0.5 T

0.85 × 0.83 × 1.5 (c.) –

33.2

I.5 T

1×1×1

14) curr. on.

15(6)

37.4

I.5 T

0.93 × 1.25 × 1.2 All off ⁎⁎⁎.

2

33(12)

34

I.5 T

0.93 × 1.25 × 1.5 (c.)

–

Before treatm.: all off ⁎⁎⁎⁎ and (15) näive. All on an M = 7 m treatm. with SSRI, fluox., sertr., or venlafax. All on a 8 w fluox. treatm.: (n = 21) resp. and (n = 17) non-resp.

Vakili et al. (2000)

38 (17) cMDD

38.5 –

–

–

–

20(9)

40.3

I.5 T

0.97 × 0.97 × 3

Frodl et al. (2002a,b)

30 (13) FE MDD inp.

40.3 –

0.71 y

40.0

–

30(13)

40.6

I.5 T

0.44 × 0.44 × 1.5 E.C.: cortisol or BDP medx in the prev. 3 m

Childhood abuse patients had b left hippo vol than MDD patients and healthy controls; no hippo vol diff. between MDD patients and healthy controls. Right hippo vol not differ between subgroups; No corr. between: hippo vol and alcohol abuse history or measures of MDD, PTSD, early trauma. Patients had bleft hippo vol (also in the right but not sign.) than healthy controls. No hippo vol diff. between both suicidal and non-suicidal patients compared to healthy controls; no corr. between: hippo vol and no. ep, MDD length or age at onset. No sign. vol diff. between patients and controls. No vol diff. between patients and controls; different left and right hippo vol in controls but not in patients. Patients and controls did not differ for hippo vol but for shape in the subiculum. No diff. between patients and healthy controls, or patient subgroups. No diff. between: untreated patients and healthy controls; patients before and after antidep. treatment; FE and ME patients and healthy controls; trend for vol hippo increase in atypical MDD subgroup after antidep. treatment. No diff. between patients and controls; Sign. I.C. between left (trend in right) hippo vol of MDD men and HDRS baseline scores. MDD female resp. had Nright hippo vol than MDD female non-resp. FE MDD males had bhippo tot and GM vol than healthy males; FE MDD females had N hippo vol than healthy females; patients had alterations of left–right asymmetry and b bilateral hippo WM fibres than controls.

V. Lorenzetti et al. / Journal of Affective Disorders 117 (2009) 1–17

↑

–

16 (10) MDD 43 in rem. outp. 7 (0) suicidal 31.4 MDD 10 (0) non-suicidal 36.5 MDD

Hastings 18 (8) cMDD outp. et al. (2004) Morys et al. 10 (−) cMDD (2003) Posner et al. (2003) Rusch et al. (2001)

33

Diagn. = diagnosis; M = mean; no. ep = number of episodes; ↓ Volumetric decrease; ↑ Volumetric increase; = no volumetric difference; inp. = inpatients; FE = first episode; MDD = Major Depressive Disorder; rMDD = recurrent MDD; cMDD = current Major Depressive Disorder; rem. = remission; ME = Multiple Past Episodes; mel. = melancholic; outp. = outpatients; TRD = Treatment Resistant Depression; recov. = recovered; non-mel. = nonmelancholic; MDE = Major Depressive Episode; r = range; w = weeks; m = months; d = days; y = years; curr. = current; prev. = previous; c. = contiguous; tot = total; antidep. = antidepressant; neurol. = neuroleptics; durat. = duration; treatm. = treatment; serot. = serotonergic; parox. = paroxetine; fluox. = fluoxetine; desipr. = desipramine; sertr. = sertraline; venlafax. = venlafaxine; TCA = tricyclic antidepressants; SSRI = selective serotonin reuptake inhibitors; SNRI = serotonin–norepinephrine reuptake inhibitors; MAOIs = monoamine oxidase inhibitors; BDP = benzodiazepines; medx = medication; resp. = responders; non-resp. = non-responders; cum. = cumulative; GM = grey matter; WM = white matter; corr. = correlation; Hippo = hippocampus, hippocampal; sign. = significantly or significant; diff. = difference; I.C. = inverse correlation; VBA = voxel based analysis; vol = volume, volumes, volumetric; E.C. = exclusion criteria; ⁎⁎ = for at least 2 weeks before the study; ⁎⁎⁎ = for at least 4 weeks before testing; ⁎⁎⁎⁎ for at least 6 weeks before the study; b = smaller; N = larger; – = not available.

7

8

Table 3 Amygdala. Study

Patients Group size (males)/diagn.

31.3

I.5 T

0.93 × 1.25 × 1.5

32

I.5 T

1.0 × 1.0 × 1.33 (c.)

Suicidal patients had N right amy than nonsuicidal; no diff. between non-suicidal patients and healthy controls; no corr. between: amy vol and no. prev. MDE, MDD length and age at onset. Patients had Namy vol than controls. Patients had a Namy vol than controls.

17(0)

23 (0)

Curr. (M)

Tot (M) y

Age onset (M)

15.6

16.0

18.6

36.5

–

9.7

26.9

3.9

21 (0) recent-onset MDD inp. 17 (0) cMDD inp.

34

17 w

5

28

1.4

34

–

5

29

2(n = 6 FE MDD) 17

32

I.5 T

1.0 × 1.0 × 1.3

10 (1) MDD in rem. 21 (6) cMDD

42.7 37.6

–

12.3 11.0

30.5 26.7

4.9 5.2

31(7)

36.7

I.5 T

38.9

–

–

23

4.7

18(8)

34.8

I.5 T

30 (13) FE MDD inp. 40.3 27 (14) rMDD inp. 49.1

–

0.75 11.7

40.0 37.4

– –

30(13) 40.6 27(14) 46.3

I.5 T

39.8

–

–

–

–

16

39.3

0.5 T

43

31 w, – r = 6–120 w (rem.)

–

2(prev.)

16

45

I.5 T

Trend towards bleft amy GM vol in MDD patients than healthy controls; No diff. in amy vol between cMDD and rem. patients. 0.85 × 0.83 × 1.5 (c.) MDD females (but not MDD males) had b right amy and a trend toward b left amy vol than healthy controls. 0.95 × 0.89 × 1.5 FE MDD patients had N amy vol than rMDD patients and healthy control; no diff. between rMDD patients and healthy controls; Sign. corr. between: right (but not left) amy and age in patients. – No vol amy diff. between: patients and controls; the hemispheres in both patients and controls. 3 Patients had bright amy vol than controls (not sign. after controlling for WBV).

Morys et al. 10 (0) cMDD (2003) Bremner 16 (10) cMDD outp. et al. (2000)

0.93 × 1.25 × 1.5

Diagn. = diagnosis; M = mean; no. ep. = number of episodes; MDD = Major Depressive Disorder; inp. = inpatients; rem. = remission; outp. = outpatients; FE = first episode; rMDD = recurrent Major Depressive Disorder; cMDD = current Major Depressive Disorder; curr. = current; MDE = major depressive episode; r = range; w = weeks; y = years; prev. = previous; c. = contiguous; amy = amygdala; diff. = differences; corr. = correlation; no. = number; vol = volume, volumes, volumetric; sign. = significant; GM = grey matter; b = smaller; N = larger; – = not available.

V. Lorenzetti et al. / Journal of Affective Disorders 117 (2009) 1–17

Findings

Group Age (M) size

–

Hastings 18 (8) cMDD outp. et al. (2004) Frodl et al. (2003)

Method Voxel/slice size(mm)

No. ep (M)

31.4

Monkul 7 (0) suicidal et al. (2007) MDD 10 (0) non-suicidal MDD Weniger et al. (2006) Lange and Irle (2004) Caetano et al. (2004)

Controls Age (M) MDD duration

V. Lorenzetti et al. / Journal of Affective Disorders 117 (2009) 1–17

depressed individuals with early onset, especially given arguments that the pathophysiology of late-onset MDD may be distinct from earlier-onset MDD (Campbell and Mac Queen, 2006; Drevets, 2001; Hickie et al., 2005; Lloyd et al., 2004). Medication effects complicate the relationship between illness duration and gender effects on hippocampal volume, as they also appear to exert a differential effect on hippocampal volume in male and female patients. For example, female responders to antidepressant treatment have been found to have larger hippocampal volumes than female non-responders, but male depressed patients did not show the same effect (Vakili et al., 2000; Vythilingam et al., 2004). Also, drug-free depressed patients have been found to have a smaller hippocampal volume than healthy controls (Saylam et al., 2006). These findings suggest that medication may have a protective effect against volumetric reduction of the hippocampus in female treatment responders, as has been previously suggested (Sheline et al., 2003), or that female responders had a larger hippocampus to begin with — potentially reflecting a protective neurobiological factor that enhances treatment efficacy. Interestingly, medication tended to have no effect in recurrent depressed patients (Neumeister et al., 2005; Vythilingam et al., 2004), despite affecting hippocampal volume in non-recurrent depressed patients (Sheline et al., 2003; Vakili et al., 2000). For example, Sheline et al. (2003) found that duration of untreated illness, but not the length of treatment, was inversely related to hippocampal volume in unipolar patients. Family history of mood disorders was ascertained in 6 studies, but only 2 directly compared whether familial and non-familial patients' hippocampal volumes were significantly different, with both reporting no effect (Caetano et al., 2004; Hastings et al., 2004). More studies are needed to clarify whether the family history of mood disorders may affect the volume of the hippocampus in depressed patients. These studies suggest that more persistent forms of MDD (e.g., multiple episodes or repeated relapses, longer illness duration) tend to have a greater impact on hippocampal volume. However, gender may mediate this relationship, as males and females exhibit different patterns of change following the illness onset. Medication effects on the hippocampus appear to interact with both the chronicity of the illness (i.e. they are larger in non-recurrent patients) and gender (i.e. female, but not male, treatment responders do not seem to show illness-related hippocampal reductions). However, the paucity of available longitudinal work makes it difficult to draw firm conclusions. 3.4. Amygdala Table 3 summarizes the findings of the eight identified studies meeting our inclusion criteria that examined amygdala volume in MDD patients. These findings, as well as previous papers (Sheline et al., 1998), suggest that amygdala size may vary in relation to illness duration, while age at onset does not seem to have a major effect (Frodl et al., 2002a, 2003; Lange and Irle, 2004; Sheline et al., 1998). Indeed, while unipolar patients earlier in the course of illness tend to have increased amygdala volume (Frodl et al., 2002a, 2003; Lange and Irle, 2004; Weniger et al., 2006), depressed patients with

9

a longer illness duration and with greater number of MDD episodes tend to show volumetric reductions (Bremner et al., 2000; Caetano et al., 2004; Hastings et al., 2004; Monkul et al., 2007). Furthermore, it is not clear whether MDD affects the left and right amygdala differentially (Caetano et al., 2004; Hastings et al., 2004; Monkul et al., 2007). For instance, Bremner et al. (2000) found a decreased right, but not left, amygdala in remitted depressed patients. However, these conclusions may be limited by the fact that several studies in unipolar depressed patients found no correlation between amygdala volumes and disorder related variables, such as age of onset, number of hospitalisations, illness duration and severity (Frodl et al., 2002a, 2003; Hastings et al., 2004; Lange and Irle, 2004). Gender also appears to influence the nature of changes in the amygdala, with females being more likely than males to show reductions. For instance, Hastings et al. (2004) found a smaller amygdala in unipolar female but not male patients. However, further investigation of gender-related differences is required, since several studies investigated samples composed exclusively of females (Lange and Irle, 2004; Monkul et al., 2007; Weniger et al., 2006). Frodl et al. (2002a, 2003) found no gender effect, while other studies have not assessed this relationship (Bremner et al., 2000; Caetano et al., 2004; Morys et al., 2003). The evidence to date reports no effects of medication (Weniger et al., 2006) or family history (Caetano et al., 2004) on amygdala volume, although few studies have directly investigated such relationships. Together, these results suggest that the amygdala is a structure whose volume is dependant on the phase of illness and gender, such that its volume is increased during the early stages of MDD and reduces as the illness progresses, especially in affected females. 3.5. Frontal lobes Eight studies investigating the frontal lobe met our inclusion criteria, and these are listed in Table 4. The emphasis of these studies has been on volumetric changes in the orbitofrontal cortical (OFC) (Bremner et al., 2000, 2002; Frodl et al., 2004, 2006; Hastings et al., 2004; Lacerda et al., 2004; Monkul et al., 2007; Shah et al., 2002). This work has consistently reported a volumetric reduction of the entire frontal lobe and/or the OFC in more severe patient groups (Bremner et al., 2002; Frodl et al., 2006; Lacerda et al., 2004; Monkul et al., 2007; Shah et al., 2002), but not in less severely ill patients (Bremner et al., 2000; Hastings et al., 2004; Lacerda et al., 2004). Accordingly, Lacerda et al. (2004) reported an inverse correlation between age and left lateral OFC in unipolar patients but not in healthy controls, suggesting that MDD duration may progressively affect the volume of the left lateral OFC. However, several studies have reported non-significant correlations between clinical variables (illness subtype, severity or duration, age of onset, number of episodes or length of remission) and the volumes of frontal structures (Bremner et al., 2000, 2002; Hastings et al., 2004; Lacerda et al., 2004; Monkul et al., 2007). Further longitudinal work is required to determine whether frontal volumes changes with illness progression in MDD. Lacerda et al. (2004) also found evidence for gender differences in changes in the medial OFC, reporting a reduction in male, but not female, patients. However, few

10

Table 4 Frontal lobes. Study

Patients Group size (males)/diagn.

Controls Age (M) MDD duration

Age (M)

Only suicidal patients had bOFC GM vol than healthy controls; no corr. between OFC vol and no. of prev. episodes, MDD length, age at onset. Patients had b F.L. GM (but not F.L. WM) vol than controls. No OPFC vol diff. between patients and controls. Patients had b GM vol in right medial and left lateral OFC than controls; I.C. between left lateral OFC vol and age in patients; male MDD patients had b bilateral medial OFC vol than male controls; dysth. patients had b right medial OFC GM vol than healthy controls; no OFC vol diff. between euth. and dysth. patients. No F.L. vol diff. between patients and controls. Patients had b mOFC vol than controls. No diff. in other frontal regions. TRD patients had b GM density in right STG (large reduction in WM density in the right MFG and STG); TRD patients had less prefrontal lobe tissue than healthy controls; I.C. between increasing cum. ECT and bilateral MFG and STG GM density in the TRD group. No diff. in F.L. vol between patients and controls.

Curr(M)

Tot (M) Age onset (M)

31.4 36.5

– –

15.6 y 9.7 y

16.0 26.9

18.6 3.9

17(0)

31.3

I.5 T

0.93 × 1.25 × 1.5

Frodl et al. (2006) Hastings et al. (2004) Lacerda et al. (2004)

34 (19) inp.: 13 FE 45.5 MDD and 20 rMDD 18 (8) cMDD: 38.9 12 inp. and 6 outp. 39.2 31 (7): 19 dysth. MDD and 12 euth. MDD

–

6.8 y

38.8

–

34(19)

43.6

I.5 T

0.4 × 0.4 × 1.5

–

–

23

4.7

18(8)

34.8

I.5 T

0.85 × 0.83 × 1.5 (c.)

–

11.4 y

27.9

–

34(12)

37.03

I.5 T

0.93 × 1.25 × 1.5 (c.)

Frodl et al. (2004) Bremner et al. (2002) Shah et al. (2002)

40 (21) cMDD inp.

27.7 m (cum.)

7.9 y

37.1

–

40(21)

41.7

I.5 T

0.4 × 0.4 × 1.5

Monkul 7 (0) suicidal MDD et al. (2007) 10 (0) non-suicidal MDD

44.4

15 (5) MDD in rem. 43

31 w, r = 6–120 w (rem.) –

–

2(prev.)

20(9)

45

I.5 T

0.93 × 0.93 × 3 (c.)

20 (13) mel. TRD 48.9 inp. and outp. 20 (13) Recov. mel. 47.7 MDD outp.

197 w (longest MDE)

263 w

2.2

20(13)

49.3

I.0 T

1.875 (c.)

46 w (longest MDE)

76 w

38.9(last MDE = 45.8) 38.2(last MDE = 44.8)

16

45

I.5 T

3

Bremner 16 (10) MDD in rem. 43 et al. (2000)

31 w, r = 6–120 w (rem.) –

–

2.5

2 (prev.)

Diagn. = diagnosis; M = mean; no. ep. = number of episodes; MDD = Major Depressive Disorder; inp. = inpatients; FE = first episode; rMDD = recurrent Major Depressive Disorder; outp. = outpatients; cMDD = Major Depressive Disorder; dysth. = dysthymic; euth. = euthymic; rem. = remission; mel. = melancholic; TRD = Treatment Resistant Depression; recov. = recovered; cum. = cumulative; r = range; w = weeks; MDE = Major Depressive Episode; y = years; prev. = previous; c. = contiguous; OFC = orbital frontal cortex; GM = grey matter; vol = volume, volumes, volumetric; corr. = correlation; no. = number; F.L. = frontal lobe; WM = white matter; diff. = differences; I.C. = inverse correlation; mOFC = medial orbital frontal cortex; OPFC = orbital pre frontal cortex; SFG = superior frontal gyrus; MFG = medial frontal gyrus; CSF = cerebral spinal fluid; ECT = electro convulsive therapy; VBA = voxel based analysis; b = smaller, reduced; N = larger; VBA = voxel based analysis; – = not available.

V. Lorenzetti et al. / Journal of Affective Disorders 117 (2009) 1–17

Group size

Method Voxel/slice size(mm)

Findings

No. ep (M)

Table 5 Anterior cingulate cortex. Study

Voxel/slice size(mm)

Detected Brodmann area

Findings

31.3

I.5 T

0.93 × 1.25 × 1.5

24

31(7)

36.7

I.5 T

0.93 × 1.25 × 1.5

24, 32

– – 4.7

18(8) – 18(8)

38.1

1.5 T

0.93 × 1.25 × 1.2

25

34.8

I.5 T

0.85 × 0.83 × 1.5 (c.)

24

–

–

38(24)

37

I.5 T

0.93 × 1.25 × 1.5

24

– –

15.2 –

– –

8 9

20.2 35.8

I.5 T

1×1×1

24

31 w, r = 6–120 w (rem.)⁎⁎⁎

–

M = 2(prev)

20(9)

45

I.5 T

0.93 × 0.93 × 3 (c.)

24, 25

No ACC vol diff. between suicidal and non suicidal patients, healthy controls; no corr. between ACC vol and no. prev. episodes, MDD length, age of onset. Patients had bbilateral ACC vol than healthy controls; rem. patients had bleft ACC vol than healthy controls; cMDD patients had (not sign.) bACC vol than rem. patients. No group diff. in SGPFC; I.C. between GM density and age in mel. patients. No diff. in right SGPFC between MDD patients and healthy controls; left SGPFC was b only in male patients compared with male controls. No diff. in SGPFC vol in fam. and nonfam. patients compared to healthy controls or in mildly depressed or euth. outp. (either fam. or non-fam.). Both adolescent and middle aged female patients had b left SGPFC vol than healthy controls. No diff. in vol of subgenual gyrus and subcallosal gyrus between patients and controls.

Controls

Group size (males)/diagn.

Age (M)

Tot (M)

Age onset (M)

Monkul et al. (2007)

7 (0) suicidal MDD 10 (0) non-suicidal MDD

31.4 36.5

15.6 y 9.7 y

Caetano et al. (2006)

31(7) outp.: 21 cMDD and 10 MDD in rem.

39.2

Pizzagalli et al. (2004) Hastings et al. (2004)

13 (−) mel. MDD outp. 17 (−) Non-mel. MDD outp. 18 (8) cMDD: 12 inp. and 6 outp.

Brambilla et al. (2002a,b)

Botteron et al. (2002) Bremner et al. (2002)

MDD duration

No. ep (M)

Group size

Age (M)

16.0 26.9

18.6 3.9

17(0)

11.4 y

27.9

5.1

36.5 33.1 38.9

– – –

– – 23

18 (1) MDD outp.: 10 dysth. and 18 euth.

42

9 y (r = 1–33 y)

30 (0) early onset⁎ MDD⁎⁎ 18 (0) early onset MDD and some rMDD. 15 (5) cMDD outp.

20.2 35.8 43

V. Lorenzetti et al. / Journal of Affective Disorders 117 (2009) 1–17

Method

Patients

Diagn. = diagnosis; M = mean; no. ep. = number of episodes; MDD = Major Depressive Disorder; outp. = outpatients; rem. = remission; mel. = melancholic; non-mel. = non-melancholic; cMDD = current Major Depressive Disorder; rMDD = recurrent Major Depressive Disorder; inp. = inpatients; dysth. = dysthymic; euth. = euthymic; r = range; y = years; w = weeks; ACC = anterior cingulate cortex; vol = volume, volumes, volumetric; diff. = differences; corr. = correlation; no. = number; prev. = previous; sign. = significant; SGPFC = Subgenual Prefrontal Cortex; I.C. = inverse correlation; GM = grey matter; fam. = familial; non-fam. = nonfamilial; ⁎ = before 18 years; ⁎⁎ = at least 2 week of duration; ⁎⁎⁎ = current duration of the disorder; b = smaller, reduced; N = larger; – = not available.

11

12

V. Lorenzetti et al. / Journal of Affective Disorders 117 (2009) 1–17

other studies have systematically investigated gender effects, making it difficult to draw firm conclusions (Bremner et al., 2000, 2002; Hastings et al., 2004; Shah et al., 2002). The effect of medication and family history is still unclear, given that no study has investigated these issues. Together, these findings suggest that frontal lobe structures may be affected in more severely depressed patients. Moreover, it appears that the left lateral and medial regions of the OFC may be influenced by distinct clinical and demographic characteristics (i.e. length of illness and gender, respectively). 3.6. Anterior cingulate cortex Several volumetric studies have investigated whether depression may be related to alterations in the anterior cingulate cortex (ACC) (see Table 5), particularly a sub-region ventral to the genu of the corpus callosum commonly termed the sub-genual pre-frontal cortex (SGPFC). Contradictory findings have emerged from these studies, possibly due to both the different clinical and demographical features of the patient samples and the different methods for classifying ACC sub-regions. No volumetric SGPFC alterations have been found in less severely depressed samples composed of either remitted or mainly euthymic patients (Brambilla et al., 2002b; Bremner et al., 2002; Pizzagalli et al., 2004), an exception being the study by Monkul et al. (2007). In contrast, smaller volume of the cingulate gyrus (excluding the subgenual area), or of the left ACC, has been found in samples composed primarily of currently ill patients, who also show ACC reductions relative to patients in remission (Caetano et al., 2006). Pizzagalli et al. (2004) found no volumetric alteration in a sample of melancholic patients, but did report a negative correlation between SGPFC grey matter density and age in melancholic patients. However, several studies have found no correlations between structural findings and clinical variables such as age at onset, length and severity of illness, and number of episodes (Brambilla et al., 2002b; Caetano et al., 2006; Hastings et al., 2004). There are also contradictory findings with regard to patterns of SGPFC volumetric changes related to the gender of the patients. Indeed, while Hastings et al. (2004) found a smaller left SGPFC in depressed males but not females, Botteron et al. (2002) detected a volumetric reduction of the left SGPFC in depressed females. These contradictory results suggest that volumetric changes in this region may be specifically related to the gender of the depressed patients, although the precise nature of this interaction remains unclear. On the other hand, it may be that the absence of uniform tracing protocol across studies is responsible for the variability of the findings to date. One factor complicating attempts to assess ACC changes in depression is the considerable variability in sulcal and gyral anatomy of the area (Ono et al., 1990), which differs between males and females (Paus et al., 1996; Yücel et al., 2001), and has been shown to affect regional cytoarchitecture and volume (Fornito et al., 2006). Unfortunately, no studies of MDD patients to date have explicitly considered the influence of such variability, making it difficult to draw firm conclusions regarding the nature of the underlying changes. Family history of mood disorder has been hypothesized to play a critical role in the volumetric changes of the ACC,

particularly the SGPFC (Drevets et al., 1998, 1997), although the structural findings of familial unipolar patients are contradictory (Botteron et al., 2002; Brambilla et al., 2002b; Drevets et al., 1998; Hastings et al., 2004; Pizzagalli et al., 2004). Furthermore, while many studies have reported the rate of family history of mental illness amongst patients, they did not statistically assess the influence of this variable on measures of brain structure (Bremner et al., 2002; Caetano et al., 2006; Hastings et al., 2004). As such this relationship remains poorly understood. No studies to date have examined the relationship between medication and ACC volume in MDD. In summary, while the functional neuroimaging literature has consistently supported alterations in the SGPFC (or Brodmann's Area 25) in patients with MDD (Gotlib et al., 2005; Pizzagalli et al., 2004), such consistency has not emerged with the use of structural neuroimaging methods in the same region (Bremner et al., 2002; Drevets et al., 1998, 1997; Pizzagalli et al., 2004). Future studies systematically investigating the influence of gender, medication, illness progression and family history, and anatomical variability of the region, will be necessary to further characterize the nature of ACC anatomical changes in MDD. 3.7. Basal ganglia Only 3 volumetric studies, summarized in Table 6, have investigated whether the basal ganglia may be affected in patients with MDD, and since the characteristics of the clinical samples vary from study to study, it is difficult to determine the nature of the underlying changes. Studies using a ROI approach have generally failed to detect any changes in basal ganglia volumes (Bremner et al., 2000; Lacerda et al., 2003; Shah et al., 2002), despite the fact that previous evidence from other structural MRI studies has supported volumetric alterations in these structures (Bonelli et al., 2006; Hickie et al., 2006; Pillay et al., 1998). Shah et al. (2002), using a voxel-based-analysis (VBA) method, found that treatment resistant depressed patients had less caudate and putamen tissue than recovered patients and healthy controls. This finding suggests that those structures may be particularly affected in more persistent subtypes of MDD, or may reflect the effect of continued electroconvulsive therapy that this clinical sample underwent, the effects of which are largely unknown. Moreover, Lacerda et al. (2003) reported findings supporting the hypothesis that illness progression may affect the left globus pallidus and putamen. Thus, the negative findings reported by Bremner et al. (2000), might possibly be explained by the fact that they examined a less severe patient sample than did other studies (Lacerda et al., 2003; Shah et al., 2002). The research to date has not investigated either gender or medication related effects on basal ganglia. For example the effect of change in medication could not be examined as the patients in all the studies were either off medication, or on consistent dosages, for at least two weeks preceding the study (Bremner et al., 2000; Lacerda et al., 2003; Shah et al., 2002). These studies suggest that the caudate nucleus, putamen and globus pallidus may be impaired in more severe subtypes of depression. However, the lack of research on the basal ganglia makes difficult to draw firm conclusion about their involvement in the neurobiology of the MDD.

Table 6 Basal ganglia. Patients Group size (males)/diagnosis Lacerda et al. (2003)

Shah et al. (2002)

Controls Age (M) Duration of disorder

Method Voxel/slice size(mm)

Currently (M)

Totally (M) Age at onset (M)

–

11.8 y

29.4

4.21

48(19)

35.06

I.5 T

48.9

197 w (longest MDE)

263 w

FE = 38.9, last MDE = 45.8

2.2

20(13)

49.3

1.0 T

47.7

46 w 76 w (longest MDE) 31 w, r = 6–120 w – (rem.)

FE = 38.2 last MDE = 44.8 –

2.5 16(10)

45

I.5 T

25 (4) cMDD outp.: 41.2 10 euth., 15 dysth.

20 (13) mel. TRD with endogenous symptoms inp. and outp. 20 (13) recov. mel. MDD outp. Bremner et al. 16 (10) in rem. (2000) MDD outp.

No. ep (M) Group size Age (M)

43

2(prev)

Findings

0.93 × 1.25 × 1.5 (c.) No B.G. vol diff. between: patients and controls or euth. and dysth. patients or female patients and female controls; patients had decreased asymmetry in globus pallidus vol compared to controls. I.C. between left putamen vol and MDD length; Corr. between left globus pallidus vol and no. ep; no corr. between HDRS and B.G. vol 1.875 (c.) TRD patients had less right caudate tissue and right putamen tissue density than both controls and recov. patients; I.C. between cum. ECT and bilateral caudate GM density in TRD group.

5

No diff. in caudate vol between patients and controls.

Diagn. = diagnosis; M = mean; no. ep. = number of episodes; cMDD = current Major Depressive Disorder; outp. = outpatients; euth. = euthymic; dysth.= dysthymic; mel. = melancholic; TRD = Treatment Resistant Depression; inp. = inpatients; recov. = recovered; rem. = remission; r = range; w = weeks; y = years; MDE = Major Depressive Episode; FE = first episode; prev. = previous; c. = contiguous; B.G. = basal ganglia; vol = volume, volumes, volumetric; I.C. = inverse correlation; corr. = correlation; no. = number; HDRS = Hamilton Depression Rating Scale score; ECT = electro convulsive therapy; GM = grey matter; diff. = difference; VBA = voxel-based analysis; b = smaller, reduced; N = larger; – = not available.

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Study

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4. Discussion The evidence to date supports the contention that neuroanatomical alterations in limbic and cortical structures are observable in adult MDD patients with a longer course or a more severe illness, as previously suggested (Pattern, 2006). Specifically, we have noted that volumetric reductions of the hippocampus, basal ganglia and OFC and SGPFC tend to be consistent in the reviewed literature. Interestingly, amygdala volume changes appear to be dynamic throughout the course of illness, being enlarged in the first period, and reduced as the illness progresses and appears to vary as a function of gender, with more pronounced reductions in female than male patients. Moreover, studies that assessed specific temporal lobe regions (e.g., STG) are more likely to observe volumetric changes than the ones investigating the whole temporal lobe volume, which resulted in no group differences. This may suggest that specific temporal lobe regions that are presumably part of a relevant functional network, may be associated with MDD. Indeed, the STG has connections with the caudate and the putamen (Yeterian and Pandya, 1999), which also altered in MDD. The changes discussed above are unlikely to be due to differences in total brain or intracranial volume, as these measures were controlled for in most studies. These findings are broadly consistent with contemporary neurobiological models of depression that posit dysregulation of limbic and cortical regions involved in emotional regulation and experience (Davidson et al., 2002; Mayberg, 1997; Phillips et al., 2003a,b). These include regions of a ‘dorsal’ network that regulates emotions (e.g., dorsal PFC sub-regions), and a ‘ventral’ network involved in emotional experience (e.g., hippocampus, amygdala, ventral ACC, OFC and basal ganglia). 4.1. Mechanisms of neurobiological alterations A number of studies have identified hypothalamus– pituitary–adrenal (HPA) axis hyperactivity, which leads to excessive and prolonged hypercortisolemia, as a core feature of MDD (Barden et al., 1995; Davidson et al., 2002; Pariante, 2003; Pariante and Miller, 2001; Sheline, 2000; Swaab et al., 2005; Sala et al., 2004). This mechanism may play an important role in the volumetric alteration of several brain areas with a high concentration of glucocorticoid (GC) receptors such as the hippocampus (Herman et al., 2003; Szot et al., 1994), where loss of neurons has been associated with hypercortisolemia in MDD (Davidson et al., 2002; Garner, 2004; Gold et al., 1984; Holsboer et al., 1987; Pariante, 2003; Pariante and Miller, 2001; Sapolsky et al., 1991; Sheline, 2000; Young et al., 1991), as previously suggested (Campbell et al., 2004). Similar findings have been found in the PFC (Herman et al., 2003; Szot et al.,1994) — medial OFC (Sheline, 2000) and ACC (Cerqueira et al., 2005; Chao et al., 1989; Diorio et al., 1993) — and the amygdala (Davidson et al., 2002). As such, stress-induced neurotoxicity mechanisms (due to HPA axis activity alteration) may lead to regional brain volumetric alterations as they tend to be present in more persistent depressive subtypes. However, it is also possible that the brain volumetric changes proceed (or lead to) alterations in HPA axis activity (Cerqueira et al., 2005, 2007a,b; Diorio et al., 1993; Drevets et al., 1998; Sala et al., 2004; Sullivan and Gratton, 1999). Moreover, there is evidence that medication

and gender may moderate the relationship between MDD and neurobiological changes, as previously suggested (Campbell et al., 2004). Indeed, medication seems to block the effect of ongoing MDD illness on hippocampal volume reductions. Also, unipolar males and females show different and inconsistent patterns of alteration with respect to the magnitude, side, and direction of the changes observed across brain regions such as the hippocampus, amygdala, medial OFC and left SGFC. Future work examining the interaction between gender, medication, HPA axis activity and structural brain changes will be essential to characterize the general laws that govern such relationships, if any. It is difficult to speculate about the cellular, functional, cognitive and stress-related mechanisms underlying the reported volumetric abnormalities, as structural MRI provides a relatively gross measure of brain abnormality. Post-mortem findings in MDD seem to suggest that the observed volumetric reductions may reflect cellular or glial atrophy and/or loss in brain areas such as amygdala (Bowley et al., 2002; Manji et al., 2001), basal ganglia, ACC (Manji et al., 2001), SGPFC (Manji et al., 2001; Öngür et al., 1998; Rajkowska, 2000), PFC (Manji et al., 2001; Rajkowska et al.,1999) and OFC (Manji et al., 2001; Rajkowska, 2000; Rajkowska et al., 1999). 4.2. Limitations of research to date Future research endeavours in this area should be cautious when drawing conclusions regarding the effects of potential moderators such as medication and gender, because they have not been systematically evaluated, as previously noted (Campbell et al., 2004). Indeed, few studies have assessed the relationship between medication and structural brain measures and most research samples were composed exclusively (Botteron et al., 2002; Lange and Irle, 2004; Monkul et al., 2007; Sheline et al., 2003; Vythilingam et al., 2002; Weniger et al., 2006) or mainly of females. While previous research has stressed the role of family history of mental illness as an important factor in the neurobiology of depression (Drevets et al., 1998, 1997), we did not find consistent evidence for this. However, only a few studies (Brambilla et al., 2002b; Caetano et al., 2004; Vythilingam et al., 2004) have investigated this relationship. Another issue is the use of different classification methods and tracing protocols across studies, which may affect the consistency and the generalizability of the findings, as previously noted (Campbell et al., 2004). For example, some studies have classified the SGPFC as Brodmann's area 25, while others classify it as Brodmann's area 24 (Botteron et al., 2002; Brambilla et al., 2002b; Bremner et al., 2002; Caetano et al., 2006; Hastings et al., 2004), although these are understood to be functionally distinct areas. Therefore, the contradictory findings regarding the SGPFC may be partly explained by the different methods of classification that were used. This may be true also for other reviewed brain regions (e.g., STG, BTA, hippocampus, amygdala, OFC, basal ganglia), which boundaries have been distinctly classified by different studies. Notably, there is a paucity of studies investigating the basal ganglia, and this may be due to the absence of well defined tracing protocols for their boundaries (i.e., which may be related to image contrast issues, that are improving in more recent sMRI images), as previously suggested (Bonelli et al., 2006).

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Although the present review consistently supports neurobiological alterations in more severely and persistently ill patients with MDD, the included studies have mainly used samples with heterogeneous depression subtypes and clinical variables. Also, many studies have investigated the different MDD subtypes by dividing the main sample in smaller subgroups, weakening the statistical power to detect findings. Moreover, seventeen out of twenty-nine studies have been authored by 4 groups of researchers who are likely to have used the same (or similar) clinical sample in multiple studies, which may compromise the generalizability of the results. However, we have tried to limit this issue by considering only the data from the most recent publication of the group. 5. Conclusions This review of structural MRI findings in adults with MDD suggests that changes in temporal (e.g., STG, hippocampus, amygdala) and frontal (e.g., ACC and OFC) brain regions are associated with the disorder, and that they are generally more apparent in patients with more severe or persistent forms of the illness. While gender and medication appear to influence the precise nature of the findings, further work is necessary to better understand these effects. Together, the data support the notion that MDD involves pathological alterations of limbic and cortical structures, although more research is required to comprehensively characterize the pathophysiology of this debilitating disorder. A particularly important agenda for future work will be to incorporate longitudinal assessments, to better characterize the progression and behavioural significance of such abnormalities. Role of the funding source Funding for this study was provided by grants from the Australian Research Council (I.D. DP0557663); NHMRC Program Grant (I.D. 350241), the Colonial Foundation; J.N. Peters Fellowship; Faculty of Psychology scholarship of The University of Bologna. All the aforementioned funding sources had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Conflict of interest All the authors declare that they have no conflict of interest.

Acknowledgements This research was supported by grants from the Australian Research Council (I.D. DP0557663) Dr Yücel is supported by a NHMRC Program Grant (I.D. 350241) and the Colonial Foundation. Dr Fornito is supported by a J.N. Peters Fellowship and by a NHMRC CJ Martin Fellowship (ID: 454797). Valentina Lorenzetti is supported by a scholarship of the Faculty of Psychology, The University of Bologna; by the International Postgraduate Research Scholarship, and by the Melbourne International Research Scholarship. References Barden, N., Reul, J.M., Holsboer, F., 1995. Do antidepressants stabilize mood through actions on the hypothalamic–pituitary–adrenocortical system? Trends Neurosci. 18, 6–11. Beyer, J.L., Krishnan, K.R.R., 2002. Serotonin volumetric brain imaging findings in mood disorders. Bipolar Disord. 4, 89–104.

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