Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Neuroscience. Author manuscript; available in PMC 2010 November 24.
Published in final edited form as:
PMCID: PMC2760612

Imaging Phenotypes of Major Depressive Disorder: Genetic Correlates


Imaging techniques are a potentially powerful method of identifying phenotypes that are associated with, or are indicative of a vulnerability to developing major depressive disorder (MDD). Here we identify seven promising MDD-associated traits identified by magnetic resonance imaging (MRI) or positron emission tomography (PET). We evaluate whether these traits are state-independent, heritable endophenotypes, or state-dependent phenotypes that may be useful markers of treatment efficacy. In MDD, increased activity of the amygdala in response to negative stimuli appears to be a mood-congruent phenomenon, and is likely moderated by the serotonin transporter gene (SLC6A4) promoter polymorphism (5-HTTLPR). Hippocampal volume loss is characteristic of elderly or chronically-ill samples and may be impacted by the val66met brain-derived neurotrophic factor (BDNF) gene variant and the 5-HTTLPR SLC6A4 polymorphism. White matter pathology is salient in elderly MDD cohorts but is associated with cerebrovascular disease, and is unlikely to be a useful marker of a latent MDD diathesis. Increased blood flow or metabolism of the subgenual anterior cingulate cortex (sgACC), together with gray matter volume loss in this region, is a well-replicated finding in MDD. An attenuation of the usual pattern of fronto-limbic connectivity, particularly a decreased temporal correlation in amygdala-anterior cingulate cortex (ACC) activity, is another MDD-associated trait. Concerning neuroreceptor PET imaging, decreased 5-HT1A binding potential in the raphe, medial temporal lobe, and medial prefrontal cortex (mPFC) has been strongly associated with MDD, and may be impacted by a functional single nucleotide polymorphism in the promoter region of the 5-HT1A gene (HTR1A: –1019C/G; rs6295). Potentially indicative of inter-study variation in MDD etiology or mood state, both increased and decreased binding potential of the serotonin transporter has been reported. Challenges facing the field include the problem of phenotypic and etiological heterogeneity, technological limitations, the confounding effects of medication, and non-disease related inter-individual variation in brain morphology and function. Further advances are likely as epigenetic, copy-number variant, gene-gene interaction, and genome-wide association (GWA) approaches are brought to bear on imaging data.


The last decade has been characterized by intensive efforts to elucidate the genetic basis of psychiatric conditions such as major depressive disorder (MDD); a quest that has met with modest success due to the complexity of disease phenotypes. The putative additive effect of multiple loci of small effect size, the contribution of unknown or unquantifiable environmental factors, and the phenotypically and genetically heterogeneous nature of MDD has frustrated the efforts of researchers. While the use of DSM-IV criteria has enhanced the reliability of psychiatric research, the current diagnostic system has drawbacks for psychiatric genetic investigations because it is not based on the underlying neurobiology of psychiatric disorders.

These difficulties have encouraged alternative methodological approaches such as the use of endophenotypes; a term first introduced by (Gottesman and Shields, 1973) who referred to internal phenotypes discoverable by biochemical assays. An endophenotype is a heritable, intermediate phenotype that is associated with the disease of interest, but presumably has a simpler genetic basis, making it more amenable to genetic analysis (Gottesman and Gould, 2003).

Currently, some of the best tools in our armory for identifying endophenotypes are neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET). In the section of the paper to follow, entitled, “Imaging Major Depressive Disorder”, we discuss what in our subjective opinion, are some of the more promising imaging phenotypes associated with MDD and review what is known about their genetic basis. In addition, we evaluate whether these neurophysiological changes qualify as endophenotypes. The next section of the paper entitled, “Theoretical Challenges” addresses some of the more salient challenges facing the field. Finally, we end the paper by discussing potential future directions of the imaging genetics enterprise (“Future Directions” pp. 34).

Imaging Major Depressive Disorder


(1) The Amygdala: An Emotional Processing Bias

Patients with MDD have repeatedly demonstrated increased amygdala reactivity to negative stimuli as evinced by functional MRI (fMRI) (table 1). (Siegle et al., 2002) found that amygdalar responses to negative words were no longer visible after 10 seconds in healthy controls but persisted in depressed patients for a mean of 25 seconds. Similarly, depressed individuals reportedly remember negative words better than positive words (Watkins et al., 1992), a finding that correlates with increased BOLD activity of the right amygdala (Hamilton and Gotlib, 2008). Increased activity of the amygdala is also seen in conjunction with the expectation of a negative stimulus. MDD patients who were receiving treatment with antidepressant medication (AD), and were cued to anticipate the arrival of disgusting pictures, displayed greater BOLD activation in a broad region which encompassed the dorsal amygdala and the sublenticular nucleus compared with healthy subjects (Abler et al., 2007). In contrast, a group of MDD subjects, receiving AD were found not to differ from healthy control subjects when presented with sad or fearful faces (Lawrence et al., 2004).

Table 1
Endophenotype 1. Amygdala Reactivity in Subjects with MDD.

The amygdala-associated emotional processing bias appears to hold for stimuli presented below the threshold of conscious awareness. (Sheline et al., 2001) reported that MDD patients displayed a greater BOLD response in the left but not right amygdala in response to masked fearful faces. Furthermore, this exaggerated response was no longer present after 8 weeks of treatment with sertraline. More recently, (Dannlowski et al., 2007a) reported that a greater amygdala response to masked sad or angry faces, was found to coincide with an unconscious, negative judgment bias in a group of AD-treated MDD patients.

An insertion/deletion promoter polymorphism (5-HTTLPR) of the serotonin transporter gene (SLC6A4) has been shown to impact transcriptional activity, anxiety-related traits (Lesch et al., 1996) (Savitz and Ramesar, 2004), and resilience to adversity (Caspi et al., 2003) (Stein et al., 2008). Substantial evidence that altered transcriptional activity of the serotonin transporter also impacts intermediate brain phenotypes, including an MDD-associated negative processing bias, can be found in the literature.

In healthy volunteers, the short (s) allele of the 5-HTTLPR polymorphism has been associated with increased amygdala activation in response to negatively valenced faces or decreased amygdala activation in response to neutral stimuli (Hariri et al., 2002) (Canli et al., 2005b) (Hariri et al., 2005) (Heinz et al., 2005) (Canli et al., 2008). Similar results have been reported using different paradigms such as emotionally-valenced pictures (Heinz et al., 2007) (Smolka et al., 2007), and public speaking (Furmark et al., 2004). The impact of SLC6A4 genotype on amygdala function also appears to hold in stressed rhesus monkeys (Kalin et al., 2008), phobia-prone individuals (Bertolino et al., 2005), and patients with MDD (Dannlowski et al., 2007b) (Dannlowski et al., 2008). Furthermore, the s allele has been associated with elevated baseline amygdala activity (Rao et al., 2007) and reduced amygdala volume in healthy subjects (Pezawas et al., 2005) (Pezawas et al., 2008); although see (Canli et al., 2005b) who argue that increased amygdala activation in response to negative stimuli is an artifact of decreased response to neutral stimuli in s allele carriers.

One possibility is that these SLC6A4-amygdala associations are mediated by an attentional bias. (Beevers et al., 2007) explored this hypothesis using a dot-probe task to measure reaction time to masked and unmasked words designed to elicit anxiety or dysphoria. Patients with various different mood disorders who carried the s allele showed a greater bias towards anxious stimuli than l/l homozygotes. This result was replicated by (Osinsky et al., 2008) who found that healthy s allele carriers selectively shifted their attention towards pictures of spiders compared with their counerparts homozygous for the l allele. In a similar vein, the s allele has been associated with a stronger startle response to bursts of noise in healthy individuals (Brocke et al., 2006).

The SLC6A4 gene promoter variant has also been shown to modulate neurophysiological response to aversive stimuli in regions of the brain that are directly or indirectly connected to the amygdala, namely the orbital prefrontal cortex (OFC), basal nucleus of the stria terminalus (BNST) (Kalin et al., 2008), and the fusiform gyrus (Surguladze et al., 2008).

On the other hand, (Domschke et al., 2006), in a sample of patients with panic disorder, found that s allele carriers showed greater amygdala response to happy faces compared with neutral cues. Similarly, a fluorodeoxyglucose (FDG) PET study reported that during tryptophan depletion, MDD carriers of the s allele showed reduced glucose metabolism of the left amygdala compared with l/l homozygotes (Neumeister et al., 2006b).(Lee and Ham, 2008a) found that the 5-HTTLPR l allele was associated with greater BOLD response to angry versus neutral faces in healthy individuals. (Lau et al., 2009) reported that healthy adolescent carriers of the s allele exhibited stronger amygdala responses to fearful faces but anxious or depressed patients homozygous for the l allele had greater right, but not left amygdalar activity when exposed to fearful faces.

The serotonin 1A receptor which is coded for by the HTR1A gene, plays a critical role in serotonergic signaling and has been strongly implicated in MDD (Savitz et al., 2009). (Dannlowski et al., 2007b) reported that the G allele of a functional single-nucleotide polymorphism (SNP rs6295) was associated with greater amygdala reactivity in response to emotionally-valenced faces in a MDD sample. Similarly, after correcting for the effects of SLC6A4 genotype, (Fakra et al., 2009) found that the G allele of rs6295 was associated with strength of amygdala activation in response to threat-related stimuli and level of trait anxiety in healthy individuals.

The tryptophan hydroxylase-2 (TPH2) gene is another strong candidate for impacting amygdala function. Tryptophan hydroxylase-2 catalyses the rate-limiting step in the synthesis of neuronal serotonin. We are aware of 5 studies that have reported significant effects of the TPH2 rs4570625 SNP on amygdala function in the context of emotional processing (Brown et al., 2005) (Canli et al., 2005a) (Canli et al., 2008) (Furmark et al., 2008) (Lee and Ham, 2008a). These studies have largely been carried out with healthy volunteers. (Brown et al., 2005) reported that the T allele of rs4570625 was associated with greater amygdala response to angry or fearful faces while (Canli et al., 2005a) found that the effect of the rs4570625 variant on amygdala function extended to both positively and negatively valenced stimuli. In a later study, (Canli et al., 2008) reported an additive effect of the TPH2 and SLC6A4 genes on amygdala reactivity that was most robust for sad or fearful faces: carriers of the T and s alleles displayed a 0.24% greater BOLD response in the amygdala than subjects who did not possess either a T or an s allele. These data derive further support from a positron emission tomography (PET) study. (Furmark et al., 2008) showed that the TPH2 G allele predicted a placebo-induced improvement in social anxiety that was associated with a reduction in amygdala activity. In contrast, (Lee and Ham, 2008a) reported that individuals homozygous for the G allele of rs4570625 showed higher levels of amygdala activity in response to sad (but not angry) faces than their counterparts who did not carry the G allele.

Polymorphisms of the brain-derived neurotrophic factor (BDNF) (Montag et al., 2008), catechol-o-methyltransferase (COMT) (Smolka et al., 2005) (Smolka et al., 2007) (Domschke et al., 2008), and monoamine oxidase A (MAO-A) (Lee and Ham, 2008b) genes have also been associated with degree of amygdala reactivity in healthy controls and different patient groups. Further, a 4-marker haplotype of the regulator of G-protein signaling 2 (RGS2) gene was found to correlate with both self-reported levels of introversion and amygdala reactivity to emotionally-valenced faces (Smoller et al., 2008).

The negative processing bias seen in MDD may be reversed by antidepressant (AD) treatment. (Sheline et al., 2001) showed that the elevated BOLD response seen in the left amygdala of depressed patients in response to masked fearful faces was reduced by sertraline. This finding has received support from more recent studies (Fu et al., 2004) (Chen et al., 2007b). Moreover, the ADs, citalopram (Harmer et al., 2006), reboxetine (Norbury et al., 2007), and escitalopram (Arce et al., 2008) have been reported to attenuate neural response of the amygdala to negatively valenced faces in healthy individuals. (Fu et al., 2008) showed that the increased BOLD activity in the right amydala-hippocampus region observed in their sample of patients with MDD was normalized following cognitive-behavior therapy (CBT). Nevertheless, 2 previous PET studies making use of interpersonal therapy and CBT, respectively, were unable to detect any changes in the glucose metabolic rate of the amygdala (Brody et al., 2001) (Goldapple et al., 2004).

The positive impact of AD treatment on amygdala reactivity raises the question of whether the MDD-associated emotional processing bias is only seen in the acute stage of depression or is a permanent trait. This is an important issue because a true endophenotype should be mood-independent (Gottesman and Gould, 2003).

A number of studies suggest that amygdala activation is a mood-congruent, temporally-limited phenomenon. Transient sadness concomitant with amygdala activation has been induced by sad facial expressions (Schneider et al., 1997) (Posse et al., 2003) (Habel et al., 2005), movie clips (Aalto et al., 2002) (Wang et al., 2006), and recall of negative life events (George et al., 1995). In fact, it is known that direct electrical stimulation of the amygdala in humans may temporarily elicit positive and especially, negative emotions (Gloor et al., 1982) (Lanteaume et al., 2007).

On the other hand, at least 2 studies have suggested that increased amygdala reactivity is salient early in life in humans and monkeys with an anxious temperament. (Fox et al., 2008) showed that rhesus monkeys with an anxious disposition showed increased glucose metabolism (measured with PET FDG) of the amygdala and a downstream circuit, including the BNST and PAG. This echoes the result of a longitudinal study in humans demonstrating that infants classified as “inhibited” displayed a greater BOLD response in the amygdala when viewing novel faces as adults than their counterparts who were classified as “uninhibited” infants (Schwartz et al., 2003).

Consistent with these data, (Neumeister et al., 2006a) reported increased blood flow to the amygdala, as measured by O15 H2O PET in unmedicated, remitted MDD patients. Further, we have recently found that currently remitted MDD patients show a reduced hemodynamic response to masked happy faces compared with healthy controls (Ferguson et al., 2008). The issue of facial masking may be relevant to the endophenotypic criterion of heritability.

A number of studies have provided evidence that greater amygdala activation to negatively-valenced faces is characteristic of MDD even when these stimuli are masked, and no conscious processing of the faces is possible (Sheline et al., 2001) (Dannlowski et al., 2007a). Certainly, this does not prove that MDD-associated hyper-reactivity to socio-emotional stimuli is heritable, but the automatic, limbic system-mediated nature of the phenomena does raise the possibility that genetic factors at play.

To the best of our knowledge, only one study has examined facial processing biases in a high-risk sample. (Monk et al., 2008) reported that the pediatric offspring of parents with MDD showed a greater amygdala response to passively-viewed fearful faces than their healthy counterparts with no family history of affective illness. Nevertheless, more than half of the high-risk group had been diagnosed with an anxiety disorder, limiting the conclusions that can be drawn from the study.

Other studies shed partial light on the issue of state versus trait. Trait anxiety as measured by the State-Trait Anxiety Inventory (STAI) was found to correlate (r=0.74) significantly with basolateral amygdala activity in response to masked fearful faces in healthy volunteers (Etkin et al., 2004). Analogous findings have since been reported (Stein et al., 2007) (Dickie and Armony, 2008). In a similar vein, healthy individuals have demonstrated long-term (1–2 years) stability of right amygdala BOLD responses to angry faces (Manuck et al., 2007). (van der Veen et al., 2007) reported that healthy individuals with a family history of MDD showed a lowering of mood together with greater amygdala activation in response to fearful faces after tryptophan depletion. A latent emotional processing bias in high-risk individuals may thus be precipitated by some kind of “insult”, whether pharmacological or environmental.

In sum, greater amygdala reactivity in response to negatively valenced cues appears to be at least partly mood-state independent. Extant data suggest that the s allele of the SLC6A4 5-HTTLPR variant contributes to this “risk” phenotype. Nevertheless, not all studies are consistent (Domschke et al., 2006) (Lee and Ham, 2008a) (Lau et al., 2009).

Despite the apparent early onset of exaggerated amygdala reactivity, the status of the emotional-processing bias phenotype as an endophenotype for MDD remains unclear given the attenuating effects of AD medication and the dearth of family studies.

(2) Hippocampal Volume Loss in MDD

Hippocampal volume reduction is a common finding in patients with MDD (Sheline et al., 1996) (Sheline et al., 1999) (Mervaala et al., 2000) (MacQueen et al., 2003) (Janssen et al., 2004) (Lloyd et al., 2004) (O’Brien et al., 2004) (Hickie et al., 2005) (Neumeister et al., 2005) (Frodl et al., 2006) (Janssen et al., 2007) (Macmaster et al., 2007) (Ballmaier et al., 2007) (table 2). These data are supported by recent longitudinal studies. MDD patients with smaller hippocampal volumes are reportedly less likely to remit after a 1 year follow-up (Frodl et al., 2004a). A 3-year follow-up by the same group showed a greater decrease in hippocampal volumes over time in the MDD group (Frodl et al., 2008b). Similarly, (Kronmuller et al., 2008) reported that male patients who relapsed within a 2 year follow-up period displayed smaller hippocampal volumes than healthy controls. Congruent with these data, a 36% increase in hippocampal neuronal density together with a 20% reduction in neuronal size, indicative of neuropil loss, has been detected at post-mortem (Stockmeier et al., 2004).

Table 2
Endophenotype 2. Hippocampal Volume Reduction.

(Pezawas et al., 2004) showed that the met allele of a common functional SNP (val66met) in the brain-derived neurotrophic factor (BDNF) gene was associated with smaller hippocampal volumes in a healthy sample, and similar effect has since been noted in both healthy subjects and individuals with schizophrenia or bipolar disorder (BD) (Szeszko et al., 2005) (Bueller et al., 2006) (Ho et al., 2006) (Takahashi et al., 2008) (Chepenik et al., 2009). According to a recent study, the association between the met allele and reduced hippocampal volume may be more salient in healthy people exposed to early life stress (Gatt et al., 2009) and healthy subjects with higher levels neuroticism as measured by the NEO-Five Factor Personality Inventory, and trait depression as measured by the Depression Anxiety Stress Scale (DASS-42) (Joffe et al., 2008). To our knowledge, only one study has examined the effect of the val66met SNP on hippocampal volume in MDD: (Frodl et al., 2007) found smaller hippocampal volumes in both controls and acutely ill, medicated MDD patients carrying the met allele.

The SLC6A4 gene has also been postulated to modulate the association between MDD and hippocampal volume. (Frodl et al., 2004b) (Frodl et al., 2008a) found that l allele MDD homozygotes had smaller hippocampal volumes than s allele carriers with MDD. (Taylor et al., 2005a) noted that in patients with late onset depression (> 50 years), l allele homozygotes displayed smaller right hippocampal volumes, but in MDD patients with early illness-onset (< 50 years), the s allele homozygotes had smaller hippocampal volumes. Further, the s allele has been reported to be associated with lower hippocampal concentrations of N-acetylaspartate (NAA), a neuronal and axonal marker of damage to the brain (Gallinat et al., 2005).

Other genes reported to impact hippocampal volume in MDD or healthy subjects include COMT (Cerasa et al., 2008), vascular endothelial growth factor (VEGF) (Blumberg et al., 2008) and the glucocorticoid receptor (NR3C1) (Zobel et al., 2008).

Although hippocampal volume decrements are widely reported in MDD the data are contradictory. For negative results see (Axelson et al., 1993) (Pantel et al., 1997) (Ashtari et al., 1999) (Vakili et al., 2000) (von Gunten et al., 2000) (Rusch et al., 2001) (Hastings et al., 2004) (Inagaki et al., 2004) (Rydmark et al., 2006). One hypothesis is that hippocampal atrophy is more pronounced in elderly, middle-aged or chronically ill populations. A hypothalamic-pituitary-adrenal (HPA) axis-driven excitotoxic process is one heuristic model of hippocampal volume loss and associated MDD that is consistent with the impact of age and length of illness. Since, at least in rodents, the hippocampus is believed to exert inhibitory control over the amygdala and HPA axis (Jacobson and Sapolsky, 1991) (Barden, 2004), hippocampal tissue loss may activate a positive feedback loop which further potentiates the release of cortisol and hippocampal excitotoxicity.

On the other hand, hippocampal volume reduction has been reported in children (MacMaster and Kusumakar, 2004) (MacMaster et al., 2008) and young adults with MDD (Lange and Irle, 2004) (Vythilingam et al., 2002). Nevertheless, the sample studied by (Vythilingam et al., 2002) had a history of significant childhood abuse. It is also questionable whether findings from the pediatric literature can be extrapolated to adult samples.

If neurophysiological changes to the hippocampus are indeed stress-related, then this limits the utility of this imaging trait as an endophenotype. Clearly, HPA-induced hippocampal atrophy may be a latent predisposition which manifests itself only under particular environmental conditions. As such, it will not readily identify people at risk for future depressive episodes precipitated by situational adversity. Nevertheless, interrogation of the genetic correlates of hippocampal volume reduction in acutely ill patients remains valuable. For example, the association between hippocampal volume and the BDNF val66met polymorphism is intuitively compelling based on animal data showing decreased expression of BDNF in the hippocampus after exposure to corticosteroids or stressors (Gronli et al., 2006) (Jacobsen and Mork, 2006) (Tsankova et al., 2006) (Xu et al., 2006).

(3). Increased Incidence of Deep White Matter Hyperintensities

White Matter Hyperintensities (WMH), seen on T2-weighted MRI scans are probably indicative of leukoaraiosis: a decrease in the density of white matter due to demyelination, atrophy of the neuropil, or ischemia-associated microangiopathy (Ovbiagele and Saver, 2006). The increased incidence of MDD seen in elderly individuals led to the concept of “vascular depression”, a condition associated with multiple subcortical infarcts of an ischemic origin (Alexopoulos et al., 1997) (Krishnan et al., 1997). At least 20 studies have reported a robust relationship between the presence of WM lesions and depression in elderly samples (table 3). For recent publications see (Godin et al., 2007) (Janssen et al., 2007) (Sheline et al., 2008) (Sneed et al., 2008). Younger adult or middle aged MDD samples do not usually provide evidence of WM disease (Dupont et al., 1995a) (Iosifescu et al., 2006), although see (Sassi et al., 2003).

Table 3
Endophenotype 3. White Matter Hyperintensities in MDD.

Consistent with some of the data, post-mortem analyses have reported altered expression of genes impacting myelin or oligodendrocyte function in MDD (Aston et al., 2005) (Sequeira et al., 2006). Variants of this gene class such as oligodendrocyte lineage transcription factor 2 (OLIG2), Neuregulin 1 (NRG1), and v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ERBB4) have been directly associated with affective illness (Carter, 2007) (Sokolov, 2007).

The specificity of WMH to age-associated vascular depression (Sneed et al., 2008) reinforces the notion that MDD is a heterogenous disorder. Although the data suggest that T-2 weighted WMH are related to late-onset MDD, reports suggestive of microstructural WM changes as evinced by diffusion tensor imaging (DTI) in young adults with MDD have been published in the literature (Li et al., 2007) (Ma et al., 2007). The age-associated relationship between WMH and MDD may preclude the use of this trait to identify young individuals at risk of developing MDD. Nevertheless, an understanding of the mechanisms by which microvascular lesions lead to depression may help elucidate important pathophysiological pathways and facilitate the development of new treatments.

(4). Stuctural and Functional Alterations of the Subgenual Anterior Cingulate Cortex (sgACC)

The term sgACC was originally used to refer to Brodmann areas (BA) 24b and, to a lesser extent, 24a anteriorly, and BA25 posteriorly (Ongur et al., 2003). This region was initially shown by (Drevets et al., 1997b) to display an MDD-associated reduction in blood flow and glucose metabolism, with a corresponding reduction in GM volume of the left sgACC. Later, we refined our anatomical characterization of the region, separating the sgACC into cytoarchitectonically distinct anterior and posterior components, which correspond approximately to BA 24 and 25, respectively (Ongur et al., 2003).

Since our initial report, reduced sgACC volume has been independently reported [reviewed in (Drevets et al., 2008)] (table 4). (Botteron et al., 2002) observed reduced left sgACC volumes in an early-onset sample of largely unmedicated MDD cases, while (Hastings et al., 2004) detected a similar effect in males but not females. A sex-specific effect was also reported by (Boes et al., 2008) who found volume reductions of the broader left perigenual ACC in boys but not girls with subclinical depression.

Table 4
Endophenotype 4. Volumetric Abnormalities of the sgACC in MDD.

The posterior sgACC (infralimbic cortex or BA 25) was found to be reduced in volume in MDD cases with psychotic features, but not in a psychiatric control group with schizophrenia (Coryell et al., 2005). Furthermore, the MDD group showed an increase in posterior sgACC GM volume after 2 years of naturalistic treatment. Consistent with this finding, chronic lithium treatment, which exerts neurotrophic effects in animal models, has been associated with a recovery of GM volume of the sgACC in treatment responders (Moore, 2008). (Yucel et al., 2008) also reported a decrease in volume of the infralimbic cortex in a MDD sample treated for an average of one month with AD prior to scanning. There was no significant difference in sgACC (BA 24) volume between the MDD and its healthy comparison group. However, when the MDD group was stratified by AD exposure, it was found that the AD-exposed MDD patients had smaller sgACC volumes than both healthy subjects and their drug-naïve counterparts with MDD (Yucel et al., 2008).

The imaging data are supported by a histopathological analysis of BA 24, which suggested that the volume reduction seen on MRI was associated with a reduction in neuropil (Ongur et al., 1998).

Imaging studies that assessed sgACC activity in designs that controlled for partial volume effects, are indicative of increased resting glucose metabolism or BOLD activity in the sgACC and infralimbic cortex of depressed patients (Inagaki et al., 2007) (Kumano et al., 2007) (Mah et al., 2007) (table 5). In addition, (Greicius et al., 2007) conducted a resting-state connectivity analysis of persons with MDD and interpret their data to suggest that the altered pattern of resting state connectivity in MDD is driven primarily by elevated activity of the sgACC. In line with these data, sgACC metabolism and cerebral blood flow (CBF) are higher in the depressed, unmedicated phase versus the remitted phase within MDD subjects (Mayberg et al., 1999) (Drevets et al., 2002) (Neumeister et al., 2004) (Hasler et al., 2008). Elevated sgACC BOLD activity has also been observed in MDD patients performing the stop-signal test (Yang et al., 2009) and an emotional interference task (Fales et al., 2008).

Table 5
Endophenotype 4. Neurophysiological Abnormalities of the sgACC.

The impact of increased neural activity on brain structure is not fully understood. One possibility is stress-induced dendritic remodeling, observed as increases or decreases in GM volume on MRI scans. Glucocorticoid hormones, which are thought to be over-secreted in MDD and other stress-related conditions, regulate glutamate release through the inhibition of glutamate transporter expression, the upregulation of N-methyl-D-aspartate (NMDA) glutamate receptor subunit expression, and the activation of voltage-gated sodium channels, thereby modulating intracellular calcium influx (McEwen and Magarinos, 2001) (Lee et al., 2002). Since glucose metabolism is primarily reflective of the level of glutamatergic transmission in the brain (Patel et al., 2004) (Shulman et al., 2004), increased glucose metabolism may explain the decreased sgACC GM volume reported in MDD.

We are aware of 2 studies that investigated the effects of the 5-HTTLPR variant on perigenual ACC volume in healthy subjects. (Canli et al., 2005b) found that the s allele was associated with reduced left middle frontal gyral (BA 9: −27; 31; 46) and pregenual ACC (−10; 35; 17) volume; while (Pezawas et al., 2005) reported an s-allele associated volume reduction of the subgenual (−3; 33; −2) and pregenual (reported as “supragenual” 0; 30; 4 and 0; 35; 13) ACC. Short allele carriers also show reduced structural covariation between the amygdala and perigenual ACC, suggestive of attenuated functional coupling between these two regions (Pezawas et al., 2005). The association between reduced volume of BA 9 and the short 5-HTTLPR allele (Canli et al., 2005b) is interesting because glial cell loss and a reduction in neuronal size at post-mortem has also been reported in this region in MDD (Rajkowska et al., 1999).

Consistent with observations that experimentally-induced sadness increases blood-flow to the sgACC (George et al., 1995) (Mayberg et al., 1999), the severity of depressive symptomatology in MDD and BD subjects was shown by (Osuch et al., 2000) to be correlated with glucose metabolism of this region. Moreover, various treatment paradigms including antidepressant treatment (Mayberg et al., 2000) (Holthoff et al., 2004), electroconvulsive therapy (ECT) (Nobler et al., 2001), and deep brain stimulation of the sgACC (Mayberg et al., 2005) result in decreased activity of the sgACC. On the other hand, (Drevets et al., 1997b) found that altered sgACC glucose metabolism persisted during antidepressant drug treatment and was present in both the manic and depressed phases of BD.

State-trait issues have received less attention in the structural imaging literature, and most studies have imaged currently depressed patients. One recent study showed that response to lithium treatment was associated with a recovery of GM volume of the sgACC of individuals with BD (Moore, 2008), and another found initial and progressive loss of GM volume in BD subjects, most of whom were not receiving lithium (Koo et al., 2008).

Studies of individuals who are at high familial risk for developing mood disorders are unfortunately rare. (Boes et al., 2008) found that the left perigenual ACC volume was smaller in boys with sub-clinical depression, and that the negative correlation between left sgACC volume and depression symptoms was strongest in boys with a family history of depression. Similarly reduced sgACC volumes have been reported in the unaffected relatives of patients with bipolar disorder (McDonald et al., 2004). In a recent fMRI study, (Mannie et al., 2008) found that children of parents with MDD showed an absence of activation in the pregenual ACC in response to emotionally valenced stimuli (emotional Stroop) compared with their control group. How these data related to the structural MRI findings are unclear.

(5). Disrupted Fronto-Limbic Connectivity

A heuristic model of MDD is a loss of top-down, PFC control over limbic regions such as the amygdala, leading to the emotional, behavioral, cognitive and endocrine changes characteristic of the disorder (Savitz and Drevets, 2009). Partly consistent with this model, reduced fronto-limbic connectivity (measured by the degree of temporal correlation in activity across different brain regions) has been consistently reported in the fMRI literature (table 6). What is less clear, however, is the specific region of the PFC that is functionally-decoupled from the amygdala.

Table 6
Endophenotype 5. Impaired Fronto-Limbic Connectivity in MDD.

(Anand et al., 2005a) reported a decreased correlation between activity in the broader ACC and the amygdala in both the resting state and during exposure to neutral, negative and positively valenced pictures in their MDD sample. After 6 weeks of treatment with sertraline, the same MDD sample displayed an increase in ACC-limbic connectivity in the resting state and during exposure to neutral and positive, but not negative pictures (Anand et al., 2005b). Similarly, (Chen et al., 2008) found that the reduced functional coupling of the medial and ventral PFC with the amygdala observed in their MDD sample during exposure to sad faces, was ameliorated by 8 weeks of treatment with fluoxetine.

(Siegle et al., 2007) reported that MDD subjects demonstrated greater activation of the amygdala in response to affectively-valenced words, and reduced activity of the left DLPFC during a working memory task than healthy control subjects. Further, the temporal association between DLPFC and amygdala activity was reduced in the MDD sample compared with the healthy control sample. These data are consistent with the results of a previous study reporting an inverse correlation between amygdala and DLPFC activation in response to the presentation of negatively valenced words (Siegle et al., 2002). Most recently, a functional correlation between activity in the amygdala and three PFC regions, the DLPFC, the dACC, and the ventrolateral PFC (vlPFC), was shown to be reduced in individuals with MDD (Dannlowski et al., 2009).

The vlPFC was also implicated by (Johnstone et al., 2007) who reported an inverse relationship between left vlPFC and amygdala activation in healthy controls but the opposite effect in MDD cases. (Johnstone et al., 2007) attribute this vlPFC-amygdala disconnect to dysfunction of the ventromedial PFC (vmPFC) which serves as an inhibitory link between the lateral PFC and the amygdala. (Matthews et al., 2008) reported increased functional connectivity between the broader amygdala region and the sgACC but decreased functional connectivity between the extended amygdala and the supragenual ACC in response to the presentation of emotional faces.

Anxiety may be an important confounding factor. (Kienast et al., 2008) reported a negative correlation between trait anxiety in healthy males and the degree of functional connectivity between the sgACC (BA24) and the amygdala in response to negatively-valenced visual stimuli. In addition, degree of habituation to emotional go-no-go stimuli has been reported to be negatively correlated with functional connectivity of the ventral PFC and the amygdala in healthy controls with higher levels of self-reported anxiety (Hare et al., 2008).

The genetic basis of this abnormal PFC-limbic functional coupling is in the early stage of investigation. (Pezawas et al., 2005) found that the s allele of the 5-HTTLPR polymorphism was associated with reduced functional coupling between the supragenual ACC, but increased functional coupling between the vmPFC and the amygdala in healthy controls exposed to threatening faces. Additionally, the degree of functional coupling between the perigenual ACC and the amygdala predicted approximately 30% of the variance in scores on the harm avoidance subscale of the Temperament and Personality Questionnaire (Pezawas et al., 2005). The greater vmACC-amygdala coupling observed in s 5-HTTLPR allele carriers replicated the finding of (Heinz et al., 2005) who observed a similar effect in healthy volunteers shown aversive pictures.

(Dannlowski et al., 2009) reported that the inverse functional correlation between dACC and amygdala activity observed in their healthy control sample, was attenuated in carriers of the high activity monoamine oxidase A (MAOA) promoter polymorphism alleles (3.5R or 4R). Further, MDD cases with the high activity MAOA variants showed the weakest amygdala-dACC coupling and the most severe course of illness. (Buckholtz et al., 2008) had earlier reported increased vmPFC-amygdala coupling in healthy male carriers of the low activity MAOA VNTR alleles, an effect which predicted higher harm avoidance personality scores in this sample.

In sum, the extant data suggest that a functional decoupling exists within the neural circuits connecting PFC and amygdala areas that are involved in the cognitive control of emotions in MDD. The anatomical correlates of these neural circuits are not entirely clear but may include both dorsomedial, ventromedial and dorsolateral aspects of the PFC. Conversely there is some evidence for enhanced functional connectivity between the amygdala and the vmPFC in MDD. Given reports of an AD-induced strengthening in PFC-limbic coupling (Anand et al., 2005b) (Chen et al., 2008), the utility of this trait as a biomarker for the efficacy of AD-treatment is deserving of greater exploration.

PET Neuroreceptor Studies

(1). 5-HT1A Receptor-Signaling Abnormalities in MDD

The 5-HT1A (serotonin 1A) receptor is a G-protein-coupled receptor concentrated in regions which receive serotonergic input from the raphe nuclei such as the frontal cortex, amygdala, hippocampus, and hypothalamus (Lesch and Gutknecht, 2004) (Sharp et al., 2007). The 5-HT1A receptor serves as the predominant release- and synthesis-controlling autoreceptor for the serotonergic neurons in the raphe nuclei, reducing the serotonergic transmission to its projection areas (Kreiss and Lucki, 1994). In these frontal and limbic projection regions, the 5-HT1A receptor is distributed post-synaptically (Sharp et al., 2007). The 5-HT1A receptor modulates neuronal migration, neurite outgrowth and synapse during development as well as serotonergic activity in the mature brain (Whitaker-Azmitia et al., 1996).

The PET data are largely suggestive of reduced 5-HT1A receptor binding potential (BP) in MDD [reviewed in (Savitz et al., 2009)]. BP usually refers to the product of receptor number and affinity. In an [11C]WAY-100635 PET study, (Drevets et al., 1999) (Drevets et al., 2000) found that depressed bipolar disorder and MDD patients with a familial form of illness exhibited reduced BP in the medial temporal cortex and hippocampus (25–33%), as well as the midbrain raphe (42%) compared with healthy controls. We recently replicated this result, detecting a mean 5-HT1A receptor BP reduction of 26% in the medial temporal cortex and 43% in the raphe nucleus in non-medicated recurrent depressives (Drevets et al., 2007). This finding is supported by other groups (table 7). (Sargent et al., 2000) reported a wide-spread reduction (frontal, temporal and limbic cortices) in 5-HT1A receptor binding in both medicated and unmedicated individuals with MDD. (Hirvonen et al., 2008) reported 9–25% reductions in receptor binding across large regions of the brain (but not the raphe) in drug-naïve individuals with MDD, and (Bhagwagar et al., 2004) replicated this finding in remitted, as well as currently depressed patients. Reduced BP in the dorsal raphe nucleus of elderly depressed subjects (Meltzer et al., 2004), and the sgACC, pgACC, lateral orbital, and mesiotemporal cortices of post-partum MDD cases (Moses-Kolko et al., 2008), has also been reported.

Table 7
Endophenotype 6. Altered 5-HT1A Receptor Binding Potential in MDD.

The animal literature is generally consistent with the decreased 5-HT1A receptor BP. Subordinate monkeys who showed behavioral signs of depression after exposure to social defeat, had reduced 5-HT1A receptor binding in the raphe nuclei, amygdala, hippocampus, and anterior cingulate cortex (Shively et al., 2006). Furthermore, parentally-deprived monkeys display reduced hippocampal 5-HT1A receptor binding and mRNA expression relative to their normally-reared siblings although in males 5-HT1A receptor binding was actually increased in the dentate gyrus and CA3 (Law et al., 2008). The decrease in 5-HT1A receptor binding is consistent with studies reporting reduced postsynaptic 5-HT1A receptor density and mRNA expression in the hippocampus and other brain regions in rats and tree shrews exposed to repeated or chronic stress (Mendelson and McEwen, 1991) (Chalmers et al., 1993) (McKittrick et al., 1995) (Meijer et al., 1997) (Flugge et al., 1998) (Lopez et al., 1998).

Post-mortem studies provide further evidence for reduced 5-HT1A receptor binding or numbers in the ventrolateral prefrontal cortex and the temporal polar cortex (Bowen et al., 1989); caudal aspects of the dorsal raphe nucleus (Arango et al., 2001) (Boldrini et al., 2007); DLPFC (Lopez-Figueroa et al., 2004), and hippocampus (Lopez et al., 1998). In contrast, in the rostral portion of the dorsal raphe nucleus the 5-HT1A receptor density was elevated in depressed suicide victims, demonstrating that a rostral-caudal difference exists within the dorsal raphe nucleus (i.e., abnormally increased rostrally, but decreased caudally in depression) may exist below the spatial resolution of PET (Stockmeier et al., 1998) (Boldrini et al., 2007). Clearly, the data are not altogether consistent, and the contradictory or negative results reported in other PET studies of MDD subjects (Parsey et al., 2006a) or post mortem studies of depressed suicides (Arranz et al., 1994) (Arango et al., 1995) (Lowther et al., 1997) suggest that substantial heterogeneity exists within the pathophysiology underlying MDD and other psychiatric disorders that predispose to suicide.

A single nucleotide polymorphism SNP (HTR1A: –1019C/G; rs6295) has been reported to regulate gene expression of the 5-HT1A receptor (Lemonde et al., 2003). The G allele is believed to disrupt an inhibitory transcription factor-binding site, thereby up-regulating autoreceptor expression in presynaptic raphe neurons, decreasing the firing rate of these cells, and reducing serotonergic neurotransmission in projection areas (Lemonde et al., 2003).

(Lemonde et al., 2003) reported a two-fold increase in the frequency of the rs6295 G/G genotype in patients with MDD, and a four-fold increase in the frequency of the G/G genotype in suicide attempters. These data have been independently replicated in another MDD sample (Parsey et al., 2006a), as well as elderly patients who became depressed after suffering hip-fractures (Lenze et al., 2008), and hepatitis C patients with interferon-induced depression (Kraus et al., 2007). A recent paper reported an over-representation of the G allele and G/G genotype in an MDD sample, and a subsequent linkage analysis conditional on possession of at least one G allele generated a significant signal on chromosome 10, suggesting a possible epistatic interaction with a gene in this region (Neff et al., 2008). As in all psychiatric genetic studies, negative results are also common (Zill P, 2001) (Huang et al., 2004) (David et al., 2005) (Hettema et al., 2007).

MDD may be associated with abnormal sensitivity of 5-HT1A autoreceptors in sub-nuclei of the raphe, together with a reduction in post-synaptic 5-HT1A receptor sensitivity in limbic regions. The genetic expression of 5-HT1A receptor mRNA is tonically inhibited by glucocorticoid receptor stimulation, and thus the phenomenon may be secondary to a disturbance in hypothalamic-pituitary-adrenal (HPA) axis function. If this is indeed the case, then changes to 5-HT1A receptor BP may not identify at-risk individuals unless HPA disturbances are prodromal. Not enough research has been completed in order to properly address this issue.

(2). Changes in Serotonin Transporter Binding in MDD

The serotonin transporter (5-HTT) contributes to the regulation of serotonergic neurotransmission through the reuptake of serotonin in the synaptic cleft. An inverse relationship exists between 5-HTT BP and extracellular serotonin levels.

A study making use of [11C](+)McN5652, which measures 5-HTT BP in the thalamus and midbrain, reported a 23% increase in thalamic (but not midbrain) 5-HTT BP in medication-free MDD subjects compared with controls (Ichimiya et al., 2002). Similarly, a small sample (N=4) of MDD subjects yielded evidence of larger distribution volume (DV) ratios in the left prefrontal cortex (24%) and the right anterior cingulate cortex (18%) compared with controls (Reivich et al., 2004). On the other hand, (Parsey et al., 2006b) reported decreased 5-HTT BP in the amygdala and midbrain but no change in other regions of the brain using [11C](+)McN5652. The same group later reported that lower 5-HTT BP in the midbrain, amygdala and ACC predicted the absence of remission at one year (Miller et al., 2008). Nevertheless, this ligand has been reported to show non-specific binding, biasing results (Buck et al., 2000). More recent studies have been carried out with the [11C] DASB ligand which has a greater ratio of specific to non-specific binding, and therefore allows for the measurement of BP in cortical as well as subcortical brain regions (Meyer, 2007).

In one such study, (Reimold et al., 2008) reported reduced 5-HTT BP in the thalami (but not other regions such as the amygdala and midbrain) of people with MDD, and a negative correlation between 5-HTT availability in the thalamus and amygdala, and depression and anxiety scores. In contrast, although no overall intergroup difference in 5-HTT BP was detected by (Meyer et al., 2004), scores on the Dysfunctional Attitude Scale (DAS) were found to be positively correlated with an increase in BP in the anterior cingulate, putamen and thalamus. This finding is consistent with the data of (Cannon et al., 2007) who showed that relative to healthy subjects, depressed, unmedicated MDD patients had increased BP in the thalamus (24%), periaqueductal gray matter (PAG) (22%), insula (15%), and striatum (12%). Furthermore, the depression-associated personality trait, neuroticism, is reportedly associated with higher thalamic BP (Takano et al., 2007), and clinically depressed patients with Parkinson’s disease (PD) show increased 5-HTT BP in the PFC compared with HC (Boileau et al., 2008).

An increase in 5-HTT BP might be indicative of greater serotonin reuptake capacity in response to elevated serotonin secretion during stress or depression (Cannon et al., 2007). Conversely, lower 5-HTT BP might reflect a downregulation of 5-HTT in response to lower intrasynaptic levels of serotonin, a loss of raphe serotonergic projections to corticolimbic regions, or a decrease in SLC6A4 gene expression (Frokjaer et al., 2009). Although the 5-HTTLPR polymorphism is known to affect mRNA transcription in vitro (Lesch et al., 1996) (Hu et al., 2006), the impact of the polymorphism on in vivo 5-HTT binding is less clear. While some studies have reported that the l allele is associated with higher 5-HTT BP in the putamen (Praschak-Rieder et al., 2007), others have found no relationship between 5-HTTLPR genotype and 5-HTT BP as measured by the radioligand [11C](+)McN5652 (Parsey et al., 2006c). Further, (Willeit et al., 2008) found no 5-HTTLPR-Vmax or Bmax association in platelet cells.

The PET imaging data may be confounded by a number of factors. For instance, the magnitude of 5-HTT BP may be seasonal in nature. (Praschak-Rieder et al., 2008) observed higher BP in diverse brain regions in the fall and winter months compared with spring and summer. Further, 5-HTT BP correlated negatively with daily hours of sunshine, suggesting a potential pathophysiological mechanism for seasonal affective disorder (SAD). (Willeit et al., 2008) reported increased platelet 5-HTT function in the guise of increased uptake velocity (Vmax) in depressed patients with SAD but no group differences in substrate affinity (Km) or binding capacity (Bmax) were detected. It is unclear, however, if the Vmax changes seen in the platelets from the (Willeit et al., 2008) sample extend to the CNS of patients with MDD.

As in the case of other imaging phenotypes associated with MDD, the impact of clinical state at the time of scanning has not been resolved. In the only study of unmedicated remitted patients with MDD of which we are aware, (Bhagwagar et al., 2007) failed to discern significant abnormalities in 5-HTT binding in a number of anatomical regions such as the amygdala, anterior cingulate, hippocampus, and thalamus. Further, in the studies of (Cannon et al., 2007) and (Reimold et al., 2008), DASB binding was significantly correlated with severity of depression and anxiety.

The preclinical literature largely supports the hypothesis that 5-HTT binding is stress-sensitive. Reduced 5-HTT mRNA expression has been noted in the CA1, CA2 and CA3 regions of the hippocampus (but not the raphe or dentate gyrus) of subordinate and dominant, and therefore stressed rodents (McKittrick et al., 2000). Nevertheless, these stressed rats also showed apical dendritic atrophy of the CA3 pyramidal neurons, raising the possibility that the decrease in 5-HTT binding was secondary to a reduction in dendritic arborization. Acute immobilization stress has been reported to decrease 5-HTT mRNA levels in the dorsomedial hypothalamus (Hoffman et al., 1998) and raphe pontis (Vollmayr et al., 2000), but not other raphe nuclei. In monkeys, stress sensitive females showed decreased 5-HTT mRNA levels in the caudal region of the dorsal raphe but again this result may reflect a corresponding loss of raphe neurons in the stress-sensitive animals (Bethea et al., 2005).

In contrast, rats exposed to stressors or threats show increased serotonin turnover in the mPFC, striatum, amygdala and lateral hypothalamus (Inoue et al., 1994), and rats selectively bred for high-anxiety phenotypes, which show depression-like behaviors in the forced swim test, have increased hippocampal 5-HTT levels (Keck et al., 2005). A similarly complex pattern is evident in olfactory-bulbectomized rats (a putative rodent model of depression), which show elevated 5-HTT density, serotonin concentrations (Grecksch et al., 1997) (Zhou et al., 1998), and serotonin turnover in the frontal and cingulate cortices, thalamus, medial forebrain bundle and hippocampus, but reduced serotonin synthesis rates in the dorsal and median raphe nuclei (Watanabe et al., 2003). Although the pattern of 5-HTT binding abnormalities in these rodent models of stress and depression resemble those found in depressed humans (Cannon et al., 2007), if acute illness or stress is indeed impacting 5-HTT transporter numbers or binding in MDD, then this may restrict the utility of the phenotype as a marker of vulnerability to MDD.

(Frokjaer et al., 2009) found that healthy individuals who were at high-risk of developing MDD by virtue of having a co-twin with the disorder, displayed reduced 5-HTT BP in the DLPFC and to a lesser extent, the anterior cingulate cortex. Nevertheless, given the nature of this study, it is unclear if the reduction in 5-HTT BP is indicative of a genetic vulnerability to MDD or whether it reflects an adaptive compensation for impaired serotonergic function.

Theoretical Challenges

(a). Phenotypic Heterogeneity

A great deal of genetic and phenotypic variation is encompassed within current nosological categories, and it is thus likely that the exact pattern of MDD-associated neuropathology will vary across subgroups of affectively ill patients. The relatively embryonic state of the field has unfortunately meant that these issues have thus far been largely neglected.

For example, there is some evidence that patients who are recurrently ill and those subjects who have experienced one life-time episode of depression may differ from each other genetically or clinically (Zubenko et al., 2002) (Smith et al., 2005) (Mondimore et al., 2007). Other important sources of heterogeneity include age-of-onset (Alpert et al., 1999) (Hammen et al., 2008), chronicity of course (Mondimore et al., 2007) (Eaton et al., 2008), family history of MDD or BD illness (Mannie et al., 2007) (Verhagen et al., 2008), and the effect of exposure to childhood trauma (Brodsky et al., 2008) (Danese et al., 2008).

Clearly the use of endophenotypes is designed to overcome these very difficulties. Nevertheless, the failure to carefully parse clinically heterogeneous samples into more refined subgroups attenuates the statistical power needed to identify intermediate phenotypes. In this sense, until genuine breakthroughs are achieved, the endophenotypic strategy remains beholden to less biological, clinical methodologies.

(b). Defining Remission

An endophenotype is by definition a trait which is present in both ill and remitted individuals. Not all individuals remit spontaneously, however. Many remissions are treatment-induced and it is unclear if AD or other interventions mask intermediate traits which would otherwise be present if the illness followed its natural course. Our opinion (based on anecdotal observations) is that MDD patients who are capable of spontaneous remission, and remain well for years at a time, are clinically different from their counterparts who are chronically ill. Thus caution should be exercised when evaluating potential endophenotypes using the state versus trait criterion.

(c). Non-Disease Related Inter-Individual Variation in Brain Morphology and Function

The ability to distinguish disease-associated functional or anatomical changes from natural, non-clinically related inter-individual variation presents a formidable challenge. For example, (Paus et al., 1996; Fornito et al., 2006) have described how the shape and therefore the volume of the anterior cingulate gyrus, a region of the brain that has been implicated in affective illness, varies significantly among healthy individuals. Specifically, 30–60% of individuals possess a paracingulate sulcus, which runs dorsal and parallel to the cingulate sulcus, and may or may not have functional significance (Fornito et al., 2006).

Reductions in hippocampal volume have been associated with MDD (Sheline, 1996) (Neumeister et al., 2005), and in healthy individuals are often viewed as a precursor to a senescence-associated cognitive decline. Nevertheless, (Lupien et al., 2007) found that there was just as much variability in the hippocampal volumes of healthy young adults as older individuals. A quarter of their subjects in the 18–24-year age group had hippocampal volumes as small as the average hippocampal size in their 60–75-year-old sample, and the mean difference in hippocampal volumes between the upper and lower quartiles of the young age group (12–16%) was greater than volumetric reductions typically reported in depressed samples (Lupien et al., 2007).

Distinguishing between adaptive and non-adaptive compensatory responses to brain insults may also become a pernicious source of bias. For example, Alzheimer’s disease (AD) researchers have grappled with the problem of whether the phosphorylation of tau proteins which make up the neurofibrillary tangles seen at post-mortem, is a protective, compensatory response to oxidative stress, or is the primary causal process underpinning the disease (Lee et al., 2005).

A hint of this difficulty already exists in the MDD literature. While a potentially stress-induced, excitotoxicity-driven process has been reported to produce dendritic atrophy in the basolateral amygdala (BLA) (Vyas et al., 2002) of rodents, other studies demonstrate hypertrophy in response to immobilization stress (Radley and Morrison, 2005) (Vyas et al., 2006) which persists for at least 21 days (Vyas et al., 2004). This pattern may be recapitulated in MRI-analyses of MDD patients with studies indicative of both volumetric reductions (Sheline et al., 1998) (Tang et al., 2007) and increases (Lange and Irle, 2004) in amygdala volume.

(d). The Specificity of Phenotypes or Endophenotypes

Understanding the genetic basis of certain imaging phenomena such as volumetric changes, increased BOLD response of the amygdala and white matter hyperintensities will be invaluable, but will not necessarily elucidate the susceptibility variants that make MDD unique from other forms of psychiatric illness.

For example, in addition to MDD, hippocampal GM loss has been reported in schizophrenia (Steen et al., 2006), bipolar disorder (Moorhead et al., 2007), post-traumatic stress disorder (PTSD) (Karl et al., 2006); borderline personality disorder (Tebartz van Elst et al., 2003), antisocial personality disorder (Laakso et al., 2001), obsessive compulsive disorder (Kwon et al., 2003), autism (Aylward et al., 1999) and old age (Convit et al., 1995). White matter hyperintensities are characteristic of multiple sclerosis, and have been noted in MDD (Taylor et al., 2005b) (Godin et al., 2007), schizophrenic (Sachdev and Brodaty, 1999), BD (McDonald et al., 1999), substance abuse (Lyoo et al., 2004), autistic (Wong, 2007), and elderly (Kertesz et al., 1988) samples.

The counter argument to this potential problem of non-specificity is that we are guilty of the reification of DSM-IV psychiatric categories. The raison d’etre of endophenotyping is the avoidance of DSM categorization. If supposedly distinct categories of psychiatric illnesses share genetic risk factors then this may be indicative of the failure of current diagnostic systems rather than the inferiority of the relevant endophenotype. Nevertheless, the presence of the same biological trait across such clinically diverse samples raises questions about the explanatory power of any disease model derived from the imaging endophenotype.

(e). The Effects of Medication

Given the difficulty of recruiting unmedicated patients for research, perhaps the most important confounding variable is medical treatment. While, recent studies have detailed the neurotrophic effects of lithium and mood stabilizers on hippocampal and other neural tissue, there has been some suggestion that antidepressants, long considered not to impact neuronal or gray matter volumes, may also exert a neurotrophic effect in particular regions of the brain (Stewart and Reid, 2000) (Rocher et al., 2004) (Duman and Monteggia, 2006). These data are supported by an fMRI study which showed that depressed patients suffer from reduced functional coupling of the amygdala with diverse brain regions including the hippocampus, caudate, putamen, and ACC; an effect reversed by treatment with fluoxetine (Chen et al., 2007b). Similarly, with respect to amygdala hypermetabolism, a decrease in left amygdala activity to normal has been observed after antidepressant treatment (Drevets et al., 2002). Interestingly, a decrement in amygdala activity in response to aversive stimuli also been observed in healthy individuals treated with citalopram (Harmer et al., 2006) and reboxetine (Norbury et al., 2007).

(f). Methodological Variability

Data acquisition, data analysis, and in the case of some functional imaging studies, the choice of experimental paradigm may make inter-study comparison difficult. A detailed discussion of methodological issues is beyond the scope of this review. One brief example concerns the primary philosophical orientations to imaging data analysis; voxel-wise analysis which compares the differences between two or more subject groups at each individual voxel in the brain (Ashburner and Friston, 2000), and MRI-based region-of-interest analysis, which relies on extant empirical or theoretical data to identify candidate regions that may show inter-group differences.

Voxelwise analyses are highly sensitive to Type II errors because spatial normalization algorithms cannot precisely overlay small structures like the amygdala and subgenual ACC across subjects, exaggerating the statistical variance. On the other hand, the ROI approach is time and resource intensive especially when subject groups are large. The strength of the method is critically dependent on the quality of the tracing, as well as the reproducibility of the anatomical landmarks chosen to delineate the structure.

(g). Technological Limitations and Reification of Imagible Units

The limited spatial and temporal resolution of current neuroimaging technologies are important bottlenecks to progress in the field. Current structural imaging platforms do not have the necessary spatial resolution to accurately detail volumetric changes in diminutive anatomical structures such as the amygdala and periaqueductal gray. The impact of this limitation can be felt in the functional imaging literature where perfusion or metabolic measurements are subject to the problem of partial volume effects. That is, inadequate spatial resolution of the region-of-interest causes adjacent white matter (WM) and neural tissue with lower metabolic rates to be included in the analysis, leading to an underestimation of metabolic activity.

While technology will no doubt improve over the coming years, finite limits to PET resolution exist because of Compton scattering (leading to non-colinearity of emitted photon pairs), and positron range (the distance that the positron travels before annihilating with an electron and emitting a photon pair). Regarding PET measures of glucose metabolism, it is the neuropil (where the greatest degree of ion pumping across cell membranes occurs) that has the greatest metabolic demand. Thus elevated glucose metabolism as measured by PET FDG, does not necessarily reflect local activity but increased activity of distal neurons projecting to the region in question (Herscovitch, 2003). The obverse is also true. Loss of neuronal projections from damage in one region may decrease glucose metabolism in its projection field. Similarly, draining vein effects place fundamental limits on the accuracy of spatial localization that can be obtained with blood oxygenation level dependent (BOLD) changes measured by fMRI.

There is a danger that these limitations may lead to the implicit reification of neuroanatomical function; that is, the notion that gross anatomical structures should be uniformly affected by mood disorders simply because they are imagable units. For example, the amygdala is a heterogeneous structure made up of at least 14 different nuclei (Bachevalier and Loveland, 2006), some of which may be homologous to the ventral striatum and olfactory cortex (Swanson and Petrovich, 1998).

(h). Targeted Hypotheses or Genome Wide Association (GWA)?

Genetic association studies are plagued by false positive results because the large number of genes expressed in the brain translates into a low a priori probability of a true association. In response, journal editors are demanding increasingly stringent corrections for multiple testing, a trend that reaches its zenith in GWA studies which typically have a significance threshold of at least 5×10−7. GWA studies have proven highly successful at detecting disease-predisposing variations in complex disorders such as prostate cancer and diabetes mellitus (reviewed in (Seng and Seng, 2008)), although the chorus of excitement has been more muted in the case of psychiatric disorders (Wellcome-Trust-Case-Control-Consortium, 2007) (Kirov et al., 2008) (Sklar et al., 2008) (Shifman et al., 2008a).

A wave of GWA studies of imaging phenotypes is likely to follow on the heels of DSM-IV-based GWA analyses. The suitability of this “brute-force” approach to analyzing imaging phenotypes remains, however, unclear. Certainly, GWA analyses hold out great promise for uncovering disease causing polymorphisms, but imaging samples are by nature small, especially in the case of functional studies. The problem becomes all too clear in the context of GWA studies of diseases like type II diabetes where sample sizes of over 1000 are the norm, and a meta-analysis of approximately 14,000 cases and 18,000 controls produced promising results (Zeggini et al., 2008). (Manolio et al., 2008) point out that to in order to obtain 80% power to identify a risk allele with a frequency of 10% and an odds ratio of 1.5, 1,590 cases and 1,590 controls are needed to breach the statistical threshold of 5 × 10−7.

Whether the imaging data are “clean” enough to compensate for the loss of statistical power inherent to small samples is currently unknown. On the positive side, as noted by David Goldman (Goldman, 2008, personal communication), many of the highly significant results obtained in GWA studies conducted to date [reviewed in (Manolio et al., 2008)] have been obtained with intermediate phenotypes as well as traditional clinical diagnoses. Nevertheless, the substantial inter-individual variability in the volumes of anatomical subregions of the brain should inject a note of caution into the discussion.

We recently reported an association between a SNP in the galactose mutarotase (GALM) gene and serotonin transporter binding potential (measured with [11C] DASB) which survived a genome-wide correction for multiple testing (Liu et al., 2008), thus suggesting that GWA studies are in principle feasible even in very small samples. Nevertheless, the veracity of this result awaits replication.

GWA approaches raise other problematic issues such as whether structural scans obtained on different MRI scanners or functional data obtained with similar experimental paradigms can be pooled together. Certainly, this would be considered methodologically unsound in a traditional imaging study. These difficulties can be partially ameliorated by classical genetic association approaches although the strength of any finding likely depends on the depth of convergent evidence implicating the gene in a disease or relevant physiological process.

(i). Is the Genetic Architecture of an Imaging Phenotype or Endophenotype Really Simple?

An exaggerated BOLD response of the amygdala to negatively valenced faces or disease-association reductions in brain volume, are likely complex traits underpinned by multiple genetic and environmental factors. Elucidating the genetic basis of these traits may thus be deceptively difficult. Perhaps the one exception to this rule is PET-based neuroreceptor mapping which allows for quantification of the binding potential of individual receptor types in the brain. Nevertheless, the financial and logistical challenges inherent to scanning large numbers of subjects reduces statistical power, and essentially limits researchers to the testing of common, high frequency alleles.

(j). The Heritability of Endophenotypes

Ideally, the imaging phenotype found to be associated with MDD should be heritable (Gottesman and Gould, 2003) but testing this hypothesis is difficult because it requires large numbers of related individuals to undergo scanning. Besides logistical challenges, the effects of age, gender, and medication may bias intra, as well as inter-familial analyses.

(k). Evaluation of the Evidence

While our knowledge of the genetic basis of brain function remains in statu nascendi, imaging genetics faces a problem of evidence evaluation. While some relatively clear-cut instances of replication are likely to occur (the 5-HTTLPR polymorphisms is probably one such example), in many cases the data will likely be contradictory, and numerous (Popperian) ad hoc hypotheses will be forwarded to explain away positive or negative gene-phenotype associations. Examples of ad hoc hypotheses that can be used to justify results include gene-gene interactions, gene-environment interactions, genetic heterogeneity, type II errors due to lack of statistical power, and false positive results due to low a priori probability of a true effect.

The problem can be ameliorated to some extent by collecting convergent bioinformatic, biochemical, neuropathological, or animal-based data supportive of the proposed gene-imaging phenotype association. Nevertheless, unless pending GWA studies produce a rash of replicable findings, progress is likely to be slow, and this is underscored by the current inability of researchers to agree on a definitive list of true MDD-associated genetic variants.

Future Directions

(a). Gene-Gene Interactions

Assuming the veracity of the common disease-common variant (CDCV) hypothesis, analyzing the additive effects of common polymorphisms on imaging phenotypes, and by extension, genetic risk for MDD, is an important project. Evidence for gene-gene interactions are beginning to emerge in the literature. The SLC6A4 gene has been reported to interact with BDNF to impact amygdala and anterior cingulate cortex volume (Pezawas et al., 2008); tryptophan hydroxylase 2 (TPH2) (Canli et al., 2008), and catechol-o-methytransferase (COMT) (Smolka et al., 2007), to modulate amygdala response to negatively valenced stimuli.

(b). Epigenetics

Epigenetic inheritance refers to a regulated pattern of gene expression which is transmitted intact from one or other parent to their offspring. The process is mediated by the methylation and histone acetylation of cytosine residues and chromatin, respectively, leading to the activation or silencing of particular genes. The phenomenon is epi-genetic because it results in phenotypic traits that are inherited independently of the informational content of DNA.

Evidence is accumulating that these epigenetic mechanisms allow for a dynamic response to the environment. Rodent studies, for instance, have demonstrated that stress sensitivity in rat pups is modulated by parental grooming behavior which exerts its effect through a histone modification-driven regulation of glucocorticoid receptor gene expression (Meaney and Szyf, 2005). If these biological mechanisms generalize to humans then exposure to adversity may modify gene expression in pathways that impact neuroplasticity. (Philibert et al., 2008) for instance, recently reported that CpG methylation of a motif surrounding exon 1 of the 5-HTT gene was increased (trended towards statistical significance) in individuals with a life time history of MDD. In a similar vein, the GABAA receptor gene has been reported to be hypermethylated in suicide victims (Poulter et al., 2008). Since human lymphoblast cell lines reportedly maintain their transcriptional signature (Philibert et al., 2007), searching for methylation pattern-imaging phenotype associations in SLC6A4 and other genes may prove feasible and informative.

(c). Modeling the Impact of Medication

Evaluating medication-induced changes in neurophysiological function may allow researchers to “work backwards” in order to identify MDD-associated imaging abnormalities in much the same way that the efficacy of tricyclic AD and selective serotonin reuptake inhibitors implicated the serotonergic system in MDD. As noted above, a decrease in left amygdala activity to normal has been observed in MDD patients following AD treatment (Drevets et al., 2002) and a similar decrement in amygdala activity in response to aversive stimuli has been observed in healthy individuals treated with citalopram (Harmer et al., 2006) and reboxetine (Norbury et al., 2007). Medication-induced recovery from depression has also been associated with a recovery of dorsolateral prefrontal cortex BOLD signal (Fales et al., 2008) or glucose metabolism (Kennedy et al., 2001). Thus, imaging phenotypes which are state sensitive, and therefore by definition, poor endophenotypes, may nevertheless be useful, objective markers of treatment efficacy.

(d). Perturbing the System

Clearly ethical considerations prevent researchers from deliberately placing subjects under enough stress to precipitate any latent vulnerability to MDD. Nevertheless, certain approaches to perturbing neurophysiological function are open to researchers. Chief among these, are administration of drugs which temporarily deplete serotonin or catecholamines. For example, in a recent catecholamine depletion study (Hasler et al., 2008) showed that under depletion, metabolism (as measured by fluorodeoxyglucose (FDG) PET) increased in remitted MDD subjects, but decreased in healthy controls in diverse areas of the brain. These regions included the ventromedial frontal polar cortex, right thalamus, left ventral striatum (ventral putamen), infralimbic cortex, left superior temporal gyrus, left inferior parietal lobe, and left precentral gyrus.

Serotonin depletion may also uncover a genetic vulnerability to depression: Six out of 20 healthy males with a family-history of affective illness but 0 out of 19 male controls without a family-history of MDD displayed a lowering of mood in response to tryptophan depletion (Benkelfat et al., 1994). Similarly, (van der Veen et al., 2007) reported that healthy individuals with a family history of MDD showed a lowering of mood together with greater amygdala activation in response to fearful faces after tryptophan depletion.

(e). Beyond SNPs?

Copy number variants (CNV) refer to microstructural chromosomal changes: deletions, duplications, inversions; variable number tandem repeats (VNTRs), and microsatellites. Approximately 18,000 CNV have been identified to date (

De novo CN mutations have been shown to be strongly associated with sporadic cases of schizophrenia (Xu et al., 2008); autism (Marshall et al., 2008) (Weiss et al., 2008), and perhaps bipolar disorder (Lachman et al., 2007). Further, a recent GWA study of the anxiety-related personality trait, Neuroticism, found that SNPs in regions of the genome known to have CNV, yielded a disproportionate number of low p-values (Shifman et al., 2008b). If changes in CNV are associated with subtypes of MDD, then the identification of correlated imaging phenotypes, perhaps through array hybridization techniques, may help to clarify the pathophysiological mechanisms underpinning mood disorders.

(f). Beyond Psychology?

The importance of testing for gene-environment interactions as an adjunct to traditional psychiatric genetic association studies is now well established in the literature. To date, the emphasis has been placed on psychological phenomena such as early childhood abuse (Caspi et al., 2003) (Kaufman et al., 2006) (Ducci et al., 2007) (Reif et al., 2007) (Savitz et al., 2007) (Perroud et al., 2008) (Savitz et al., 2008) (Stein et al., 2008) but other, perhaps less subjective phenomena may prove equally valuable to examine. Examples include low birth-weight/fetal growth (Raikkonen et al., 2008) (Schmidt et al., 2008), paternal or maternal age at conception (Reichenberg et al., 2006) (Laursen et al., 2007), viral infections (Dickerson et al., 2006) (Fatemi et al., 2008), pre or postnatal exposure to drugs like nicotine, marijuana, and alcohol (Williams and Ross, 2007) (Becker et al., 2008) (Caldwell et al., 2008), as well as other potential environmental toxins such as lead (de Souza Lisboa et al., 2005) (Stewart et al., 2006) (Cecil et al., 2008), methylmercury (Onishchenko et al., 2008), and polychlorinated biphenyls (PCBs) (Fitzgerald et al., 2008).

(g). Beyond Neurons?

Intriguing evidence of a systemic dysregulation of immune function in MDD is beginning to surface in the literature. The leitmotif running through many of these studies is that of a cytokine-induced proinflammatory state associated with physical or psychological stress which impacts monoaminergic neurotransmission and HPA axis function (Schiepers et al., 2005). Cytokines such as interleukin-1, interleukin-6, C-reactive protein, and the pro-inflammatory enzyme, myeloperoxidase (MPO), have been found to be elevated in the blood and cerebrospinal fluid (CSF) of patients with MDD (Lanquillon et al., 2000) (Ford and Erlinger, 2004) (Vaccarino et al., 2008); a phenomenon that may be ameliorated with AD treatment (Myint et al., 2005) (Malemud and Miller, 2008). Consistent with these data, variants of genes such as tumour necrosis factor alpha (TNF-α), interleukin 1 (Fertuzinhos et al., 2004), and T-BET (TBX21) and proteosome beta4 subunit (PSMB4), which are involved in T-cell function (Wong et al., 2008), have been reported to be overrepresented in MDD populations.

Theoretically, therefore, molecular signatures of inflammation may be useful intermediate phenotypes or treatment markers for MDD. PET ligands such as [C11](R) PK11195 which quantify peripheral benzodiazepine receptors (Fujita et al., 2008), a marker of inflammation, are currently under development.


We have discussed 7 (MRI and PET) imaging phenotypes which appear to be strongly associated with MDD. Strictly speaking, an endophenotype is a heritable trait present in periods of illness and remission that should be found in biological relatives of affected individuals at a greater frequency than the general population (Gottesman and Gould, 2003). The extant literature is not mature enough to allow us to evaluate whether the neurophysiological markers discussed above qualify as endophenotypes. More family-based studies are needed. Nevertheless, what seems clear is that useful imaging phenotypes (correlates of MDD) have been identified. These (presumably) simpler traits have led to early progress in identifying the pathophysiological and genetic basis of MDD.

Table 8
Endophenotype 7. Altered Serotonin-Transporter Binding Potential in MDD.


Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.


  • Aalto S, Naatanen P, Wallius E, Metsahonkala L, Stenman H, Niem PM, Karlsson H. Neuroanatomical substrata of amusement and sadness: a PET activation study using film stimuli. Neuroreport. 2002;13:67–73. [PubMed]
  • Abler B, Erk S, Herwig U, Walter H. Anticipation of aversive stimuli activates extended amygdala in unipolar depression. J Psychiatr Res. 2007;41:511–522. [PubMed]
  • Alexopoulos GS, Meyers BS, Young RC, Campbell S, Silbersweig D, Charlson M. ‘Vascular depression’ hypothesis. Arch Gen Psychiatry. 1997;54:915–922. [PubMed]
  • Alpert JE, Fava M, Uebelacker LA, Nierenberg AA, Pava JA, Worthington JJ, 3rd, Rosenbaum JF. Patterns of axis I comorbidity in early-onset versus late-onset major depressive disorder. Biol Psychiatry. 1999;46:202–211. [PubMed]
  • Anand A, Li Y, Wang Y, Wu J, Gao S, Bukhari L, Mathews VP, Kalnin A, Lowe MJ. Activity and connectivity of brain mood regulating circuit in depression: a functional magnetic resonance study. Biol Psychiatry. 2005a;57:1079–1088. [PubMed]
  • Anand A, Li Y, Wang Y, Wu J, Gao S, Bukhari L, Mathews VP, Kalnin A, Lowe MJ. Antidepressant effect on connectivity of the mood-regulating circuit: an FMRI study. Neuropsychopharmacology. 2005b;30:1334–1344. [PubMed]
  • Arango V, Underwood MD, Gubbi AV, Mann JJ. Localized alterations in pre- and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims. Brain Res. 1995;688:121–133. [PubMed]
  • Arango V, Underwood MD, Boldrini M, Tamir H, Kassir SA, Hsiung S, Chen JJ, Mann JJ. Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology. 2001;25:892–903. [PubMed]
  • Arce E, Simmons AN, Lovero KL, Stein MB, Paulus MP. Escitalopram effects on insula and amygdala BOLD activation during emotional processing. Psychopharmacology (Berl) 2008;196:661–672. [PMC free article] [PubMed]
  • Arranz B, Eriksson A, Mellerup E, Plenge P, Marcusson J. Brain 5-HT1A, 5-HT1D, and 5-HT2 receptors in suicide victims. Biol Psychiatry. 1994;35:457–463. [PubMed]
  • Ashburner J, Friston KJ. Voxel-based morphometry--the methods. Neuroimage. 2000;11:805–821. [PubMed]
  • Ashtari M, Greenwald BS, Kramer-Ginsberg E, Hu J, Wu H, Patel M, Aupperle P, Pollack S. Hippocampal/amygdala volumes in geriatric depression. Psychol Med. 1999;29:629–638. [PubMed]
  • Aston C, Jiang L, Sokolov BP. Transcriptional profiling reveals evidence for signaling and oligodendroglial abnormalities in the temporal cortex from patients with major depressive disorder. Mol Psychiatry. 2005;10:309–322. [PubMed]
  • Axelson DA, Doraiswamy PM, McDonald WM, Boyko OB, Tupler LA, Patterson LJ, Nemeroff CB, Ellinwood EH, Jr, Krishnan KR. Hypercortisolemia and hippocampal changes in depression. Psychiatry Res. 1993;47:163–173. [PubMed]
  • Aylward EH, Minshew NJ, Goldstein G, Honeycutt NA, Augustine AM, Yates KO, Barta PE, Pearlson GD. MRI volumes of amygdala and hippocampus in non-mentally retarded autistic adolescents and adults. Neurology. 1999;53:2145–2150. [PubMed]
  • Bachevalier J, Loveland KA. The orbitofrontal-amygdala circuit and self-regulation of social-emotional behavior in autism. Neurosci Biobehav Rev. 2006;30:97–117. [PubMed]
  • Ballmaier M, Narr KL, Toga AW, Elderkin-Thompson V, Thompson PM, Hamilton L, Haroon E, Pham D, Heinz A, Kumar A. Hippocampal Morphology and Distinguishing Late-Onset From Early-Onset Elderly Depression. Am J Psychiatry 2007 [PMC free article] [PubMed]
  • Barden N. Implication of the hypothalamic-pituitary-adrenal axis in the physiopathology of depression. J Psychiatry Neurosci. 2004;29:185–193. [PMC free article] [PubMed]
  • Becker K, El-Faddagh M, Schmidt MH, Esser G, Laucht M. Interaction of dopamine transporter genotype with prenatal smoke exposure on ADHD symptoms. J Pediatr. 2008;152:263–269. [PubMed]
  • Beevers CG, Gibb BE, McGeary JE, Miller IW. Serotonin transporter genetic variation and biased attention for emotional word stimuli among psychiatric inpatients. J Abnorm Psychol. 2007;116:208–212. [PubMed]
  • Benkelfat C, Ellenbogen MA, Dean P, Palmour RM, Young SN. Mood-lowering effect of tryptophan depletion. Enhanced susceptibility in young men at genetic risk for major affective disorders. Arch Gen Psychiatry. 1994;51:687–697. [PubMed]
  • Bertolino A, Arciero G, Rubino V, Latorre V, De Candia M, Mazzola V, Blasi G, Caforio G, Hariri A, Kolachana B, Nardini M, Weinberger DR, Scarabino T. Variation of human amygdala response during threatening stimuli as a function of 5′HTTLPR genotype and personality style. Biol Psychiatry. 2005;57:1517–1525. [PubMed]
  • Bethea CL, Streicher JM, Mirkes SJ, Sanchez RL, Reddy AP, Cameron JL. Serotonin-related gene expression in female monkeys with individual sensitivity to stress. Neuroscience. 2005;132:151–166. [PubMed]
  • Bhagwagar Z, Rabiner EA, Sargent PA, Grasby PM, Cowen PJ. Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635. Mol Psychiatry. 2004;9:386–392. [PubMed]
  • Bhagwagar Z, Murthy N, Selvaraj S, Hinz R, Taylor M, Fancy S, Grasby P, Cowen P. 5-HTT binding in recovered depressed patients and healthy volunteers: a positron emission tomography study with [11C]DASB. Am J Psychiatry. 2007;164:1858–1865. [PubMed]
  • Blumberg HP, Wang F, Chepenik LG, Kalmar JH, Edmiston E, Duman RS, Gelernter J. Influence of vascular endothelial growth factor variation on human hippocampus morphology. Biol Psychiatry. 2008;64:901–903. [PMC free article] [PubMed]
  • Boes AD, McCormick LM, Coryell WH, Nopoulos P. Rostral anterior cingulate cortex volume correlates with depressed mood in normal healthy children. Biol Psychiatry. 2008;63:391–397. [PMC free article] [PubMed]
  • Boileau I, Warsh JJ, Guttman M, Saint-Cyr JA, McCluskey T, Rusjan P, Houle S, Wilson AA, Meyer JH, Kish SJ. Elevated serotonin transporter binding in depressed patients with Parkinson’s disease: a preliminary PET study with [11C]DASB. Mov Disord. 2008;23:1776–1780. [PubMed]
  • Boldrini M, Underwood MD, Mann JJ, Arango V. Serotonin-1A autoreceptor binding in the dorsal raphe nucleus of depressed suicides. J Psychiatr Res 2007 [PMC free article] [PubMed]
  • Botteron KN, Raichle ME, Drevets WC, Heath AC, Todd RD. Volumetric reduction in left subgenual prefrontal cortex in early onset depression. Biol Psychiatry. 2002;51:342–344. [PubMed]
  • Bowen DM, Najlerahim A, Procter AW, Francis PT, Murphy E. Circumscribed changes of the cerebral cortex in neuropsychiatric disorders of later life. Proc Natl Acad Sci U S A. 1989;86:9504–9508. [PubMed]
  • Brocke B, Armbruster D, Muller J, Hensch T, Jacob CP, Lesch KP, Kirschbaum C, Strobel A. Serotonin transporter gene variation impacts innate fear processing: Acoustic startle response and emotional startle. Mol Psychiatry. 2006;11:1106–1112. [PubMed]
  • Brodsky BS, Mann JJ, Stanley B, Tin A, Oquendo M, Birmaher B, Greenhill L, Kolko D, Zelazny J, Burke AK, Melhem NM, Brent D. Familial transmission of suicidal behavior: factors mediating the relationship between childhood abuse and offspring suicide attempts. J Clin Psychiatry. 2008;69:584–596. [PMC free article] [PubMed]
  • Brody AL, Saxena S, Stoessel P, Gillies LA, Fairbanks LA, Alborzian S, Phelps ME, Huang SC, Wu HM, Ho ML, Ho MK, Au SC, Maidment K, Baxter LR., Jr Regional brain metabolic changes in patients with major depression treated with either paroxetine or interpersonal therapy: preliminary findings. Arch Gen Psychiatry. 2001;58:631–640. [PubMed]
  • Brown SM, Peet E, Manuck SB, Williamson DE, Dahl RE, Ferrell RE, Hariri AR. A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity. Mol Psychiatry. 2005;10:884–888. 805. [PubMed]
  • Buck A, Gucker PM, Schonbachler RD, Arigoni M, Kneifel S, Vollenweider FX, Ametamey SM, Burger C. Evaluation of serotonergic transporters using PET and [11C](+)McN-5652: assessment of methods. J Cereb Blood Flow Metab. 2000;20:253–262. [PubMed]
  • Buckholtz JW, Callicott JH, Kolachana B, Hariri AR, Goldberg TE, Genderson M, Egan MF, Mattay VS, Weinberger DR, Meyer-Lindenberg A. Genetic variation in MAOA modulates ventromedial prefrontal circuitry mediating individual differences in human personality. Mol Psychiatry. 2008;13:313–324. [PubMed]
  • Bueller JA, Aftab M, Sen S, Gomez-Hassan D, Burmeister M, Zubieta JK. BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry. 2006;59:812–815. [PubMed]
  • Caldwell KK, Sheema S, Paz RD, Samudio-Ruiz SL, Laughlin MH, Spence NE, Roehlk MJ, Alcon SN, Allan AM. Fetal alcohol spectrum disorder-associated depression: Evidence for reductions in the levels of brain-derived neurotrophic factor in a mouse model. Pharmacol Biochem Behav 2008 [PMC free article] [PubMed]
  • Canli T, Congdon E, Todd Constable R, Lesch KP. Additive effects of serotonin transporter and tryptophan hydroxylase-2 gene variation on neural correlates of affective processing. Biol Psychol. 2008;79:118–125. [PubMed]
  • Canli T, Congdon E, Gutknecht L, Constable RT, Lesch KP. Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation. J Neural Transm. 2005a;112:1479–1485. [PubMed]
  • Canli T, Omura K, Haas BW, Fallgatter A, Constable RT, Lesch KP. Beyond affect: a role for genetic variation of the serotonin transporter in neural activation during a cognitive attention task. Proc Natl Acad Sci U S A. 2005b;102:12224–12229. [PubMed]
  • Cannon DM, Ichise M, Rollis D, Klaver JM, Gandhi SK, Charney DS, Manji HK, Drevets WC. Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [11C]DASB; comparison with bipolar disorder. Biol Psychiatry. 2007;62:870–877. [PubMed]
  • Carter CJ. eIF2B and oligodendrocyte survival: where nature and nurture meet in bipolar disorder and schizophrenia? Schizophr Bull. 2007;33:1343–1353. [PMC free article] [PubMed]
  • Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:386–389. [PubMed]
  • Cecil KM, Brubaker CJ, Adler CM, Dietrich KN, Altaye M, Egelhoff JC, Wessel S, Elangovan I, Hornung R, Jarvis K, Lanphear BP. Decreased brain volume in adults with childhood lead exposure. PLoS Med. 2008;5:e112. [PMC free article] [PubMed]
  • Cerasa A, Gioia MC, Labate A, Liguori M, Lanza P, Quattrone A. Impact of catechol-O-methyltransferase Val(108/158) Met genotype on hippocampal and prefrontal gray matter volume. Neuroreport. 2008;19:405–408. [PubMed]
  • Chalmers DT, Kwak SP, Mansour A, Akil H, Watson SJ. Corticosteroids regulate brain hippocampal 5-HT1A receptor mRNA expression. J Neurosci. 1993;13:914–923. [PubMed]
  • Chen CH, Ridler K, Suckling J, Williams S, Fu CH, Merlo-Pich E, Bullmore E. Brain Imaging Correlates of Depressive Symptom Severity and Predictors of Symptom Improvement After Antidepressant Treatment. Biol Psychiatry 2007a [PubMed]
  • Chen CH, Suckling J, Ooi C, Fu CH, Williams SC, Walsh ND, Mitterschiffthaler MT, Pich EM, Bullmore E. Functional Coupling of the Amygdala in Depressed Patients Treated with Antidepressant Medication. Neuropsychopharmacology 2007b [PubMed]
  • Chen CH, Suckling J, Ooi C, Fu CH, Williams SC, Walsh ND, Mitterschiffthaler MT, Pich EM, Bullmore E. Functional coupling of the amygdala in depressed patients treated with antidepressant medication. Neuropsychopharmacology. 2008;33:1909–1918. [PubMed]
  • Chen PS, McQuoid DR, Payne ME, Steffens DC. White matter and subcortical gray matter lesion volume changes and late-life depression outcome: a 4-year magnetic resonance imaging study. Int Psychogeriatr. 2006;18:445–456. [PubMed]
  • Chepenik LG, Fredericks C, Papademetris X, Spencer L, Lacadie C, Wang F, Pittman B, Duncan JS, Staib LH, Duman RS, Gelernter J, Blumberg HP. Effects of the brain-derived neurotrophic growth factor val66met variation on hippocampus morphology in bipolar disorder. Neuropsychopharmacology. 2009;34:944–951. [PMC free article] [PubMed]
  • Coffey CE, Figiel GS, Djang WT, Saunders WB, Weiner RD. White matter hyperintensity on magnetic resonance imaging: clinical and neuroanatomic correlates in the depressed elderly. J Neuropsychiatry Clin Neurosci. 1989;1:135–144. [PubMed]
  • Convit A, de Leon MJ, Tarshish C, De Santi S, Kluger A, Rusinek H, George AE. Hippocampal volume losses in minimally impaired elderly. Lancet. 1995;345:266. [PubMed]
  • Coryell W, Nopoulos P, Drevets W, Wilson T, Andreasen NC. Subgenual prefrontal cortex volumes in major depressive disorder and schizophrenia: diagnostic specificity and prognostic implications. Am J Psychiatry. 2005;162:1706–1712. [PubMed]
  • Danese A, Moffitt TE, Pariante CM, Ambler A, Poulton R, Caspi A. Elevated inflammation levels in depressed adults with a history of childhood maltreatment. Arch Gen Psychiatry. 2008;65:409–415. [PMC free article] [PubMed]
  • Dannlowski U, Ohrmann P, Bauer J, Kugel H, Arolt V, Heindel W, Kersting A, Baune BT, Suslow T. Amygdala reactivity to masked negative faces is associated with automatic judgmental bias in major depression: a 3 T fMRI study. J Psychiatry Neurosci. 2007a;32:423–429. [PMC free article] [PubMed]
  • Dannlowski U, Ohrmann P, Bauer J, Kugel H, Baune BT, Hohoff C, Kersting A, Arolt V, Heindel W, Deckert J, Suslow T. Serotonergic genes modulate amygdala activity in major depression. Genes Brain Behav. 2007b;6:672–676. [PubMed]
  • Dannlowski U, Ohrmann P, Bauer J, Deckert J, Hohoff C, Kugel H, Arolt V, Heindel W, Kersting A, Baune BT, Suslow T. 5-HTTLPR biases amygdala activity in response to masked facial expressions in major depression. Neuropsychopharmacology. 2008;33:418–424. [PubMed]
  • Dannlowski U, Ohrmann P, Konrad C, Domschke K, Bauer J, Kugel H, Hohoff C, Schoning S, Kersting A, Baune BT, Mortensen LS, Arolt V, Zwitserlood P, Deckert J, Heindel W, Suslow T. Reduced amygdala-prefrontal coupling in major depression: association with MAOA genotype and illness severity. Int J Neuropsychopharmacol. 2009;12:11–22. [PubMed]
  • David SP, Murthy NV, Rabiner EA, Munafo MR, Johnstone EC, Jacob R, Walton RT, Grasby PM. A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans. J Neurosci. 2005;25:2586–2590. [PMC free article] [PubMed]
  • Davidson RJ, Irwin W, Anderle MJ, Kalin NH. The neural substrates of affective processing in depressed patients treated with venlafaxine. Am J Psychiatry. 2003;160:64–75. [PubMed]
  • de Souza Lisboa SF, Goncalves G, Komatsu F, Queiroz CA, Almeida AA, Moreira EG. Developmental lead exposure induces depressive-like behavior in female rats. Drug Chem Toxicol. 2005;28:67–77. [PubMed]
  • Dickerson FB, Boronow JJ, Stallings C, Origoni AE, Cole S, Leister F, Krivogorsky B, Yolken RH. The catechol O-methyltransferase Val158Met polymorphism and herpes simplex virus type 1 infection are risk factors for cognitive impairment in bipolar disorder: additive gene-environmental effects in a complex human psychiatric disorder. Bipolar Disord. 2006;8:124–132. [PubMed]
  • Dickie EW, Armony JL. Amygdala responses to unattended fearful faces: Interaction between sex and trait anxiety. Psychiatry Res. 2008;162:51–57. [PubMed]
  • Domschke K, Braun M, Ohrmann P, Suslow T, Kugel H, Bauer J, Hohoff C, Kersting A, Engelien A, Arolt V, Heindel W, Deckert J. Association of the functional -1019C/G 5-HT1A polymorphism with prefrontal cortex and amygdala activation measured with 3 T fMRI in panic disorder. Int J Neuropsychopharmacol. 2006;9:349–355. [PubMed]
  • Domschke K, Ohrmann P, Braun M, Suslow T, Bauer J, Hohoff C, Kersting A, Engelien A, Arolt V, Heindel W, Deckert J, Kugel H. Influence of the catechol-O-methyltransferase val158met genotype on amygdala and prefrontal cortex emotional processing in panic disorder. Psychiatry Res. 2008;163:13–20. [PubMed]
  • Drevets WC, Bogers W, Raichle ME. Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism. Eur Neuropsychopharmacol. 2002;12:527–544. [PubMed]
  • Drevets WC, Savitz J, Trimble M. The subgenual anterior cingulate cortex in mood disorders. CNS Spectr. 2008;13:663–681. [PMC free article] [PubMed]
  • Drevets WC, Frank E, Price JC, Kupfer DJ, Greer PJ, Mathis C. Serotonin type-1A receptor imaging in depression. Nucl Med Biol. 2000;27:499–507. [PubMed]
  • Drevets WC, Price JL, Simpson JR, Todd RD, Reich T, Vannier M, Raichle ME. Subgenual prefrontal cortex abnormalities in mood disorders. Nature. 1997a;386:824–827. [PubMed]
  • Drevets WC, Price JL, Simpson JR, Jr, Todd RD, Reich T, Vannier M, Raichle ME. Subgenual prefrontal cortex abnormalities in mood disorders. Nature. 1997b;386:824–827. [PubMed]
  • Drevets WC, Thase ME, Moses-Kolko EL, Price J, Frank E, Kupfer DJ, Mathis C. Serotonin-1A receptor imaging in recurrent depression: replication and literature review. Nucl Med Biol. 2007;34:865–877. [PMC free article] [PubMed]
  • Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ, Huang Y, Gautier C, Mathis C. PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry. 1999;46:1375–1387. [PubMed]
  • Ducci F, Enoch MA, Hodgkinson C, Xu K, Catena M, Robin RW, Goldman D. Interaction between a functional MAOA locus and childhood sexual abuse predicts alcoholism and antisocial personality disorder in adult women. Mol Psychiatry 2007 [PubMed]
  • Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59:1116–1127. [PubMed]
  • Dupont RM, Butters N, Schafer K, Wilson T, Hesselink J, Gillin JC. Diagnostic specificity of focal white matter abnormalities in bipolar and unipolar mood disorder. Biol Psychiatry. 1995a;38:482–486. [PubMed]
  • Dupont RM, Jernigan TL, Heindel W, Butters N, Shafer K, Wilson T, Hesselink J, Gillin JC. Magnetic resonance imaging and mood disorders. Localization of white matter and other subcortical abnormalities. Arch Gen Psychiatry. 1995b;52:747–755. [PubMed]
  • Eaton WW, Shao H, Nestadt G, Lee BH, Bienvenu OJ, Zandi P. Population-based study of first onset and chronicity in major depressive disorder. Arch Gen Psychiatry. 2008;65:513–520. [PMC free article] [PubMed]
  • Etkin A, Klemenhagen KC, Dudman JT, Rogan MT, Hen R, Kandel ER, Hirsch J. Individual differences in trait anxiety predict the response of the basolateral amygdala to unconsciously processed fearful faces. Neuron. 2004;44:1043–1055. [PubMed]
  • Fakra E, Hyde LW, Gorka A, Fisher PM, Munoz KE, Kimak M, Halder I, Ferrell RE, Manuck SB, Hariri AR. Effects of HTR1A C(-1019)G on amygdala reactivity and trait anxiety. Arch Gen Psychiatry. 2009;66:33–40. [PMC free article] [PubMed]
  • Fales CL, Barch DM, Rundle MM, Mintun MA, Snyder AZ, Cohen JD, Mathews J, Sheline YI. Altered emotional interference processing in affective and cognitive-control brain circuitry in major depression. Biol Psychiatry. 2008;63:377–384. [PMC free article] [PubMed]
  • Fatemi SH, Reutiman TJ, Folsom TD, Huang H, Oishi K, Mori S, Smee DF, Pearce DA, Winter C, Sohr R, Juckel G. Maternal infection leads to abnormal gene regulation and brain atrophy in mouse offspring: implications for genesis of neurodevelopmental disorders. Schizophr Res. 2008;99:56–70. [PMC free article] [PubMed]
  • Ferguson TA, Furey M, Fromm S, Iwamoto H, Öhman A, Drevets WC. Mood-Congruent Processing Biases in Amygdala Response to Masked Sad and Happy Faces in Major Depressive Disorder. 2008 Submitted.
  • Fertuzinhos SM, Oliveira JR, Nishimura AL, Pontual D, Carvalho DR, Sougey EB, Otto PA, Zatz M. Analysis of IL-1alpha, IL-1beta, and IL-1RA [correction of IL-RA] polymorphisms in dysthymia. J Mol Neurosci. 2004;22:251–256. [PubMed]
  • Fitzgerald EF, Belanger EE, Gomez MI, Cayo M, McCaffrey RJ, Seegal RF, Jansing RL, Hwang SA, Hicks HE. Polychlorinated biphenyl exposure and neuropsychological status among older residents of upper Hudson River communities. Environ Health Perspect. 2008;116:209–215. [PMC free article] [PubMed]
  • Flugge G, Kramer M, Rensing S, Fuchs E. 5HT1A-receptors and behaviour under chronic stress: selective counteraction by testosterone. Eur J Neurosci. 1998;10:2685–2693. [PubMed]
  • Ford DE, Erlinger TP. Depression and C-reactive protein in US adults: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2004;164:1010–1014. [PubMed]
  • Fornito A, Whittle S, Wood SJ, Velakoulis D, Pantelis C, Yucel M. The influence of sulcal variability on morphometry of the human anterior cingulate and paracingulate cortex. Neuroimage. 2006;33:843–854. [PubMed]
  • Fox AS, Shelton SE, Oakes TR, Davidson RJ, Kalin NH. Trait-like brain activity during adolescence predicts anxious temperament in primates. PLoS ONE. 2008;3:e2570. [PMC free article] [PubMed]
  • Frodl T, Meisenzahl EM, Zetzsche T, Born C, Groll C, Jager M, Leinsinger G, Bottlender R, Hahn K, Moller HJ. Hippocampal changes in patients with a first episode of major depression. Am J Psychiatry. 2002;159:1112–1118. [PubMed]
  • Frodl T, Zill P, Baghai T, Schule C, Rupprecht R, Zetzsche T, Bondy B, Reiser M, Moller HJ, Meisenzahl EM. Reduced hippocampal volumes associated with the long variant of the tri- and diallelic serotonin transporter polymorphism in major depression. Am J Med Genet B Neuropsychiatr Genet. 2008a;147B:1003–1007. [PubMed]
  • Frodl T, Meisenzahl EM, Zetzsche T, Hohne T, Banac S, Schorr C, Jager M, Leinsinger G, Bottlender R, Reiser M, Moller HJ. Hippocampal and amygdala changes in patients with major depressive disorder and healthy controls during a 1-year follow-up. J Clin Psychiatry. 2004a;65:492–499. [PubMed]
  • Frodl T, Schule C, Schmitt G, Born C, Baghai T, Zill P, Bottlender R, Rupprecht R, Bondy B, Reiser M, Moller HJ, Meisenzahl EM. Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression. Arch Gen Psychiatry. 2007;64:410–416. [PubMed]
  • Frodl T, Schaub A, Banac S, Charypar M, Jager M, Kummler P, Bottlender R, Zetzsche T, Born C, Leinsinger G, Reiser M, Moller HJ, Meisenzahl EM. Reduced hippocampal volume correlates with executive dysfunctioning in major depression. J Psychiatry Neurosci. 2006;31:316–323. [PMC free article] [PubMed]
  • Frodl T, Meisenzahl EM, Zill P, Baghai T, Rujescu D, Leinsinger G, Bottlender R, Schule C, Zwanzger P, Engel RR, Rupprecht R, Bondy B, Reiser M, Moller HJ. Reduced hippocampal volumes associated with the long variant of the serotonin transporter polymorphism in major depression. Arch Gen Psychiatry. 2004b;61:177–183. [PubMed]
  • Frodl TS, Koutsouleris N, Bottlender R, Born C, Jager M, Scupin I, Reiser M, Moller HJ, Meisenzahl EM. Depression-related variation in brain morphology over 3 years: effects of stress? Arch Gen Psychiatry. 2008b;65:1156–1165. [PubMed]
  • Frokjaer VG, Vinberg M, Erritzoe D, Svarer C, Baare W, Budtz-Joergensen E, Madsen K, Madsen J, Kessing LV, Knudsen GM. High familial risk for mood disorder is associated with low dorsolateral prefrontal cortex serotonin transporter binding. Neuroimage 2009 [PubMed]
  • Fu CH, Williams SC, Cleare AJ, Scott J, Mitterschiffthaler MT, Walsh ND, Donaldson C, Suckling J, Andrew C, Steiner H, Murray RM. Neural responses to sad facial expressions in major depression following cognitive behavioral therapy. Biol Psychiatry. 2008;64:505–512. [PubMed]
  • Fu CH, Williams SC, Cleare AJ, Brammer MJ, Walsh ND, Kim J, Andrew CM, Pich EM, Williams PM, Reed LJ, Mitterschiffthaler MT, Suckling J, Bullmore ET. Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study. Arch Gen Psychiatry. 2004;61:877–889. [PubMed]
  • Fujita M, Imaizumi M, Zoghbi SS, Fujimura Y, Farris AG, Suhara T, Hong J, Pike VW, Innis RB. Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation. Neuroimage. 2008;40:43–52. [PMC free article] [PubMed]
  • Furmark T, Tillfors M, Garpenstrand H, Marteinsdottir I, Langstrom B, Oreland L, Fredrikson M. Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobia. Neurosci Lett. 2004;362:189–192. [PubMed]
  • Furmark T, Appel L, Henningsson S, Ahs F, Faria V, Linnman C, Pissiota A, Frans O, Bani M, Bettica P, Pich EM, Jacobsson E, Wahlstedt K, Oreland L, Langstrom B, Eriksson E, Fredrikson M. A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety. J Neurosci. 2008;28:13066–13074. [PubMed]
  • Gallinat J, Strohle A, Lang UE, Bajbouj M, Kalus P, Montag C, Seifert F, Wernicke C, Rommelspacher H, Rinneberg H, Schubert F. Association of human hippocampal neurochemistry, serotonin transporter genetic variation, and anxiety. Neuroimage. 2005;26:123–131. [PubMed]
  • Gatt JM, Nemeroff CB, Dobson-Stone C, Paul RH, Bryant RA, Schofield PR, Gordon E, Kemp AH, Williams LM. Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety. Mol Psychiatry 2009 [PubMed]
  • George MS, Ketter TA, Parekh PI, Horwitz B, Herscovitch P, Post RM. Brain activity during transient sadness and happiness in healthy women. Am J Psychiatry. 1995;152:341–351. [PubMed]
  • Gloor P, Olivier A, Quesney LF, Andermann F, Horowitz S. The role of the limbic system in experiential phenomena of temporal lobe epilepsy. Ann Neurol. 1982;12:129–144. [PubMed]
  • Godin O, Dufouil C, Maillard P, Delcroix N, Mazoyer B, Crivello F, Alperovitch A, Tzourio C. White Matter Lesions as a Predictor of Depression in the Elderly: The 3C-Dijon Study. Biol Psychiatry 2007 [PubMed]
  • Goldapple K, Segal Z, Garson C, Lau M, Bieling P, Kennedy S, Mayberg H. Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behavior therapy. Arch Gen Psychiatry. 2004;61:34–41. [PubMed]
  • Gotlib IH, Sivers H, Gabrieli JD, Whitfield-Gabrieli S, Goldin P, Minor KL, Canli T. Subgenual anterior cingulate activation to valenced emotional stimuli in major depression. Neuroreport. 2005;16:1731–1734. [PubMed]
  • Gottesman II, Shields J. Genetic theorizing and schizophrenia. Br J Psychiatry. 1973;122:15–30. [PubMed]
  • Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160:636–645. [PubMed]
  • Grecksch G, Zhou D, Franke C, Schroder U, Sabel B, Becker A, Huether G. Influence of olfactory bulbectomy and subsequent imipramine treatment on 5-hydroxytryptaminergic presynapses in the rat frontal cortex: behavioural correlates. Br J Pharmacol. 1997;122:1725–1731. [PMC free article] [PubMed]
  • Greenwald BS, Kramer-Ginsberg E, Krishnan RR, Ashtari M, Aupperle PM, Patel M. MRI signal hyperintensities in geriatric depression. Am J Psychiatry. 1996;153:1212–1215. [PubMed]
  • Greenwald BS, Kramer-Ginsberg E, Krishnan KR, Ashtari M, Auerbach C, Patel M. Neuroanatomic localization of magnetic resonance imaging signal hyperintensities in geriatric depression. Stroke. 1998;29:613–617. [PubMed]
  • Greicius MD, Flores BH, Menon V, Glover GH, Solvason HB, Kenna H, Reiss AL, Schatzberg AF. Resting-state functional connectivity in major depression: abnormally increased contributions from subgenual cingulate cortex and thalamus. Biol Psychiatry. 2007;62:429–437. [PMC free article] [PubMed]
  • Gronli J, Bramham C, Murison R, Kanhema T, Fiske E, Bjorvatn B, Ursin R, Portas CM. Chronic mild stress inhibits BDNF protein expression and CREB activation in the dentate gyrus but not in the hippocampus proper. Pharmacol Biochem Behav. 2006;85:842–849. [PubMed]
  • Guze BH, Szuba MP. Leukoencephalopathy and major depression: a preliminary report. Psychiatry Res. 1992;45:169–175. [PubMed]
  • Habel U, Klein M, Kellermann T, Shah NJ, Schneider F. Same or different? Neural correlates of happy and sad mood in healthy males. Neuroimage. 2005;26:206–214. [PubMed]
  • Hamilton JP, Gotlib IH. Neural Substrates of Increased Memory Sensitivity for Negative Stimuli in Major Depression. Biol Psychiatry 2008 [PMC free article] [PubMed]
  • Hammen C, Brennan PA, Keenan-Miller D, Herr NR. Early onset recurrent subtype of adolescent depression: clinical and psychosocial correlates. J Child Psychol Psychiatry. 2008;49:433–440. [PubMed]
  • Hannestad J, Taylor WD, McQuoid DR, Payne ME, Krishnan KR, Steffens DC, Macfall JR. White matter lesion volumes and caudate volumes in late-life depression. Int J Geriatr Psychiatry. 2006;21:1193–1198. [PubMed]
  • Hare TA, Tottenham N, Galvan A, Voss HU, Glover GH, Casey BJ. Biological substrates of emotional reactivity and regulation in adolescence during an emotional go-nogo task. Biol Psychiatry. 2008;63:927–934. [PMC free article] [PubMed]
  • Hariri AR, Drabant EM, Munoz KE, Kolachana BS, Mattay VS, Egan MF, Weinberger DR. A susceptibility gene for affective disorders and the response of the human amygdala. Arch Gen Psychiatry. 2005;62:146–152. [PubMed]
  • Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D, Egan MF, Weinberger DR. Serotonin transporter genetic variation and the response of the human amygdala. Science. 2002;297:400–403. [PubMed]
  • Harmer CJ, Mackay CE, Reid CB, Cowen PJ, Goodwin GM. Antidepressant drug treatment modifies the neural processing of nonconscious threat cues. Biol Psychiatry. 2006;59:816–820. [PubMed]
  • Hasler G, Fromm S, Carlson PJ, Luckenbaugh DA, Waldeck T, Geraci M, Roiser JP, Neumeister A, Meyers N, Charney DS, Drevets WC. Neural response to catecholamine depletion in unmedicated subjects with major depressive disorder in remission and healthy subjects. Arch Gen Psychiatry. 2008;65:521–531. [PMC free article] [PubMed]
  • Hastings RS, Parsey RV, Oquendo MA, Arango V, Mann JJ. Volumetric analysis of the prefrontal cortex, amygdala, and hippocampus in major depression. Neuropsychopharmacology. 2004;29:952–959. [PubMed]
  • Heinz A, Smolka MN, Braus DF, Wrase J, Beck A, Flor H, Mann K, Schumann G, Buchel C, Hariri AR, Weinberger DR. Serotonin transporter genotype (5-HTTLPR): effects of neutral and undefined conditions on amygdala activation. Biol Psychiatry. 2007;61:1011–1014. [PubMed]
  • Heinz A, Braus DF, Smolka MN, Wrase J, Puls I, Hermann D, Klein S, Grusser SM, Flor H, Schumann G, Mann K, Buchel C. Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter. Nat Neurosci. 2005;8:20–21. [PubMed]
  • Herscovitch P. Cerebral Physiologic Measurements with PET. In: Valk PE, Bailey DL, Townsend DW, Maisey MN, editors. Positron Emission Tomography: Basic Science and Clinical Practice. London: Springer; 2003. pp. 283–308.
  • Hettema JM, An SS, van den Oord EJ, Neale MC, Kendler KS, Chen X. Association study between the serotonin 1A receptor (HTR1A) gene and neuroticism, major depression, and anxiety disorders. Am J Med Genet B Neuropsychiatr Genet 2007 [PMC free article] [PubMed]
  • Hickie I, Scott E, Mitchell P, Wilhelm K, Austin MP, Bennett B. Subcortical hyperintensities on magnetic resonance imaging: clinical correlates and prognostic significance in patients with severe depression. Biol Psychiatry. 1995;37:151–160. [PubMed]
  • Hickie I, Naismith S, Ward PB, Turner K, Scott E, Mitchell P, Wilhelm K, Parker G. Reduced hippocampal volumes and memory loss in patients with early- and late-onset depression. Br J Psychiatry. 2005;186:197–202. [PubMed]
  • Hirvonen J, Karlsson H, Kajander J, Lepola A, Markkula J, Rasi-Hakala H, Nagren K, Salminen JK, Hietala J. Decreased brain serotonin 5-HT1A receptor availability in medication-naive patients with major depressive disorder: an in-vivo imaging study using PET and [carbonyl-11C]WAY-100635. Int J Neuropsychopharmacol. 2008;11:465–476. [PubMed]
  • Ho BC, Milev P, O’Leary DS, Librant A, Andreasen NC, Wassink TH. Cognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers. Arch Gen Psychiatry. 2006;63:731–740. [PMC free article] [PubMed]
  • Hoffman BJ, Hansson SR, Mezey E, Palkovits M. Localization and dynamic regulation of biogenic amine transporters in the mammalian central nervous system. Front Neuroendocrinol. 1998;19:187–231. [PubMed]
  • Holthoff VA, Beuthien-Baumann B, Zundorf G, Triemer A, Ludecke S, Winiecki P, Koch R, Fuchtner F, Herholz K. Changes in brain metabolism associated with remission in unipolar major depression. Acta Psychiatr Scand. 2004;110:184–194. [PubMed]
  • Hu XZ, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Greenberg BD, Xu K, Arnold PD, Richter MA, Kennedy JL, Murphy DL, Goldman D. Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet. 2006;78:815–826. [PubMed]
  • Huang YY, Battistuzzi C, Oquendo MA, Harkavy-Friedman J, Greenhill L, Zalsman G, Brodsky B, Arango V, Brent DA, Mann JJ. Human 5-HT1A receptor C(-1019)G polymorphism and psychopathology. Int J Neuropsychopharmacol. 2004;7:441–451. [PubMed]
  • Ichimiya T, Suhara T, Sudo Y, Okubo Y, Nakayama K, Nankai M, Inoue M, Yasuno F, Takano A, Maeda J, Shibuya H. Serotonin transporter binding in patients with mood disorders: a PET study with [11C](+)McN5652. Biol Psychiatry. 2002;51:715–722. [PubMed]
  • Inagaki M, Matsuoka Y, Sugahara Y, Nakano T, Akechi T, Fujimori M, Imoto S, Murakami K, Uchitomi Y. Hippocampal volume and first major depressive episode after cancer diagnosis in breast cancer survivors. Am J Psychiatry. 2004;161:2263–2270. [PubMed]
  • Inagaki M, Yoshikawa E, Kobayakawa M, Matsuoka Y, Sugawara Y, Nakano T, Akizuki N, Fujimori M, Akechi T, Kinoshita T, Furuse J, Murakami K, Uchitomi Y. Regional cerebral glucose metabolism in patients with secondary depressive episodes after fatal pancreatic cancer diagnosis. J Affect Disord. 2007;99:231–236. [PubMed]
  • Inoue T, Tsuchiya K, Koyama T. Regional changes in dopamine and serotonin activation with various intensity of physical and psychological stress in the rat brain. Pharmacol Biochem Behav. 1994;49:911–920. [PubMed]
  • Iosifescu DV, Renshaw PF, Lyoo IK, Lee HK, Perlis RH, Papakostas GI, Nierenberg AA, Fava M. Brain white-matter hyperintensities and treatment outcome in major depressive disorder. Br J Psychiatry. 2006;188:180–185. [PubMed]
  • Jacobsen JP, Mork A. Chronic corticosterone decreases brain-derived neurotrophic factor (BDNF) mRNA and protein in the hippocampus, but not in the frontal cortex, of the rat. Brain Res. 2006;1110:221–225. [PubMed]
  • Jacobson L, Sapolsky R. The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endocrine Reviews. 1991;12:118–134. [PubMed]
  • Janssen J, Hulshoff Pol HE, Lampe IK, Schnack HG, de Leeuw FE, Kahn RS, Heeren TJ. Hippocampal changes and white matter lesions in early-onset depression. Biol Psychiatry. 2004;56:825–831. [PubMed]
  • Janssen J, Hulshoff Pol HE, de Leeuw FE, Schnack HS, Lampe IK, Kok RM, Kahn RS, Heeren TJ. Hippocampal volume and subcortical white matter lesions in late-life depression: comparison of early- and late-onset depression. J Neurol Neurosurg Psychiatry 2007 [PMC free article] [PubMed]
  • Joffe RT, Gatt JM, Kemp AH, Grieve S, Dobson-Stone C, Kuan SA, Schofield PR, Gordon E, Williams LM. Brain derived neurotrophic factor Val66Met polymorphism, the five factor model of personality and hippocampal volume: Implications for depressive illness. Hum Brain Mapp 2008 [PubMed]
  • Johnstone T, van Reekum CM, Urry HL, Kalin NH, Davidson RJ. Failure to regulate: counterproductive recruitment of top-down prefrontal-subcortical circuitry in major depression. J Neurosci. 2007;27:8877–8884. [PubMed]
  • Kalin NH, Shelton SE, Fox AS, Rogers J, Oakes TR, Davidson RJ. The serotonin transporter genotype is associated with intermediate brain phenotypes that depend on the context of eliciting stressor. Mol Psychiatry 2008 [PMC free article] [PubMed]
  • Karl A, Schaefer M, Malta LS, Dorfel D, Rohleder N, Werner A. A meta-analysis of structural brain abnormalities in PTSD. Neurosci Biobehav Rev. 2006;30:1004–1031. [PubMed]
  • Kaufman J, Yang BZ, Douglas-Palumberi H, Grasso D, Lipschitz D, Houshyar S, Krystal JH, Gelernter J. Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biol Psychiatry. 2006;59:673–680. [PubMed]
  • Keck ME, Sartori SB, Welt T, Muller MB, Ohl F, Holsboer F, Landgraf R, Singewald N. Differences in serotonergic neurotransmission between rats displaying high or low anxiety/depression-like behaviour: effects of chronic paroxetine treatment. J Neurochem. 2005;92:1170–1179. [PubMed]
  • Keedwell P, Drapier D, Surguladze S, Giampietro V, Brammer M, Phillips M. Neural markers of symptomatic improvement during antidepressant therapy in severe depression: subgenual cingulate and visual cortical responses to sad, but not happy, facial stimuli are correlated with changes in symptom score. J Psychopharmacol 2008 [PubMed]
  • Kegeles LS, Malone KM, Slifstein M, Ellis SP, Xanthopoulos E, Keilp JG, Campbell C, Oquendo M, Van Heertum RL, Mann JJ. Response of cortical metabolic deficits to serotonergic challenge in familial mood disorders. Am J Psychiatry. 2003;160:76–82. [PubMed]
  • Kennedy SH, Evans KR, Kruger S, Mayberg HS, Meyer JH, McCann S, Arifuzzman AI, Houle S, Vaccarino FJ. Changes in regional brain glucose metabolism measured with positron emission tomography after paroxetine treatment of major depression. Am J Psychiatry. 2001;158:899–905. [PubMed]
  • Kertesz A, Black SE, Tokar G, Benke T, Carr T, Nicholson L. Periventricular and subcortical hyperintensities on magnetic resonance imaging. ‘Rims, caps, and unidentified bright objects’ Arch Neurol. 1988;45:404–408. [PubMed]
  • Kienast T, Hariri AR, Schlagenhauf F, Wrase J, Sterzer P, Buchholz HG, Smolka MN, Grunder G, Cumming P, Kumakura Y, Bartenstein P, Dolan RJ, Heinz A. Dopamine in amygdala gates limbic processing of aversive stimuli in humans. Nat Neurosci. 2008;11:1381–1382. [PubMed]
  • Kirov G, Zaharieva I, Georgieva L, Moskvina V, Nikolov I, Cichon S, Hillmer A, Toncheva D, Owen MJ, O’Donovan MC. A genome-wide association study in 574 schizophrenia trios using DNA pooling. Mol Psychiatry 2008 [PubMed]
  • Koo MS, Levitt JJ, Salisbury DF, Nakamura M, Shenton ME, McCarley RW. A cross-sectional and longitudinal magnetic resonance imaging study of cingulate gyrus gray matter volume abnormalities in first-episode schizophrenia and first-episode affective psychosis. Arch Gen Psychiatry. 2008;65:746–760. [PMC free article] [PubMed]
  • Kraus MR, Al-Taie O, Schafer A, Pfersdorff M, Lesch KP, Scheurlen M. Serotonin-1A receptor gene HTR1A variation predicts interferon-induced depression in chronic hepatitis C. Gastroenterology. 2007;132:1279–1286. [PubMed]
  • Kreiss DS, Lucki I. Differential regulation of serotonin (5-HT) release in the striatum and hippocampus by 5-HT1A autoreceptors of the dorsal and median raphe nuclei. J Pharmacol Exp Ther. 1994;269:1268–1279. [PubMed]
  • Krishnan KR, Hays JC, Blazer DG. MRI-defined vascular depression. Am J Psychiatry. 1997;154:497–501. [PubMed]
  • Kronmuller KT, Pantel J, Kohler S, Victor D, Giesel F, Magnotta VA, Mundt C, Essig M, Schroder J. Hippocampal volume and 2-year outcome in depression. Br J Psychiatry. 2008;192:472–473. [PubMed]
  • Kumano H, Ida I, Oshima A, Takahashi K, Yuuki N, Amanuma M, Oriuchi N, Endo K, Matsuda H, Mikuni M. Brain metabolic changes associated with predispotion to onset of major depressive disorder and adjustment disorder in cancer patients -A preliminary PET study. J Psychiatr Res 2006 [PubMed]
  • Kumano H, Ida I, Oshima A, Takahashi K, Yuuki N, Amanuma M, Oriuchi N, Endo K, Matsuda H, Mikuni M. Brain metabolic changes associated with predispotion to onset of major depressive disorder and adjustment disorder in cancer patients--a preliminary PET study. J Psychiatr Res. 2007;41:591–599. [PubMed]
  • Kumar A, Bilker W, Jin Z, Udupa J. Atrophy and high intensity lesions: complementary neurobiological mechanisms in late-life major depression. Neuropsychopharmacology. 2000;22:264–274. [PubMed]
  • Kwon JS, Shin YW, Kim CW, Kim YI, Youn T, Han MH, Chang KH, Kim JJ. Similarity and disparity of obsessive-compulsive disorder and schizophrenia in MR volumetric abnormalities of the hippocampus-amygdala complex. J Neurol Neurosurg Psychiatry. 2003;74:962–964. [PMC free article] [PubMed]
  • Laakso MP, Vaurio O, Koivisto E, Savolainen L, Eronen M, Aronen HJ, Hakola P, Repo E, Soininen H, Tiihonen J. Psychopathy and the posterior hippocampus. Behav Brain Res. 2001;118:187–193. [PubMed]
  • Lachman HM, Pedrosa E, Petruolo OA, Cockerham M, Papolos A, Novak T, Papolos DF, Stopkova P. Increase in GSK3beta gene copy number variation in bipolar disorder. Am J Med Genet B Neuropsychiatr Genet. 2007;144:259–265. [PubMed]
  • Lange C, Irle E. Enlarged amygdala volume and reduced hippocampal volume in young women with major depression. Psychol Med. 2004;34:1059–1064. [PubMed]
  • Lanquillon S, Krieg JC, Bening-Abu-Shach U, Vedder H. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology. 2000;22:370–379. [PubMed]
  • Lanteaume L, Khalfa S, Regis J, Marquis P, Chauvel P, Bartolomei F. Emotion induction after direct intracerebral stimulations of human amygdala. Cereb Cortex. 2007;17:1307–1313. [PubMed]
  • Lau JY, Goldman D, Buzas B, Fromm SJ, Guyer AE, Hodgkinson C, Monk CS, Nelson EE, Shen PH, Pine DS, Ernst M. Amygdala function and 5-HTT gene variants in adolescent anxiety and major depressive disorder. Biol Psychiatry. 2009;65:349–355. [PMC free article] [PubMed]
  • Laursen TM, Munk-Olsen T, Nordentoft M, Bo Mortensen P. A comparison of selected risk factors for unipolar depressive disorder, bipolar affective disorder, schizoaffective disorder, and schizophrenia from a danish population-based cohort. J Clin Psychiatry. 2007;68:1673–1681. [PubMed]
  • Law AJ, Pei Q, Walker M, Gordon-Andrews H, Weickert CS, Feldon J, Pryce CR, Harrison PJ. Early Parental Deprivation in the Marmoset Monkey Produces Long-Term Changes in Hippocampal Expression of Genes Involved in Synaptic Plasticity and Implicated in Mood Disorder. Neuropsychopharmacology 2008 [PMC free article] [PubMed]
  • Lawrence NS, Williams AM, Surguladze S, Giampietro V, Brammer MJ, Andrew C, Frangou S, Ecker C, Phillips ML. Subcortical and ventral prefrontal cortical neural responses to facial expressions distinguish patients with bipolar disorder and major depression. Biol Psychiatry. 2004;55:578–587. [PubMed]
  • Lee AL, Ogle WO, Sapolsky RM. Stress and depression: possible links to neuron death in the hippocampus. Bipolar Disord. 2002;4:117–128. [PubMed]
  • Lee BT, Ham BJ. Serotonergic genes and amygdala activity in response to negative affective facial stimuli in Korean women. Genes Brain Behav. 2008a;7:899–905. [PubMed]
  • Lee BT, Ham BJ. Monoamine oxidase A-uVNTR genotype affects limbic brain activity in response to affective facial stimuli. Neuroreport. 2008b;19:515–519. [PubMed]
  • Lee HG, Perry G, Moreira PI, Garrett MR, Liu Q, Zhu X, Takeda A, Nunomura A, Smith MA. Tau phosphorylation in Alzheimer’s disease: pathogen or protector? Trends Mol Med. 2005;11:164–169. [PubMed]
  • Lemonde S, Turecki G, Bakish D, Du L, Hrdina PD, Bown CD, Sequeira A, Kushwaha N, Morris SJ, Basak A, Ou XM, Albert PR. Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci. 2003;23:8788–8799. [PubMed]
  • Lenze E, Cross D, McKeel D, Neuman RJ, Sheline YI. White matter hyperintensities and gray matter lesions in physically healthy depressed subjects. Am J Psychiatry. 1999;156:1602–1607. [PubMed]
  • Lenze EJ, Shardell M, Ferrell RE, Orwig D, Yu-Yahiro J, Hawkes W, Fredman L, Miller R, Magaziner J. Association of serotonin-1A and 2A receptor promoter polymorphisms with depressive symptoms and functional recovery in elderly persons after hip fracture. J Affect Disord 2008 [PMC free article] [PubMed]
  • Lesch KP, Gutknecht L. Focus on The 5-HT1A receptor: emerging role of a gene regulatory variant in psychopathology and pharmacogenetics. Int J Neuropsychopharmacol. 2004;7:381–385. [PubMed]
  • Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996;274:1527–1531. [PubMed]
  • Lewine RR, Hudgins P, Brown F, Caudle J, Risch SC. Differences in qualitative brain morphology findings in schizophrenia, major depression, bipolar disorder, and normal volunteers. Schizophr Res. 1995;15:253–259. [PubMed]
  • Li L, Ma N, Li Z, Tan L, Liu J, Gong G, Shu N, He Z, Jiang T, Xu L. Prefrontal white matter abnormalities in young adult with major depressive disorder: a diffusion tensor imaging study. Brain Res. 2007;1168:124–128. [PubMed]
  • Liu X, Cannon DM, Drevets W, McMahon FJ. Genome-Wide Association Study of PET Scan Phenotypes. Biological Psychiatry. 2008:186S.
  • Lloyd AJ, Ferrier IN, Barber R, Gholkar A, Young AH, O’Brien JT. Hippocampal volume change in depression: late- and early-onset illness compared. Br J Psychiatry. 2004;184:488–495. [PubMed]
  • Lopez-Figueroa AL, Norton CS, Lopez-Figueroa MO, Armellini-Dodel D, Burke S, Akil H, Lopez JF, Watson SJ. Serotonin 5-HT1A, 5-HT1B, and 5-HT2A receptor mRNA expression in subjects with major depression, bipolar disorder, and schizophrenia. Biol Psychiatry. 2004;55:225–233. [PubMed]
  • Lopez JF, Chalmers DT, Little KY, Watson SJ. A.E. Bennett Research Award. Regulation of serotonin1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for the neurobiology of depression. Biol Psychiatry. 1998;43:547–573. [PubMed]
  • Lowther S, De Paermentier F, Cheetham SC, Crompton MR, Katona CL, Horton RW. 5-HT1A receptor binding sites in post-mortem brain samples from depressed suicides and controls. J Affect Disord. 1997;42:199–207. [PubMed]
  • Lupien SJ, Evans A, Lord C, Miles J, Pruessner M, Pike B, Pruessner JC. Hippocampal volume is as variable in young as in older adults: Implications for the notion of hippocampal atrophy in humans. Neuroimage. 2007;34:479–485. [PubMed]
  • Lyoo IK, Streeter CC, Ahn KH, Lee HK, Pollack MH, Silveri MM, Nassar L, Levin JM, Sarid-Segal O, Ciraulo DA, Renshaw PF, Kaufman MJ. White matter hyperintensities in subjects with cocaine and opiate dependence and healthy comparison subjects. Psychiatry Res. 2004;131:135–145. [PubMed]
  • Ma N, Li L, Shu N, Liu J, Gong G, He Z, Li Z, Tan L, Stone WS, Zhang Z, Xu L, Jiang T. White matter abnormalities in first-episode, treatment-naive young adults with major depressive disorder. Am J Psychiatry. 2007;164:823–826. [PubMed]
  • MacFall JR, Payne ME, Provenzale JE, Krishnan KR. Medial orbital frontal lesions in late-onset depression. Biol Psychiatry. 2001;49:803–806. [PubMed]
  • MacMaster FP, Kusumakar V. Hippocampal volume in early onset depression. BMC Med. 2004;2:2. [PMC free article] [PubMed]
  • Macmaster FP, Mirza Y, Szeszko PR, Kmiecik LE, Easter PC, Taormina SP, Lynch M, Rose M, Moore GJ, Rosenberg DR. Amygdala and Hippocampal Volumes in Familial Early Onset Major Depressive Disorder. Biol Psychiatry 2007 [PMC free article] [PubMed]
  • MacMaster FP, Mirza Y, Szeszko PR, Kmiecik LE, Easter PC, Taormina SP, Lynch M, Rose M, Moore GJ, Rosenberg DR. Amygdala and hippocampal volumes in familial early onset major depressive disorder. Biol Psychiatry. 2008;63:385–390. [PMC free article] [PubMed]
  • MacQueen GM, Campbell S, McEwen BS, Macdonald K, Amano S, Joffe RT, Nahmias C, Young LT. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci U S A. 2003;100:1387–1392. [PubMed]
  • Mah L, Zarate CA, Jr, Singh J, Duan YF, Luckenbaugh DA, Manji HK, Drevets WC. Regional cerebral glucose metabolic abnormalities in bipolar II depression. Biol Psychiatry. 2007;61:765–775. [PubMed]
  • Malemud CJ, Miller AH. Pro-inflammatory cytokine-induced SAPK/MAPK and JAK/STAT in rheumatoid arthritis and the new anti-depression drugs. Expert Opin Ther Targets. 2008;12:171–183. [PubMed]
  • Mannie ZN, Bristow GC, Harmer CJ, Cowen PJ. Impaired emotional categorisation in young people at increased familial risk of depression. Neuropsychologia. 2007;45:2975–2980. [PubMed]
  • Mannie ZN, Norbury R, Murphy SE, Inkster B, Harmer CJ, Cowen PJ. Affective modulation of anterior cingulate cortex in young people at increased familial risk of depression. Br J Psychiatry. 2008;192:356–361. [PubMed]
  • Manolio TA, Brooks LD, Collins FS. A HapMap harvest of insights into the genetics of common disease. J Clin Invest. 2008;118:1590–1605. [PMC free article] [PubMed]
  • Manuck SB, Brown SM, Forbes EE, Hariri AR. Temporal stability of individual differences in amygdala reactivity. Am J Psychiatry. 2007;164:1613–1614. [PubMed]
  • Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, Shago M, Moessner R, Pinto D, Ren Y, Thiruvahindrapduram B, Fiebig A, Schreiber S, Friedman J, Ketelaars CE, Vos YJ, Ficicioglu C, Kirkpatrick S, Nicolson R, Sloman L, Summers A, Gibbons CA, Teebi A, Chitayat D, Weksberg R, Thompson A, Vardy C, Crosbie V, Luscombe S, Baatjes R, Zwaigenbaum L, Roberts W, Fernandez B, Szatmari P, Scherer SW. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008;82:477–488. [PubMed]
  • Matthews SC, Strigo IA, Simmons AN, Yang TT, Paulus MP. Decreased functional coupling of the amygdala and supragenual cingulate is related to increased depression in unmedicated individuals with current major depressive disorder. J Affect Disord. 2008;111:13–20. [PubMed]
  • Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA. Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry. 2000;48:830–843. [PubMed]
  • Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45:651–660. [PubMed]
  • Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, Silva JA, Tekell JL, Martin CC, Lancaster JL, Fox PT. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry. 1999;156:675–682. [PubMed]
  • McDonald C, Bullmore ET, Sham PC, Chitnis X, Wickham H, Bramon E, Murray RM. Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes. Arch Gen Psychiatry. 2004;61:974–984. [PubMed]
  • McDonald WM, Tupler LA, Marsteller FA, Figiel GS, DiSouza S, Nemeroff CB, Krishnan KR. Hyperintense lesions on magnetic resonance images in bipolar disorder. Biol Psychiatry. 1999;45:965–971. [PubMed]
  • McEwen BS, Magarinos AM. Stress and hippocampal plasticity: implications for the pathophysiology of affective disorders. Hum Psychopharmacol. 2001;16:S7–S19. [PubMed]
  • McKittrick CR, Blanchard DC, Blanchard RJ, McEwen BS, Sakai RR. Serotonin receptor binding in a colony model of chronic social stress. Biol Psychiatry. 1995;37:383–393. [PubMed]
  • McKittrick CR, Magarinos AM, Blanchard DC, Blanchard RJ, McEwen BS, Sakai RR. Chronic social stress reduces dendritic arbors in CA3 of hippocampus and decreases binding to serotonin transporter sites. Synapse. 2000;36:85–94. [PubMed]
  • Meaney MJ, Szyf M. Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome. Dialogues Clin Neurosci. 2005;7:103–123. [PMC free article] [PubMed]
  • Meijer OC, Cole TJ, Schmid W, Schutz G, Joels M, De Kloet ER. Regulation of hippocampal 5-HT1A receptor mRNA and binding in transgenic mice with a targeted disruption of the glucocorticoid receptor. Brain Res Mol Brain Res. 1997;46:290–296. [PubMed]
  • Meltzer CC, Price JC, Mathis CA, Butters MA, Ziolko SK, Moses-Kolko E, Mazumdar S, Mulsant BH, Houck PR, Lopresti BJ, Weissfeld LA, Reynolds CF. Serotonin 1A receptor binding and treatment response in late-life depression. Neuropsychopharmacology. 2004;29:2258–2265. [PubMed]
  • Mendelson SD, McEwen BS. Autoradiographic analyses of the effects of restraint-induced stress on 5-HT1A, 5-HT1C and 5-HT2 receptors in the dorsal hippocampus of male and female rats. Neuroendocrinology. 1991;54:454–461. [PubMed]
  • Mervaala E, Fohr J, Kononen M, Valkonen-Korhonen M, Vainio P, Partanen K, Partanen J, Tiihonen J, Viinamaki H, Karjalainen AK, Lehtonen J. Quantitative MRI of the hippocampus and amygdala in severe depression. Psychological Medicine. 2000;30:117–125. [PubMed]
  • Meyer JH. Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. J Psychiatry Neurosci. 2007;32:86–102. [PMC free article] [PubMed]
  • Meyer JH, Houle S, Sagrati S, Carella A, Hussey DF, Ginovart N, Goulding V, Kennedy J, Wilson AA. Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes. Arch Gen Psychiatry. 2004;61:1271–1279. [PubMed]
  • Mickey BJ, Ducci F, Hodgkinson CA, Langenecker SA, Goldman D, Zubieta JK. Monoamine oxidase A genotype predicts human serotonin 1A receptor availability in vivo. J Neurosci. 2008;28:11354–11359. [PMC free article] [PubMed]
  • Miller JM, Oquendo MA, Ogden RT, Mann JJ, Parsey RV. Serotonin transporter binding as a possible predictor of one-year remission in major depressive disorder. J Psychiatr Res. 2008;42:1137–1144. [PMC free article] [PubMed]
  • Mondimore FM, Zandi PP, MacKinnon DF, McInnis MG, Miller EB, Schweizer B, Crowe RP, Scheftner WA, Weissman MM, Levinson DF, DePaulo JR, Jr, Potash JB. A comparison of the familiality of chronic depression in recurrent early-onset depression pedigrees using different definitions of chronicity. J Affect Disord. 2007;100:171–177. [PMC free article] [PubMed]
  • Monk CS, Klein RG, Telzer EH, Schroth EA, Mannuzza S, Moulton JL, 3rd, Guardino M, Masten CL, McClure-Tone EB, Fromm S, Blair RJ, Pine DS, Ernst M. Amygdala and nucleus accumbens activation to emotional facial expressions in children and adolescents at risk for major depression. Am J Psychiatry. 2008;165:90–98. [PubMed]
  • Montag C, Reuter M, Newport B, Elger C, Weber B. The BDNF Val66Met polymorphism affects amygdala activity in response to emotional stimuli: evidence from a genetic imaging study. Neuroimage. 2008;42:1554–1559. [PubMed]
  • Moore G, Cortese B, Glitz D, Zajac-Benitez C, Quiroz JA, Uhde TW, Drevets WC, Manji HK. Chronic Lithium Increases Prefrontal and Subgenual Prefrontal Gray Matter in Patients with Bipolar Disorder: A Longitudinal High Resolution Volumetric MRI Study. J Clin Psychiatry 2008
  • Moorhead TW, McKirdy J, Sussmann JE, Hall J, Lawrie SM, Johnstone EC, McIntosh AM. Progressive gray matter loss in patients with bipolar disorder. Biol Psychiatry. 2007;62:894–900. [PubMed]
  • Moses-Kolko EL, Wisner KL, Price JC, Berga SL, Drevets WC, Hanusa BH, Loucks TL, Meltzer CC. Serotonin 1A receptor reductions in postpartum depression: a positron emission tomography study. Fertil Steril. 2008;89:685–692. [PMC free article] [PubMed]
  • Murata T, Kimura H, Omori M, Kado H, Kosaka H, Iidaka T, Itoh H, Wada Y. MRI white matter hyperintensities, (1)H-MR spectroscopy and cognitive function in geriatric depression: a comparison of early- and late-onset cases. Int J Geriatr Psychiatry. 2001;16:1129–1135. [PubMed]
  • Myint AM, Leonard BE, Steinbusch HW, Kim YK. Th1, Th2, and Th3 cytokine alterations in major depression. J Affect Disord. 2005;88:167–173. [PubMed]
  • Nahas Z, Teneback C, Chae JH, Mu Q, Molnar C, Kozel FA, Walker J, Anderson B, Koola J, Kose S, Lomarev M, Bohning DE, George MS. Serial Vagus Nerve Stimulation Functional MRI in Treatment-Resistant Depression. Neuropsychopharmacology 2007 [PubMed]
  • Neff CD, Abkevich V, Packer JC, Chen Y, Potter J, Riley R, Davenport C, Degrado Warren J, Jammulapati S, Bhathena A, Choi WS, Kroeger PE, Metzger RE, Gutin A, Skolnick MH, Shattuck D, Katz DA. Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression. Mol Psychiatry 2008 [PubMed]
  • Neumeister A, Wood S, Bonne O, Nugent AC, Luckenbaugh DA, Young T, Bain EE, Charney DS, Drevets WC. Reduced hippocampal volume in unmedicated, remitted patients with major depression versus control subjects. Biol Psychiatry. 2005;57:935–937. [PubMed]
  • Neumeister A, Drevets WC, Belfer I, Luckenbaugh DA, Henry S, Bonne O, Herscovitch P, Goldman D, Charney DS. Effects of a alpha 2C-adrenoreceptor gene polymorphism on neural responses to facial expressions in depression. Neuropsychopharmacology. 2006a;31:1750–1756. [PubMed]
  • Neumeister A, Hu XZ, Luckenbaugh DA, Schwarz M, Nugent AC, Bonne O, Herscovitch P, Goldman D, Drevets WC, Charney DS. Differential effects of 5-HTTLPR genotypes on the behavioral and neural responses to tryptophan depletion in patients with major depression and controls. Arch Gen Psychiatry. 2006b;63:978–986. [PubMed]
  • Neumeister A, Nugent AC, Waldeck T, Geraci M, Schwarz M, Bonne O, Bain EE, Luckenbaugh DA, Herscovitch P, Charney DS, Drevets WC. Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls. Arch Gen Psychiatry. 2004;61:765–773. [PubMed]
  • Nobler MS, Oquendo MA, Kegeles LS, Malone KM, Campbell CC, Sackeim HA, Mann JJ. Decreased regional brain metabolism after ect. Am J Psychiatry. 2001;158:305–308. [PubMed]
  • Norbury R, Mackay CE, Cowen PJ, Goodwin GM, Harmer CJ. Short-term antidepressant treatment and facial processing. Functional magnetic resonance imaging study. Br J Psychiatry. 2007;190:531–532. [PubMed]
  • O’Brien J, Desmond P, Ames D, Schweitzer I, Harrigan S, Tress B. A magnetic resonance imaging study of white matter lesions in depression and Alzheimer’s disease. Br J Psychiatry. 1996;168:477–485. [PubMed]
  • O’Brien JT, Lloyd A, McKeith I, Gholkar A, Ferrier N. A longitudinal study of hippocampal volume, cortisol levels, and cognition in older depressed subjects. Am J Psychiatry. 2004;161:2081–2090. [PubMed]
  • Ongur D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci U S A. 1998;95:13290–13295. [PubMed]
  • Ongur D, Ferry AT, Price JL. Architectonic subdivision of the human orbital and medial prefrontal cortex. J Comp Neurol. 2003;460:425–449. [PubMed]
  • Onishchenko N, Karpova N, Sabri F, Castren E, Ceccatelli S. Long-lasting depression-like behavior and epigenetic changes of BDNF gene expression induced by perinatal exposure to methylmercury. J Neurochem 2008 [PubMed]
  • Osinsky R, Reuter M, Kupper Y, Schmitz A, Kozyra E, Alexander N, Hennig J. Variation in the serotonin transporter gene modulates selective attention to threat. Emotion. 2008;8:584–588. [PubMed]
  • Osuch EA, Ketter TA, Kimbrell TA, George MS, Benson BE, Willis MW, Herscovitch P, Post RM. Regional cerebral metabolism associated with anxiety symptoms in affective disorder patients. Biol Psychiatry. 2000;48:1020–1023. [PubMed]
  • Ovbiagele B, Saver JL. Cerebral white matter hyperintensities on MRI: Current concepts and therapeutic implications. Cerebrovasc Dis. 2006;22:83–90. [PubMed]
  • Pantel J, Schroder J, Essig M, Popp D, Dech H, Knopp MV, Schad LR, Eysenbach K, Backenstrass M, Friedlinger M. Quantitative magnetic resonance imaging in geriatric depression and primary degenerative dementia. J Affect Disord. 1997;42:69–83. [PubMed]
  • Parsey RV, Oquendo MA, Ogden RT, Olvet DM, Simpson N, Huang YY, Van Heertum RL, Arango V, Mann JJ. Altered serotonin 1A binding in major depression: a [carbonyl-C-11]WAY100635 positron emission tomography study. Biol Psychiatry. 2006a;59:106–113. [PubMed]
  • Parsey RV, Hastings RS, Oquendo MA, Huang YY, Simpson N, Arcement J, Huang Y, Ogden RT, Van Heertum RL, Arango V, Mann JJ. Lower serotonin transporter binding potential in the human brain during major depressive episodes. Am J Psychiatry. 2006b;163:52–58. [PubMed]
  • Parsey RV, Hastings RS, Oquendo MA, Hu X, Goldman D, Huang YY, Simpson N, Arcement J, Huang Y, Ogden RT, Van Heertum RL, Arango V, Mann JJ. Effect of a triallelic functional polymorphism of the serotonin-transporter-linked promoter region on expression of serotonin transporter in the human brain. Am J Psychiatry. 2006c;163:48–51. [PubMed]
  • Patel AB, de Graaf RA, Mason GF, Kanamatsu T, Rothman DL, Shulman RG, Behar KL. Glutamatergic neurotransmission and neuronal glucose oxidation are coupled during intense neuronal activation. J Cereb Blood Flow Metab. 2004;24:972–985. [PubMed]
  • Paus T, Tomaiuolo F, Otaky N, MacDonald D, Petrides M, Atlas J, Morris R, Evans AC. Human cingulate and paracingulate sulci: pattern, variability, asymmetry, and probabilistic map. Cereb Cortex. 1996;6:207–214. [PubMed]
  • Perroud N, Courtet P, Vincze I, Jaussent I, Jollant F, Bellivier F, Leboyer M, Baud P, Buresi C, Malafosse A. Interaction between BDNF Val66Met and childhood trauma on adult’s violent suicide attempt. Genes Brain Behav. 2008;7:314–322. [PubMed]
  • Pezawas L, Verchinski BA, Mattay VS, Callicott JH, Kolachana BS, Straub RE, Egan MF, Meyer-Lindenberg A, Weinberger DR. The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci. 2004;24:10099–10102. [PubMed]
  • Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger DR. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci. 2005;8:828–834. [PubMed]
  • Pezawas L, Meyer-Lindenberg A, Goldman AL, Verchinski BA, Chen G, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger DR. Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression. Mol Psychiatry. 2008;13:654, 709–616. [PubMed]
  • Philibert RA, Sandhu H, Hollenbeck N, Gunter T, Adams W, Madan A. The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:543–549. [PMC free article] [PubMed]
  • Philibert RA, Ryu GY, Yoon JG, Sandhu H, Hollenbeck N, Gunter T, Barkhurst A, Adams W, Madan A. Transcriptional profiling of subjects from the Iowa adoption studies. Am J Med Genet B Neuropsychiatr Genet. 2007;144B:683–690. [PubMed]
  • Pizzagalli DA, Oakes TR, Fox AS, Chung MK, Larson CL, Abercrombie HC, Schaefer SM, Benca RM, Davidson RJ. Functional but not structural subgenual prefrontal cortex abnormalities in melancholia. Mol Psychiatry. 2004;9:325, 393–405. [PubMed]
  • Posse S, Fitzgerald D, Gao K, Habel U, Rosenberg D, Moore GJ, Schneider F. Real-time fMRI of temporolimbic regions detects amygdala activation during single-trial self-induced sadness. Neuroimage. 2003;18:760–768. [PubMed]
  • Poulter MO, Du L, Weaver IC, Palkovits M, Faludi G, Merali Z, Szyf M, Anisman H. GABA(A) Receptor Promoter Hypermethylation in Suicide Brain: Implications for the Involvement of Epigenetic Processes. Biol Psychiatry 2008 [PubMed]
  • Praschak-Rieder N, Willeit M, Wilson AA, Houle S, Meyer JH. Seasonal variation in human brain serotonin transporter binding. Arch Gen Psychiatry. 2008;65:1072–1078. [PubMed]
  • Praschak-Rieder N, Kennedy J, Wilson AA, Hussey D, Boovariwala A, Willeit M, Ginovart N, Tharmalingam S, Masellis M, Houle S, Meyer JH. Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [(11)C] DASB positron emission tomography study. Biol Psychiatry. 2007;62:327–331. [PubMed]
  • Radley JJ, Morrison JH. Repeated stress and structural plasticity in the brain. Ageing Res Rev. 2005;4:271–287. [PubMed]
  • Raikkonen K, Pesonen AK, Heinonen K, Kajantie E, Hovi P, Jarvenpaa AL, Eriksson JG, Andersson S. Depression in young adults with very low birth weight: the Helsinki study of very low-birth-weight adults. Arch Gen Psychiatry. 2008;65:290–296. [PubMed]
  • Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY, Overholser JC, Roth BL, Stockmeier CA. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry. 1999;45:1085–1098. [PubMed]
  • Rao H, Gillihan SJ, Wang J, Korczykowski M, Sankoorikal GM, Kaercher KA, Brodkin ES, Detre JA, Farah MJ. Genetic variation in serotonin transporter alters resting brain function in healthy individuals. Biol Psychiatry. 2007;62:600–606. [PubMed]
  • Reichenberg A, Gross R, Weiser M, Bresnahan M, Silverman J, Harlap S, Rabinowitz J, Shulman C, Malaspina D, Lubin G, Knobler HY, Davidson M, Susser E. Advancing paternal age and autism. Arch Gen Psychiatry. 2006;63:1026–1032. [PubMed]
  • Reif A, Rosler M, Freitag CM, Schneider M, Eujen A, Kissling C, Wenzler D, Jacob CP, Retz-Junginger P, Thome J, Lesch KP, Retz W. Nature and nurture predispose to violent behavior: serotonergic genes and adverse childhood environment. Neuropsychopharmacology. 2007;32:2375–2383. [PubMed]
  • Reimold M, Batra A, Knobel A, Smolka MN, Zimmer A, Mann K, Solbach C, Reischl G, Schwarzler F, Grunder G, Machulla HJ, Bares R, Heinz A. Anxiety is associated with reduced central serotonin transporter availability in unmedicated patients with unipolar major depression: a [11C]DASB PET study. Mol Psychiatry. 2008;13:606–613. 557. [PubMed]
  • Reivich M, Amsterdam JD, Brunswick DJ, Shiue CY. PET brain imaging with [11C](+)McN5652 shows increased serotonin transporter availability in major depression. J Affect Disord. 2004;82:321–327. [PubMed]
  • Rocher C, Spedding M, Munoz C, Jay TM. Acute stress-induced changes in hippocampal/prefrontal circuits in rats: effects of antidepressants. Cereb Cortex. 2004;14:224–229. [PubMed]
  • Rusch BD, Abercrombie HC, Oakes TR, Schaefer SM, Davidson RJ. Hippocampal morphometry in depressed patients and control subjects: relations to anxiety symptoms. Biol Psychiatry. 2001;50:960–964. [PubMed]
  • Rydmark I, Wahlberg K, Ghatan PH, Modell S, Nygren A, Ingvar M, Asberg M, Heilig M. Neuroendocrine, cognitive and structural imaging characteristics of women on longterm sickleave with job stress-induced depression. Biol Psychiatry. 2006;60:867–873. [PubMed]
  • Sachdev P, Brodaty H. Quantitative study of signal hyperintensities on T2-weighted magnetic resonance imaging in late-onset schizophrenia. Am J Psychiatry. 1999;156:1958–1967. [PubMed]
  • Salloway S, Malloy P, Kohn R, Gillard E, Duffy J, Rogg J, Tung G, Richardson E, Thomas C, Westlake R. MRI and neuropsychological differences in early- and late-life-onset geriatric depression. Neurology. 1996;46:1567–1574. [PubMed]
  • Sargent PA, Kjaer KH, Bench CJ, Rabiner EA, Messa C, Meyer J, Gunn RN, Grasby PM, Cowen PJ. Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry. 2000;57:174–180. [PubMed]
  • Sassi RB, Brambilla P, Nicoletti M, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC. White matter hyperintensities in bipolar and unipolar patients with relatively mild-to-moderate illness severity. J Affect Disord. 2003;77:237–245. [PubMed]
  • Savitz J, Drevets WC. Bipolar and Major Depressive Disorder: Neuroimaging the Developmental-Degenerative Divide. Neuroscience and Biobehavioral Reviews. 2009 In Press. [PMC free article] [PubMed]
  • Savitz J, Lucki I, Drevets WC. 5-HT1A receptor function in major depressive disorder. Progress in Neurobiology. 2009 In press. [PMC free article] [PubMed]
  • Savitz J, van der Merwe L, Stein DJ, Solms M, Ramesar R. Genotype and childhood sexual trauma moderate neurocognitive performance: a possible role for brain-derived neurotrophic factor and apolipoprotein E variants. Biol Psychiatry. 2007;62:391–399. [PubMed]
  • Savitz JB, Ramesar RS. Genetic variants implicated in personality: a review of the more promising candidates. Am J Med Genet B Neuropsychiatr Genet. 2004;131:20–32. [PubMed]
  • Savitz JB, van der Merwe L, Newman TK, Solms M, Stein DJ, Ramesar RS. The relationship between childhood abuse and dissociation. Is it influenced by catechol-O-methyltransferase (COMT) activity? Int J Neuropsychopharmacol. 2008;11:149–161. [PubMed]
  • Schiepers OJ, Wichers MC, Maes M. Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:201–217. [PubMed]
  • Schmidt LA, Miskovic V, Boyle MH, Saigal S. Shyness and timidity in young adults who were born at extremely low birth weight. Pediatrics. 2008;122:e181–187. [PubMed]
  • Schneider F, Grodd W, Weiss U, Klose U, Mayer KR, Nagele T, Gur RC. Functional MRI reveals left amygdala activation during emotion. Psychiatry Res. 1997;76:75–82. [PubMed]
  • Schwartz CE, Wright CI, Shin LM, Kagan J, Rauch SL. Inhibited and uninhibited infants “grown up”: adult amygdalar response to novelty. Science. 2003;300:1952–1953. [PubMed]
  • Seng KC, Seng CK. The success of the genome-wide association approach: a brief story of a long struggle. Eur J Hum Genet. 2008;16:554–564. [PubMed]
  • Sequeira A, Gwadry FG, Ffrench-Mullen JM, Canetti L, Gingras Y, Casero RA, Jr, Rouleau G, Benkelfat C, Turecki G. Implication of SSAT by gene expression and genetic variation in suicide and major depression. Arch Gen Psychiatry. 2006;63:35–48. [PubMed]
  • Sharp T, Boothman L, Raley J, Queree P. Important messages in the ‘post’: recent discoveries in 5-HT neurone feedback control. Trends Pharmacol Sci. 2007;28:629–636. [PubMed]
  • Sheline YI. Hippocampal atrophy in major depression: a result of depression-induced neurotoxicity? Mol Psychiatry. 1996;1:298–299. [PubMed]
  • Sheline YI, Gado MH, Price JL. Amygdala core nuclei volumes are decreased in recurrent major depression. Neuroreport. 1998;9:2023–2028. [PubMed]
  • Sheline YI, Sanghavi M, Mintun MA, Gado MH. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci. 1999;19:5034–5043. [PubMed]
  • Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A. 1996;93:3908–3913. [PubMed]
  • Sheline YI, Barch DM, Donnelly JM, Ollinger JM, Snyder AZ, Mintun MA. Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biol Psychiatry. 2001;50:651–658. [PubMed]
  • Sheline YI, Price JL, Vaishnavi SN, Mintun MA, Barch DM, Epstein AA, Wilkins CH, Snyder AZ, Couture L, Schechtman K, McKinstry RC. Regional white matter hyperintensity burden in automated segmentation distinguishes late-life depressed subjects from comparison subjects matched for vascular risk factors. Am J Psychiatry. 2008;165:524–532. [PMC free article] [PubMed]
  • Shifman S, Johannesson M, Bronstein M, Chen SX, Collier DA, Craddock NJ, Kendler KS, Li T, O’Donovan M, O’Neill FA, Owen MJ, Walsh D, Weinberger DR, Sun C, Flint J, Darvasi A. Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. PLoS Genet. 2008a;4:e28. [PubMed]
  • Shifman S, Bhomra A, Smiley S, Wray NR, James MR, Martin NG, Hettema JM, An SS, Neale MC, van den Oord EJ, Kendler KS, Chen X, Boomsma DI, Middeldorp CM, Hottenga JJ, Slagboom PE, Flint J. A whole genome association study of neuroticism using DNA pooling. Mol Psychiatry. 2008b;13:302–312. [PMC free article] [PubMed]
  • Shively CA, Friedman DP, Gage HD, Bounds MC, Brown-Proctor C, Blair JB, Henderson JA, Smith MA, Buchheimer N. Behavioral depression and positron emission tomography-determined serotonin 1A receptor binding potential in cynomolgus monkeys. Arch Gen Psychiatry. 2006;63:396–403. [PubMed]
  • Shulman RG, Rothman DL, Behar KL, Hyder F. Energetic basis of brain activity: implications for neuroimaging. Trends Neurosci. 2004;27:489–495. [PubMed]
  • Siegle GJ, Steinhauer SR, Thase ME, Stenger VA, Carter CS. Can’t shake that feeling: event-related fMRI assessment of sustained amygdala activity in response to emotional information in depressed individuals. Biol Psychiatry. 2002;51:693–707. [PubMed]
  • Siegle GJ, Thompson W, Carter CS, Steinhauer SR, Thase ME. Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features. Biol Psychiatry. 2007;61:198–209. [PubMed]
  • Sklar P, Smoller JW, Fan J, Ferreira MA, Perlis RH, Chambert K, Nimgaonkar VL, McQueen MB, Faraone SV, Kirby A, de Bakker PI, Ogdie MN, Thase ME, Sachs GS, Todd-Brown K, Gabriel SB, Sougnez C, Gates C, Blumenstiel B, Defelice M, Ardlie KG, Franklin J, Muir WJ, McGhee KA, MacIntyre DJ, McLean A, VanBeck M, McQuillin A, Bass NJ, Robinson M, Lawrence J, Anjorin A, Curtis D, Scolnick EM, Daly MJ, Blackwood DH, Gurling HM, Purcell SM. Whole-genome association study of bipolar disorder. Mol Psychiatry. 2008;13:558–569. [PMC free article] [PubMed]
  • Smith DJ, Harrison N, Muir W, Blackwood DH. The high prevalence of bipolar spectrum disorders in young adults with recurrent depression: toward an innovative diagnostic framework. J Affect Disord. 2005;84:167–178. [PubMed]
  • Smolka MN, Schumann G, Wrase J, Grusser SM, Flor H, Mann K, Braus DF, Goldman D, Buchel C, Heinz A. Catechol-O-methyltransferase val158met genotype affects processing of emotional stimuli in the amygdala and prefrontal cortex. J Neurosci. 2005;25:836–842. [PubMed]
  • Smolka MN, Buhler M, Schumann G, Klein S, Hu XZ, Moayer M, Zimmer A, Wrase J, Flor H, Mann K, Braus DF, Goldman D, Heinz A. Gene-gene effects on central processing of aversive stimuli. Mol Psychiatry. 2007;12:307–317. [PubMed]
  • Smoller JW, Paulus MP, Fagerness JA, Purcell S, Yamaki LH, Hirshfeld-Becker D, Biederman J, Rosenbaum JF, Gelernter J, Stein MB. Influence of RGS2 on anxiety-related temperament, personality, and brain function. Arch Gen Psychiatry. 2008;65:298–308. [PubMed]
  • Sneed JR, Rindskopf D, Steffens DC, Krishnan KR, Roose SP. The vascular depression subtype: evidence of internal validity. Biol Psychiatry. 2008;64:491–497. [PMC free article] [PubMed]
  • Sokolov BP. Oligodendroglial abnormalities in schizophrenia, mood disorders and substance abuse. Comorbidity, shared traits, or molecular phenocopies? Int J Neuropsychopharmacol. 2007;1–9 [PubMed]
  • Steen RG, Mull C, McClure R, Hamer RM, Lieberman JA. Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies. Br J Psychiatry. 2006;188:510–518. [PubMed]
  • Steffens DC, Byrum CE, McQuoid DR, Greenberg DL, Payne ME, Blitchington TF, MacFall JR, Krishnan KR. Hippocampal volume in geriatric depression. Biol Psychiatry. 2000;48:301–309. [PubMed]
  • Stein MB, Schork NJ, Gelernter J. Gene-by-environment (serotonin transporter and childhood maltreatment) interaction for anxiety sensitivity, an intermediate phenotype for anxiety disorders. Neuropsychopharmacology. 2008;33:312–319. [PubMed]
  • Stein MB, Simmons AN, Feinstein JS, Paulus MP. Increased amygdala and insula activation during emotion processing in anxiety-prone subjects. Am J Psychiatry. 2007;164:318–327. [PubMed]
  • Stewart CA, Reid IC. Repeated ECS and fluoxetine administration have equivalent effects on hippocampal synaptic plasticity. Psychopharmacology (Berl) 2000;148:217–223. [PubMed]
  • Stewart WF, Schwartz BS, Davatzikos C, Shen D, Liu D, Wu X, Todd AC, Shi W, Bassett S, Youssem D. Past adult lead exposure is linked to neurodegeneration measured by brain MRI. Neurology. 2006;66:1476–1484. [PubMed]
  • Stockmeier CA, Shapiro LA, Dilley GE, Kolli TN, Friedman L, Rajkowska G. Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression-postmortem evidence for decreased serotonin activity. J Neurosci. 1998;18:7394–7401. [PubMed]
  • Stockmeier CA, Mahajan GJ, Konick LC, Overholser JC, Jurjus GJ, Meltzer HY, Uylings HB, Friedman L, Rajkowska G. Cellular changes in the postmortem hippocampus in major depression. Biol Psychiatry. 2004;56:640–650. [PMC free article] [PubMed]
  • Surguladze SA, Elkin A, Ecker C, Kalidindi S, Corsico A, Giampietro V, Lawrence N, Deeley Q, Murphy DG, Kucharska-Pietura K, Russell TA, McGuffin P, Murray R, Phillips ML. Genetic variation in the serotonin transporter modulates neural system-wide response to fearful faces. Genes Brain Behav 2008 [PubMed]
  • Swanson LW, Petrovich GD. What is the amygdala? Trends Neurosci. 1998;21:323–331. [PubMed]
  • Szeszko PR, Lipsky R, Mentschel C, Robinson D, Gunduz-Bruce H, Sevy S, Ashtari M, Napolitano B, Bilder RM, Kane JM, Goldman D, Malhotra AK. Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation. Mol Psychiatry. 2005;10:631–636. [PubMed]
  • Takahashi T, Suzuki M, Tsunoda M, Kawamura Y, Takahashi N, Tsuneki H, Kawasaki Y, Zhou SY, Kobayashi S, Sasaoka T, Seto H, Kurachi M, Ozaki N. Association between the brain-derived neurotrophic factor Val66Met polymorphism and brain morphology in a Japanese sample of schizophrenia and healthy comparisons. Neurosci Lett. 2008;435:34–39. [PubMed]
  • Takano A, Arakawa R, Hayashi M, Takahashi H, Ito H, Suhara T. Relationship between neuroticism personality trait and serotonin transporter binding. Biol Psychiatry. 2007;62:588–592. [PubMed]
  • Tang Y, Wang F, Xie G, Liu J, Li L, Su L, Liu Y, Hu X, He Z, Blumberg HP. Reduced ventral anterior cingulate and amygdala volumes in medication-naive females with major depressive disorder: A voxel-based morphometric magnetic resonance imaging study. Psychiatry Res. 2007;156:83–86. [PubMed]
  • Taylor WD, Steffens DC, Payne ME, MacFall JR, Marchuk DA, Svenson IK, Krishnan KR. Influence of serotonin transporter promoter region polymorphisms on hippocampal volumes in late-life depression. Arch Gen Psychiatry. 2005a;62:537–544. [PubMed]
  • Taylor WD, MacFall JR, Payne ME, McQuoid DR, Steffens DC, Provenzale JM, Krishnan RR. Greater MRI lesion volumes in elderly depressed subjects than in control subjects. Psychiatry Res. 2005b;139:1–7. [PubMed]
  • Tebartz van Elst L, Hesslinger B, Thiel T, Geiger E, Haegele K, Lemieux L, Lieb K, Bohus M, Hennig J, Ebert D. Frontolimbic brain abnormalities in patients with borderline personality disorder: a volumetric magnetic resonance imaging study. Biol Psychiatry. 2003;54:163–171. [PubMed]
  • Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci. 2006;9:519–525. [PubMed]
  • Tupler LA, Krishnan KR, McDonald WM, Dombeck CB, D’Souza S, Steffens DC. Anatomic location and laterality of MRI signal hyperintensities in late-life depression. J Psychosom Res. 2002;53:665–676. [PubMed]
  • Vaccarino V, Brennan ML, Miller AH, Bremner JD, Ritchie JC, Lindau F, Veledar E, Su S, Murrah NV, Jones L, Jawed F, Dai J, Goldberg J, Hazen SL. Association of Major Depressive Disorder with Serum Myeloperoxidase and Other Markers of Inflammation: A Twin Study. Biol Psychiatry 2008 [PMC free article] [PubMed]
  • Vakili K, Pillay SS, Lafer B, Fava M, Renshaw PF, Bonello-Cintron CM, Yurgelun-Todd DA. Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study. Biol Psychiatry. 2000;47:1087–1090. [PubMed]
  • van der Veen FM, Evers EA, Deutz NE, Schmitt JA. Effects of acute tryptophan depletion on mood and facial emotion perception related brain activation and performance in healthy women with and without a family history of depression. Neuropsychopharmacology. 2007;32:216–224. [PubMed]
  • Verhagen M, van der Meij A, Franke B, Vollebergh WA, de Graaf R, Buitelaar JK, Janzing JG. Familiality of major depressive disorder and patterns of lifetime comorbidity. The NEMESIS and GenMood studies : A comparison of three samples. Eur Arch Psychiatry Clin Neurosci 2008 [PubMed]
  • Vollmayr B, Keck S, Henn FA, Schloss P. Acute stress decreases serotonin transporter mRNA in the raphe pontis but not in other raphe nuclei of the rat. Neurosci Lett. 2000;290:109–112. [PubMed]
  • von Gunten A, Fox NC, Cipolotti L, Ron MA. A volumetric study of hippocampus and amygdala in depressed patients with subjective memory problems. J Neuropsychiatry Clin Neurosci. 2000;12:493–498. [PubMed]
  • Vyas A, Pillai AG, Chattarji S. Recovery after chronic stress fails to reverse amygdaloid neuronal hypertrophy and enhanced anxiety-like behavior. Neuroscience. 2004;128:667–673. [PubMed]
  • Vyas A, Jadhav S, Chattarji S. Prolonged behavioral stress enhances synaptic connectivity in the basolateral amygdala. Neuroscience. 2006;143:387–393. [PubMed]
  • Vyas A, Mitra R, Shankaranarayana Rao BS, Chattarji S. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci. 2002;22:6810–6818. [PubMed]
  • Vythilingam M, Heim C, Newport J, Miller AH, Anderson E, Bronen R, Brummer M, Staib L, Vermetten E, Charney DS, Nemeroff CB, Bremner JD. Childhood trauma associated with smaller hippocampal volume in women with major depression. Am J Psychiatry. 2002;159:2072–2080. [PMC free article] [PubMed]
  • Wang L, LaBar KS, McCarthy G. Mood alters amygdala activation to sad distractors during an attentional task. Biol Psychiatry. 2006;60:1139–1146. [PubMed]
  • Watanabe A, Tohyama Y, Nguyen KQ, Hasegawa S, Debonnel G, Diksic M. Regional brain serotonin synthesis is increased in the olfactory bulbectomy rat model of depression: an autoradiographic study. J Neurochem. 2003;85:469–475. [PubMed]
  • Watkins PC, Mathews A, Williamson DA, Fuller RD. Mood-congruent memory in depression: emotional priming or elaboration? J Abnorm Psychol. 1992;101:581–586. [PubMed]
  • Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, Saemundsen E, Stefansson H, Ferreira MA, Green T, Platt OS, Ruderfer DM, Walsh CA, Altshuler D, Chakravarti A, Tanzi RE, Stefansson K, Santangelo SL, Gusella JF, Sklar P, Wu BL, Daly MJ. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med. 2008;358:667–675. [PubMed]
  • Wellcome-Trust-Case-Control-Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–678. [PMC free article] [PubMed]
  • Whitaker-Azmitia PM, Druse M, Walker P, Lauder JM. Serotonin as a developmental signal. Behav Brain Res. 1996;73:19–29. [PubMed]
  • Willeit M, Sitte HH, Thierry N, Michalek K, Praschak-Rieder N, Zill P, Winkler D, Brannath W, Fischer MB, Bondy B, Kasper S, Singer EA. Enhanced serotonin transporter function during depression in seasonal affective disorder. Neuropsychopharmacology. 2008;33:1503–1513. [PubMed]
  • Williams JH, Ross L. Consequences of prenatal toxin exposure for mental health in children and adolescents: a systematic review. Eur Child Adolesc Psychiatry. 2007;16:243–253. [PubMed]
  • Wong ML, Dong C, Maestre-Mesa J, Licinio J. Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response. Mol Psychiatry 2008 [PMC free article] [PubMed]
  • Wong V. Occipital deep white matter hyperintensities in autism spectrum disorder. Pediatr Int. 2007;49:513–515. [PubMed]
  • Wu J, Buchsbaum MS, Gillin JC, Tang C, Cadwell S, Wiegand M, Najafi A, Klein E, Hazen K, Bunney WE, Jr, Fallon JH, Keator D. Prediction of antidepressant effects of sleep deprivation by metabolic rates in the ventral anterior cingulate and medial prefrontal cortex. Am J Psychiatry. 1999;156:1149–1158. [PubMed]
  • Xu B, Roos JL, Levy S, van Rensburg EJ, Gogos JA, Karayiorgou M. Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet. 2008;40:880–885. [PubMed]
  • Xu Y, Ku B, Tie L, Yao H, Jiang W, Ma X, Li X. Curcumin reverses the effects of chronic stress on behavior, the HPA axis, BDNF expression and phosphorylation of CREB. Brain Res. 2006;1122:56–64. [PubMed]
  • Yang TT, Simmons AN, Matthews SC, Tapert SF, Frank GK, Bischoff-Grethe A, Lansing AE, Wu J, Brown GG, Paulus MP. Depressed adolescents demonstrate greater subgenual anterior cingulate activity. Neuroreport. 2009;20:440–444. [PMC free article] [PubMed]
  • Yucel K, McKinnon MC, Chahal R, Taylor VH, Macdonald K, Joffe R, MacQueen GM. Anterior cingulate volumes in never-treated patients with major depressive disorder. Neuropsychopharmacology. 2008;33:3157–3163. [PubMed]
  • Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, de Bakker PI, Abecasis GR, Almgren P, Andersen G, Ardlie K, Bostrom KB, Bergman RN, Bonnycastle LL, Borch-Johnsen K, Burtt NP, Chen H, Chines PS, Daly MJ, Deodhar P, Ding CJ, Doney AS, Duren WL, Elliott KS, Erdos MR, Frayling TM, Freathy RM, Gianniny L, Grallert H, Grarup N, Groves CJ, Guiducci C, Hansen T, Herder C, Hitman GA, Hughes TE, Isomaa B, Jackson AU, Jorgensen T, Kong A, Kubalanza K, Kuruvilla FG, Kuusisto J, Langenberg C, Lango H, Lauritzen T, Li Y, Lindgren CM, Lyssenko V, Marvelle AF, Meisinger C, Midthjell K, Mohlke KL, Morken MA, Morris AD, Narisu N, Nilsson P, Owen KR, Palmer CN, Payne F, Perry JR, Pettersen E, Platou C, Prokopenko I, Qi L, Qin L, Rayner NW, Rees M, Roix JJ, Sandbaek A, Shields B, Sjogren M, Steinthorsdottir V, Stringham HM, Swift AJ, Thorleifsson G, Thorsteinsdottir U, Timpson NJ, Tuomi T, Tuomilehto J, Walker M, Watanabe RM, Weedon MN, Willer CJ, Illig T, Hveem K, Hu FB, Laakso M, Stefansson K, Pedersen O, Wareham NJ, Barroso I, Hattersley AT, Collins FS, Groop L, McCarthy MI, Boehnke M, Altshuler D. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet. 2008;40:638–645. [PMC free article] [PubMed]
  • Zhou D, Grecksch G, Becker A, Frank C, Pilz J, Huether G. Serotonergic hyperinnervation of the frontal cortex in an animal model of depression, the bulbectomized rat. J Neurosci Res. 1998;54:109–116. [PubMed]
  • Zill PBT, Zwanzger P, Schule C, Minov C, Behrens S, Rupprecht R, Bondy B. Association study of a common polymorphism in the human 5HT1A receptor gene in major depression. Pharmacopsychiatry. 2001;34:238. [PubMed]
  • Zobel A, Jessen F, von Widdern O, Schuhmacher A, Hofels S, Metten M, Rietschel M, Scheef L, Block W, Becker T, Schild HH, Maier W, Schwab SG. Unipolar depression and hippocampal volume: Impact of DNA sequence variants of the glucocorticoid receptor gene. Am J Med Genet B Neuropsychiatr Genet 2008 [PubMed]
  • Zubenko GS, Sullivan P, Nelson JP, Belle SH, Huff FJ, Wolf GL. Brain imaging abnormalities in mental disorders of late life. Arch Neurol. 1990;47:1107–1111. [PubMed]
  • Zubenko GS, Hughes HB, 3rd, Maher BS, Stiffler JS, Zubenko WN, Marazita ML. Genetic linkage of region containing the CREB1 gene to depressive disorders in women from families with recurrent, early-onset, major depression. Am J Med Genet. 2002;114:980–987. [PubMed]