www.elsevier.com/locate/euroneuro
European Neuropsychopharmacology 14 (2004) 135–142
Cholesterol in mood and anxiety disorders: review of the literature and
new hypotheses
George I. Papakostas *, Dost Ongur, Dan V. Iosifescu, David Mischoulon, Maurizio Fava
Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital, 15 Parkman Street, WACC #812, Boston,
MA 02114, USA
Received 3 December 2002; received in revised form 17 June 2003; accepted 17 June 2003
Abstract
Cholesterol plays an integral role in the structure and function of the cell membrane and may also affect neurotransmission in the central
nervous system. Previous work has identified abnormalities in serum cholesterol levels in patients with mood and anxiety disorders as well as
in suicidal patients. However, the biological significance of these abnormalities remains to be clarified. An understanding of how serum
cholesterol relates to the pathophysiology of mood disorders may generate biological markers that predict treatment response as well as
targets for novel therapeutic strategies. In this article, we review the literature studying the significance of cholesterol in mood and anxiety
disorders, with an emphasis on new studies focusing on the adverse impact of hypercholesterolemia on the treatment of major depressive
disorder (MDD). We then propose possible mechanisms that would account for the relationship between elevated cholesterol and treatment
non-response in MDD.
D 2003 Elsevier B.V./ECNP. All rights reserved.
Keywords: Cholesterol; Depression; Anxiety; Suicide; Membrane; Fluidity
1. Cholesterol levels in mood and anxiety disorders
1.1. Cholesterol and depression
Research suggests that patients with major depressive
disorder (MDD) may have significant differences in choles-
terol levels compared to healthy controls (Fava et al., 1996).
A number of studies report an association between low
cholesterol levels and major depression (Morgan et al.,
1993; Lindberg et al., 1994; Maes et al., 1994; Cadeddu
et al., 1995; Olusi and Fido, 1996; Horsten et al., 1997;
Suarez, 1999; Rabe-Jablonska and Poprawska, 2000; Steeg-
mans et al., 2000; Terao et al., 2000a; Rafter, 2001),
including a large Finnish study involving over 29 000
men (Partonen et al., 1989). Ghaemi and colleagues
assessed cholesterol levels in patients with various mood
disorders including bipolar disorder, MDD and schizoaffec-
tive disorder, and found significantly lower cholesterol
0924-977X/03/$ - see front matter D 2003 Elsevier B.V./ECNP. All rights reserv
doi:10.1016/S0924-977X(03)00099-3
* Corresponding author. Tel.: +1-617-726-6697; fax: +1-617-726-
7541.
E-mail address: [email protected] (G.I. Papakostas).
levels in patients experiencing manic or depressive episodes
compared to patients experiencing mixed episodes (Ghaemi
et al., 2000). Low cholesterol levels have also been found to
confer an increased risk of MDD (Partonen et al., 1989), and
to correlate with the severity of depressive symptoms in a
sample of elderly men (Morgan et al., 1993), middle-aged
women (Horsten et al., 1997), and depressed patients (Rabe-
Jablonska and Poprawska, 2000; Steegmans et al., 2000;
Rafter, 2001). Furthermore, a cholesterol-lowering diet with
increased fish intake was found to result in a decrease in
depressive symptoms (Weidner et al., 1992). In addition,
esterified cholesterol levels have been found in euthymic
relatives of depressed patients (Maes et al., 1994), suggest-
ing a possible genetic component for this phenomenon.
Other abnormalities related to lipid homeostasis described
in depressed patients include an increase in the activity of
enzymes involved in lipid oxidation and peroxidation (Bilici
et al., 2001), lower vitamin E concentrations (Maes et al.,
2000), and lower serum high-density lipoprotein-cholesterol
(HDL-C) levels (Maes et al., 1997). However, it is important
to note that not all studies suggest a relationship between
cholesterol and depression. Freedman et al. (1995), for
instance, did not find any relationship between cholesterol
ed.
G.I. Papakostas et al. / European Neuropsychopharmacology 14 (2004) 135–142136
and depression in an epidemiologic study involving 3490
men who had served in the US army. In a similar fashion,
McCallum et al. (1994) also found no relationship between
depressive symptoms and low cholesterol in a community
study of over 2800 men and women aged 60 and older.
1.2. Cholesterol and suicide
A number of studies have also associated low cholesterol
levels, especially below 160 mg/dl, with an increased risk of
death from suicide (Partonen et al., 1989; Boston et al.,
1996; Rabe-Jablonska and Poprawska, 2000; Sarchiapone et
al., 2001). Maes et al. (1997) reported lower serum high-
density lipoprotein cholesterol (HDL-C) in depressed men
with a history of serious suicide attempts. Atmaca et al.
(2002) more recently found that patients with suicide
attempts had significantly lower cholesterol levels than
controls. Patients admitted to an emergency room following
a suicide attempt were found to have lower cholesterol
levels than controls (Kunugi et al., 1997), while in a
separate study, the severity of a suicide attempt was in-
versely correlated with serum cholesterol levels (Kim et al.,
2002). A retrospective chart review of 783 psychiatric
outpatients revealed that the proportion of men with a
personal lifetime history of attempted suicide, especially if
violent, or the proportion of patients with a first degree
relative who completed suicide, was higher among the
group with cholesterol levels in the lowest quartile (Boc-
chetta et al., 2001). In a similar fashion, a retrospective chart
review of 584 psychiatric inpatients revealed that patients
who had attempted suicide had lower serum cholesterol
levels than non-suicidal patients (Modai et al., 1994).
Patients with low cholesterol levels were found to be twice
as likely to have ever made a medically serious suicide
attempt than men with levels above the 25th percentile
(Golier et al., 1995), while patients who survived a violent
suicide attempt were found to have lower cholesterol levels
than patients who survived a non-violent suicide attempt
(Alvarez et al., 2000) or controls (Alvarez et al., 1999). This
relationship between low cholesterol and suicide was further
confirmed in two epidemiologic studies (Zureik et al., 1996;
Ellison and Morrison, 2001). A number of reports also
suggest a relationship between the degree of suicidal idea-
tion and the degree of hypocholesterolemia. Papassotiro-
poulos et al. (1999), for instance, reported that the degree of
suicidal ideation in psychiatric inpatients was inversely
related to their cholesterol levels, while Sullivan et al.
(1994) reported a similar finding in outpatients with major
depressive disorder (Sullivan et al., 1994). Finally, there are
also reports of low cholesterol levels among parasuicidal
patients (Gallerani et al., 1995; Garland et al., 2000).
1.3. Low cholesterol and depression: possible mechanisms
Earlier studies suggested that very low cholesterol
levels (i.e. 160 mg/dl) may adversely effect mood result-
ing in depression, aggression, and possibly suicide by
way of a direct effect on the serotonin (5HT) system
(Hawton et al., 1993). It has been hypothesized that a
decrease in total serum cholesterol may lead to a decrease
in brain 5HT levels (Steegmans et al., 1996). In one
study, a low content of cholesterol within cell membranes
was shown to experimentally decrease the number of 5HT
receptors (Engelberg, 1992). In a separate study, monkeys
subject to a low-cholesterol diet were found to have a
blunted prolactin response to fenfluramine, indicating
reduced central 5HT activity (Muldoon et al., 1992).
Furthermore, depletion of cholesterol in human embryonic
kidney cells was reported to result in a decrease in 5HT
transporter (5HTT) activity (Scanlon et al., 2001). In
parallel, there is good evidence for an association between
reduced 5HT activity, depression and angry, aggressive
(Rosenbaum et al., 1993; Fava, 1997, 1998; Fava and
Rosenbaum, 1998; Fava et al., 2000), or suicidal behavior
(Hawton et al., 1993).
Alternative possible explanations have been offered.
Interleukin-2 (IL-2), a cytokine produced by T cells, has
been shown to cause a decrease in serum cholesterol while
suppressing melatonin secretion from the pineal gland that,
in turn, has been hypothesized to lead to depression and
suicidal ideation (Penttinen, 1995). Alternatively, genetic
variation on chromosome 16 has been reported to be
associated with both major depression and low lecithin
cholesterol acetyl-transferase activity, an enzyme involved
in the esterification of cholesterol (Maes et al., 1994).
Cholesterol-deficiency in neuronal membranes may also
have a direct averse impact on dendritic outgrowth (Fan
et al., 2000), synapse formation (Mauch et al., 2001),
and even neuronal survival (Michikawa and Yanagisawa,
1999).
More recently however, Maes et al. (1997) have pro-
posed an alternative possible mechanism that would ex-
plain the relationship between low cholesterol and
depression. The enzyme lecithin:cholesterol acetyltransfer-
ase (LCAT) is responsible for the formation of most
cholesterol esters in serum. The esterification of free
cholesterol is important in the transport and elimination
of free cholesterol from the body. After Maes et al. (1997)
found lower high-density lipoprotein cholesterol (HDL-C)
concentrations in the serum of men with MDD who had
made a serious suicide attempt than men with MDD who
had not made such an attempt, the authors proposed that
such patients may actually present with low LCAT activity
as an explanation for their lower HDL-C levels. The
authors then argued that patients with low LCAT activity
may have low or even normal serum levels of cholesterol,
however decreased elimination of body cholesterol would
actually lead to an increase in the cholesterol content of
the neuronal membrane, thereby adversely effecting neu-
ronal structure and physiology (the potential mechanisms
of such adverse effects are discussed in the latter portions
of this article).
ropsychopharmacology 14 (2004) 135–142 137
1.4. Cholesterol and anxiety
While a number of studies report low cholesterol in
patients with major depressive disorder, particularly in
suicidal patients, several studies report high cholesterol
levels in patients with anxiety disorders, or with co-morbid
depression and anxiety. Patients suffering from panic disor-
der (PD), generalized anxiety disorder (GAD), obsessive
compulsive disorder (OCD) and post-traumatic stress disor-
der (PTSD), all have been found to have higher cholesterol
levels than patients with anxiety disorders and co-morbid
MDD or healthy subjects (Hayward et al., 1989; Bajwa et
al., 1992; Kuczmierczyk et al., 1996; Agargun et al., 1998;
Kagan et al., 1999; Sevincok et al., 2001; Yamada et al.,
2001; Peter et al., 2002). Also, patients with co-morbid
depression and anger attacks were found to have elevated
cholesterol levels, even following adjustment for age, body
mass index (BMI) and gender (Fava et al., 1996). The
effects of anxiety on cholesterol may perhaps be mediated
through an increase in the activity of lipoprotein lipase
(Hayward et al., 1989), secondary to an increase in norad-
renergic tone seen in GAD (Charney and Redmond, 1983)
and PD (Villacres et al., 1987), resulting in an increase of
free fatty acids (Hayward et al., 1989). As we will discuss in
more detail in a latter section of this review, elevated
cholesterol may also directly contribute to anxiety by
altering the sensitivity of the g-aminobutyric acid (GABA)
receptors (Sooksawate and Simmonds, 1998, 2001a,b).
G.I. Papakostas et al. / European Neu
2. Serum cholesterol in the treatment of major
depressive disorder
Despite the body of evidence showing that patients with
anxiety disorders or co-morbid depression and anxiety have
high serum cholesterol levels while patients with MDD,
particularly suicidal patients, have low serum cholesterol
levels, studies exploring cholesterol in the treatment of
depression have been lacking. Studying cholesterol in
depression may help identify a factor that places these
patients at risk for non-response to treatment. Our group
recently tested whether cholesterol can serve as a marker of
clinical response to antidepressant treatment in MDD (Sona-
walla et al., 2002). Our initial conjecture, based on the
aforementioned hypothesis linking low cholesterol levels
with serotonergic dysfunction, was that patients with lower
cholesterol levels would have a poor response to treatment.
In contrast, we found that depressed patients with elevated
cholesterol levels, defined as greater than 200 mg/dl, were
more likely to be non-responders to fluoxetine treatment
than patients with non-elevated cholesterol levels (46 vs.
54%, respectively) after adjusting for age, gender and body
mass index (BMI). This surprising finding received further
support from another recent study by our group which
focused on cholesterol levels in patients with treatment
resistant depression (TRD) (Papakostas et al., 2003a). We
found that patients with TRD presented with higher triglyc-
eride levels and a trend towards higher cholesterol level at
baseline compared to depressed patients without TRD. In
the same study, high cholesterol levels also predicted poor
response to a 6-week open trial of nortriptyline (NT) in
patients with TRD.
3. Elevated cholesterol levels and antidepressant non-
response: possible mechanisms
If depressed patients have lower cholesterol levels on
average, why should elevated cholesterol levels be linked to
treatment resistance? One reason may be that elevated
cholesterol levels are a marker of vascular disease which
may be associated with poor response to antidepressants.
Several reports in the literature have suggested that vascular
risk factors—such as smoking, hypertension, and increased
serum cholesterol—play a putative role in the etiology of
depression. There is also neuropathological evidence for an
excess of atheromatous disease in the aortic and cerebral
vessels in late life depression (Thomas et al., 2001). On the
basis of such findings, several researchers have postulated a
‘vascular depression’ hypothesis (Alexopoulos et al., 1997;
Krishnan et al., 1997). This hypothesis argues that for a
subset of patients, depression may be caused by cerebro-
vascular disease manifesting as small lacunes in the subcor-
tical gray and the white matter. These lesions would then
disrupt the prefrontal systems related to mood regulation or
the white matter pathways connecting these areas with other
parts of the brain (Alexopoulos et al., 1997). As our studies
suggest, the presence of high cholesterol levels (a cardio-
vascular risk factor) is characterized by lower rates of
response to usual antidepressant therapies. While it is very
likely that vascular disease plays a key role in contributing
to antidepressant resistance in elderly hypercholesterolemic
patients, it is probably far less likely to contribute to this
phenomenon in younger patients, particularly younger
women, given the lower incidence of vascular disease in
these populations. In our studies, however, the relationship
between elevated cholesterol and treatment non-response
was present even after controlling for age and gender.
Another possibility that would explain why depressed
patients with high cholesterol levels are more likely to be
treatment non-responders may be that an excess of choles-
terol in cell membranes serves to inhibit neuronal growth. A
number of studies suggest that enhanced activity of the
enzyme g-secretase in CNS neurons inhibits neuronal and
dendritic outgrowth and promotes the formation of h-amyloid, implicated in the pathophysiology of Alzheimer’s
dementia (Wahrle et al., 2002). In contrast, inhibition of g-
secretase activity in human CNS neurons has been shown to
promote neuritic and dendritic outgrowth (Figueroa et al.,
2002). Enriching the neuronal membrane with cholesterol
has been found to stimulate the activity of the enzyme g-
secretase, while depletion of membrane cholesterol has been
G.I. Papakostas et al. / European Neuropsychopharmacology 14 (2004) 135–142138
shown to have opposite effects (Wahrle et al., 2002). In fact,
reducing serum cholesterol has been shown to result in a
decrease in neuronal formation of h-amyloid (Refolo et al.,
2001), while inducing hypercholesteremia has been shown
to have opposite effects (Shie et al., 2002). Similar to the
vascular depression hypothesis, however, one would also
expect any contribution of h-amyloid formation on antide-
pressant response to feature more prominently in the elderly.
A third possible explanation stems from research focusing
on the connection between cholesterol and the serotonergic
system.meta-Chlorophenylpiperazine (m-CPP), a metabolite
of the antidepressant trazodone, binds to a number of 5HT
receptors, primarily the 5HT-2a and -2c receptors (Kahn and
Wetzler, 1991; Terao et al., 2000b). In humans, administra-
tion of m-CPP results in stimulation of the hypothalamic–
pituitary–adrenal (HPA)-axis and cortisol secretion, while a
greater of m-CPP-induced cortisol secretion is thought to
reflect the sensitivity of these 5HT receptors (Terao et al.,
2000b). Two studies of young healthy controls revealed
serum cholesterol levels to be positively correlated with
the degree of cortisol secretion after m-CPP administration,
suggesting that a greater degree of sensitivity of these
receptors is associated with higher cholesterol levels and
vice versa (Terao et al., 1997, 2000b).
D,L-Fenfluramine is another serotonergic agent, which
acts by promoting the presynaptic release of 5HT and by
inhibiting 5HT re-uptake (McBride et al., 1990), thereby
indirectly stimulating 5HT receptors. This compound may
also bind to the 5HT transporter and exhibit presynaptic
5HT activity (Baumann et al., 1995). In healthy volunteers,
administration of D,L-fenfluramine also results in an in-
crease in plasma cortisol and prolactin (Cowen, 1993),
presumably through the activation of the 5HT-1a (Meltzer
and Maes, 1995) and 5HT-2a and -2c (Coccaro et al.,
1996) receptors, respectively. Studies of humans where
both m-CPP and D,L-fenfluramine were used as probes of
serotonergic function revealed a positive correlation be-
tween the prolactin response to D,L-fenfluramine and m-
CPP (Coccaro et al., 1997).
In a recent study our group reported that MDD patients
with elevated cholesterol levels at baseline (>200 mg/dl)
were more likely to demonstrate an attenuated cortisol
response to D,L-fenfluramine (Papakostas et al., 2003b).
There was also a trend toward significance for patients with
elevated cholesterol levels to demonstrate a blunted prolac-
tin response to D,L-fenfluramine. These results are in accor-
dance with two prior clinical reports that suggest the degree
of 5HT-receptor sensitivity, as evidenced by an elevated
secretion of cortisol or prolactin after administration of D,L-
fenfluramine, to confer a good prognosis to treatment
(Malone et al., 1993; Cleare et al., 1998). These results
are also in accordance with a study published by our group
reporting high cholesterol levels in depressed patients with
anger attacks (Fava et al., 1996), a population that also
shows evidence of attenuated serotonergic function by way
of a blunted prolactin response to D,L-fenfluramine (Fava et
al., 2000). In summary, while the former studies involving
non-depressed subjects suggest a positive relationship be-
tween serotonergic function and serum cholesterol levels
(Terao et al., 1997, 2000b), the present findings shed light
on the reciprocal relationship in patients with MDD, namely
that subjects with elevated cholesterol levels are more likely
to demonstrate attenuated serotonergic function.
4. Elevated cholesterol, attenuated serotonergic function
and treatment non-response in depression: are changes
in neuronal membrane fluidity responsible?
The above discussion suggests that the relationship
between cholesterol levels, treatment non-response, and
serotonergic function in depression are probably complex.
One possible explanation for this relationship may be that
high cholesterol levels are somehow directly responsible for
changes in serotonergic function in MDD. Incorporating
cholesterol into the neuronal phospholipid bilayer leads to a
reduction in membrane fluidity and an increase in mem-
brane mechanical strength (Barenholz, 2002), which may
serve to ‘insulate’ neurons by reducing proton and sodium
leaks through the lipid bilayer and, thereby, the amount of
energy required by each cell to maintain the transmembrane
potential. Cholesterol is also integral to the formation of
specialized microdomains within the cellular membrane
called lipid rafts (Simons and Ikonen, 1997). Neurotrans-
mitter receptors are concentrated and precisely localized in
specific areas of the neuronal membrane, and this precise
localization is critical for neurotransmission (Becher et al.,
2001). These lipid rafts have been suggested to serve as
assembly and sorting platforms for signaling complexes
necessary for the activation of signal cascades (Becher et
al., 2001). To date, a number of neurotransmitter receptors
have been found to operate within such rafts, including
GABA-B receptor (Becher et al., 2001), the a-7-subunit
acetylcholine receptor (Bruses et al., 2001) and the iono-
tropic AMPA-type glutamate receptor (Suzuki et al., 2001).
Excessive cholesterol may indirectly manipulate the confor-
mation and function of membrane-bound proteins and
receptors by reducing neuronal membrane fluidity and,
thereby, altering or disrupting the function of lipid rafts
(Ohvo-Rekika et al., 2002). Cholesterol also binds tightly to
a number of these transmembrane ion channels, enzymes
and receptors (Haines, 2002), and, as a result, may directly
affect the function these structures (Ohvo-Rekika et al.,
2002). These effects have already been described for the
GABA-A receptor. Specifically, it has been shown that both
enriching and depleting hippocampal neuronal membranes
of cholesterol results in alterations in GABA-A receptor
sensitivity that are thought to occur both indirectly, (i.e. as a
result of altered neuronal membrane fluidity; Sooksawate
and Simmonds, 2001a,b), and directly (i.e. by way of direct
binding to the GABA-A receptor itself; Sooksawate and
Simmonds, 1998).
G.I. Papakostas et al. / European Neuropsychopharmacology 14 (2004) 135–142 139
While there is no direct evidence to suggest that elevated
cholesterol may have an adverse impact on the sensitivity of
the 5HT receptors or 5HT transporter (5HTT) in the central
nervous system (CNS), a number of studies focusing on the
interactions between cholesterol, membrane fluidity, and
5HT in the peripheral vasculature of hypercholesterolemic
humans and animals provide preliminary support for such
an argument. Dilation of small arterioles in response to 5HT
administration has been described in animals, and is thought
to occur by way of a 5HT1-receptor mediated increase in the
production of nitric oxide at the level of the endothelium
(Mylecharane, 1990; Verbeuren et al., 1991; Whiting and
Cambridge, 1995; Lamping et al., 1999; McDuffie et al.,
1999). Studies involving genetic and diet-induced animal
models of hypercholesterolemia reveal that high cholesterol
levels result in blunted 5HT-mediated coronary arterial
vasodilation (Cohen et al., 1988; Shimokawa and Van-
houtte, 1989; Lamping et al., 1999). In a similar fashion,
patients with high cholesterol levels secondary to familial
combined hyperlipidemia (FCH) also showed blunted 5HT-
mediated vasodilation in forearm arteries that improved
significantly with lipid-lowering therapy (Stroes et al.,
1997). Finally, further evidence of suppression of the 5HT
system in hypercholesterolemic states in humans comes
from a study by Smith and Betteridge (1997), who demon-
strated that patients with familial hypercholesterolemia had
lower platelet 5HT concentrations than controls, and lower
collagen-mediated 5HT release in their platelets. Interest-
ingly enough, a number of studies suggest that this impair-
ment in vasodilatation is functional rather than anatomical,
as reversal of hypercholesterolemia during short-term treat-
ment with cholesterol-lowering medications results in nor-
malization of 5HT-mediated vasodilatation in humans
(Stroes et al., 1995; O’Driscoll et al., 1997; Perticone et
al., 2000).
In parallel to these reports of blunted 5HT-mediated
vasodilatory responses in the peripheral vasculature of
hypercholesterolemic animals and humans, a number of
studies report a link between changes in membrane fluidity
leading to alterations in 5HT-uptake by pulmonary-artery
endothelial cells (Block et al., 1986; Patel and Block, 1986;
Block and Edwards, 1987; Sheridan and Block, 1988). A
non-toxic decrease in the cholesterol content of the plasma
membrane, for instance, resulting in an increase in mem-
brane fluidity has been shown to decrease the rate (Vm) and
affinity (Km) of the 5HTT for 5HT (Scanlon et al., 2001).
Based on this evidence, it is quite possible that high
cholesterol levels may have a direct adverse impact on
5HT receptor function in the CNS by way of altered
membrane fluidity, as in the peripheral vasculature.
5. Conclusion
The studies reviewed here indicate an interesting rela-
tionship between cholesterol levels and the presentation
and treatment of major depressive disorder: while de-
pressed patients with low cholesterol levels (defined as
less that 160 mg/dl) appear to be at higher risk of suicide,
those with elevated levels (defined as greater than 200
mg/dl) appear more likely to be treatment-resistant, to
present with a co-morbid anxiety disorder, or to exhibit
anger attacks. Elevated as well as low cholesterol levels
may be associated with serotonergic dysfunction. A pri-
mary decrease in cholesterol levels may directly lead to
decreased brain 5HT activity through a variety of mech-
anisms, ranging from an alteration in 5HT levels, to 5HT
receptor concentration or 5HT transporter activity. Alter-
natively, the decrease in cholesterol levels seen in depres-
sion and suicide may be secondary to decreased
esterification of free cholesterol. In contrast, elevated
cholesterol levels may lead to lower 5HT receptor sensi-
tivity or 5HT transporter activity in depressed patients
compared to normal controls, either directly by binding to
the various membrane-bound 5HT receptors or transporter
or indirectly by altering the fluidity of the neuronal
membrane and thereby the conformation of these struc-
tures. If additional evidence were to further strengthen this
hypothesis, studies focusing on the use of agents that
principally operate beyond the plasma membrane in treat-
ing depressed or anxious patients with cholesterol levels
in either extreme would be warranted. Such agents include
S-adenosyl methionine (SAMe; Baldessarini, 1987), N-3fatty acids, and possibly hypericum perforatum (Thiele et
al., 2002). Other possible explanations for the relationship
between elevated cholesterol levels in depressed patients
and treatment non-response may be that elevated choles-
terol levels lead to inhibition of dendritic outgrowth, the
promotion of h-amyloid, or serve as a marker for co-
morbid vascular disease. Further studies are needed to
clarify the cellular mechanisms through which this rela-
tionship operates.
Acknowledgements
Financial support was provided by an American College
of Neuropsychopharmacology/GlaxoSmithKline Fellowship
in Clinical Neuropsychopharmacology (G.I.P.), a Harvard
Medical School/Kaplen Fellowship in Depression Research
(G.I.P.) and a Young Investigator Award from the American
Foundation for Suicide Prevention (G.I.P.).
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