APPENDIX A
Depression along the Mild Behavioral Impairment (MBI), Mild
Cognitive Impairment (MCI), and Alzheimer’s dementia (AD)
spectrum: priorities for clinical and neurobiological research
Gwenn S. Smith1, Joanne Bell2, Jovier Evans3, Yonas E. Geda4, Michael Lee5, Anton Porsteinsson6
for the Neuropsychiatric Syndromes Professional Interest Area of ISTAART
1 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore MD 21224
2 Pfizer, Neuroscience Research Unit. Alzheimer's Disease, Clinical Pfizer Global Research and Development Groton, 06340
3 Geriatric Pharmacologic Intervention, Geriatric Translational Neuroscience, & Multi-Modal Intervention Programs, Geriatrics
Research Branch National Institute of Mental Health, Bethesda, MD 20892-9634
4 Departments of Psychiatry and Neurology, Mayo Clinic, Scottsdale, AZ 85259
5 Department of Neuroscience and Center for Neurodegenerative Diseases, Institute for Translational Neuroscience. University of
Minnesota, Twin Cities, Minneapolis, MN 55455
6 Department of Psychiatry, University of Rochester School of Medicine and Dentistry Rochester, New York 14642
1
Abstract
A focus of research for the past decade has been the improvement of diagnostic criteria and outcome measures for
depression and depressive symptoms in Alzheimer’s Disease (AD), genetic and imaging studies of the
neurobiological mechanisms of this symptom cluster, and clinical trials of antidepressants. The public health
significance of depression in AD is underscored by the observations of the high prevalence of depression in mild
cognitive impairment (MCI) and AD; the prognostic significance of depression in normal aging and MCI with
respect to cognitive and functional decline, and the limited efficacy of using approved medications developed to
treat depression in younger individuals. The depression workgroup included participants with diverse expertise in
psychiatry, clinical trials, psychopharmacology, neuroimaging and neuroscience (animal models/ neuropathology)
who were affiliated with academia, government (NIH) and the pharmaceutical industry.
2
dropped. In one study, the rate of depression in AD
was found to be lower using criteria developed for
major depression (ICD-9 or DSM) compared to the
NIMH Criteria (Vilalta-Franch 2006). Using the
DSM-IV criteria as a standard for minor and major
depression (Teng 2008), Olin Criteria showed high
sensitivity (94%) and specificity (85%). Thus, the
NIMH criteria include patients who meet DSM-IV
criteria for major depression, as well as less severe
forms of depression. This may explain why higher
rates of depression are detected by the NIMH-dAD
criteria than the DSM or ICD criteria. The results of
neurobiological and treatment studies may differ
depending on the depression diagnostic criteria used
if less severely depressed patients are included.
Another issue that is important to consider regarding
diagnosis is the overlap in symptoms between
depression and apathy (Starkstein et al., 2008). Even
in studies that have used instruments to assess both
depression and apathy (discussed in the Prevalence
section below), apathy is a significant predictor of
both major and minor depression (Starkstein et al.,
2011).
Introduction
The importance of improving diagnostic criteria and
outcome measures for depression and depressive
symptoms in AD, for understanding their
neurobiological substrates, and for developing more
effective treatments has been an increasing focus of
research for the past decade. The public health
significance of depression in AD is underscored by
the observations of the high prevalence of depression
in MCI and AD; the prognostic significance of
depression in normal aging and MCI with respect to
cognitive and functional decline, and the limited
efficacy of approved pharmacotherapies developed
to treat depression in young/adult individuals. The
depression workgroup of the Neuropsychiatric
Syndromes Professional Interest Area of ISTAART
included participants with diverse expertise in
psychiatry, clinical trials, psychopharmacology,
neuroimaging and neuroscience (animal models/
neuropathology) who were affiliated with academia,
government (NIH) and the pharmaceutical industry.
In the following sections, a review of the clinical and
neurobiological studies will be presented,
followed by a discussion of research priorities.
Assessment. A table of the characteristics of well
known and often utilized scales used to assess
depressive symptoms in AD patients is shown in
Table 1. The measures used to assess depressive
symptoms in clinical and treatment studies includes
scales developed to assess depression in younger
patients (HAMD, MADRS), specific to older noncognitively impaired individuals (GDS) and
designed for patients with cognitive impairment
(CSDD and NPI). The sensitivity of the scales
(HAMD, NPI and CSDD) to detecting treatment
effects of a sertraline/placebo study has been
evaluated (Mayer et al., 2006). The CSDD detected
greater treatment effects compared to the subscales
of the HAMD or the mood subscale of the NPI.
Thus, the CSDD, which was derived from the
HAMD and involves a semi-structured interview of
both the patient and caregiver, may be the most
sensitive to detecting the antidepressant treatment
effects in AD patients with depression.
Phenomenology and Assessment
Diagnosis. The diagnostic criteria for major
depression based on the diagnostic and
statistical manual (DSM-IV) have been used to
diagnose depression in AD patients. Five of the
following symptoms must be met for a two week
period: depressed mood, decreased interest/pleasure,
weight or appetite loss/gain, insomnia/hypersomnia,
psychomotor agitation/retardation, fatigue/loss of
energy, worthlessness/guilt, decreased concentration
and thoughts of death/suicide. The recognition that
the criteria for major depression may not reflect
depression in AD led to the development of
provisional diagnostic criteria for “Depression of
AD” by a workgroup organized by the NIMH (Olin
et al., 2002). The Olin criteria differed from the
DSM-IV criteria in the following respects: three or
more symptoms were required (though not required
to be present every day), and the symptoms of
irritability and social isolation/withdrawal were
added. Loss of interest and poor concentration were
Prevalence. Of the neuropsychiatric symptoms
observed in MCI and AD, depression and affective
symptoms are the most common. The period
prevalence of depression in AD was estimated at
3
77% over 5 years (Steinberg 2008). In this
population-based study, 29% of patients had
depression at baseline and 41-47% developed
depression subsequently. In the same population
based study (Cache County), using latent class
modeling of dementia severity measures and the
NPI, an affective syndrome was identified that
included depression, irritability, and anxiety in 28%
of patients, 50-60% of whom also showed symptoms
of apathy and aberrant motor behavior. In a clinic
sample (n=971), 21% of patients met DSM-IV
criteria for major depression, 39% met criteria for
minor depression and 40% demonstrated a low level
of depression symptoms that would not be sufficient
to meet either diagnostic criteria (Starkstein 2011).
In this study, anxiety and apathy were significant
predictors of depression, not irritability. Further,
minor depression was associated with greater apathy.
At 17-month follow-up of AD patients who met
criteria for either major or minor depression, 51%
were remitted, 28% met criteria for major and 21%
criteria for minor depression. Importantly, remission
was not related to apathy, gender or antidepressant
treatment (n=99; Starkstein 2005). These findings
suggest that depressive symptoms fluctuate over the
course of AD and antidepressant treatment may not
have a substantial effect on depressive symptoms.
The question of continued use of antidepressants in
this population remains. Thus, depression in AD is
observed in a substantial number of patients assessed
with structured and semi-structured assessments
developed for major depression, as well as the NPI.
While major depression is observed in a sub-set of
patients, minor depression and depressive symptoms
are observed more frequently. As depressive
syndromes differ in symptom expression and
severity, it is possible that the definition of
depression used in treatment and neurobiological
studies may have an effect on the results obtained
and that a dimensional approach may be more
informative, as outlined in the RDOCS proposal
(Insel et al., 2010).
some (Zweig 1988, Zubenko and Moossey, 1988),
but not all studies (Hoogendijk 1999). Similarly, loss
of serotonin neurons in the raphe nuclei has been
observed in some (Zweig 1988), but not all studies
(Hendricksen 2004). Dopaminergic cell loss in the
substantia nigra has been reported, although the
meso-limbic system has not been the focus of
investigation (Zubenko et al., 1992). A relatively
consistent finding is a greater loss of hippocampal 5HT1A receptors in depressed versus non-depressed
AD patients, with a comparable loss of 5-HTT and
5-HT2A in these two AD groups relative to controls
(Lai 2011, Thomas 2006). Similarly the 33-40%
reduction in cells immunoreactive for 5HT2A and
5HT6 receptors observed in AD patients points to
the severely compromised serotonin system and may
contribute to the development of neuropsychiatric
symptoms in AD (Lorke 2006) In contrast, several
studies have shown a relative preservation of basal
forebrain cholinergic neurons in depressed versus
non-depressed AD patients (Zweig 1988, Minger
2000). With respect to the amino acid
neurotransmitters, decreased GABA levels and
higher GABA(A)/benzodiazepine receptors in
frontal and temporal cortex have been reported in
depressed versus non-depressed AD patients
(Garcia-Alloza 2006). Decreases in the vesicular
glutamate transporter (VGLUT1) in parietal and
temporal cortices are observed to a greater extent in
depressed than non-depressed AD patients (Kirvel
2006). In summary, there is evidence for greater
monoamine neuron loss in depressed versus nondepressed AD patients as well as of relative
preservation of cholinergic neurons. The cortical and
limbic projections of these systems (receptors and
transporters) have not been well characterized.
Inhibitory (GABA) and excitatory (Glutamate)
amino acid neurotransmitters are affected, as is
hypothesized to occur in major depression
(decreased GABAergic and increased glutamatergic
function). Interestingly, AD patients with a lifetime
history of major depression had greater AD
neuropathology
(hippocampal
amyloid
and
neurofibrillary tangles) than those without a history,
as well as a more rapid rate of cognitive decline
(Rapp 2006).
Neurobiology
Neuropathology. Several studies have reported
specific neuropathologic findings in depressed
versus non-depressed AD patients, although some
are controversial. Greater loss of noradrenergic
neurons in the locus coeruleus has been observed in
Genetics. With respect to genetic polymorphisms
associated with depressed compared to nondepressed AD patients, the most common
4
polymorphisms associated with AD risk, as well as
with mood disorders have been investigated. ApoE 4
was associated with depression in some studies,
particularly in women (Delano-Wood 2008, Craig
2005), but not all studies (Liu 2002, Pritchard 2007,
Chen 2012). An association of a family history of
depression in first degree relatives with the
development of AD has been shown in some (Fahim
1998, Lyketsos 1996, Pearlson 1990) but not all
studies (Heun 2002).
changes in depressed versus non-depressed AD
patients. Greater glucose metabolic deficits are
observed in frontal and parietal cortices in depressed
versus non-depressed AD patients. These findings
are in contrast to late life major depression,
including the observations of greater white matter
hyperintensities,
increased
cortical
glucose
metabolism and 5-HTT and 5-HT1A receptor loss
(as reviewed by Smith et al., 1997). However, most
neuroimaging studies use symptom ratings rather
than DSM IV or NIMH criteria for major depression
and more mildly depressed patients may have been
included in the study samples.
Mostly negative results have been obtained for the
serotonin and dopamine polymorphisms implicated
in mood disorders. The following polymorphisms
have been investigated: dopamine [ DAT1 3'-UTR
VNTR, DRD1 (A-48G), DRD2 (ser311cys; Cins/del), DRD3 (ser9gly) and DRD4 (VNTR)
(Pritchard 2008, Pritchard 2009} and serotonin
[serotonin transporter (LPR, VNTR), 5-HT1A, 5HT6 (C267T; Pritchard 2008, Assal 2004, Micheli
2006, Liu 2001]. It is noteworthy that there is
evidence linking genetic polymorphisms to both
depression and AD, including the cholinergic system
(choline acetyltransferase (G4A polymorphism,
Gruneblatt 2009), inflammation (interleukin-1 beta,
-511 variant, McCulley 2004), and neurotrophic
factors (BDNF; Val66Met, Borroni 2009).
Treatment Studies
Several randomized, placebo controlled studies of
selective serotonin reuptake inhibitors (SSRIs) have
been reported to treat depression in AD (as reviewed
by Nelson and Devanand, 2011, Lee and Lyketsos,
2003). The single site “DIADS” study (n=44) in AD
patients who met DSM-IV criteria for major
depression observed that sertraline was superior to
placebo (Lyketsos et al., 2003). In the follow-up,
multi-site “DIADS-2” (n=131) in AD patients who
met the Olin Criteria (Olin et al., 2002) no
significant sertraline/placebo differences were
observed at either 12 or 24 weeks (Rosenberg 2010,
Weintraub 2010). In this study, sertraline was not
effective in patients with a diagnosis of major
depression (Drye et al., 2011). Preliminary studies of
mixed SSRI/ selective noradrenergic reuptake
inhibitors (SNRIs) show efficacy (Milnacipran,
Mirtazapine; Mizukani 2009, Raji and Brady 2001).
However, a recent UK study comparing sertraline,
mirtazepine and placebo in patients with probable or
possible AD (n=218) who had a score of 8 or higher
on the CSDD showed no difference between either
drug or placebo for up to 39 weeks of treatment
(Study of Antidepressants for Depression in
Dementia-SADD; Bannerjee et al., 2011). While
there is evidence that positive treatment effects have
been found in studies using more (DSM-IV TR
MDD; Lyketsos 2000) versus less stringent
depression criteria (minor depression/dysthymia;
Nyth and Gottfries 1990, Petraccia 1996), this
observation has not been replicated recently (Drye et
al., 2011, Bannerjee et al., 2011). Thus, clinical trials
of SSRI and SNRI antidepressants across a range of
depression severities and treatment durations have
Neuroimaging. The majority of structural imaging
studies have not observed differences between
depressed and non-depressed AD patients in whole
brain grey matter atrophy (Berlow 2009, Bruen
2008), or white matter hyperintensities and volumes
(Berlow
2009). Studies that have observed
differences, report greater frontal lesion burden
(Mueller 2010) and smaller right hippocampal
volumes (Morra ADNI 2009) in depressed AD
patients. With respect to functional imaging, several
studies have demonstrated lower cerebral glucose
metabolism in depressed versus non-depressed AD
patients in the frontal (DFPFC, SFG, ACG) or
parietal cortex (post-central gyrus, superior and
inferior lobule; Lee 2006, Holtoff 2005, Sultzer
1995, Lopez 2001). The limited neurochemical
imaging studies have shown decreased 5-HT2A and
5-HTT in AD, but no further decreases in depressed
AD patients. One study observed that lower 5-HTT
was correlated with greater depression symptom
severity (Oichi 2009). Thus, the majority of studies
do not find greater grey or white matter structural
5
not shown that these classes of antidepressants
reduce depressive symptoms to a greater extent than
placebo. While the negative trials could be due to
issues in study design and measurement, these
observations suggest that other neurochemical or
molecular mechanisms should be considered, as well
as brain stimulation (TMS) other forms of behavior
therapy (psychotherapy, cognitive therapy).
norepinephrine and dopamine; the cholinergic
system was not significantly affected. Perhaps the
best evidence for the important role of early
intervention comes from studies in a triple transgenic
mouse model of AD. Mice treated with the SSRI,
paroxetine, prior to the onset of behavioral deficits
developed less severe spatial navigation deficits and
less hippocampal beta amyloid and tau deposition
than saline treated animals (Nelson et al., 2007).
These are two examples of the potential of animal
models in understanding the neurobiology and
developing novel treatments of depression in AD.
Treating depression in aging or MCI
to delay AD transition?
Several lines of evidence suggest that depression is
associated with an increased dementia risk. A recent
review reported a 2-5 fold increased risk of dementia
is associated with depression (6/12 studies; Byers
and Yaffe 2011). Given the prognostic significance
of depression and neuropsychiatric symptoms in
MCI and AD, there has been a recent focus on
understanding these symptoms in cognitively normal
individuals. Mild Behavioral Impairment (MBI),
defined as a persistent behavioral change with mild
psychiatric symptoms but without significant
cognitive or functional impairment (Taragano 2009),
is also associated with increased risk of AD and
fronto-temporal dementia. Since MCI is widely
considered to be an early stage of AD, treatment of
depression in MCI or MBI might delay progression
to full dementia. Thus, understanding the
neurobiology of NPS in MCI (and MBI) is a
promising approach to identifying therapeutic targets
that delay/prevent dementia.
Priorities for research
The following are research questions that are
important to understanding the nature of the
neurobiological mechanisms underlying depression
in AD so that more effective interventions can be
designed and tested:
1) Is the construct of depression in AD stable or
dynamic over time? Can the same diagnostic
criteria
and
symptom
assessment
instruments be used in normal aging, MCI
and AD? Should the focus be on depression
or on a broader mood/effective syndrome?
2) Should depression in AD be considered a
syndrome or will a dimensional approach
across multiple levels of analysis (genes,
circuits, behavior) be more useful, as
outlined in the NIMH Research Domain
Criteria project (RDoC)?
3) Do the same neurobiological mechanisms
underlie depressive symptoms in normal
aging as well as MCI and AD? How can an
understanding of alterations in affective
neural
circuitry,
neurotransmitter
modulation,
synaptic
plasticity
and
relationship to AD pathology inform the
development of more effective treatments,
such as combination pharmacologic
treatments
(e.g.
targeting
multiple
monoamine
systems
or
molecular
mechanisms
associated
with
mood
symptoms such as inflammation) or
combined pharmacologic and behavioral
interventions (e.g. drugs with antidepressant
action and cognitive behavior therapy)?
The role of transgenic animal models
Animal models have been used to understand the
earliest neurobiological changes associated with
cognitive as well as neuropsychiatric symptoms and
in identifying potential treatments even before the
development of significant AD pathology. One of
the best examples is a study in the APPswe/PS1dE9
transgenic mouse that demonstrated the development
of age-related beta-amyloid deposition in cortical
areas but no significant loss of forebrain neurons
(Liu et al., 2008). This mouse model showed that
progressive degeneration of monoamine axons is
followed by cell body atrophy and eventually
monoamine neuron loss in a pattern similar to that
observed in the early stages of AD. The serotonin
system was affected most, followed by
6
4) Can the behavioral evaluation of transgenic
animal models of AD pathology (amyloid,
tau, neuroinflammation) for depressive and
stress responses elucidate the relationship
between AD pathology and depression?
5) Will early and intensive treatment of
depressive symptoms in MBI and MCI
prevent the development of further
pathology and delay the dementia transition?
depression in these conditions and whether
the same or different treatments are
indicated across the spectrum of cognitive
impairment;
4) The design of intervention studies to
evaluate the impact of reducing depressive
symptoms in MCI on cognitive and
functional outcome and AD progression.
Both pharmacotherapy and psychotherapy or
cognitive therapy alone or in combination
should be considered (Kurz et al., 2011).
Immediate Future Directions
Conclusions
Several immediate future directions are suggested by
the data reviewed:
The diagnosis of depression in AD is complicated by
dementia symptoms and may be a milder form of
depression in some patients.
Nonetheless,
depression (as well as a lifetime history of
depression) in AD is associated with greater brain
pathology, greater cognitive deficits and functional
impairment and a more rapid course of longitudinal
decline.
Even if depression in AD and major
depression have a common origin, the severe
neurochemical (5-HT/NE) and molecular pathology
(amyloid, vascular disease) in AD may explain why
treatments effective in major depression may be
ineffective in depression in AD. These observations
underscore the importance of: 1) earlier intervention
targeting depressive symptoms in MBI and MCI that
may prevent further neurodegeneration and
progression to AD and 2) identifications of new
antidepressant
targets
as
informed
by
neurobiological data (e.g. post-synaptic 5-HT4 or 5HT6 receptors or neuroinflammatory mechanisms).
1) The secondary analysis of large longitudinal
studies in AD to understand the natural
history of depression in AD;
2) The secondary analysis of large, multicenter controlled studies (DIADS, SADD) to
assess the stability of the depression
diagnosis; the sensitivity of outcome
measures; and whether currently approved
antidepressant treatment is effective for
certain depressive symptoms (e.g. mood,
vegetative symptoms);
3) Neurobiological
studies
(genetics,
neuroimaging)
using
both
stringent
depression criteria and symptom severity
measures to study the neurochemical and
other molecular mechanisms and to compare
minor and major depression in normal aging,
MCI and AD. Such studies are critical to
understand
whether
there
are
neurobiological
differences
between
7
Table 1
Depressive symptom rating scales used in AD studies
Name of Scale
Hamilton Depression Rating Scale
Type
Informant
Rating
Semi- Structured Interview
Patient
Severity/Frequency
Semi- Structured Interview
Patient
Severity
Self-Report
Patient
Presence/Absence
Semi- Structured Interview
Patient/ Caregiver
Severity
Semi- Structured Interview
Patient/ Caregiver
Severity + Frequency
(HAMD)
Montgomery-Asberg Depression Rating Scale
(MADRS)
Geriatric Depression Scale
(GDS)
Cornell Scale of Depression in Dementia
(CSDD)
Neuropsychiatric Inventory – Clinician
Version (NPI-C)
8
Acknowledgements
We are grateful to Dr. Luis Agüera Ortiz for his valuable comments on the manuscript. Funding Support: GSS
receives research funding from the National Institute of Health (MH 086881, AG038893, AG041633), the
National Association for Research in Schizophrenia and Depression and Pfizer. Y.E.G. was supported by NIMH
grant K01-MH68351, NIA grant U01-AG006786 (the Mayo Clinic Study of Aging), National Center for
Research Resources grant RR024150 (Mayo Clinic CTSA [Career Transition Award]), and the Robert Wood
Johnson Foundation (Harold Amos Scholar) MKL receives research funding from NIA (029401), NIEHS
(ES017384, ES019267), NINDS (NS076160, NS038065),
and VA-Merit (BX001639). APP receives support from: Grant/Research Support*: Baxter, BMS, Elan,
Genentech/Roche, Janssen Alzheimer Initiative, Medivation, Pfizer, Toyama, NIH/NIA (R01 AG031348,
1RC2AG36535-01, AG024904, 501 AG10483-19), Consultant/Advisory Board*: Elan, Janssen Alzheimer
Initiative; and Speakers’ Bureau*: Forest (*past two years).
Conflict of Interest
The authors have no conflict of interest to report. The views expressed in this paper are those of the
authors, and do not necessarily represent the official views of their sponsoring agencies.
9
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