Download Schizophrenia, Psychosis, and Cerebral Spinal Fluid Homovanillic

Schizophrenia, Psychosis, and Cerebral Spinal
Fluid Homovanillic Acid Concentrations
by James W. Maas, Charles L. Bowden, Alexander L. Miller, Martin A. Javors,
Linda Q. Funderburg, Nancy Bertram, and Susan T. Weintraub
estimates of the proportion of plasma and urine HVA
coming from the central nervous system (CNS) range
from 10 to 40 percent (Maas et al. 1980; Lambert et al.
1991). Additionally, concentrations of HVA in CSF are
about fivefold higher than in plasma, and sample preparation from CSF is simpler because of its lower protein content. There is some uncertainty about the portions of HVA
in lumbar CSF that are derived from different brain
regions. Evidence that HVA in lumbar CSF is primarily
from striatum has been summarized by Amin et al.
(1992); evidence that HVA in lumbar CSF is principally
from frontal cortical areas is discussed by Pickar et al.
(1990). At least 13 studies report comparisons of HVA
levels in CSF of schizophrenia patients and control subjects (normal or psychiatric). Ten of these studies found
no differences (Bowers et al. 1969; Persson and Roos
1969; Rimon et al. 1971; Bowers 1973; Post et al. 1975;
Gomes et al. 1980; Gerner et al. 1984; Pickar et al. 1990;
Kirch et al. 1991; Maas et al. 1993a). Other studies have
reported low HVA levels in CSF in schizophrenia patients
(Bowers 1974; Bjerkenstedt et al. 1985; Lindstrom 1985).
Thus, the evidence from studies of HVA levels in CSF
strongly negates the hypothesis that dopamine turnover in
the brain is increased in patients with schizophrenia, as a
group.
In contrast to the relative lack of evidence of increased dopamine turnover as a trait marker for schizophrenia, the hypothesis that the psychotic state is related
to CNS dopamine overactivity has substantial empirical
support. The dopamine-receptor-blocking ability of most
antipsychotic drugs, as determined in animal brain tissue
in vitro, approximates the rank order of dosage required to
have clinical efficacy (Seeman 1981; Seeman et al. 1987).
Also, neuroleptic drugs not only are helpful in treating the
psychosis of schizophrenia, but also are effective thera-
Abstract
Neuroleptic drugs block brain dopamine receptors
and are effective in treating psychoses of diverse origins. This finding has become a cornerstone of the
dopamine theory of schizophrenia, but clinical studies
relating schizophrenia, per se, to brain dopamine
metabolism have ranged from controversial to negative. This article presents new evidence that cerebrospinal fluid levels of the dopamine metabolite
homovanillic acid are related to the severity of psychosis in schizophrenia. These results support the concept that homovanillic acid levels in cerebrospinal
fluid vary as a function of psychosis rather than being
related to the diagnosis of schizophrenia per se.
Schizophrenia Bulletin, 23(1): 147-154,1997.
In 1963, Carlsson and Lindqvist reported that neuroleptic
drugs, agents that are effective for the treatment of psychosis, can block dopamine receptors and increase concentrations of dopamine metabolites. This result led to the
development of the "dopamine hypothesis of schizophrenia," which predicted an increased turnover of brain
dopamine in patients with schizophrenia. Such an
increased turnover should be manifested by an increased
concentration of the major dopamine metabolite,
homovanillic acid (HVA). Brain HVA levels cannot be
measured directly in man, thus a number of studies have
attempted to test the dopamine hypothesis of schizophrenia by measuring the HVA level in cerebrospinal fluid
(CSF), plasma, or urine. This article reviews studies of the
CSF level of HVA in schizophrenia and other psychiatric
disorders and presents new data on HVA levels in CSF in
schizophrenia.
CSF has several advantages over other body fluids in
studies of brain dopamine metabolism. Principal among
these is that the HVA in CSF is entirely from the brain
(Pletscher et al. 1967; Guldberg and Yates 1968), whereas
Reprint requests should be sent to Dr. C.L. Bowden, Dept. of
Psychiatry, The University of Texas Health Science Or., 7703 Floyd
Curl Dr., San Antonio, TX 78284-7792.
147
J.W. Maasetal.
Schizophrenia Bulletin, Vol. 23, No. 1, 1997
peutic agents for psychoses of mania, depression, organic
brain disorders, and drugs. Several studies of CSF and
plasma HVA provide additional support. Treatment of
schizophrenia patients with antipsychotics increased the
ratios in CSF of HVA to hydroxyindoleacetic acid (HIAA)
and HVA methoxyhydroxy-phenylglycol (MHPG). There
was a negative relationship between the HVA and the
Brief Psychiatric Rating Scale (BPRS; Overall and
Gorham 1962) score at baseline (Hsiao et al. 1993). High
levels of plasma HVA were associated with a favorable
response to neuroleptics, whatever the type of psychosis
(Bowers et al. 1984). The decrement in plasma HVA
induced by neuroleptics was associated significantly with
the degree of patient improvement in a mixed diagnostic
group of psychiatric patients (Sharma et al. 1988);
patients responding poorly to neuroleptics had lower levels of plasma HVA (Garver et al. 1990). Several groups
have reported significant correlations between plasma
HVA concentrations and the degree of psychosis (Pickar
et al. 1984; Davis et al. 1985; Maas et al. 1988). Thus, the
hypothesis of the current study is that increases in brain
dopamine turnover in schizophrenia are associated with a
component of the illness (i.e., the psychotic state) and not
with schizophrenia per se.
Several review articles have presented the viewpoint
that psychosis and increased dopaminergic activity in the
CNS are linked; however, these investigators have not had
the data regarding HVA levels in CSF to support this conclusion (Bowers 1978; Friedhoff and Simkowitz 1989;
Davis etal. 1991).
Methods
Subjects. Patients were 27 males with schizophrenia diagnosed by Research Diagnostic Criteria (RDC; Spitzer et al.
1978) and hospitalized on a research unit at a Veterans
Affairs (VA) hospital. All patients had been off antipsychotic drugs for at least 2 weeks before obtaining the CSF
and clinical ratings presented in this study. Subjects ranged
in age from 21 to 65. This hospital admission was the first
for 2 patients. The rest had had multiple admissions and
prior treatment with a variety of antipsychotic drugs.
Approximately half of the patients received debrisoquin,
similar to guanethidine, which is a monoamine oxidase
inhibitor that does not enter the brain and does not alter
CNS dopamine metabolism or concentrations of HVA in
CSF (Medina et al. 1969; Maas et al. 1979a, 1988). Control
subjects were a group of 10 age-matched males. The control subjects were free of diagnosable psychopathology
using RDC criteria as determined by two psychiatrists.
Control subjects also were hospitalized at the VA hospital
on a general clinical research unit. All subjects gave
informed consent after having the procedures and risks of
the study thoroughly explained to them. Chloral hydrate
was available to patients for treatment of insomnia or agitation in doses up to 4 grams per day. However, no chloral
hydrate was given to patients for at least 8 hours before the
lumbar puncture and assessment of behavior.
Ratings. Scoring of the severity of psychosis used the sum
of the five items from the Schedule for Affective Disorders
and Schizophrenia-Current and Lifetime versions
(SADS-C; Spitzer and Endicott 1979) that make up the
psychosis subscale: severity of delusions, severity of hallucinations, impaired understanding, inappropriate affect, and
bizarre behavior. The patients were rated on the same day
that their CSF samples were taken.
Lumbar Puncture. The lumbar puncture was done in the
morning before patients had taken anything by mouth (having had nothing but water since midnight). The lumbar
punctures were done with the subjects in the sitting position
and the needle inserted in the lumbar 4-5 interspace.
Approximately 14 mLof CSF was taken from each subject.
Assays. HVA levels in CSF were assessed by mass spectrometry (Maas et al. 1979a, 19796, 1980) for some of the
patients. For other patients, high-performance liquid chromatography (HPLC) with electrochemical detection was
used to measure the HVA level in CSF (Javors et al. 1984).
In a study by Javors et al. (1984), the values obtained by
the two analytic methods correlated significantly (r = 0.92)
and did not differ significantly in absolute quantitation. The
data on HVA levels in CSF determined by gas chromatography-mass spectroscopy (GC-MS) have been published
(Maas et al. 1993b). The correlation between HVA levels in
CSF and the severity of psychosis has not yet been published.
Data Analysis. The principal analysis was a Pearson product moment correlation between HVA levels in CSF and the
psychosis ratings made from the five items comprising the
SADS-C psychosis factor. Each of the five SADS-C items
was correlated separately with HVA levels in CSF.
Results
HVA levels in CSF did not differ between schizophrenia
patients and control subjects (41.3 ± 22.8 ng/ml vs.
28.3 ± 17.9 ng/ml, p = not significant). However, when
patient psychosis scores and CSF levels of HVA were
plotted against each other (figure 1), there was a highly
significant relationship (r = 0.536; p - 0.004; n = 27).
When the data were analyzed separately for patients on
148
Schizophrenia Bulletin, Vol. 23, No. 1, 1997
Schizophrenia, Psychosis, and Cerebral Spinal Fluid
phrenia (with the exception that the mixed groups of
Bowers [1973] and Bowers et al. [1980] included some
schizophrenia subjects). Table 2 lists studies in which psychosis in schizophrenia patients was examined. The
results in nonschizophrenia patients generally support the
thesis that higher levels of HVA in CSF are associated
with the presence of psychotic or psychoticlike symptoms
across a spectrum of illnesses, whereas the reports on psychosis in schizophrenia patients are more variable in their
results. Some reports on schizophrenia patients do note a
relationship between the level of HVA in CSF and psychosis or global impairment of performance. However,
one study did not find that the HVA level in CSF correlated with psychosis (van Kammen et al. 1990), and two
found HVA levels in CSF to be correlated negatively with
Figure 1. A plot of the homovanillic acid (HVA)
concentration (ng/ml) in cerebrospinal fluid
(CSF) versus the SADS-C psychosis factor
r = 0.536
p = 0.004
N = 27
20
40
60
80
Table 1. Homovanillic acid (HVA) in the
cerebrospinal fluid (CSF) of nonschizophrenic
psychotic disorders
100
CSF HVA (ng/ml)
Subjects
Findings
Bowers (1973)
Mixed group
HVA higher in
patients without
Schneiderian symptoms compared with
patients with
Schneiderian symptoms
Sweeney et al.
(1978)
Depressed
females
HVA higher in delusional group
Bowers et al.
(1980)
Mixed group
HVA correlated with
disorganized thought,
global illness;
HVA not correlated
with psychosis
(BPRS)
Aberg-Wistedt
etal. (1985)
Depressives
HVA higher in delusional group
Study
The correlation coefficient was 0.536 with p = 0.004 and n = 27.
SADS-C = Schedule for Affective Disorders and
Schizophrenia-Current and Lifetime versions (Spitzer and
Endicott 1979).
debrisoquin (GC-MS assay) and not on debrisoquin
(HPLC assay), the correlations also were significant for
each group {r - 0.767; p - 0.006; n = 11; r - 0.680; p 0.004; n = 16, respectively). For the five individual
SADS-C items, the correlations of CSF levels of HVA
with delusions and inappropriate affect were significant
(0.53 and 0.55, p < .004, respectively); the correlations of
CSF levels of HVA with impaired understanding and hallucinations were nearly significant (r = 0.36 and r = 0.34,
respectively). The correlation with bizarre behavior was
0.31.
Eleven schizophrenia patients also had been rated
using the BPRS. The anxiety-agitation factor from this
scale did not correlate with CSF levels of HVA (r =
-0.241;/? = 0.475; n = 11).
Borgetal. (1986) Alcoholics in
withdrawal
Discussion
The principal finding of this study is a strong relationship
between the severity of psychosis and the HVA level in
CSF. This finding must be examined in light of earlier
reports on CSF levels of HVA in schizophrenia and other
psychotic illnesses. Other studies reporting data on psychosis (or psychoticlike symptomatology) and HVA levels
in CSF are summarized in tables 1 and 2. Table 1 lists
studies of groups other than patients with chronic schizo-
HVA correlated with
severity of hallucinations, decreased concentration
Gillberg and
Svennerholm
(1987)
Children with
HVA higher in psyautism and other chotic group, compsychoses
pared with normal
and neurological control subjects
Siever et al.
(1993)
Schizotypal
personality
HVA correlated
number of psychoticlike symptoms
Note.—All patients had been off antipsychotic drugs for at least 1
week at the time of CSF sampling. BPRS = Brief Psychiatric
Rating Scale (Overall and Gorham 1962).
149
Schizophrenia Bulletin, Vol. 23, No. 1, 1997
J.W. Maas et al.
All patients in the studies reviewed had at least some
elements of psychosis. Assuming that CSF levels of HVA
are a function of the level of psychosis, why was the
range of their CSF levels of HVA not above that of the
controls? There are at least two possible explanations for
this observation. The first postulates regional differences
in dopaminergic activity in schizophrenia, with prefrontal
hypoactivity relating to low HVA production in CSF and
negative symptoms, and limbic/striatal dopamine hyperactivity relating to high HVA production in CSF and positive symptoms. This view, and some of the evidence supporting it, has been explained in a review by Davis et al.
(1991). Because HVA in CSF receives contributions from
both regions, the level of HVA in CSF can be normal even
though regional output is abnormal. A second explanation
would be that dopamine receptor responsivity is altered in
schizophrenia (i.e., even normal rates of release of
dopamine produce abnormal responses). The controversial positron-emission tomography data on increased D 2
receptors are consistent with this hypothesis (Wong et al.
1986).
In principle, both physical agitation and enhanced
CNS noradrenergic activity could contribute to increases
in HVA levels in CSF. Because there is a steep concentration gradient of HVA from the cerebral ventricles to the
lumbar area, physical agitation could increase the lumbar
CSF concentration of HVA by increasing the rate of mixing, independent of changes in HVA production in the
CNS. An early report (van Praag and Korf 1975) noted
that agitation correlated with HVA levels in CSF.
Conversely, no such correlation was found in a group of
patients whose movements were measured carefully by
telemetry (Kirstein et al. 1976). Mania ratings, which are
influenced heavily by physical hyperactivity, did not correlate with HVA levels in CSF (Swann et al. 1983; Gerner
et al. 1984). Moreover, in a subset of the patients reported
in the present study, the BPRS agitation factor did not
correlate with HVA levels in CSF. It also seems unlikely
that the positive correlation between HVA levels in CSF
and psychoticlike symptoms in schizotypal personality
disorder would be attributable to agitation (Siever et al.
1993). Thus, the weight of the evidence does not favor the
hypothesis that physical agitation in psychosis accounts
for the relationship between HVA levels in CSF and psychosis, but this explanation has not been excluded.
HVA is produced by noradrenergic and dopaminergic
neurons (for review, see Kopin 1985). The proportion of
lumbar CSF levels of HVA from each source is unknown,
and there are several reports of positive correlations
between MHPG levels and psychosis (Bowers et al. 1984;
van Kammen et al. 1990; Maas et al. 1993a). However,
Table 2. Psychosis and cerebrospinal fluid
(CSF) levels of homovanillic acid (HVA) in
schizophrenia subjects
Subjects
Findings
Rimon et al.
(1971)
First-admission
schizophrenia
patients
HVA correlated with
delusions/hallucinations
Houston et al.
(1986)
Chronic schizophrenia patients
HVA negatively correlated with GAS
Hsiao et al.
(1993)
Chronic schizophrenia patients
HVA negatively correlated with psychosis
van Kammen
etal. (1986)
Chronic schizophrenia patients
HVA correlated with
unusual thought
content in patients
without cerebral
atrophy
Pickar et al.
(1990)
Chronic schizophrenia patients
HVA negatively correlated with
psychosis
van Kammen
etal. (1990)
Chronic schizophrenia patients
HVA not correlated
with psychosis; HVA
not higher in relapsers
vs. nonrelapsers
Study
Note.—All patients had been off antipsychotic drugs for at least 1
week at the time of CSF samplings. GAS = Global Assessment
Scale (Endicott et al. 1976).
psychosis (Pickar et al. 1990; Hsiao et al. 1993). In a multiple regression analysis of CSF biogenic amines and their
metabolites in chronic schizophrenia patients not receiving neuroleptic medications, Issa et al. (1994) reported
that another dopamine metabolite, dihydroxyphenylacetic
acid (DOPAC), was significantly predictive of overall
psychopathology on an expanded version of the BPRS.
Overall, the literature on CSF levels in HVA in psychotic disorders supports the hypothesis that there is
increased CNS turnover of dopamine in the psychotic
state that is not specific diagnostically. Because most
studies have been conducted cross-sectionally, it remains
possible that an elevated CSF level of HVA is a trait
marker for the predisposition to psychosis. This possibility is not supported by the results of van Kammen et al.
(1990), who reported a progressive increase in HVA levels
in CSF after discontinuing antipsychotic drugs. Moreover,
several studies have found decreases in plasma HVA during treatment (Pickar et al. 1984, 1986; Doran et al. 1985;
Chang et al. 1988, 1990; Farde et al. 1988; Alfredsson and
Wiesel 1989; Bowers et al. 1989). These latter studies,
however, are difficult to interpret because patients were
on neuroleptic treatment concurrently, and such treatment
has independent effects on dopamine systems.
150
Schizophrenia Bulletin, Vol. 23, No. 1, 1997
Schizophrenia, Psychosis, and Cerebral Spinal Fluid
tion over the course of chronic schizophrenia tend to
obscure the relationship between CSF levels of HVA and
psychosis in this illness.
one large-scale study reported that drugs that significantly
lower MHPG levels in CSF had no effect on HVA levels
in CSF (Bowden et al. 1985).
These results on HVA levels in CSF are compelling
in magnitude of effect and are among the most recent
studies in a series dating back more than 25 years on catecholamine perturbations in psychiatric disorders. Despite
this long-term work, there has been only a modest impact
on clinical practice. The reasons for this lack of impact
may include the heterogeneity of the diseases studied
(Sweeney et al. 1978; Davis et al. 1991), the continued
modest effects of treatments for schizophrenia, even with
clozapine (Kane et al. 1988), and the difficulty of assessing patients who are not fully able to provide current or
historical information about their diseases. The relatively
small number of studies of CSF samples can be attributed
to methodological complexities. For meaningful assessment, such studies require hospitalization of patients
while off medications for a period sufficient to yield
results that are a function of disease, not of treatments of
the disease. CSF is difficult to undertake primarily
because of the difficulty in obtaining informed consent.
Similarly, urine collections are daunting because of the
potential patient interference with the intended collection.
Borison (1994), writing of his experiences in obtaining
24-hour urine collections from patients, noted "the difficulty of which can only be appreciated by those who have
attempted to make such collections from patients. The
obstacles we faced with enuretic patients are only slight
when compared to the problems posed by irritable manic
patients who had a predilection for tossing their twogallon urine containers at staff" (p. 113). We have
adopted a 3/^-hour procedure for urine collection with
continuous monitoring of the patient, in part, for these
reasons. These and other methodological points are timeconsuming and nearly impossible to apply in nonresearch
settings.
Finally, these techniques primarily reflect presynaptic
neuronal activity. Despite the ability to measure related
indices of postsynaptic function (e.g., phosphatidylinositol turnover, protein kinase c activity, and hormonal activity such as prolactin), it has been difficult to relate these
functions coherently to amine and amine-metabolite measures.
In summary, a substantial number of studies, including the current one, have found levels of HVA in CSF and
the severity of psychosis to be significantly correlated.
The evidence from nonschizophrenia patient populations
is, if anything, stronger than that in schizophrenia
patients. It is possible that in the schizophrenia group the
effects of long-term treatment with dopamine-receptorblocking agents and changes in CNS dopaminergic func-
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This study was supported by grant number MH-40935
from the National Institute of Mental Health and by the
Audie Murphy Memorial Veterans Hospital. The authors
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The Authors
James W. Maas, M.D. (deceased), was Hugo A. Auler
Professor of Psychiatry and Pharmacology; Charles L.
Bowden, M.D., is Chief, Division of Biological
Psychiatry and Karren Professor of Psychiatry and
Pharmacology; Alexander L. Miller, M.D., is Professor of
Psychiatry and Pharmacology; Martin A. Javors, Ph.D., is
Associate Professor, Department of Psychiatry; Linda G.
Funderburg, M.D., is Assistant Professor, Department of
Psychiatry; Susan T. Weintraub, Ph.D., is Professor,
Department of Biochemistry, The University of Texas
Health Science Center, San Antonio, TX. Nancy Berman,
Ph.D., is Assistant Professor, Department of Pediatrics,
Harbor-University of California, Los Angeles Medical
Center, Torrance, CA.
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