Translational Research in Late-Life Mood Disorders:
Implications for Future Intervention and Prevention Research
Gwenn S Smith*,1,2, Faith M Gunning-Dixon3, Francis E Lotrich4, Warren D Taylor5and Jovier D Evans6
1PET Centre, Centre for Addiction and Mental Health, Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON,
Canada;2Department of Psychiatry Research, the Zucker Hillside Hospital, Glen Oaks, NY, USA;3Department of Psychiatry, Weil Medical
College of Cornell University, White Plains, NY, USA;4Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh
School of Medicine, Pittsburgh, PA, USA;5Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC,
USA;6Geriatrics Translational Neuroscience and Psychopharmacologic Intervention Programs, Geriatrics Research Branch, National Institute of
Mental Health, Bethesda, MD, USA
Clinical and epidemiological studies have consistently observed the heterogeneous symptomatology and course of geriatric depression.
Given the importance of genetic and environmental risk factors, aging processes, neurodegenerative and cerebrovascular disease
processes, and medical comorbidity, the integration of basic and clinical neuroscience research approaches is critical for the
understanding of the variability in illness course, as well as the development of prevention and intervention strategies that are more
effective. These considerations were the impetus for a workshop, sponsored by the Geriatrics Research Branch in the Division of Adult
Translational Research and Treatment Development of the National Institute of Mental Health that was held on September 7–8, 2005.
The primary goal of the workshop was to bring together investigators in geriatric psychiatry research with researchers in specific topic
areas outside of geriatric mental health to identify priority areas to advance translational research in geriatric depression. As described in
this report, the workshop focused on a discussion of the development and application of integrative approaches combining genetics and
neuroimaging methods to understand such complex issues as treatment response variability, the role of medical comorbidity in
depression, and the potential overlap between depression and dementia. Future directions for integrative research were identified.
Understanding the nature of geriatric depression requires the application of translational research and interdisciplinary research
approaches. Geriatric depression could serve as a model for translational research integrating basic and clinical neuroscience approaches
that would have implications for the study of other neuropsychiatric disorders.
Neuropsychopharmacology (2007) 32, 1857–1875; doi:10.1038/sj.npp.1301333; published online 28 February 2007
Keywords: geriatric depression; genetics; magnetic resonance imaging; positron emission tomography (PET); neuropsychology;
In the recent commentary entitled ‘Psychiatry as a Clinical
Neuroscience Discipline’, Insel and Quirion, 2005 discuss
the importance of ‘applying the revolutionary insights from
neuroscience to the care of those with brain disorders.’ In
understanding the neurobiology of geriatric depression and
developing more effective prevention and intervention
strategies, the integration of basic and clinical neuroscience
research is critical. Geriatric depression is characterized by
substantial variability in treatment response and long-term
illness course, as well as heterogeneity in the extent of
cognitive dysfunction and structural and functional brain
alterations (as reviewed by Lebowitz et al, 1997). The
importance of understanding the neurobiology of geriatric
depression is underscored by the association between
depression in late-life and functional disability, the
increased rate of completed suicide in older depressed
patients, greater mortality associated with depression in the
medically ill, and the increased risk for the development of
Alzheimer’s Disease (AD) as suggested by the epidemio-
logical literature (Alexopoulos et al, 1996a,b; Henriksson
et al, 1995; Conwell et al, 1996; Bruce and Leaf, 1989; Arfken
et al, 1999; Jorm et al, 1991; Meyers and Bruce, 1998).
Factors related to aging processes, medical comorbidity,
cerebrovascular, and neurodegenerative disease must be
considered in understanding the variability observed.
These considerations were the impetus for a workshop,
sponsored by the Geriatrics Research Branch in the Division
Received 21 August 2006; revised 11 December 2006; accepted 18
*Correspondence: Dr GS Smith, PET Centre, Centre for Addiction
and Mental Health, Department of Psychiatry, Faculty of Medicine,
University of Toronto, 250 College Street, Toronto, ON, Canada M5T
1R8, Tel: +416 535 8501 X7379, Fax: +416 979-4656,
Neuropsychopharmacology (2007) 32, 1857–1875
& 2007 Nature Publishing Group All rights reserved 0893-133X/07 $30.00
of Adult Translational Research and Treatment Develop-
ment of the National Institute of Mental Health (NIMH) that
was held on September 7–8, 2005. The primary goal of the
workshop was to bring together investigators in geriatric
psychiatry research with researchers in specific topic areas
outside of geriatric mental health to advance translational
research in geriatric depression. Investigators in the fields
of genetics, neuroimaging, psychopharmacology, neuropsy-
chology, and neuropathology presented their research. The
discussion focused on integrating research findings across
disciplines and identifying future directions for research.
The workshop was also designed to encourage dialogue
between basic and clinical researchers and to broaden
crosstalk among junior, mid-career, and senior investiga-
tors. The workshop focused on developing and applying
integrative approaches to understand such complex issues
as treatment response variability, the role of medical
comorbidity in depression, and the depression-dementia
continuum. The meeting concluded with a discussion of the
role of genetics and neuroimaging research approaches in
the drug discovery and drug development process. It is
important to note that the meeting focused on the study of
unipolar major depressive disorder in the elderly, including
both recurrent depression with an onset throughout the
lifespan, as well as late onset depression. The meeting did
not focus on the important areas of psychotic depression or
bipolar disorders in the elderly that are currently the focus
of large-scale, multi-center trials (eg, Meyers et al, 2005;
Young et al, 2004), nor late-life anxiety disorders, which are
extremely common in the elderly and represent challenges
in clinical management (Flint, 1994, 1998). The following
sections will focus on a summary of the status of research in
genetics, structural, functional, and neurochemical imaging
relevant to geriatric depression. The decision to focus on
genetics and neuroimaging for the purposes of this report is
that these methods best represent the interface between
clinical and basic neuroscience research. Future directions
for research were discussed and will be outlined at the end
of the report.
THE NEUROBIOLOGY OF GERIATRIC DEPRESSION
Neuropsychological, neuroimaging, and neuropathological
studies in geriatric depression have revealed deficits
consistent with the normal aging process, cerebrovascular,
and neurodegenerative disease processes. The integration of
these data have led to the development of multifactorial
models of pathophysiology (eg, Kumar et al, 2000;
Alexopoulos, 2005). This section will summarize the status
of research on the clinical course of geriatric depression,
profiles of cognitive impairment, and neuropathological
studies to provide a basis for the following discussion of
neuroimaging and genetics research.
Studies characterizing the clinical course and outcomes of
antidepressant treatment in geriatric depression have
observed greater variability in response, increased rate of
relapse, and a significant impact of age at onset, stress, and
anxiety symptoms on treatment response (Reynolds et al,
1996, 1998, 1999; Dew et al, 1997; Mazure et al, 2002; Lenze
et al, 2000; Flint and Rifat, 1999). Significant variability in
the trajectories of acute and long-term treatment response
have been observed, in addition to the observation of
significant numbers of patients who are treatment resistant
(about 25% across studies; Dew et al, 1997; Little et al,
1998). It is noteworthy that geriatric patients respond as
well if not better than younger patients do to electro-
convulsive therapy (ECT; Tew et al, 1999; O’Connor et al,
2001). The neurobiological substrates of the differences in
treatment trajectories are not well understood and are
beginning to be investigated by serial cognitive and
neuroimaging studies performed during the course of
treatment (Nebes et al, 2003; Smith et al, 2002a,c). Clinical
and epidemiological studies have identified some of the
psychosocial and medical factors associated with depres-
sion, vulnerability, and prevention strategies have been
evaluated in some instances (eg, bereavement, post-stroke
depression, and interferon induced depression; Shear et al,
2005; Narushima et al, 2002; Whyte et al, 2004, Musselman
et al, 2001). Although the choice of therapeutic agents for
these prevention studies have focused on standard phar-
macological and psychosocial interventions, emerging
neurobiological data will potentially inform the develop-
ment of novel therapeutic strategies. These strategies will be
more focused on specific aspects of symptoms and cognitive
deficits that are less responsive to standard pharmaco-
Several domains of cognitive impairment have been
reported in geriatric depression. As will be reviewed in
subsequent sections, the cognitive deficits observed in
geriatric depression using standard neuropsychological
tests have informed the design of neuroimaging studies to
visualize changes in functional neural circuitry associated
with these deficits. These neuroimaging studies have used
validated cognitive neuroscience approaches that are based
on specific cognitive constructs. The most consistent
cognitive deficits observed in depressed patients who do
not meet criteria for early AD or other dementias, are
slowed speed of processing, deficits in executive function,
and memory (Kramer-Ginsberg et al, 1999; Lockwood et al,
2000, 2002; Nebes et al, 2003; Butters et al, 2000, 2004;
O’Brien et al, 2004). A major focus of neuropsychological
study in geriatric depression has been executive dysfunc-
tion, given the reproducibility of findings and the observa-
tion that executive function deficits often persist, despite
remission of mood symptoms (Alexopoulos et al, 2002;
Elderkin-Thompson et al, 2003; Lockwood et al, 2002;
Nebes et al, 2001; Butters et al, 2000; Nebes et al, 2003).
Executive dysfunction and/or slowed processing speed, both
putative indices of fronto-striatal dysfunction, mediate
other cognitive weaknesses in geriatric depression including
poor visual spatial skills, and episodic memory (Butters
et al, 2004; Elderkin-Thompson et al, 2004). It has been
suggested that measures of executive function, compared to
other cognitive domains, may have good prognostic value
regarding response to treatment, whereas measures of
global cognitive function and memory may identify patients
‘at risk’ for dementia (Lockwood et al, 2000).
Neuropathological studies are extremely important to
understanding the pathophysiology of geriatric depression,
interpreting the findings from clinical and neuroimaging
studies and identifying new areas of in vivo mechanistic
studies and therapeutic targets. The initial, preliminary
neuropathological studies of patients with geriatric depres-
Translational research in late-life mood disorders
GS Smith et al
sion that have been clinically well characterized before
death have been published (Sweet et al, 2004; Rajkowska
et al, 2005). In a sample of patients, many of whom (70%)
demonstrated cognitive deficits before death, evidence of
cerebrovascular alterations, neurofibrillary tangles, amyloid
plaques, and diffuse lewy bodies was observed (Sweet et al,
2004). To follow-up on reports of decreased orbitofrontal
cortex volume identified on magnetic resonance scans
(Lee et al, 2003), Rajkowska et al (2005) demonstrated a
decreased packing density of pyramidal neurons and
reductions to a greater extent in cortical layers IIIc and V,
the source of prefrontal-striatal, prefrontal-cortical, and
prefrontal-amygdala projections. These neuropathological
studies have provided support for the observations of
cerebrovascular and neurodegenerative pathology as ob-
served with neuroimaging methods. The neuropathology of
major depression with respect to neurochemical abnorm-
alities has been reviewed extensively (Arango et al, 2002;
Schatzberg et al, 2002). The majority of these studies have
been performed in younger patients and the extension of
these observations into older patients represents an
important area of investigation. Future studies of the
neuropathology of late-life depression will extend the
observations made by these initial studies (Sweet et al,
2004; Rajkowska et al, 2005) to larger sample sizes and
further integrate the post-mortem findings with clinical and
The application of an interdisciplinary research approach is
critical to understanding of such issues in geriatric
depression as treatment response variability, the increased
morbidity, and mortality associated with depression in late-
life and the role of depression as a possible risk factor for
dementia. Future mechanistic research in geriatric depres-
sion is influenced by methodological developments in
genetics, affective, and cognitive neuroscience and neuroi-
maging, by the ability to integrate information across
different research modalities and by using the information
obtained to generate new hypotheses and therapeutic
strategies. The following sections will summarize the
existing literature in structural, functional, and neurochem-
ical brain imaging and genetics, as well as the integration of
these approaches. Future
research studies will be described. It is important to note
that in some areas, the data reviewed will focus on studies in
geriatric depression. In other areas, in which limited data in
older subjects is available, the discussion will include the
identification of methodological issues relevant to the study
of geriatric patients and the identification of directions for
research based on data obtained in younger depressed
directions for translational
Converging evidence from clinical, neuroimaging, and
neuropathological studies suggest that biological suscept-
ibility to geriatric mood disorders is likely mediated by
compromise in fronto-striatal-limbic functions with con-
tributions from genetic, vascular, neurochemical, neuro-
degenerative, and other aging-related factors. Structural and
neurochemical imaging methods, in addition to neuroima-
ging studies using cognitive and affective neuroscience
approaches can be used to investigate the relationship
among potential contributing factors to neural network
abnormalities, and relate these findings to the clinical
features and course of geriatric mood disorders. The
following sections will provide a review of the literature
concerning the application of structural, functional, and
neurochemical imaging methods, comments regarding the
findings in these three areas and the identification of future
research directions for geriatric depression.
Structural brain imaging.
Introduction: Structural magnetic resonance (MR) ima-
ging studies of geriatric depression have emphasized two
lines of research: the evaluation of gray matter volumes and
cortical and subcortical gray and white matter hyperinten-
sities (Krishnan, 2002; Alexopoulos, 2005). Structural
alterations have been observed in many components of
the cortico-striatal limbic networks implicated in depres-
sion that have been described in the literature (eg, Mayberg,
2003; Adler et al, 2006).
The consistency of such findings as white matter
hyperintensities and hyperintense areas in subcortical gray
matter structures has drawn attention to the role of
cerebrovascular disease in geriatric depression (Greenwald
et al, 1996, 1998; Krishnan et al, 1997; Taylor et al, 2005a).
These observations have led to the ‘vascular depression
hypothesis’ (Krishnan et al, 1997; Alexopoulos et al,
1997a,b). This hypothesis is supported by the observations
that there is a high rate of depression in patients with
hypertension, diabetes, and coronary artery disease. There
is also a high rate of depression in patients who have had
strokes and/or silent strokes. White matter hyperintensities
frequently occur in late onset depression. Vascular features
in geriatric depressed patients are associated with greater
overall cognitive impairment, greater impairments in word
fluency, and naming, more psychomotor retardation, less
agitation, less guilt feelings and greater lack of insight.
These symptoms were observed to be similar to a
frontal lobe syndrome that would result from disruption
of cortico-striato-pallido-thalamo-cortico pathways (Alex-
opoulos et al, 1997a).
Summary of the literature: The primary volumetric
findings in geriatric depression compared to comparison
subjects include decreased gray matter volumes in pre-
frontal, anterior cingulate, and orbitofrontal cortex hippo-
campus, amygdala, and basal ganglia (O’Brien et al, 2004;
Ballmaier et al, 2004; Bremner et al, 2002; Lai et al, 2000; Lee
et al, 2003; Ballmaier et al, 2004; Krishnan, 1993; Kumar
et al, 1998; Sheline et al, 1996, 1998, 1999; Ashtari et al,
1999). With respect to clinical correlates of these findings,
the primary observations are the association between
reduced hippocampal volume and later age-of-depression
onset (Steffens et al, 2000, 2002), vascular risk factors, such
as coronary artery disease (Koschack and Irle, 2005), and
repeated episodes of depression (Bell-McGinty et al, 2002;
Butters et al, 2000; Sheline et al, 1996, 1999, 2003) and
greater degree of atrophic changes associated with poorer
Translational research in late-life mood disorders
GS Smith et al
treatment outcome (Pillay et al, 1998; Young et al, 1999).
It has been suggested that antidepressant treatment may
reverse some of these volume reductions (Jacobs et al, 2000;
Vythilingam et al, 2004).
Gray and white matter hyperintensities, particularly in the
deep gray matter, in geriatric depressed patients have been
associated with poorer performance compared to depressed
patients without such lesions or normal elderly subjects
with or without deep white matter changes in multiple
domains of cognition including general and delayed recall
memory measures (Wechsler Memory Scale-general mem-
ory index, delayed recall index), executive functioning
(animal naming test), and language testing (Boston Naming
Test) (Lesser et al, 1996; Kramer-Ginsberg et al, 1999).
Several studies have also demonstrated that poorer treat-
ment outcome is associated with greater subcortical and
white matter hyperintensities (Fujikawa et al, 1996; Hickie
et al, 1995; Leuchter et al, 1997; Simpson et al, 1997; Steffens
et al, 2001).
Comment: Several recent methodological developments
with respect to MR sequence development and analytic
methods will have an important impact on the evaluating
of volumetric alterations, the detection of white matter
changes and the ability to visualize connectivity. Higher-
resolution images acquired at higher magnetic field
strengths, new methods of shape analysis (Posener et al,
2003; Styner et al, 2004) and the use of data-driven, voxel
based approaches, may yield novel observations of struc-
tural brain alterations and the relationship to course of
More sophisticated methods have been developed to
evaluating white matter lesions quantitatively (Firbank et al,
2004) and with improved regional localization (Macfall et al,
2005). Diffusion tensor imaging has been used to examine
the biophysical characteristics of white matter and for fiber
tract mapping (Pierpaoli and Basser, 1996; Wakana et al,
2004). In patients with geriatric depression there is
preliminary evidence to demonstrate frontal and temporal
cortical differences in white matter structure in older
depressed subjects (Nobuhara et al, 2006; Taylor et al,
2004), as well as alterations in specific anterior regions that
were associated with poorer antidepressant response
(Alexopoulos et al, 2002). Magnetization transfer is a
method that may be particularly sensitive to detecting
changes in myelin-related proteins and hence of great use in
demyelinating disorders. This technique may reveal areas
that may be compromised in normal-appearing regions in
older depressed subjects (Kumar et al, 2004). The develop-
ment and implementation of these new MR sequences has
the potential to contribute unique pathophysiological
information with respect to cerebrovascular and neurode-
generative mechanisms underlying white matter pathology
in geriatric depression.
changes in the brains of patients with geriatric depression
should be further integrated with clinical and cognitive
measures, genetics and functional imaging data to under-
stand the significance of the structural changes and to
address such questions as: (1) are structural brain changes
directions: Theobservations of structural
related to differential treatment response or cognitive
deficits; (2) what is the relationship between structural
brain alterations and genetic polymorphisms that have
been associated with antidepressant response, cognitive
function, and neurotrophic factors; (3) how do structural
changes relate to a differential functional response to
cognitive or pharmacological activation? Another critical
aspect of future MR research is studies to correlate the
neuroimaging findings with post-mortem data. The objec-
tives of such studies are to identify the pathophysiology
underlying the alterations in gray matter volumes and in the
white matter hyperintensities, addressing whether these
white matter changes are owing to cerebrovascular com-
pared to demyelinating processes, an issue that has been
debated for over two decades (George et al, 1986a,b;
Thomas et al, 2002).
Functional imaging: cognitive, and affective neuroscience
Introduction: As described in the introduction deficits in
executive function, speed of processing, and memory have
been the major findings of neuropsychological studies in
geriatric depression. Thus, the integrity of fronto-striatal
and fronto-limbic circuitry hypothesized to underlie these
deficits has been the major focus of cognitive and affective
activation studies in geriatric depression. The following
section will briefly summarize these findings, in addition to
other promising areas of research in younger patients that
may have important applications to the study of older
Summary of the literature:
1. With respect to affective processing, neuroimaging
studies in young and middle aged individuals with major
depression have most consistently shown abnormal
activation in fronto-limbic regions specifically hyper-
activation of ventral limbic regions. In contrast, execu-
tive processing is usually accompanied by hypoactivation
of dorsolateral prefrontal and dorsal anterior cingulate
regions (eg, Canli et al, 2004; Davidson et al, 2003; Elliott
et al, 2002; Surguladze et al, 2005; Rose et al, 2006).
2. Preliminary studies in patients with late-life depression
using executive (standard Stroop task) and affective
(emotional Stroop task) tasks suggest that relative to
comparison subjects, elderly depressed patients show
less activation of the dorsal anterior cingulate during
executive processing and greater activation of the
subgenual cingulate and dorsomedial prefrontal cortex
in response to negatively valenced words (Gunning-
Dixon et al, 2005).
3. Verbal fluency tasks (eg, phonemic word generation)
demonstrated bilateral hypoactivation of the dorsal
anterior cingulate and the hippocampus in severely
depressed geriatric patients relative to comparison
subjects (de Asis et al, 2001) with the disruption in
hippocampal activation in depressed patients predicting
poor memory performance.
4. Explicit sequence learning tasks have shown in patients,
compared to age-matched comparison subjects, de-
creased prefrontal activation in addition to increased
caudate activation (Aizenstein et al, 2005b).
Translational research in late-life mood disorders
GS Smith et al
5. With respect to episodic memory, patients with geriatric
depression demonstrate decreased activation of tem-
poro-limbic structures relative to control subjects, but
a greater response of these regions and potentially
a greater capacity for compensation compared to AD
patients (Gron et al, 2002).
Comment: The systematic evaluation of the activation
response in normal aging and the comparison of the
activation responses in younger compared to older
depressed patients represent two priorities for functional
neuroimaging studies. Such studies would have implica-
tions for the understanding of the contribution of age-
related changes in brain function to the pathogenesis of
geriatric depression, as well as the understanding of
abnormalities or compensatory mechanisms that may be
associated with the onset of depression in late life, as well as
the impact of repeated depressive episodes. Results from
fMRI studies of non-depressed older adults provide
evidence for the vulnerability of fronto-limbic regions to
the influence of aging. While processing affective stimuli,
older adults reveal diminished activation of the amygdala
relative to younger adults (Gunning-Dixon et al, 2003;
Iidaka et al, 2002; Tessitore et al, 2005), within the context
of the older adults demonstrating greater activation of
prefrontal regions than the young comparison groups
(Gunning-Dixon et al, 2003; Tessitore et al, 2005). Activa-
tion results from both episodic memory and executive
function studies indicate that older adults often recruit
additional frontal regions when compared with young
adults (Cabeza et al, 2000, 2002, 2004; Lamar et al, 2004;
Nielson et al, 2002, 2004). Thus, these data suggest that the
activation patterns in older depressed individuals may differ
from the patterns observed in young and middle-aged
depressed patients and the direct comparison of these
groups may provide important information about the
influence of aging-related brain changes on the pathophy-
siology of geriatric depression.
With respect to the application of recent methodological
advances, correlating the time course of the blood oxygen
level-dependent response between brain regions can be
used as a measure of functional connectivity and is a
promising technique that has only recently been applied to
the study of geriatric mood disorders. In a study of geriatric
depression, Aizenstein et al (2005a) used an executive probe
in an event-related fMRI paradigm to activate the dorso-
lateral prefrontal cortex and the dorsal anterior cingulate.
During baseline scanning, depressed patients revealed
hypoactivation of the dorsolateral prefrontal cortex and
the anterior cingulate as well as decreased functional
connectivity between these regions relative to comparison
subjects. Hypoactivation in these regions resolved following
12 weeks of treatment with paroxetine, but the decreased
functional connectivity persisted (Aizenstein et al, 2005a).
Furthermore, preliminary evidence suggests that abnormal
activation of some regions may resolve with treatment,
whereas a lack of functional connectivity between regions
may persist. Coupled with the findings summarized above,
this study suggests that not only specific regions of fronto-
striatal and fronto-limbic networks exhibits abnormal
activation, but a disconnection syndrome affecting these
systems may exist in geriatric depression.
Future directions: Although traditional neuropsycholo-
gical tests have contributed valuable data about the general
cognitive domains affected in geriatric depression, these
tests assess complex cognitive functions that are not ideal
for studies of specific neural networks. In contrast, simpler
cognitive tests, in some cases originating from non-human
primate studies of neural circuitry should be used to study
of specific cerebral network abnormalities in geriatric
depression. Examples of such assessments are the tests
included in the Cambridge Neuropsychological Test Auto-
mated Battery (Sahakian and Owen, 1992). This battery
includes tests developed to evaluate the neural substrates of
cognition in non-human primates that were adapted to the
study of human subjects. Some of the tests have been
evaluated using fMRI and psychopharmacologic interven-
tions to characterize further the neural circuitry and
neurochemical mechanisms underlying task performance.
One example of the application of a well-characterized
cognitive paradigm to geriatric depression is the study by
Murphy and Alexopoulos (2006) who have used the
well-established Attention Network Test (Fan et al, 2002)
to assess the efficiency of the executive, orienting, and
vigilance attention networks and their association to
treatment response in older patients with major depression.
Preliminary evidence indicates that executive-related per-
formance, but not orienting- or vigilance-related perfor-
mance, was correlated with time to remission.
In addition to characterizing changes in cerebral activa-
tion patterns following treatment, functional MRI should be
used to identify cerebral network abnormalities that predict
treatment outcomes, including core depressive symptoms,
as well as cognitive deficits. An example of such a study in
younger depressed patients, greater activation in the
amygdala in response to emotional facial expressions
predicted better treatment outcome several months follow-
ing treatment, even after controlling for depression severity
and medication status (Canli et al, 2005). The use of
cognitive and affective fMRI paradigms within the context
of controlled treatment trials for geriatric depression would
not only advance our knowledge of the pathogenesis of
geriatric depression, but also allow us to identify biomar-
kers of individuals who are at risk for poor treatment
Further studies comparing cognitive and affective activa-
tion responses in patients with geriatric depression and AD
(especially longitudinal studies in subjects who decline
cognitively compared to those who do not) may be useful in
identifying whether there are overlapping or independent
patterns of neurodegeneration in geriatric depression
compared to AD. The evaluation of medication effects
would address the issue of whether antidepressant agents
improve function and whether treatment with cognitive
enhancing agents may be indicated.
Our understanding of the nature and role of fronto-
striatal-limbic network anomalies in the presentation and
course of geriatric depression may be enhanced signifi-
cantly by the combination of fMRI with other imaging
modalities. For example, rapid advancements in imaging
processing and analysis techniques should enable combina-
tion of data across fMRI and DTI-imaging modalities
allowing a more comprehensive analysis of functional
connectivity in geriatric depression.
Translational research in late-life mood disorders
GS Smith et al
Neurochemical imaging approaches.
Introduction: The major emphasis of neurochemical
imaging studies using positron emission tomography and
single photon emission computed tomography in major
depressive disorder has been the evaluation of the mono-
amine hypothesis of affective disorders (Schildkraut, 1965).
Advances in radiochemistry over the past two decades have
made possible the visualization of monoamine metabolism,
transporter and receptor binding, as well as other poten-
tially relevant neurochemical mechanisms (as reviewed by
Fowler et al, 2003; Smith et al, 2004)). There are other
approaches for evaluating neurochemical function includ-
ing the combination of pharmacologic challenges with the
measurement of cerebral blood flow and glucose metabo-
lism in the resting state or during cognitive or affective
processing tasks. MR spectroscopy studies can potentially
complement the PET and SPECT imaging methods and
permits the evaluation of concentrations of amino acids
(GABA, glutamate) and membrane lipids in the brain.
For example, studies conducted in patients with geriatric
depression have demonstrated increased myo-inositol/
creatine ratios in frontal white matter (Kumar et al, 2002).
Summary of the literature: The PET and SPECT studies
performed thus far have been conducted mainly in patients
with midlife depression. The major findings of the studies
comparing depressed patients to demographically matched
comparison subjects are (1) reduced serotonin precursor
uptake and synthesis (Agren et al, 1991; Rosa-Neto et al,
2004); (2) modest or no reductions in serotonin transporter,
5-HT1A, and 5-HT2A binding (Malison et al, 1998; Meyer
et al, 2004, 2001a,c; Parsey et al, 2006; Drevets et al, 1999;
Sargent et al, 2000; Meltzer et al, 1999; Zanardi et al, 2001;
Yatham et al, 1999); (3) modest changes in dopamine
metabolism, dopamine transporter, and D1 and D2 receptor
binding (Agren and Reibring, 1994; Meyer et al, 2001b;
Suhara et al, 1992) and (4) most recently, a significant
(average 34%) elevation of monoamine oxidase A concen-
trations in depressed patients compared to comparison
subjects (Meyer et al, 2006). Thus, studies of monoamine
transporter and receptor binding have shown limited
sensitivity in differentiating depressed patients from
comparison subjects. Studies evaluating the PET measures
relative to symptom and genetic measures have observed
(1) increased serotonin transporter and 5-HT2A binding
associated with negative dysfunctional attitudes (Meyer
et al, 2003, 2004); and (2) higher 5-HT1A binding associated
with no previous antidepressant treatment, poorer anti-
depressant outcome and homozygosity for the functional
5-HT(1A) G(-1019) allele of the promoter polymorphism
(Parsey et al, 2006). Thus, the variability in transporter and
receptor binding may be explained by symptom or genetic
changes in transporter and receptor binding in patients
compared to comparison subjects have been observed. In
addition, a lack of correlation between the magnitude of
occupancy of a drug to the initial target site of action with
clinical response has been observed across a variety of
disorders, including SSRIs in patients with depression,
antipsychotics in patients with schizophrenia, cholinester-
described above, relatively modest
ase inhibitors in Alzheimer’s disease (eg, Meyer et al, 2004;
Wolkin et al, 1989; Farde et al, 1992; Kuhl et al, 2000). These
observations suggest that measuring the dynamic aspects
of monoamine function may be more revealing of patho-
physiology and treatment mechanisms than measures of
transporter or receptor binding.
On the basis of these observations, methodology devel-
opment was initiated over a decade ago to evaluate dynamic
measure of monoamine function and interactions between
monoamine systems The early focus of this work was on the
measurement of striatal dopamine concentrations (eg,
Dewey et al, 1993; Volkow et al, 1994) and modulation by
other neurotransmitter systems (eg, serotonin, glutamate; as
reviewed by Smith et al, 2004). Thus far, studies have not
observed differences in striatal dopamine concentrations in
midlife depressed patients (Anand et al, 2000; Parsey et al,
2001). However, developments in the imaging of extra-
striatal D2/D3 receptor in cortical and limbic related areas
(including the ventral striatum; Willeit et al, 2006) may have
important implications for imaging dopamine function in
brain regions that may be more relevant to depression and
reward circuitry. The potential role of dopamine as a
therapeutic target has been suggested by recent methylphe-
nidate augmentation studies (Lavretsky and Kumar, 2001).
More recent studies have focused on the development and
application of a method to measure serotonin function in
vivo (Meyer et al, 1999; Hume et al, 2001; Smith et al, 1999,
2002b, 2004). Studies conducted thus far in geriatric
depression combining acute and chronic SSRI treatment
(citalopram) with measures of cerebral glucose metabolism
have shown a differential lateralized pattern of acute
metabolic effects in the patients in contrast to comparison
subjects that are similar to the response in normal subjects
who have a s allele of the serotonin transporter promoter
polymorphism compared to those normal subjects with a l
allele (Smith et al, 2004).
Thus, in the case of depressive disorders the combination
of rCBF or glucose metabolism measures with a pharma-
cologically selective intervention may further enhance the
predictive value of these measures with respect to identify-
ing the functional differences between treatment responders
and non-responders. After identifying the functional
neuroanatomic changes, mechanistic studies using neuro-
receptor radiotracers can be designed based on the
functional circuitry altered to identify the neurochemical
substrates underlying the metabolic effects. Similar phar-
macologic intervention studies could be conducted with
fMRI methods and would be extremely informative,
especially with respect to monoamine regulation of the
neural circuitry involved in cognition.
Future directions: The application of neurochemical
imaging methods has focused on the investigation of
monoamine transporters and receptors in depression and
occupancy by antidepressant medications. Much of this
work has been performed in younger patients. Some of the
most intriguing results obtained thus far have involved
integrating the neurochemical imaging measures with
clinical variables and genetic polymorphisms.
The question embedded in this discussion is why these
transporter and receptor measures are not more sensitive to
Translational research in late-life mood disorders
GS Smith et al
identifying pathophysiology, especially in brain regions that
have shown glucose metabolic alterations. The limited data
available in geriatric patients suggest that these effects are
even more modest in older compared with younger patients
(eg, Meltzer et al, 1999). Is the lack of a more dramatic effect
telling us something about the adaptive function and
compensatory mechanisms of these systems? As described,
dynamic measures of monoamine function may be more
sensitive than static measures such as transporter or
receptor availability. Regarding other potentially relevant
neurochemical systems, radiotracers development for both
adrenergic and glucocorticoid systems are active areas at
the present time, and development of radiotracers for these
systems would have important implications for mechanistic
studies in geriatric depression. Another important area of
investigation would be to understand further the mechan-
ism of action of antidepressant medications relative to
promoting trophic responses in geriatric depressed patients
as has been shown in laboratory animals (Duman et al,
PET methods can be applied to examine specific
neurodegenerative processes in vivo that have been
characterized in the post-mortem brain in patients with
depression and with AD. In vivo imaging can be applied to
evaluate when the neuropathologic process emerges in the
illness and how it relates to the course of the illness with
respect to treatment response and onset of cognitive
impairment. As amyloid deposition has been observed in
the brains of geriatric depressed patients, amyloid imaging
agents would be important to evaluate in patients relative to
cognition dysfunction (Sweet et al, 2004; Klunk et al, 2004).
In addition, given the reports of increased neuroinflamma-
tory markers in post-mortem brain and increased concen-
trations of pro-inflammatory cytokines in plasma (Thomas
et al, 2000, 2005), the use of the peripheral benzodiazepine
radiotracer [11C]-PK 11195 (Groom et al, 1995) would be
extremely interesting to evaluate in patients with and
without cerebrovascular disease and also to evaluate the
impact of antidepressant medication and other pharmaco-
logic interventions. Another aspect of understanding
neurodegeneration and cognitive impairment in geriatric
depression is the application of radiotracer-binding meth-
ods to elucidate a potential cholinergic deficit. Preliminary
post-mortem studies in geriatric depression report patho-
logical changes in both monoaminergic and cholinergic
neurons in geriatric depression (Sweet et al, 2004). The
cholinergic system in depression is very much under-
studied. On the basis post-mortem studies in mild cognitive
impairment and AD, there may be evidence of a compensa-
tory cholinergic process early in the course of cognitive
impairment and an actual cholinergic deficit may not
appear until the later stages of impairment (DeKosky et al,
2002). The cholinergic system may similarly be involved as
substrate of cognitive deficits in geriatric depression
Other aspects of geriatric depression research that merit
further neurochemical imaging studies include the compar-
ison of younger depressed patients to older depressed
patients to determine whether the initial onset of depression
in mid-life compared to late-life patients involves the same
neurochemical substrates and to determine the impact of
repeated depressive episodes on neurochemical function.
Such studies are critical in addressing such fundamental
questions as to whether depression in late-life is a distinct
neurochemical entity, whether there are distinct neuro-
chemical alterations that occur in patients who develop
dementia, whether depression is a neurobiological pro-
drome of dementia or a consequence of neuronal loss. The
mechanism of action of interventions that are effective in
treatment-resistant patients such as ECT should be further
investigated. The neurobiological effects of such treatments
remain poorly understood (Mann, 1998; Szuba et al, 2000).
Mechanisms such as greater enhancements of monoami-
nergic function and increased trophic responses have been
suggested to underlie the greater efficacy of ECT compared
to antidepressant medications. Finally, neurochemical
imaging studies in psychosocial (bereavement; Shear et al,
2005) and medical (interferon induced depression; Mussel-
man et al, 2001) circumstances, in which depressive
symptoms occur in a subset of vulnerable individuals
would be extremely interesting in terms of identifying
neurobiological markers of vulnerability. Similar considera-
tions apply to geriatric bipolar disorder and psychotic
depression. These disease entities are studied conditions
that are clinically challenging and associated with cognitive
deficits and increased mortality in the case of psychotic
depression (Vythilingam et al, 2003).
Introduction: Genetic influences may be associated with
vulnerability to both psychosocial and medical triggers of
depression, as well as variable phenotypic expression and
treatment sensitivity. As the data regarding candidate gene
studies and pharmacogenetic studies have been reviewed
extensively (eg, Nemeroff and Vale, 2005; Hattori et al, 2005;
Paez-Pereda, 2005; Craddock and Forty, 2006; Binder and
Holsboer, 2006; Lesch and Gutknecht, 2005; Serretti et al,
2005; Wong and Licinio, 2004; Levinson, 2006), this section
will primarily focus on observations relevant to future
genetic association studies of geriatric depression.
Summary of the candidate gene selection literature: In
one of the few studies conducted in elderly subjects, the
serotonin transporter promoter has been associated with
depression following a hip fracture in the elderly (Lenze
et al, 2005), consistent with the interaction of this
polymorphism with psychosocial stress (Caspi et al, 2003).
However, most candidate genes have been primarily
examined in younger populations. These include enzymes
for serotonin synthesis (Zhang et al, 2005; Zill et al, 2004),
serotonin transporters and receptors (5-HT1A and 5-HT2A
receptors, Lesch et al, 1996; Arias et al, 2005), the
norepinephrine transporter (as reviewed by Leonardo and
Hen, 2006), second-messenger systems (eg, Zubenko et al,
2002), glucocorticoids (Van Rossum et al, 2006; van West
et al, 2006), neuroendocrine hormones (Binder et al, 2004)
and brain-derived neurotrophic factor (BDNF: eg, Ryba-
kowski et al, 2003; Strauss et al, 2004). These genes may
have either much weaker or more predominant roles in
older adults, hypotheses that await testing.
Previously unsuspected candidate genes are also being
identified using genomic micro-arrays, animal studies, and
genome-wide searches (Bunney et al, 2003), with potential
sources of messenger ribonucleic acid (mRNA) from post-
Translational research in late-life mood disorders
GS Smith et al
mortem brains (Evans et al, 2004; Erraji-Benchekroun et al,
2005; Sibille et al, 2004), brain tissue from animal models
of depression (Yamada et al 2001, 2000; Landgrebe et al,
2002; Alfonso et al, 2004), peripheral sources such as
lymphocytes in living depressed subjects (Gladkevich et al,
2004), and cell cultures (Chen et al, 2003). Fibroblast growth
factor gene expression was shown to be dysregulated in
post-mortem brain tissue from depressed patients (Evans
et al, 2004). Growth associated protein mRNA was increased
in hippocampal cultures following desipramine treatment
(Chen et al, 2003). Electroconvulsive stimulation in rodents
identified potential roles for BNDF, second-messenger
systems involving cAMP and related neurotrophic factors
(Altar et al, 2004). In combination, studies such as these
provide possible clues, regarding which gene systems, such
as those involved in neurogenesis, to examine further in
associational analyses. However, an important considera-
tion is that many mRNA transcripts may change either with
healthy aging or with other age-related disease processes
(Lukiw, 2004; Ricciarelli et al, 2004; Toescu et al, 2004).
Thus, it will be crucial to consider the aging process and
associated disease processes in interpreting data specifically
related to geriatric depression.
Whole genome associational studies are utilizing dense
maps of genetic variation to examine the entire genome for
possible candidates (Craig and Stephan, 2005; Ehm et al,
2005). A recently completed haplotype map of the human
genome (Altshuler et al, 2005) has provided a dense array
of SNPs for use in several different populations. The
technology for this whole genome approach is nascent but
should also provide a complimentary approach to hypo-
thesis-based studies of genetic association.
Pharmacogenetic studies performed thus far in patients
with geriatric depression have observed
between speed of response and antidepressant side effects
and the serotonintransporter promoter
ism (slower spend of response and greater side effects
response associated with the s allele; Pollock et al, 2000;
Murphy et al, 2004). Future pharmacogenetic studies will
require controlling for differences in exposure to the
pharmacologic stimulus (Lotrich et al, 2006). In particular,
there can be large variability in exposure to medications,
which may be an important confound to address, as
different genotypes may be associated with dissimilar
concentration–response relationships (Lotrich et al, 2006).
This is particularly salient in the elderly who can have
substantial variations in drug concentrations as well as
markedly different sensitivities to medications (Lotrich and
Comment: Future genetic association studies should
include (i) an explicit account of the selection of candidate
genes and haplotypes, with appropriate statistical control
for multiple testing, (ii) a comprehensive description of the
psychiatric phenotype including course, pattern, and
comorbidity, given the likely complexity of geriatric
depression, (iii) statistical attention to the potential for
population stratification, an issue that can be particularly
problematic in neuroimaging studies with small sample
sizes, and (iv) an analysis of linkage between polymorph-
isms within a gene and the potential for intra-genetic
In geriatric depression, many co-morbidities are fre-
quently present, most notably vascular disease and inflam-
mation. For example, consistent with proposed theories
that inflammatory cytokines induce a subtype of geriatric
depression, late-life depression is associated with increases
in interleukin 1b (Thomas et al, 2005), elevated interleukin
6 (Tiemeier et al, 2003), and an enhanced inflammatory
response (Glaser et al, 2003). These co-morbidities may
influence the relative role of genes in late life. Several
possible causal genetic pathways have been suggested: (i)
genes influence co-morbid illness that subsequently causes
depression, (ii) genes moderate the ability of co-morbid
illness to cause depression, (iii) genes directly influence
depression that subsequently triggers co-morbid illness,
(iv) genes moderate the ability of depression to cause a co-
morbid illness, and (v) similar genes simultaneously
influence both depression and co-morbid illness. Prospec-
tive studies will be needed to dissect the role of genetic
vulnerability in these bi-directional pathways. The observa-
tion that comorbidity with depression is the rule rather than
the exception suggests that these complex diagnostic issues
should not be ignored in neurobiological studies of late-life
mood disorder. Several of these hypotheses may be
addressed in future studies that integrate neuroimaging
studies with genetics, a technique reviewed in later sections.
For interpreting forthcoming associational studies, genet-
ic influences on protein expression and function will
require characterization. For instance, a common single
nucleotide polymorphisms (SNP) in the upstream regula-
tory region for tryptophan hydroxylase 2 (TPH2) has
recently been associated with changes in amygdala reactiv-
ity (Brown et al, 2005) during midlife, and may affect
binding for several transcriptional regulators such as MSX-1
and MSX-2. However, whether this polymorphism is
functional, whether this functionality changes with age, or
whether it is in linkage disequilibrium with another
functional variant requires determination. Moreover, func-
tional effects may depend upon cell type. For example, a
variant in the upstream promoter region of the 5-HT1A
receptor has been associated with impaired regulation by
NUDR/Deaf-1, major depression (Lemonde et al, 2003), and
altered sensitivity to an acute challenge with a 5-HT1A
receptor agonist (Lesch and Gutknecht, 2004). However, the
genetic influence on expression may differ between pre-
synaptic and post-synaptic cells in the raphe nucleus
(Lemonde et al, 2003). Strategies for assessing intra-gene
epistasis are also needed. For example, within the dopamine
transporter (DAT), particular combinations of polymorph-
isms, both upstream and downstream, may interact to
influence DAT expression (Greenwood and Kelsoe, 2003).
characteristics that potentially distinguish it from earlier
onset depression. Included are the numerous medical,
inflammatory, and vascular co-morbidities, as well as the
potential relationship to dementia. Changes in receptor
levels and mRNA expression patterns with aging may also
result in differences from midlife depression, as well as
differential sensitivity to pharmacologic agents. These
differences provide challenges in extrapolating results of
genetic studies using younger adults to older subjects.
However, these differences may also provide the opportu-
directions: Late-lifedepressionhas many
Translational research in late-life mood disorders
GS Smith et al
nity to understand more fully the etiology of depression and
Additionally, although cross-sectional studies are infor-
mative, prospective longitudinal designs may ultimately be
necessary for answering causal questions. Geriatric depres-
sion represents a unique opportunity for the conduct of
prospective studies of specified depression subtypes and
possibly for characterizing patients before the onset of
depression. For example, vulnerability factors that may
place euthymic individuals at high risk include loss of
spouse (Vinkers et al, 2004), caregiver burden (Gallagher
et al, 1989; Schulz et al, 1995), medical comorbidity (Cole
and Dendukuri, 2003), cancer (Illman et al, 2005), and
stroke (Antai-Otong, 2004). Another example is interferon-
induced depression, in which many euthymic patients
develop psychiatric symptoms including depression follow-
ing the initiation of treatment (Valentine et al, 1998;
Musselman et al, 2001). Longitudinal studies of these ‘at-
risk’ populations may help inform how genetic vulnerability
and resilience mechanistically influence the onset and
development of depression. Relatedly, the interaction of
genes and environment will be enhanced by studies that are
focused on specific populations that are exposed to
potential depressogenic triggers.
Guided by differences in patterns of drug response in the
geriatric population (Lotrich and Pollock, 2005a), as well as
medical triggers (eg, cardiac disease, menopause) of
depression, other biologically plausible candidates for
further investigation include the dopamine system, NMDA
receptor subunits (eg, NR1), apolipoprotein E, vasopression
and angiotensin receptors, inflammatory cytokine receptors
(eg, TNF-a receptor), glucocorticoid receptors and chaper-
ones (eg, FKBP5), nitric oxide (eg, nitric oxide synthetase),
thyroid hormone receptors, estrogen, testosterone, G-
proteins subunits (eg, a and b3 subunits), adenylyl cyclases
(eg, PKA regulatory subunit IIb), phospholipases (eg, PLC
g1) phosphodiesterases isoforms (eg, phosphodiesterase 4),
protein phosphatases (eg, PP2A and PP2B), and regulatory
proteins that influence intracellular transduction (eg, A
kinase anchoring protein 79/150; Lotrich and Pollock
2005b). Specifically guided by studies of menopause, a gene
involved in estrogen metabolism has been implicated in
perimenopausal depression (Kravitz et al, 2006). Similarly,
the relative roles of these other systems in other potential
subtypes of geriatric depression will require further
The identification of multiple and varied ‘at risk’ elderly
populations may provide useful cohorts to examine
prospectively the interaction of genetic variation and
various triggers of depression. Interactions between genetic
risk and other potential sources of risk (including
cardiovascular, inflammatory, psychosocial losses, early
dementia) may provide meaningful insights into the
pathophysiologic pathways leading to depression. Results
from micro-array studies and from preliminary association
analyses in midlife depression, have provided numerous
plausible candidates for biologically guided future research.
Moreover, although genetic studies in geriatric depression
are only now beginning, statistical solutions to multiple
testing, population stratification, and haplotype phasing are
being addressed and will be feasible and appropriate to
implement for the next generation of studies.
Potential causal mechanisms of genetic variation can be
investigated using functional and structural neuroimaging.
In this regard, the length polymorphism in the serotonin
transporter promoter (5-HTTLPR) has been connected to
glucocorticoids and cytokines (Glatz et al, 2003; Mossner
et al, 2001), and this polymorphism has been associated
with altered sensitivity to serotonergic challenges and
functional differences in frontal-limbic pathways following
both pharmacologic and affective challenges (eg, Smith
et al, 2004; Hariri et al, 2002, 2005). These investigations
are converging on an answer to the question of how this
polymorphism may functionally influence the etiology of
depression and the response to treatment. This single
example illustrates how greater integration of genetics,
neuroimaging, and pharmacologic challenges will be
important in characterizing the functional consequences
of other polymorphisms. In summary, genetics and its
integration with other techniques appears to hold great
promise in delineating the underlying pathways that
influence the development, as well as the treatment of
Integrating Neuroimaging and Genetics
Introduction. The majority of studies combining genetic
and neuroimaging methods have focused on several genetic
polymorphisms including the serotonin transporter pro-
moter, apolipoprotein E (ApoE), catechol-O-methyltrans-
ferase (COMT), disrupted-in-schizophrenia (DISC1) and
BDNF polymorphisms (as reviewed by Roffman et al, 2006;
Meyer-Lindenberg and Weinberger, 2006; Hariri et al, 2006;
Scarmeas and Stern 2005; Lehtovirta et al, 2000; Heinz and
Smolka, 2006). The following summary of the literature will
highlight the findings potentially relevant to the study of
Summary of the literature. In normal subjects, the s allele
of the 5HTTLPR gene has been associated with structural
brain alterations such as reduced perigenual cingulate and
amygdala gray matter volumes and functional uncoupling
of the amygdala-prefrontal circuitry (Pezawas et al, 2005;
Heinz et al, 2005). The s allele has also been associated
with alterations in functional brain responses such as
an increased amygdala activation response to fearful or
anxiety-producing stimuli or a differentially lateralized
cerebral metabolic response to serotonergic challenge
(Hariri et al, 2002, 2005; Smith, et al, 2004). In patients
with depression, the ll genotype has been associated with
smaller hippocampal volumes (Frodl et al, 2004). In older
patients with the ll genotype, later depression onset is
associated with smaller hippocampal volumes, whereas
earlier age of onset was associated with smaller volumes
in individuals homozygous for the s allele (Taylor et al,
2005b). BDNF polymorphisms have also been associated
with memory deficits and smaller hippocampal volumes
(Egan et al, 2003; Hariri et al, 2003; Pezawas et al, 2004).
Other genetic polymorphisms, such as COMT (Ho et al,
2005), DISC1 (Callicott et al, 2005), and myelination-related
polymorphisms (Hakak et al, 2001) may also be related to
structural alterations in gray and white matter. The COMT
polymorphisms have been shown to be associated with
differences in the processing of affective (greater amygdala
Translational research in late-life mood disorders
GS Smith et al
response to unpleasant stimuli associated with the met158
allele) and cognitive tasks (a more focused activation
response in working memory and attention control tasks
associated with the val158 allele; as reviewed by Heinz and
Smolka, 2006). At the present time, the transition from
identifying a genetic polymorphisms related to a particular
behavior and activation response and evaluating a medica-
tion targeted at the particular mechanism is best evidenced
by the evaluating of the COMT inhibitor tolcopone for
augmenting working memory and attentional control
processes in normal subjects (Apud et al, 2006).
With respect to genetic and neuroimaging studies
of monoamine receptor or transporter polymorphisms,
the 5-HTTLPR and several dopamine (D2) polymorphisms
have been the focus of study (Willeit et al, 2001; Heinz et al,
2000; Shioe et al, 2003). With respect to the 5-HTTLPR,
an association between the polyporphisms and in vivo
binding has not been shown in normal subjects (Shioe et al,
2003; Willeit et al, 2001), but an association has been
shown in subjects who abuse alcohol (Heinz et al, 2000).
With respect to the D2/D3 receptor, decreased D2/D3
receptor availability associated with the A1 allele of the
TaqIA polymorphism has been reported in a study
with [11C]-raclopride (Hirvonen et al, 2004), as observed
previously in a post-mortem autoradiographic study
(Thompson et al, 1997). The variability in the magni-
tude of change in D2 receptor availability induced
by smoking a cigarette was shown to be associated
with COMT, the dopamine transporter and D4 receptor
variable nucleotide tandem repeats and the D2 receptor
Taq A1/A2 polymorphisms (Brody et al, 2006). The
subjects with polymorphisms associated with low dopamine
tone were related to greater changes in D2 receptor
Vascular risk genes such as methylenetetrahydrofolate
reductase (MTHFR) (Chen et al, 2005; Naismith et al, 2002)
and potentially the 5HTTLPR (Ramasubbu, 2003) genotype
may be associated with increased severity of cerebral
hyperintense lesions and associated cognitive impairment
(eg, psychomotor speed). With respect to the ApoE4 allele,
Reiman et al (1998, 2001) initially demonstrated an
association between the ApoE4 allele and low rates of
glucose utilization, in addition to lower hippocampal
volumes and worse long-term memory performance in
cognitively normal subjects. These findings have been
replicated by other groups and have been extended to
aspects of pathophysiology associated with aging such as
white matter structural integrity and hyperintensities and
functional activation responses (as reviewed by Scarmeas
and Stern, 2005).
Comment: Genetic associations of candidate genes in
future neuroimaging experiments will involve the same
challenges and caveats as those reviewed in the genetics
section. In addition to these issues, there are several
statistical issues with respect to appropriate statistical
control for multiple testing and the fact that the sample
sizes in neuroimaging studies are typically smaller than
studies that involve less invasive and costly clinical outcome
measures. In neuroimaging studies that involve drug
challenges, attention to differences in drug exposure are
critical (Lotrich et al, 2006). Moreover, although the
majority of studies conducted thus far are cross-sectional,
prospective longitudinal designs may ultimately be neces-
sary for answering mechanistic and causal questions.
With respect to the structural and functional neuroima-
ging studies, intriguing observations have been reported
with respect to several genetic polymorphisms as described
above and the findings are generally internally consistent.
With respect to the neurochemical imaging literature, the
data are more limited. The available data suggest that
dynamic measures of neurotransmitter function may be
more informative with respect to understanding the
functional neurochemical significance of genetic poly-
morphism than more static measures of neuroreceptor
availability or number of binding sites. Thus, employing the
dynamic imaging methods described in the neurochemical
imaging section to combine acute pharmacologic interven-
tion paradigms and measures of cerebral metabolism or
blood flow or neuroreceptor availability represents a
potentially important line of investigation and may lead to
the elucidation of compensatory mechanisms.
As described in the genetics section, the identification of
previously unsuspected genes is critical for advancing
mechanistic and therapeutic research. Approaches to
identifying potentially relevant genes include the study of
animal models of aging, depression, and cognitive impair-
ment, as well as the application of proteomic approaches to
the study of post-mortem brain tissue of elderly subjects
and patients with mood and neurodegenerative disorders
(as reviewed by Vercauteren et al, 2004). The identification
of new potentially relevant genes may also inform the
development and evaluation of neurobiological targets for
pharmacologic intervention studies and radiotracer devel-
opment, as well as for therapeutics.
Future directions: The integration of genetic with
neuroimaging methods may provide important information
regarding the significance of specific genetic polymorph-
isms with respect to structural and functional neural
circuitry and neurotransmitter pathways, as well as an
understanding of between-subject variability in the neuro-
imaging measures and whether the same associations are
observed in normal function and in disease. The integration
of genetic and neuroimaging data may provide a better
delineation of neurobiological subtypes of depression that
might relate to different patterns of disease course or
Several priorities for neuroimaging and genetics research
have been articulated consistently in previous sections.
These themes include the importance of understanding the
neurobiological mechanism underlying heterogeneity in
normal aging, depression vulnerability, medical comorbid-
ity (cerebrovascular disease and neuroinflammation, in
particular) variability in treatment response and the
pathophysiology of cognitive impairment. In this section,
the potential contribution of integrating genetics and
neuroimaging methods to addressing these themes will be
With respect to the normal aging process, substantial
variability in cognition, as well as in brain structure and the
functional integrity of neural circuitry and neurochemical
pathways has been observed. The evaluation of the
Translational research in late-life mood disorders
GS Smith et al
neuroimaging measures relative to genetic polymorphisms
is critical to identifying, which genes are associated with
changes in the brain that result in cognitive impairment,
and which genes are associated with compensatory
processes identified by functional imaging methods to
maintain cognitive function in the presence of brain
structural and neurochemical alterations. The comparison
of the associations between genes, cognition and brain
structural and functional integrity in the normal aging
process and the contrast with depressive disorders with
onset across the lifespan could provide important neuro-
biological and therapeutic information. With respect to
depression vulnerability, the study of depression in late life
provides a unique opportunity to study vulnerability as the
result of change in life circumstances and stress (eg,
bereavement, caregiver burden, recovery from medical
illness). The investigation of the neurochemical processes
associated with genes related to depression risk may
identify targets for more effective prevention and treatment
With respect to understanding variability in treatment
response, the integration of genetic and neuroimaging
measures may identify neurochemical subtypes of depres-
sion that may be associated with different speeds and rates
of treatment response to different classes of antidepressant
medications or to interventions, such as ECT, deep brain
stimulation or transcranial magnetic stimulation. With
respect to understanding mechanisms and developing
interventions for cognitive impairment and the conse-
quences of medical comorbidity (eg, hypertension, dia-
betes), serial neuroimaging studies could be used to
monitor whether patterns of alterations are associated with
specific genetic polymorphisms over time to determine
whether the longitudinal course of geriatric depression
could be altered in individuals depending on genotype with
a particular class of agents (eg, antidepressant, cholinester-
ase inhibitors, diabetogenic agents or antihypertensives),
who are potentially at greater risk for depression relapse
and cognitive impairment.
For the goals of delineating the etiologies of depression,
the mechanisms underlying vulnerability and resilience, the
relationships between depression and other co-morbidities,
and specific targets for individualized treatment and
prevention, the inclusion of genetic analyses in neuroima-
ging is an exciting new direction.
Several directions for future research follow from the
? The study of specific subject samples to ask questions
about (1) the neurobiological differences in the early vs
late onset of depression and the impact of repeated
depressive episodes across the life span; (2) the
neurobiology of treatment-resistant depression, including
psychotic depression; (3) neurobiological vulnerability
markers and prevention strategies by studying such ‘at-
risk’ subject samples, including patients with depression
secondary to significant psychosocial stressors (bereave-
ment, caregiver burden, as reviewed by Arean and
Reynolds, 2005) medical illness (cardiovascular disease,
hip fracture or stroke), or medical interventions (inter-
feron-induced symptoms, b-blocker-induced depressive
? The application of genetic methods using candidate gene
and micro-array strategies in patients and animal models
(1) to characterize the genetic basis of treatment response
variability and genetic polymorphisms related to specific
cognitive deficits; (2) to identify the significance of
genetic polymorphisms related to the structural neuro-
anatomic, functional and neurochemical alterations
identified by neuroimaging studies (eg, white matter
hyperintensities, hippocampal atrophy, decreased mono-
amine receptor binding, altered brain response to
pharmacologic interventions); (3) to characterize genetic
polymorphisms related to vulnerability to depression
in the ‘at-risk’ samples as described above, and (4) to
identify novel targets for radiotracer development and
? The development and application of affective and
cognitive neuroscience approaches to characterize further
the neural circuitry underlying deficits in speed of
processing, affective processing, executive function, and
memory using validated tasks combined with fMRI
methods; (2) to characterize the domains of cognitive
function that improve with antidepressant treatment,
compared to those that remain impaired after remission
of mood symptoms and, in addition, the cognitive
domains that show decline longitudinally; (3) to evaluate
the impact of novel acute and chronic pharmacologic
interventions on the functional activation responses to
inform the development of effective treatments to target
these symptoms; and (4) to evaluate the variability in the
functional activation response relative to structural brain
changes and to genetic polymorphisms.
? The development and application of neurochemical
imaging methods (1) to identify the acute and chronic
neurochemical consequences of antidepressant treat-
ment; (2) to characterize the neurochemical deficits that
persist after antidepressant treatment and are related to
residual mood and cognitive symptoms; (3) to develop
and apply new radiotracers to target the same neuro-
chemical systems, for which genetic polymorphisms
have been shown to be related to treatment response
variability and specific symptom domains; and (4) to
understand the variability observed in the neurochemical
measurements relative to relevant genetic polymorphisms
for neurotransmitter metabolism, transporter or receptor
? The directions for future research involving the integra-
tion of basic with clinical neuroscience research, include
? The important area of post-mortem studies include (1) the
further characterization of the pathophysiology of
geriatric depression to inform the design of genetic,
neuroimaging and neuropsychological studies; (2) the
correlation of post-mortem data with cognitive and
neuroimaging findings to understand the substrates of
persistent mood and cognitive symptoms such as
anhedonia and executive dysfunction; and (3) the
correlation of postmortem and imaging findings to
understand the underlying pathophysiology of volu-
Translational research in late-life mood disorders
GS Smith et al
metric loss, white matter hyperintensities and neuro-
chemical imaging findings.
? The development of animal models of geriatric depres-
sion has not been a focus of research, given the challenges
in developing an animal model of depression and the
practical constraints of studying aged animals. Models
developed in younger animals could potentially be
applied to aged animals (Cryan et al, 2005). Specific
strains of rodents (eg, spontaneously hypertensive rats,
cognitively impaired aged rats) could be used to mimic
some aspects of pathophysiology. Knockout mice for the
genetic targets that have been identified in the human
studies as important to treatment response or cognitive
impairment should be evaluated with respect to the
functional or neurochemical response to pharmacologic
agents for mood and cognitive symptoms. Conversely, the
study of knockout mice that display similar behavioral or
neurobiological features as geriatric depressed patients
should be informative as well (Cryan and Holmes, 2005).
Understanding the complex nature of geriatric depression
requires a translational and integrative approach. Neuro-
biological studies in geriatric depression represent unique
opportunities for the identification of mechanisms of
depression pathophysiology and vulnerability, which could
potentially inform the development of intervention and
prevention strategies. Such strategies may have relevance to
the treatment of younger depressed patients, as well as to
patients with depression secondary to other neuropsychia-
tric or medical illnesses (eg, Alzheimer’s disease, Parkin-
son’s disease, cerebrovascular
development of integrative, conceptual models that could
be applied to the study of other neuropsychiatric disorders.
The translational research studies needed to address such
neurobiologically complex questions require an integration
of basic and clinical neuroscience approaches, including
genetic and neuroimaging methods. Although the workshop
and this report focus on unipolar major depression, the
importance of research into psychotic depression, and
bipolar disorder in late-life should be underscored. Two
large scale multi-center trials in psychotic depression and
bipolar disorder have been undertaken in the past few years,
with an emphasis on the study of geriatric patients (Meyers
et al, 2005; Young et al, 2004). The results of these clinical
trials and the ancillary genetic and neuroimaging studies
will provide important information to inform the design
of neurobiological studies for these disabling disorders in
the future. For hypothesis-driven, mechanistic research
to evolve, continued interaction between investigators
across disciplines (including geriatric psychiatry, genetics,
neuropsychology, neuroimaging, and neuropathology) is
This manuscript was generated from data presented and
discussion at an NIMH sponsored workshop entitled
‘Translational Research in Late-life Mood Disorders:
Implications for FutureIntervention and Prevention
Research.’ The participants included Gwenn Smith (Depart-
ment of Psychiatry and Behavioral Sciences, Albert Einstein
College of Medicine), KRR Krishnan (Department of
Psychiatry and Behavioral Sciences, Duke University;
Co-Chairs), Jovier D Evans, National Institute of Mental
Health, George Niederehe, National Institute of Mental
Health, Victoria Arango (Department of Psychiatry, Division
of Neuroscience, College of Physicians and Surgeons
of Columbia University), Warren Taylor (Department of
Psychiatry and Behavioral Sciences, Duke University),
Anand Kumar (Department of Psychiatry and Behavioral
Sciences, University of California at Los Angeles), Richard
Shelton (Department of Psychiatry, Vanderbilt University),
Susan Resnick (Intramural Program, National Institute on
Aging), James Kennedy (Centre for Addiction and Mental
Health, Department of Psychiatry, University of Toronto),
Ramin Parsey (Department of Psychiatry, Division of
Neuroscience, College of Physicians and Surgeons of
Columbia University), Bruce Pollock (Department of
Psychiatry, University of Toronto) Meryl Butters (Depart-
ment of Psychiatry, University of Pittsburgh School of
Medicine), David Steffens (Department of Psychiatry and
Behavioral Sciences, Duke University), Eric Reiman (De-
partment of Psychiatry and Behavioral Sciences, University
of Arizona), Francis Lotrich (Department of Psychiatry,
University of Pittsburgh School of Medicine), George
Alexopoulos (Department of Psychiatry, Weil Medical
College of Cornell University), Herb Harris (Jazz Pharma-
ceuticals, Incorporated), William Z Potter (Clinical Neuro-
science, Merck Research Laboratories, Merck and Com-
pany, Inc.), C Anthony Altar (Psychiatric Genomics,
Incorporated), Barry Lebowitz (Department of Psychiatry,
University of California at San Diego).
Supported in part by National Institute of Health: K02
MH01621 (GSS), RO1 MH064823 (GSS), K23 MH074818,
(FGD), K23 MH65939 (WDT), K23 MH074012 (FEL), and
The views expressed in this paper are those of the authors
and should not be construed as official or as reflecting those
of the NIMH, NIH, or Federal Government.
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