Lower cerebrospinal fluid homovanillic acid levels in depressed suicide attempters

Abstract

Studies suggest that the dopaminergic system is involved in the pathogenesis of major depression, Axis II disorders, and suicidal behavior. Depressed suicide attempters constitute a heterogenous group and important differences may exist between depressed suicide attempters with or without Axis II disorders. Therefore, we compared demographic and clinical parameters, and cerebrospinal fluid (CSF) homovanillic acid (HVA) levels in depressed suicide attempters without comorbid Axis II disorders, depressed non-attempters without comorbid Axis II disorders, and normal controls.
Thirty-one depressed subjects with a history of a suicide attempt, 27 depressed subjects without a history of a suicide attempt, and 50 healthy controls were included in the study. Subjects with comorbid Axis II disorders were excluded. Demographic and clinical parameters, and CSF HVA levels were examined.
The two depressed groups did not differ with regard to depression, aggression, hopelessness, and total hostility scale scores. Depressed suicide attempters had higher current suicidal ideation scores compared to depressed non-attempters. Depressed suicide attempters had lower CSF HVA levels compared to depressed non-attempters (t = 4.4, df = 56, p < 0.0001) and to controls (t = -4.09, df = 79, p < 0.0001). There was no difference in CSF HVA levels between depressed non-attempters and controls (t < 1, df = 75, NS).
Dopaminergic abnormalities are associated with suicidality but not with depression. The variability in the rates of comorbid Axis II disorders and in the prevalence of suicide attempters in different patient populations may affect both clinical and biological results of studies of mood disorders.

Full text

Brief report
Lower cerebrospinal fluid homovanillic acid levels
in depressed suicide attempters
Leo Sher
a,
*, J. John Mann
a
, Lil Traskman-Bendz
b
, Ronald Winchel
a
,
Yung-yu Huang
a
, Eric Fertuck
a
, Barbara H. Stanley
a
a
Division of Neuroscience, Department of Psychiatry, Columbia University, and New York State Psychiatric Institute,
1051 Riverside Drive, Suite 2917, Box 42, New York, NY 10032, USA
b
Department of Psychiatry, University of Lund, Lund, Sweden
Received 28 July 2005; received in revised form 6 October 2005; accepted 10 October 2005
Available online 28 November 2005
Abstract
Background: Studies suggest that the dopaminergic system is involved in the pathogenesis of major depression, Axis II disorders,
and suicidal behavior. Depressed suicide attempters constitute a heterogenous group and important differences may exist between
depressed suicide attempters with or without Axis II disorders. Therefore, we compared demographic and clinical parameters, and
cerebrospinal fluid (CSF) homovanillic acid (HVA) levels in depressed suicide attempters without comorbid Axis II disorders,
depressed non-attempters without comorbid Axis II disorders, and normal controls.
Methods: Thirty-one depressed subjects with a history of a suicide attempt, 27 depressed subjects without a history of a suicide
attempt, and 50 healthy controls were included in the study. Subjects with comorbid Axis II disorders were excluded. Demographic
and clinical parameters, and CSF HVA levels were examined.
Results: The two depressed groups did not differ with regard to depression, aggression, hopelessness, and total hostility scale
scores. Depressed suicide attempters had higher current suicidal ideation scores compared to depressed non-attempters. Depressed
suicide attempters had lower CSF HVA levels compared to depressed non-attempters (t= 4.4, df =56, pb0.0001) and to controls
(t=4.09, df = 79, pb0.0001). There was no difference in CSF HVA levels between depressed non-attempters and controls (tb1,
df = 75, NS).
Conclusions: Dopaminergic abnormalities are associated with suicidality but not with depression. The variability in the rates of
comorbid Axis II disorders and in the prevalence of suicide attempters in different patient populations may affect both clinical and
biological results of studies of mood disorders.
D2005 Elsevier B.V. All rights reserved.
Keywords: Depression; Suicide; Cerebrospinal fluid; Homovanillic acid; Dopamine
1. Introduction
Low serotonergic activity is associated with suicidal
behavior independently of psychiatric diagnosis (Mann,
2003; Sher and Mann, 2003). A possible role of altered
dopaminergic function in suicidal behavior indepen-
dently of depression has not been extensively studied.
0165-0327/$ - see front matter D2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jad.2005.10.002
* Corresponding author. Tel.: +1 212 543 6240; fax: +1 212 543
6017.
E-mail address: LS2003@columbia.edu (L. Sher).
Journal of Affective Disorders 90 (2006) 83 – 89
www.elsevier.com/locate/jad

Cerebrospinal fluid (CSF) homovanillic acid (HVA),
a metabolite of dopamine, reflects functional activity of
the dopamine-containing neurons localized mainly in
the substantia nigra pars compacta, the ventral tegmen-
tal area and the hypothalamus (Papeschi et al., 1971;
Stanley et al., 1985; Blennow et al., 1993). The major-
ity of dopamine cells, which synthesize approximately
three-fourth of all of the dopamine in the brain, are
located in the anterior midbrain or mesencephalon
(Melchitzky et al., 2000). Whereas 5-hydroxyindolace-
tic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylgly-
col (MHPG) concentrations in lumbar CSF are thought
to include some contributions from spinal cord and
peripheral nervous system sources, lumbar CSF HVA
exclusively reflects brain metabolism of dopamine
(Post and Goodwin, 1978). It is important to note,
however, that the results of CSF HVA studies may be
affected by some non-specific factors such as the motor
activity of the patient or the size of the sample (Asberg
et al., 1984; Degrell and Nagy, 1990).
An association between CSF HVA levels and suicid-
ality was found by Traskman et al. (1981), Montgomery
and Montgomery (1982), Agren (1983), Roy et al.
(1986), Roy et al. (1989), Jones et al. (1990), Engstro¨m
et al. (1999) but not by Berrettini et al. (1986) and
Cremniter et al. (1999). Post-mortem studies of suicides
have also provided conflicting results reporting higher
HVA concentrations in the hippocampus (Crow et al.,
1984) and prefrontal cortex (Ohmori et al., 1992), lower
dihydroxyphenylacetic acid (DOPA) in the basal gan-
glia (Bowden et al., 1997) and no change in cortex
(Crow et al., 1984; Arranz et al., 1997).
The dopaminergic system also plays a role in the
neurobiology of Axis II disorders. Dopamine abnormal-
ities are reported in borderline personality disorder
(Schulz et al., 1985; Szigethy and Schulz, 1997; Coc-
caro, 1998; Chotai et al., 1998; Chengappa et al., 1999;
Rocca et al., 2002; Friedel, 2004), antisocial traits
(Gabel et al., 1995; van Goozen et al., 1999; Vanyukov
et al., 2000; Soderstrom et al., 2001; Gerra et al., 2003)
and schizoid personality disorder (Blum et al., 1997;
Rosmond et al., 2001), schizotypal (Siever et al., 1991,
1993; Siever and Davis, 2004; Abi-Dargham et al.,
2004), and paranoid personality disorder (Rosmond
et al., 2001).
Depressed suicide attempters frequently have
comorbid Axis II disorders. Including both Axis II
and non-Axis II subjects in prior studies could obscure
the relationship between dopamine and suicidal behav-
ior in patients with major depression. Indeed, depressed
suicide attempters constitute a heterogeneous group and
important differences may exist in attempt behavior
between depressed suicide attempters with or without
Axis II disorders. Therefore, to determine the relation-
ship of dopaminergic function to major depression and
to suicidal behavior, we compared CSF HVA levels in
depressed suicide attempters without comorbid Axis II
disorders, depressed non-attempters without comorbid
Axis II disorders, and normal controls.
2. Methods
2.1. Subjects
Thirty-one depressed subjects with a history of a
suicide attempt, 27 depressed subjects without a history
of a suicide attempt, and 50 healthy controls participated
in the study after giving written informed consent. The
study was approved by the Institutional Review Board.
All patients had a DSM-III-R diagnosis of major de-
pressive disorder. Exclusion criteria included presence
of any Axis II disorders; current substance use disor-
ders; a cognitive disorder which interfered with the
patient’s ability to answer clinician-administered and
self report rating scales; a history of head trauma result-
ing in coma; and more than mild mental retardation. The
depressed subjects were divided into two groups accord-
ing to the presence or absence of a history of a suicide
attempt. A suicide attempt was defined as a self-destruc-
tive act committed with some intent to end one’s life.
2.2. Diagnostic assessment
Patients were assigned DSM-III-R diagnoses follow-
ing a structured clinical interview. Interrater reliability
for the primary diagnosis was high (j= 0.90). Current
severity of depression was assessed by the Hamilton
Depression Rating Scale (HDRS) (Hamilton, 1960) and
Beck Depression Inventory (BDI) (Beck et al., 1961).
Lifetime aggression was assessed with the Brown–
Goodwin Aggression History Scale (Brown and Good-
win, 1986). Hostility was rated on the Buss–Durkee
Hostility Inventory (Buss and Durkee et al., 1957),
which includes subscales of assault, irritability, resent-
ment, indirect hostility, negativism, suspiciousness, ver-
bal hostility, and guilt. Current hopelessness was
measured with the Beck Hopelessness Scale (Beck
et al., 1974a). A lifetime history of all suicide attempts
was recorded. The degree of suicide intent at the time of
the most lethal suicide attempt was rated with the
Suicide Intent Scale (Beck et al., 1974b). The Scale
for Suicide Ideation (Beck et al., 1979) was used to
measure the severity of suicidal ideation during the
week prior to index hospitalization. The Recent Life
L. Sher et al. / Journal of Affective Disorders 90 (2006) 83–8984

Changes Questionnaire was used to document and
quantify events in the two years prior to assessment
(Rahe, 1975). Psychometric evaluation also included
the Brief Psychiatric Rating Scale (Overall and Gor-
ham, 1962).
2.3. Lumbar puncture
The lumbar puncture was performed between 8:00
a.m. and 10:00 a.m., following a night of supervised
bed rest and a fast of at least 8 h. Before the lumbar
puncture, patients were in bed in a prone position. The
lumbar puncture was carried out under sterile condi-
tions by a research psychiatrist using a fine-gauge
(20 G) spinal needle, with the patient lying in a left
lateral knee–chest position. CSF samples were obtained
from the space between the third and fourth lumbar
vertebrae. Eighteen milliliters of CSF were collected in
three aliquots of 2, 15, and 1 ml. The 15-ml aliquot was
centrifuged (750 gfor 5 min) and divided into 1-ml
aliquots. All aliquots were stored at 80 8C until
assayed. CSF HVA was assayed by high-performance
liquid chromatography with electrochemical detection
(Scheinin et al., 1983).
2.4. Data analysis
The three groups were compared on demographic
parameters using Analysis of Variance and Chi-square
Analysis, as appropriate. The CSF HVA levels in the
three groups were compared using Analysis of Vari-
ance. The two depressed groups were compared on
psychiatric measures using two-tailed Student’s t-tests
for continuous variables, and Chi-square Analysis for
categorical variables. In addition, correlations were
computed to examine relationships between psychiatric
measures and CSF HVA levels. These data were col-
lected in 1985–2000. These analyses have not been
published before.
3. Results
Demographic and clinical characteristics of subjects
in the three groups are presented in Tables 1 and 2.No
Table 1
Demographic characteristics of controls and depressed groups
Variable name Healthy volunteers (n= 50) Depressed subjects without
a history of a suicide
attempt (n= 27)
Depressed subjects with
a history of a suicide
attempt (n=31)
Analysis
Mean or (N) SD or (%) Mean or (N) SD or (%) Mean or (N) SD or (%) F/v
2
df P
Age (years) 38.2 18.3 43.5 15.4 41.3 14.6 0.9 2 n.s.
Gender (% males) (25) (50%) (13) (48%) (15) (48%) 0.2 2 n.s.
Race (% white) (18) (53%) (18) (75%) (22) (71%) 8.5 2 n.s.
Marital status (% married) (4) (12%) (9) (38%) (10) (32%) 5.9 2 n.s.
Education
(% some college or more)
(29) (85%) (12) (52%) (17) (55%) 9.3 2 0.01*
* Healthy volunteers are different from depressed subjects without a history of suicide attempt and depressed subjects with a history of suicide
attempt at pb0.05.
Table 2
Clinical characteristics of depressed subjects with or without a history of a suicide attempt
Measure Depressed subjects without
a history of a suicide
attempt (n=27)
Depressed subjects with
a history of a suicide
attempt (n= 31)
Analysis
Mean SD Mean SD tdfP
Number of previous psychiatric hospitalizations 1.0 2.2 2.2 3.4 1.4 50 n.s.
Hamilton Depression Rating Scale 22.9 9.2 26.2 10.3 1.2 52 n.s.
Beck Depression Inventory 23.3 11.2 21.1 10.8 0.5 25 n.s.
Brief Psychiatric Rating Scale 39.8 7.2 39.2 9.2 0.3 45 n.s.
Aggression History Scale 15.3 4.5 16.2 4.1 0.7 47 n.s.
Buss–Durke Hostility Scale 30.6 11.5 35.7 12.1 1.5 46 n.s.
Beck Hopelessness Scale 7.3 6.0 8.9 6.3 0.9 45 n.s.
Suicide Ideation Scale 3.2 4.8 12.8 10.8 3.5 45 0.001
Suicide Intent Scale N/A N/A 17.8 16.5 N/A N/A N/A
Life changes 0–6 months 3.4 4.0 3.7 3.6 0.2 33 n.s.
L. Sher et al. / Journal of Affective Disorders 90 (2006) 83–89 85

differences were found in age, gender, ethnicity, and
marital status. Healthy volunteers were more educated
than depressed patients in the both groups.
There was no difference between the two depressed
groups with regard to Hamilton Depression Rating
Scale, Beck Depression Inventory, Brief Psychiatric
Rating Scale, Aggression History Scale, Buss–Durke
Hostility Scale, Beck Hopelessness Scale, and Recent
Life Changes Questionnaire scores, and number of pre-
vious psychiatric hospitalizations (Table 2). Depressed
suicide attempters had higher current suicide ideation
score compared to non-attempters (Table 2), and higher
hostility subscales scores on negativism (2.7 F1.6 vs.
1.7 F1.6, t=2.3, df = 46, pb0.03) and guil t (5.6 F2.4
vs. 3.2 F1.8, t=3.8, df = 46, pb0.0001) compared
with depressed non-attempters. Psychiatric measures
did not correlate with CSF HVA levels (data not
shown).
Depressed suicide attempters had lower CSF HVA
compared with depressed non-attempters and controls
(Table 3). There was no difference in CSF HVA levels
between depressed non-attempters and controls. We
found no correlations between CSF HVA levels and
the number of previous suicide attempts (data not
shown).
4. Discussion
Depressed suicide attempters without Axis II dis-
orders have lower CSF HVA levels compared to de-
pressed non-attempters without Axis II disorders and
healthy controls. Depressed nonattempters have CSF
HVA levels comparable to healthy controls. These
results suggest that the dopaminergic system is in-
volved in the pathophysiology of the diathesis for
suicidality but not in the mood disorder in major
depression.
Our results may help to clarify the inconsistent
findings regarding suicidal behavior and CSF HVA
and underscore the importance of taking Axis II diag-
nosis into account in biological studies. Our findings
are in agreement with several previous studies. Indeed,
Traskman et al (1981) found lower levels of CSF HVA
in patients with a history of either violent or nonviolent
suicide attempts than in normal controls. Roy et al.
(1986) and Jones et al. (1990) found that depressed
suicide attempters had lower CSF HVA levels com-
pared to depressed non-attempters. Lower levels of
CSF HVA have been found in depressed patients with
a history of either violent or nonviolent suicide attempts
than in controls (Engstro¨m et al., 1999). Other studies
that did not find an association between CSF HVA and
suicidal behavior (Berrettini et al., 1986; Cremniter et
al., 1999) may have included Axis II diagnosis which
may have an independent association with the dopami-
nergic system and, thus, have obscured the potential
findings.
In a 5-year longitudinal study, Roy et al. (1989)
observed that patients who reattempted suicide during
the follow-up had lower CSF HVA levels compared to
controls. This predictive value of low CSF HVA con-
centrations has been confirmed in another longitudinal
study over a period of 2 years (Tra¨skman-Bendz et al.,
1993). Montgomery and Montgomery (1982) and
Agren (1983) also showed a highly significant relation-
ship between low CSF HVA levels and suicidal behav-
ior. According to Montgomery and Montgomery
(1982) and Agren (1983), who studied both CSF
HVA and 5-HIAA in depressed patients, low CSF
HVA levels could be a more reliable index of suicidal
behavior than low CSF 5-HIAA concentrations. Roy et
al (1986) also lend support to the hypothesis that low
CSF HVA levels could be a more potent predictive
index of suicide than low CSF 5-HIAA concentrations.
Several studies using measures other than CSF HVA
have also implicated the dopaminergic system in sui-
cidal behavior. The growth hormone (GH) response to
apomorphine, a selective dopaminergic agonist, in de-
pressed patients with a history of suicide attempts is
low compared to patients who never attempted suicide
(Pitchot et al., 1992; Pitchot et al., 2001; Pitchot et al.,
2003). Bergquist et al. (2002) found high CSF DA-IgG
in suicide attempters compared with control subjects
undergoing neurological investigation. This result indi-
cates that an autoimmune mechanism may affect the
dopaminergic neurotransmitter system and may play a
role in the pathophysiology of suicidal behavior. Sub-
sets of gamma-aminobutyric acid interneurons and py-
ramidal glutamatergic neurons in the prefrontal cortex
Table 3
CSF HVA levels in depressed subjects with or without a history of a
suicide attempt, and healthy volunteers
NMean
(pmol/ml)
SD Analysis
FdfP
Healthy volunteers 50 196.9 76.3 10.02 2 b0.0001*
Depressed subjects
without a history
of a suicide attempt
27 210.7 86.1
Depressed subjects
with a history of
a suicide attempt
31 133.4 50.9
* Depressed subjects with a history of suicide attempt are different
from depressed subjects without a history of suicide attempt and
healthy volunteers at pb0.0001.
L. Sher et al. / Journal of Affective Disorders 90 (2006) 83–8986

which receives significant dopaminergic input, contain
cholecystokinin. Cholecystokinin mRNA levels are el-
evated in the prefrontal cortex in suicide victims
(Bachus et al., 1997).
We observed no significant difference in CSF HVA
levels between depressed non-attempters and controls
which is consistent with findings by Koslow et al.
(1983) and Westenberg and Verhoeven (1988).Vester-
gaard et al. (1978) reported higher and Reddy et al.
(1992) reported lower CSF HVA levels in depressed
patients compared to controls. Possibly, the variability
in the rates of comorbid Axis II disorders and preva-
lence of suicide attempters in different patient popula-
tions play a role in the inconsistency of findings
regarding CSF HVA levels in depressed subjects.
Studies have demonstrated that the dopamine me-
tabolite HVA and the serotonin metabolite 5-HIAA are
correlated in human CSF (Reddy et al., 1992; Sher
et al., 2003, 2005; Stuerenburg et al., 2004). Therefore,
5-HIAA data from the same patients might have
reflected the same association with suicidal behavior,
independent of the diagnosis of depression.
CSF HVA appears to be a biologic marker of sui-
cidal behavior in depressed patients. Axis II diagnoses
having dopaminergic abnormalities may obscure rela-
tionships of the dopaminergic system to other frequent-
ly comorbid psychopathologies such as mood disorders
and suicidal behavior.
Future studies of dopaminergic function in depres-
sion and suicidal behavior should include neuroimaging
techniques. Functional imaging techniques such as pos-
itron emission tomography (PET), single photon emis-
sion computed tomography (SPECT), or functional
magnetic resonance imaging (fMRI) can provide more
valuable information than CSF HVA measurements and
significantly help in understanding the pathophysiology
of mood disorders and suicide. These techniques can
also provide a better understanding of the effects of
different treatments.
Acknowledgements
The authors thank Ms. Anny Castillo for the help in
preparing the manuscript.
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