STANFORD UNIVERSITY

                    Depression, antidepressants, and theshrinking hippocampus
Robert M. Sapolsky*
Department of Biological Sciences, Stanford University, and Department of Neurology, Stanford University School of Medicine, Gilbert Laboratory, MC 5020,
Stanford, CA 94305-5020
               Throughout human history, it has been
apparent that few medical maladies
are as devastating in their effects as major
depression. And since the 1950s, with the
advent of the first generation of antidepressants,
it has been apparent that depression
is a biological disorder. This has
generated the tremendous intellectual
challenge of how to understand the material,
reductive bases of a disease of malignant
sadness.
Both the tragic components and the
intellectual challenge of depression have
deepened in the last decade with a series
of high-visibility reports that indicate prolonged,
major depression is associated
with atrophy within the central nervous
system. A report in this issue of PNAS by
Czeh et al. (1) adds support to a possible
route for reversing these morphological
changes.
Such atrophy is centered in a brain
region called the hippocampus. This structure
plays a critical role in learning and
memory, and the magnitude of the hippocampal
volume loss (nearly 20% in
some reports; refs. 24) helps explain
some well-documented cognitive deficits
that accompany major depression. These
were careful and well-controlled studies,
in that the atrophy was demonstrable after
controlling for total cerebral volume and
could be dissociated from variables such
as history of antidepressant treatment,
electroconvulsive therapy, or alcohol use.
               Moreover, more prolonged depressions
were associated with more severe atrophy.
These findings of hippocampal atrophy
raise immediate questions. First, is it permanent?
Tentatively, this appears to be
the case, as the atrophy persisted for up to
decades after the depressions were in remission.
In addition, the extent of atrophy
did not lessen with increasing duration of
remission (24).
               Next, does the hippocampal atrophy
arise as a result of depression, or does it
precede and even predispose toward depression?
There is little evidence for the
latter (discussed in ref. 5), and most in the
field tacitly assume that this morphological
change is a consequence of the biology
underlying the affective (mood) aspects of
the disease.
More challenging, what are the cellular
bases of the persistent atrophy? Some
plausible candidate mechanisms exist, all
built around the numerous ways in which
major depression is, ultimately, a stressrelated
disorder. Sustained stress has
three relevant adverse effects on hippocampal
morphology. First, it can cause
retraction of dendritic processes in hippocampal
neurons (reviewed in ref. 6).
Although this could cause atrophy of total
hippocampal volume secondary to loss of
neuropil volume, it is unlikely to be relevant
here, in that the retraction readily
reverses with the abatement of stress. A
second adverse effect of stress is the inhibition
of neurogenesis in the adult hippocampus
(reviewed in ref. 7). Finally, in
some, but not all, studies sustained stress
can cause loss of preexisting hippocampal
neurons (i.e., neurotoxicity) (reviewed in
ref. 8). Both stress-induced inhibition of
neurogenesis andyor neurotoxicity could
be relevant to the hippocampal atrophy. A
number of heroically obsessive studies
have reported the results of postmortem
cell counts in frontal cortical regions of
the brains of depressives, indicating cell
loss (9, 10); similar studies must be done in
the hippocampus to determine which cellular
mechanism(s) underlies the volume
loss.
An even more challenging question is
what is the proximal cause of the volume
loss. A usual suspect is the class of hormones
called glucocorticoids (with the
human version being cortisol). These steroids
are secreted by the adrenal gland in
response to stress, and decades of work
have shown them to have a variety of
adverse effects in the brain, centered in
the hippocampus (which contains considerable
quantities of receptors for glucocorticoids).
               The effects include retraction
of dendritic processes, inhibition of
neurogenesis, and neurotoxicity (reviewed
in ref. 8). Moreover, hippocampal
volume loss occurs in Cushings syndrome
(in which there is hypersecretion of cortisol,
secondary to a tumor) (11). In addition,
about half of individuals with major
depression hypersecrete cortisol.
               Finally, the individuals in these studies
demonstrating hippocampal atrophy were
most likely to have suffered from the
subtype of depression with the highest
rates of hypercortisolism (2, 3). Thus, considerable
correlative evidence implicates
glucocorticoids. Nonetheless, no study
has yet demonstrated that such atrophy
only occurs, or even is more likely to
occur, among depressives who are
hypercortisolemic.
With these various pieces emerging in
recent years, another reasonable question
is whether anything can be done about the
atrophy, and this is where the exciting
findings of Czeh et al. (1) come in. A
number of studies using rodents indicate
that some of the standard treatments for
depression, namely administration of antidepressant
drugs or the use of electroconvulsive
therapy, have effects on the
hippocampus that should counter those
reported in major depression. For example,
one class of antidepressant drugs prevents
stress-induced retraction of dendritic
processes (12, 13). In addition, both
antidepressant drugs and electroconvulsive
therapy increase adult neurogenesis
in the hippocampus (14, 15). The work of
Czeh et al. represents an important extension
of these findings in two ways. First,
they now report similar effects of an antidepressant
drug in the primate hippocampus.
And critically, this is the first
such demonstration with an animal model
of depression, rather than in undepressed
subjects.
               The study involved tree shrews, a prosimian
primate that the authors have long
used in a model of depression induced by
psychosocial conflict and social subordinance
(16). Subjects underwent 5 weeks of
such stress, with treatment during the last
four with vehicle or the antidepressant
tianeptine. Thus, in a way that is obviously
artificial, the time course of stress and
antidepressant treatment roughly models
See companion article on page 12796.
*E-mail: Sapolsky@stanford.edu.
1232012322 u PNAS u October 23, 2001 u vol. 98 u no. 22 www.pnas.orgycgiydoiy10.1073ypnas.231475998
what a depressed and medicated human
might experience.
               The authors first demonstrated that in
animals not treated with tianeptine, psychosocial
stress induced some neurobiological
and physiological alterations reminiscent
of those seen in human
depressives. Basal cortisol levels increased
'50%. Proton magnetic resonance spectroscopy
of the cerebrum indicated 13
15% decreases in measures of neuronal
viability and function (the neuroaxonal
marker N-acetyle-aspartate), cerebral metabolism
(creatine and phosphocreatine),
and membrane turnover (choline-containing
compounds). In contrast, there was no
change in a glial marker of viability (myoinositol).
Furthermore, psychosocial
stress caused a roughly 30% decrease in
proliferation of new cells in the hippocampus.
               Finally, such stress was associated
with a nonsignificant trend toward a decrease
in total hippocampal volume.
Then, to complete the story, the authors
showed that tianeptine prevented many of
these stress-induced changes. These included
the spectroscopic alterations, the
inhibition of cell proliferation, and a significant
increase in hippocampal volume
(as compared with stress 1 vehicle animals).
Of significance (see below), tianeptine
did not prevent the stress-induced rise
in cortisol levels.
Overall, these are impressive and important
findings. Czeh et al. have shown
that a primate model of stress-induced
depression induces signs of decreased
neuronal metabolism and function, as well
as decreased cell proliferation. Moreover,
the fact that there was only a trend toward
decreased hippocampal volume is readily
explained as reflecting the relatively short
duration of the stressor; human studies
suggest that hippocampal atrophy is demonstrable
only after major depression on
the scale of years. Finally, the authors
show that antidepressant treatment prevents
these neurobiological alterations.
                Naturally, these findings raise some
questions, and a number of pieces of this
puzzle do not yet fit in place.
At first glance, one exciting implication
of this study is the suggestion that the
hippocampal volume loss in prolonged
depression arises from inhibition of hippocampal
cell proliferation, and that antidepressant
treatment normalizes the
former by preventing the latter. However,
the careful data of Czeh et al. argue
against this idea, at least in their model.
Neurogenesis in the adult hippocampus is
restricted to the subgranular zone, and
newborn neurons appear to migrate only
as far as the nearby dentate granule layer.
For hippocampal neuroanatomy neophytes,
this means that the revolution in
adult neurogenesis occurs entirely in a
fairly small subsection of the hippocampus;
there has been some debate over just
how much adult neurogenesis occurs and
how much turnover there is in adult dentate
gyrus neurons (17). Thus, if changes
in overall hippocampal volume are secondary
to changes in cell proliferation,
one would predict that (i) psychosocial
stress would lead to a marked reduction in
the volume of the dentate granule layer,
and (ii) this would be prevented by tianeptine.
Instead, neither was observed.
It is not immediately obvious how much
these findings generalize to other antidepressants.
               The vast majority of antidepressants
in clinical use work by increasing the
synaptic availability of monoamine neurotransmitters.
Although the best known of
these are the specific serotonin reuptake
inhibitors such as Prozac, other efficacious
drugs also block the reuptake of norepinephrine
andyor dopamine. Nicely commensurate
with the involvement of serotonin,
there is some evidence that
increased serotonin availability can stimulate
cell proliferation in the hippocampus
(18, 19). However, tianeptine is a distinctly
atypical antidepressant (with, reputedly,
only limited clinical efficacy), which increases
serotonin reuptake. Thus, it decreases
synaptic serotonin concentrations,
rather than enhancing them.
Embedded in the human clinical studies
is more evidence that these findings may
not automatically extend to other antidepressants.
In the broadest statement of
what the current study suggests, administration
of antidepressants not only can
cure the affective symptoms of depression,
but also can reverse some disquieting neurobiological
correlates of depression as
well. However, it should be recalled that
the original studies linking depression
with hippocampal atrophy did not demonstrate
such atrophy in depressed individuals.
Instead, they demonstrated the
link in individuals years or decades into
remission from depression, with such remissions
arising, in most cases, from the
therapeutic efficacy of antidepressant
drugs (24). Tianeptine was introduced
only recently and currently is used only in
Europe. Thus, the human literature (in
which all studies were from Americanbased
groups) suggests that hippocampal
atrophy can still occur in depression (and
persist despite depression remission) in
individuals treated with the older, more
traditional antidepressants.
               A final set of questions swirl around the
complex issue of causal links among the
correlates uncovered. Which factors contribute
to and which are consequences of
depression? A number of scenarios can be
constructed. In the first (Fig. 1A), an array
of interacting factors involving stress and
a biological vulnerability give rise to a
depression and its associated affective
symptoms (arrow 1). Hypercortisolism occurs
in approximately half of subjects. An
extensive literature demonstrates that
such hypercortisolism can be both a response
to the stressors preceding depression
(arrow 2) and to depression itself
(arrow 3), and can, in turn, contribute to
the affective symptomology (arrow 4)
(20). In this model, these symptoms give
rise to the hippocampal abnormalities (arrow
5), which then contribute to the cognitive
deficits of sustained depression (arrow
6).
               In a second, related scenario (Fig. 1B),
the affective symptoms and hypercortisolism
arise for the same reasons as in Fig.
1A. In this model, the hypercortisolism is
directly responsible for the structural and
functional alterations in the hippocampus
(Fig. 1B, arrow 5).
Most in the field, I suspect, would subscribe
to some version of Fig. 1 A or B.
Some investigators, however, have posited
a very different model (cf. ref. 21; Fig. 1C),
one in which there is impaired hippocampal
neurogenesis as a starting point (reflecting
some sort of developmental abnormality).
In this model, such blunted
neurogenesis precedes and predisposes toward
depression and its affective and cognitive
symptoms (Fig. 1C, arrow 1), and
the loss of overall hippocampal volume is
a direct consequence of the impaired neurogenesis
(Fig. 1C, arrow 2). In variants on
this model, the hypercortisolism may or
may not precede the impaired neurogenesis,
and may or may not directly contribute
to it. Most in the field appear to be
skeptical about this model, in part, because
there is little biological rationale
connecting the rate of neurogenesis in the
hippocampus with affective states such as
grief, helplessness, and anhedonia. Moreover,
there is a problem with specificity:
whereas antidepressants (in addition to
often curing the affective symptoms of
depression) increase rates of neurogenesis,
the drug lithium (in addition to often
curing the symptoms of mania) increases
rates of neurogenesis (22).
               What do the findings of Czeh et al.
suggest about these models? Given the
obvious caveat that psychosocial stress in
tree shrews cannot be identical to a major
human depression, they suggest a number
of things. Their data fit well with Fig. 1A.
The specific findings do not allow one to
distinguish between tianeptine preventing
the hippocampal alterations by blocking
the link between stress and affective depression
(i.e., Fig. 1A, arrow 1), or by
preventing the link between the affective
symptoms and the hippocampus (Fig. 1A,
arrow 5).Although there is next to nothing
known about the biology of what might
create arrow 5 in Fig. 1A, arrow 1 is well
understood and constitutes the primary
point where antidepressants are traditionally
thought to exert their action.