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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. 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Acknowledgments Spitzer, R.L.; Endicott, J.; and Robins, E. Research Diagnostic Criteria: Rationale and reliability. Archives of General Psychiatry, 35:773-782, 1978. 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 thank Betsy Cuvelier and Ray Benavides for technical assistance in assays and statistical analyses. Swann, A.; Secunda, S.; Davis, J.M.; Robins, E.; Hanin, I.; Koslow, S.H.; and Maas, J.W. CSF monoamine metabolites in mania. American Journal of Psychiatry, 140:396-400, 1983. Sweeney, D.; Nelson, C ; Bowers, M.B., Jr.; Maas, J.W.; and Heninger, G.R. Delusional versus nondelusional depression: Neurochemical differences. Lancet, 1:100-101, 1978. 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. van Kammen, D.P.; Peters, J.; Yao, J.; van Kammen, W.B.; Neylan, T.; Shaw, D.; and Linnoila, M. Norepinephrine in acute exacerbations of chronic schizophrenia. Archives of General Psychiatry, 47:161-168, 1990. van Kammen, D.P.; van Kammen, W.B.; Mann, L.S.; Seppala, T.; and Linnoila, M. 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