Lower cerebrospinal fluid homovanillic acid levels in depressed suicide attempters

www.elsevier.com/locate/jad

Journal of Affective Disor

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, USAb 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, p b0.0001) and to controls

(t =�4.09, df =79, p b0.0001). There was no difference in CSF HVA levels between depressed non-attempters and controls (t b1,

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.

D 2005 Elsevier B.V. All rights reserved.

Keywords: Depression; Suicide; Cerebrospinal fluid; Homovanillic acid; Dopamine

0165-0327/$ - see front matter D 2005 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: [email protected] (L. Sher).

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.

ders 90 (2006) 83–89

L. Sher et al. / Journal of Affective Disorders 90 (2006) 83–8984

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), Engstrom

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

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 /v2 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 p b0.05.

L. Sher et al. / Journal of Affective Disorders 90 (2006) 83–89 85

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 �g for 5 min) and divided into 1-ml

aliquots. All aliquots were stored at �80 8C until

assayed. CSF HVA was assayed by high-performance

Table 2

Clinical characteristics of depressed subjects with or without a history of a

Measure Depressed subjects w

a history of a suicide

attempt (n =27)

Mean SD

Number of previous psychiatric hospitalizations 1.0 2.2

Hamilton Depression Rating Scale 22.9 9.2

Beck Depression Inventory 23.3 11.2

Brief Psychiatric Rating Scale 39.8 7.2

Aggression History Scale 15.3 4.5

Buss–Durke Hostility Scale 30.6 11.5

Beck Hopelessness Scale 7.3 6.0

Suicide Ideation Scale 3.2 4.8

Suicide Intent Scale N/A N/A

Life changes 0–6 months 3.4 4.0

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

suicide attempt

ithout Depressed subjects with

a history of a suicide

attempt (n =31)

Analysis

Mean SD t df P

2.2 3.4 �1.4 50 n.s.

26.2 10.3 �1.2 52 n.s.

21.1 10.8 0.5 25 n.s.

39.2 9.2 0.3 45 n.s.

16.2 4.1 �0.7 47 n.s.

35.7 12.1 �1.5 46 n.s.

8.9 6.3 �0.9 45 n.s.

12.8 10.8 �3.5 45 0.001

17.8 16.5 N/A N/A N/A

3.7 3.6 �0.2 33 n.s.

Table 3

CSF HVA levels in depressed subjects with or without a history of a

suicide attempt, and healthy volunteers

N Mean

(pmol/ml)

SD Analysis

F df P

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 p b0.0001.

L. Sher et al. / Journal of Affective Disorders 90 (2006) 83–8986

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 (2.7F1.6 vs.

1.7F1.6, t=�2.3, df =46, p b0.03) and guilt (5.6F2.4

vs. 3.2F1.8, 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 (Engstrom 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 (Traskman-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

L. Sher et al. / Journal of Affective Disorders 90 (2006) 83–89 87

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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