Cholesterol in mood and anxiety disorders: review of the literature and new hypotheses

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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.).

References

Agargun, M.Y., Algun, E., Sekeroglu, R., Kara, H., Tarakcioglu, M., 1998.

Low cholesterol level in patients with panic disorder: the association

with major depression. J. Affect. Disord. 50, 29–32.

Alexopoulos, G.S., Meyers, B.S., Young, R.C., Campbell, S., Silbersweig,

D., Charlson, M., 1997. ‘Vascular depression’ hypothesis. Arch. Gen.

Psychiatry 54 (10), 915–922.

G.I. Papakostas et al. / European Neuropsychopharmacology 14 (2004) 135–142140

Alvarez, J.C., Cremniter, D., Lesieur, P., Gregoire, A., Gilton, A., Macquin-

Mavier, I. et al., 1999. Low blood cholesterol and low platelet serotonin

levels in violent suicide attempters. Biol. Psychiatry 45 (8), 1066–1069.

Alvarez, J.C., Cremniter, D., Gluck, N., Quintin, P., Leboyer, M., Berlin, I.

et al., 2000. Low serum cholesterol in violent but not in non-violent

suicide attempters. Psychiatry Res. 95 (2), 103–108.

Atmaca, M., Kuloglu, M., Tezcan, E., Ustundag, B., Gecici, O., Firidin, B.,

2002. Serum leptin and cholesterol values in suicide attempters. Neuro-

psychobiology 45, 124–127.

Bajwa, W.K., Asnis, G.M., Sanderson, W.C. et al., 1992. High choles-

terol levels in patients with panic disorder. Am. J. Psychiatry 149

(3), 376–378.

Baldessarini, R.J., 1987. The neuropharmacology of S-adenosyl-L-methio-

nine. Am. J. Med. 83, 95–103.

Barenholz, Y., 2002. Cholesterol and other membrane active sterols: from

membrane evolution to rafts. Prog. Lipid Res. 41, 1–5.

Baumann, M.H., Mash, D.C., Staley, J.K., 1995. The serotonin agonist

m-chlorophenylpiperazine (mCPP) binds to serotonin transporter sites

in human brain. Neuroreport 6 (16), 2150–2152.

Becher, A., White, J., McIlhinney, R., Jeffrey, R.A., 2001. The [gamma]-

aminobutyric acid receptor B, but not the metabotropic glutamate

receptor type-1, associates with lipid rafts in the rat cerebellum.

J. Neurochem. 79 (4), 787–795.

Bilici, M., Efe, H., Koroglu, M.A., Uydu, H.A., Bekaroglu, M., Deger, O.,

2001. Antioxidative enzyme activities and lipid peroxidation in major

depression: alterations by antidepressant treatment. J. Affect. Disord. 64

(1), 43–51.

Block, E.R., Edwards, D., 1987. Effect of plasma membrane fluidity on

serotonin transport by endothelial cells. Am. J. Physiol. 243 (5 Pt 1),

C672–C678.

Block, E.R., Patel, J.M., Angelides, K.J., Sheridan, N.P., Garg, L.C., 1986.

Hyperoxia reduces plasma membrane fluidity: a mechanism for endo-

thelial cell dysfunction. J. Appl. Physiol. 60 (3), 826–835.

Bocchetta, A., Chillotti, C., Carboni, G., Oi, A., Ponti, M., Del Zompo, M.,

2001. Association of personal and familial suicide risk with low serum

cholesterol concentration in male lithium patients. Acta Psychiatr.

Scand. 104 (1), 37–41.

Boston, P.F., Dursun, S.M., Reveley, M.A., 1996. Cholesterol and mental

disorder. Br. J. Psychiatry 169 (6), 682–695.

Bruses, J.L., Chauvet, N., Rutishauer, U., 2001. Membrane lipid rafts are

necessary for the maintenance of alpha 7 nicotinic acetylcholine recep-

tor in somatic spines of ciliary neurons. J. Neurosci. 21, 504–512.

Cadeddu, G., Fioravanti, P., Antonicelli, R. et al., 1995. Relationship be-

tween cholesterol levels and depression in the elderly. Minerva Med. 86

(6), 251–256.

Charney, D.S., Redmond, E.E., 1983. Neurobiological mechanisms in hu-

man anxiety: evidence supporting central noradrenergic hyperactivity.

Neuropharmacology 22, 1531–1536.

Cleare, A.J., Murray, R.M., O’Keane, V., 1998. Assessment of serotonergic

function in major depression using D-fenfluramine: relation to clinical

variables and antidepressant response. Biol. Psychiatry 44 (7), 555–561.

Coccaro, E.F., Kavoussi, R.J., Oakes, M., Cooper, T.B., Hauger, R., 1996.

5-HT2a/2c receptor blockade by amesergide fully attenuates prolactin

response to D-fenfluramine challenge in physically healthy human sub-

jects. Psychopharmacology (Berlin) 126 (1), 24–30.

Coccaro, E.F., Kavoussi, R.J., Trestman, R.L., Gabriel, S.M., Cooper, T.B.,

Siever, L.J., 1997. Serotonin function in human subjects: intercorrela-

tions among central 5-HT indices and aggressiveness. Psychiatry Res.

73 (1–2), 1–14.

Cohen, R.A., Zitnay, K.M., Haudenschild, C.C., Cunningham, L.D., 1988.

Loss of selective endothelial cell vasoactive functions caused by hyper-

cholesterolemia in pig coronary arteries. Circ. Res. 63 (5), 903–910.

Cowen, P.J., 1993. Serotonin receptor subtypes in depression: evidence

from studies in neuroendocrine regulation. Clin. Neuropharmacol. 16

(Suppl. 3), S6–S18.

Ellison, L.F., Morrison, H.I., 2001. Low serum cholesterol concentration

and risk of suicide. Epidemiology 12 (2), 168–172.

Engelberg, H., 1992. Low serum cholesterol and suicide. Lancet 339,

727–729.

Fan, Q.W., Yu, W., Gong, J.S., Zou, K., Sawamura, N., Senda, T. et al.,

2000. Cholesterol-dependent modulation of dendrite outgrowth and

microtubule stability in cultured neurons. J. Neurochem. 80 (1),

178–190.

Fava, M., 1997. Anger outbursts in unipolar depressive disorders. Ence-

phale 23 (Spec. No. 3), 39–42.

Fava, M., 1998. Depression with anger attacks. J. Clin. Psychiatry 59

(Suppl. 8), 18–22.

Fava, M., Rosenbaum, J.F., 1998. Anger attacks in depression. Depress.

Anxiety 8 (Suppl), 59–63.

Fava, M., Abraham, M., Pava, J., Shuster, J., Rosenbaum, J., 1996. Car-

diovascular risk factors in depression: the role of anxiety and anger.

Psychosomatics 37, 31–37.

Fava, M., Vuolo, R.D., Wright, E.C., Nierenberg, A.A., Alpert, J.E.,

Rosenbaum, J.F., 2000. Fenfluramine challenge in unipolar depression

with and without anger attacks. Psychol. Res. 94 (1), 9–18.

Figueroa, D.J., Morris, J.A., Ma, L., Kandpal, G., Chen, E., Li, Y., Austin,

C., 2002. Presenilin-dependant gamma-secretase activity modulates

neurite outgrowth. Neurobiol. Dis. 9, 49–60.

Freedman, D.S., Byers, T., Barrett, D.H. et al., 1995. Plasma lipid levels

and psychologic characteristics in men. Am. J. Epidemiol. 141 (6),

507–517.

Gallerani, M., Manfredini, R., Caracciolo, S., Scapoli, C., Molinari, S.,

Fersini, C., 1995. Serum cholesterol concentrations in parasuicide. Br.

Med. J. 310 (6995), 1632–1636.

Garland, M., Hickey, D., Corvin, A., Golden, J., Fitzpatrick, P., Cunning-

ham, S. et al., 2000. Total serum cholesterol in relation to psychological

correlates in parasuicide. Br. J. Psychiatry 177, 77–83.

Ghaemi, S.M., Shields, G.S., Hegarty, J.D. et al., 2000. Cholesterol levels

in mood disorders: high or low? Bipolar Disord. 2, 60–64.

Golier, J.A., Marzuk, P.M., Weiner, C., Tardiff, K., 1995. Low serum

cholesterol level and attempted suicide. Am. J. Psychiatry 152 (3),

419–423.

Haines, T.H., 2002. Do sterols reduce proton and sodium leaks through

lipid bilayers? Prog. Lipid Res. 40, 299–324.

Hawton, K., Cowen, P., Owens, D. et al., 1993. Low serum cholesterol and

suicide. Br. J. Psychiatry 162, 818–825.

Hayward, C., Taylor, C.B., Roth, W.T., King, R., Agras, W.S., 1989.

Plasma lipid levels in patients with panic disorder or agoraphobia.

Am. J. Psychiatry 146, 917–919.

Horsten, M., Wamala, S.P., Vingerhoets, A., Orth-Gomer, K., 1997.

Depressive symptoms, social support, and lipid profile in healthy

middle-aged women. Psychosom. Med. 59, 521–528.

Kagan, B.L., Leskin, G., Haas, B., Wilkins, J., Foy, D., 1999. Elevated lipid

levels in Vietnam veterans with chronic posttraumatic stress disorder.

Biol. Pscyhiatry 45, 374–377.

Kahn, R.S., Wetzler, S., 1991. m-Chlorophenylpiperazine as a probe of

serotonin function. Biol. Psychiatry 30 (11), 1139–1166.

Kim, Y.K., Lee, H.J., Yoon, D.K., Choi, S.H., Lee, M.S., 2002. Low serum

cholesterol is correlated to suicidality in a Korean sample. Acta Psy-

chiatr. Scand. 105 (2), 141–148.

Krishnan, K.R., Hays, J.C., Blazer, D.G., 1997. MRI-defined vascular

depression. Am. J. Psychiatry 154 (4), 497–501.

Kuczmierczyk, A.R., Barbee, J.G., Bologna, N.A., Townsend, M.H., 1996.

Serum cholesterol levels in patients with generalized anxiety disorder

(GAD) and with GAD and comorbid depression. Can. J. Psychiatry 41,

465–468.

Kunugi, H., Takei, N., Aoki, H., Nanko, S., 1997. Low serum cholesterol in

suicide attempters. Biol. Psychiatry 41 (2), 196–200.

Lamping, K.G., Nuno, D.W., Chappell, D.A., Faraci, F.M., 1999. Agonist-

specific impairment of coronary vascular function in genetically altered,

hyperlipidemic mice. Am. J. Physiol. 276 (4 Pt 2), R1023–1029.

Lindberg, G., Larsson, G., Setterlind, S., Rastam, L., 1994. Serum lipids

and mood in working men and women in Sweden. Epidemiol. Com-

mun. Health 48, 360–363.

G.I. Papakostas et al. / European Neuropsychopharmacology 14 (2004) 135–142 141

Maes, M., Delanghe, J., Meltzer, H.Y. et al., 1994. Lower degree of ester-

ification of serum cholesterol in depression: relevance for depression

and suicide research. Acta Psychiatr. Scand. 90, 252–258.

Maes, M., Smith, R., Christophe, A., Vandooleaghe, E., Van Gastel, A.,

Neels, H. et al., 1997. Lower serum high-density lipoprotein cholesterol

(HDL-C) in major depression and in depressed men with serious sui-

cidal attempts: relationship with immune-inflammatory markers. Acta

Psychiatr. Scand. 95 (3), 212–221.

Maes, M., De Vos, N., Pioli, R., Demets, P., Wauters, A., Neels, H. et al.,

2000. Lower serum vitamin E concentrations in major depression.

Another marker of lowered antioxidant defenses in that illness. J.

Affect. Disord. 58 (3), 241–246.

Malone, K.M., Thase, M.E., Mieczkowski, T., Myers, J.E., Stull, S.D.,

Cooper, T.B. et al., 1993. Fenfluramine challenge test as a predictor

of outcome in major depression. Psychopharmacol. Bull. 29 (2),

155–161.

Mauch, D.H., Nagler, K., Schumacher, S., Goritz, C., Muller, E.C., Otto, A.

et al., 2001. CNS synaptogenesis promoted by glia-derived cholesterol.

Science 294 (5545), 1354–1355.

McBride, P.A., Tierney, H., DeMeo, M., Chen, J.S., Mann, J.J., 1990.

Effects of age and gender on CNS serotonergic responsivity in normal

adults. Biol. Psychiatry 27 (10), 1143–1155.

McCallum, J., Simons, L., Simons, J. et al., 1994. Low serum cholesterol is

not associated with depression in the elderly: data from an Australian

community study. Aust. NZ J. Med. 24 (5), 561–564.

McDuffie, J.E., Coaxum, S.D., Maleque, M.A., 1999. 5-Hydroxytryp-

tamine evokes endothelial nitric oxide synthase activation in bovine

aortic endothelial cell cultures. Proc. Soc. Exp. Biol. Med. 221 (4),

386–390.

Meltzer, H.Y., Maes, M., 1995. Pindolol pretreatment blocks stimulation by

meta-chlorophenylpiperazine of prolactin but not cortisol secretion in

normal men. Psychiatry Res. 58 (2), 89–98.

Michikawa, M., Yanagisawa, K., 1999. Inhibition of cholesterol production

but not of non-sterol isoprenoid products induces neuronal cell death.

J. Neurochem. 72 (6), 2278–3385.

Modai, I., Valevski, A., Dror, S., Weizman, A., 1994. Serum cholesterol

levels and suicidal tendencies in psychiatric inpatients. J. Clin. Psychia-

try 55 (6), 252–254.

Morgan, R.E., Palinkas, L.A., Barrett-Connor, E.L., Wingard, D.L., 1993.

Plasma cholesterol and depressive symptoms in older men. Lancet 341

(8837), 75–79.

Muldoon, M.F., Rossouw, J.E., Manuch, S.B. et al., 1992. Effects of a low-

fat diet on brain serotonergic responsivity in cynomolgus monkeys.

Biol. Psychiatry 31, 739–742.

Mylecharane, E.J., 1990. Mechanisms involved in serotonin-induced vaso-

dilatation. Blood Vessels 27 (2-5), 116–126.

O’Driscoll, G., Green, D., Taylor, R.R., 1997. Simvastatin, an HMG-coen-

zyme: a reductase inhibitor, improve endothelial function within 1

month. Circulation 94, 258–265.

Ohvo-Rekika, H., Ramtedt, B., Leppimaki, P., Slotte, P., 2002. Cholesterol

interactions with phospholipids in membranes. Prog. Lipid Res. 41,

66–97.

Olusi, S.O., Fido, A.A., 1996. Serum lipid concentrations in patients with

major depressive disorder. Biol. Psychiatry 40 (11), 1128–1131.

Papakostas, G.I., Petersen, T., Sonawalla, S., Merens, W., Alpert, J.E.,

Iosifescu, D.V., Fava, M., Nierenberg, A.A., 2003a. Serum cholesterol

in treatment-resistant depression. Neuropsychobiology 47 (3), 146–151.

Papakostas, G.I., Petersen, T., Hughes, M., Fava, M., 2003b. Serum choles-

terol and serotonergic-receptor sensitivity in major depressive disorder.

Psychiatry Res. 118 (2), 137–145.

Papassotiropoulos, A., Hawellek, B., Frahnert, C., Rao, G.S., Rao, M.L.,

1999. The risk of acute suicidality in psychiatric inpatients increases

with low plasma cholesterol. Pharmacopsychiatry 32 (1), 1–4.

Partonen, T., Haukka, J., Virtamo, J., Taylor, P.R., Lonnqvist, J., 1989.

Association of low serum total cholesterol with major depression and

suicide. Br. J. Psychiatry 175 (9), 259–262.

Patel, J.M., Block, E.R., 1986. Nitrogen dioxide-induced changes in cell

membrane fluidity and function. Am. Rev. Respir. Dis. 134 (6),

1196–1202.

Penttinen, J., 1995. Hypothesis: low serum cholesterol, suicide and inter-

leukin-2. Am. J. Epidemiol. 141, 716–718.

Perticone, F., Ceravalo, R., Miao, R., Cloro, C., Candigliota, M.,

Scozzafava, A., Mongiardo, A., Masrtoroberto, P., Chello, M., Mattioli,

P.L., 2000. Effects of atorvastatin and vitamin C on endothelial function

of hypercholesterolemic patients. Atherosclerosis 152, 511–518.

Peter, H., Hand, I., Hohagen, F., Koenig, A., Mindermann, O., Oeder, F.,

Wittich, W., 2002. Serum cholesterol level comparison: control sub-

jects, anxiety disorder patients, and obsessive-compulsive disorder pa-

tients. Can. J. Psychiatry 47 (6), 557–561.

Rabe-Jablonska, J., Poprawska, I., 2000. Levels of serum total cholesterol

and LDL-cholesterol in patients with major depression in acute period

and remission. Med. Sci. Monit. 6 (3), 539–547.

Rafter, D., 2001. Biochemical markers of anxiety and depression. Psychia-

try Res. 103 (1), 93–96.

Refolo, L.M., Pappolla, M.A., LaFrancois, J., Malester, B., Schmidt, S.D.,

Thomas-Bryandt, T. et al., 2001. A cholesterol-lowering drug reduces

h-amyloid pathology in a transgenic mouse model of Alzheimer’s dis-

ease. Neurobiol. Dis. 8 (5), 890–899.

Rosenbaum, J.F., Fava, M., Pava, J.A., McCarthy, M.K., Steingard, R.J.,

Bouffides, E., 1993. Anger attacks in unipolar depression, Part 2:

Neuroendocrine correlates and changes following fluoxetine treatment.

Am. J. Psychiatry 150 (8), 1164–1168.

Sarchiapone, M., Camardese, G., Roy, A., Della Casa, S., Satta, M.A.,

Gonzalez, B. et al., 2001. Cholesterol and serotonin indices in depressed

and suicidal patients. J. Affect. Disord. 62 (3), 217–219.

Scanlon, S.M., Williams, D.C., Schloss, P., 2001. Membrane cholesterol

modulates serotonin transporter activity. Biochemistry 40 (35),

10507–10513.

Sevincok, L., Buyukozturk, A., Dereboy, F., 2001. Serum lipid concentra-

tions in patients with comorbid generalized anxiety disorder and major

depressive disorder. Can. J. Psychiatry 46, 68–71.

Sheridan, N.P., Block, E.R., 1988. Serotonin transport and fluidity in

plasma membrane vesicles: effects of hyperoxia. Am. J. Physiol. 256

(6 Pt 1), C781–787.

Shie, F.S., Jin, L.W., Cook, D.G., Leverenz, J.B., LeBoeuf, R.C., 2002.

Diet-induced hypercholesterolemia enhances brain A beta accumulation

in transgenic mice. Neuroreport 13 (4), 455–459.

Shimokawa, H., Vanhoutte, P.M., 1989. Impaired endothelium-dependent

relaxation to aggregating platelets and related vasoactive substances in

porcine coronary arteries in hypercholesterolemia and atherosclerosis.

Circ. Res. 64 (5), 900–914.

Simons, K., Ikonen, E.L., 1997. Functional rafts in cell membranes. Nature

87, 569–572.

Smith, C.C., Betteridge, D.J., 1997. Reduced platelet serotonin content and

release in familial hypercholesterolaemia. Atherosclerosis 130 (1–2),

87–92.

Sonawalla, S., Papakostas, G.I., Petersen, T., Smith, M., Sickinger, A.H.,

Israel, J.A. et al., 2002. Elevated cholesterol levels in major depressive

disorder associated with non-response to fluoxetine treatment. Psycho-

somatics 43 (4), 310–316.

Sooksawate, T., Simmonds, M.A., 1998. Increased membrane cholesterol

reduces the potentiation of GAAB(A) currents by neurosteroids in dis-

sociated hippocampal neurons. Neuropharmacology 37 (9), 1103–1110.

Sooksawate, T., Simmonds, M.A., 2001. Effects of membrane cholesterol

on the sensitivity of the GABA(A) receptor to GABA in acutely

dissociated rat hippocampal neurones. Neuropharmacology 40 (2),

178–184.

Sooksawate, T., Simmonds, M.A., 2001. Influence of membrane choles-

terol on modulation of the GABA(A) receptor by neuroactive steroids

and other potentiators. Br. J. Pharmacol. 134 (6), 1303–1311.

Steegmans, P.H.A., Fekkes, D., Hoes, A.W. et al., 1996. Low serum cho-

lesterol concentration and serotonin metabolism in men. Br. Med. J.

312, 21.

Steegmans, P.H., Hoes, A.W., Bak, A.A., Van der Does, E., Grobbee, D.E.,

G.I. Papakostas et al. / European Neuropsychopharmacology 14 (2004) 135–142142

2000. Higher prevalence of depressive symptoms in middle-aged men

with low serum cholesterol levels. Psychosom. Med. 62 (2), 205–211.

Stroes, E.S.G., Koomans, H.A., Bruin, T.W.A., de Rabelink, T.J., 1995.

Vascular function in the forearm of hypercholesterolaemic patients off

and on lipid-lowering medication. Lancet 346, 467–471.

Stroes, E., de Bruin, T., de Valk, H., Erkelens, W., Banga, J.D., van Rijn, H.

et al., 1997. NO activity in familial combined hyperlipidemia: potential

role of cholesterol remnants. Cardiovasc. Res. 36 (3), 445–452.

Suarez, E.C., 1999. Relations of trait depression and anxiety to low lipid

and lipoprotein concentrations in healthy young adult women. Psycho-

som. Med. 61, 273–279.

Sullivan, P.F., Joyce, P.R., Bulik, C.M., Mulder, R.T., Oakley-Browne, M.,

1994. Total cholesterol and suicidality in depression. Biol. Psychiatry

36 (7), 472–477.

Suzuki, T., Ito, J., Takagi, H., Saitho, F., Shimizu, H., 2001. Biochemical

evidence localization of AMPA-type glutamate receptor subunits in the

dendritic raft. Brain Res. Mol. Brain Res. 89 (1–2), 20–28.

Terao, T., Yoshimura, R., Ohmori, O., Takano, T., Takahashi, N., Iwata, N.

et al., 1997. Effect of serum cholesterol levels on meta-chloro-

phenylpiperazine-evoked neuroendocrine responses in healthy subjects.

Biol. Psychiatry 41 (9), 974–978.

Terao, T., Iwata, N., Kanazawa, K., Takano, T., Takahashi, N., Hayashi, T.,

Sugawara, Y., 2000. Low serum cholesterol levels and depressive state

in human dock visitors. Acta Psychiatr. Scand. 101 (3), 231–234.

Terao, T., Nakamura, J., Yoshimura, R., Ohmori, O., Takahashi, N.,

Kojima, H. et al., 2000. Relationship between serum cholesterol levels

and meta-chlorophenylpiperazine-induced cortisol responses in healthy

men and women. Psychiatry Res. 96, 167–173.

Thiele, B., Brink, I., Ploch, M., 2002. Modulation of cytokine expression

by hypericum extract. J. Geriatr. Psychiatry Neurol. 7 (Suppl. 1),

S60–S62.

Thomas, A.J., Ferrier, I.N., Kalaria, R.N., Perry, R.H., Brown, A.,

O’Brien, J.T., 2001. A neuropathological study of vascular factors in

late-life depression. J. Neurol. Neurosurg. Psychiatry 70, 83–87.

Verbeuren, T.J., Mennecier, P., Laubie, M., 1991. 5-Hydroxytryptamine-

induced vasodilatation in the isolated perfused rat kidney: are endothe-

lial 5-HT1A receptors involved?. Eur. J. Pharmacol. 201 (1), 17–27.

Villacres, E.C., Hollifield, M., Katon, W.J., 1987. Sympathetic nervous

system activity in panic disorder. Psychiatry Res. 21, 213–221.

Wahrle, S., Das, P., Nyborg, A.C., McLendon, C., Shoji, M., Kawara-

bayashi, T. et al., 2002. Cholesterol-dependant g-secretase activity in

buoyant cholesterol-rich membrane microdomains. Neurobiol. Dis. 9,

11–23.

Weidner, G., Connor, S.L., Hollis, J.F., Connor, W.E., 1992. Improvements

in hostility and depression in relation to dietary change and cholesterol

lowering: The Family Heart Study. Ann. Intern. Med. 117, 820–823.

Whiting, M.V., Cambridge, D., 1995. Canine renovascular responses to

sumatriptan and 5-carboxamidotryptamine: modulation through endo-

thelial 5-HT1-like receptors by endogenous nitric oxide. Br. J. Pharma-

col. 114 (5), 969–974.

Yamada, K., Tsutsumi, T., Fujii, I., 2001. Serum cholesterol levels in pa-

tients with panic disorders: a comparison with major depression and

schizophrenia. Psychiatry Res. 102 (2), 153–162.

Zureik, M., Courbon, D., Ducimetierre, P., 1996. Serum cholesterol and

death from suicide in men: Paris prospective study I. Br. Med. J. 313

(7058), 649–651.