PsJ’chiatry Research, 16, 22 I-226 Elsevier

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CSF Dopamine Turnover and Positive Schizophrenic Symptoms After Withdrawal of Long-term Neuroleptic Treatment

Ede Frecska, Andrds Per&@, Gyijrgy Bagdy, and Katalin RBvai

Received November 21, 1984; revised version received March 27, 1985; accepted May I, 1985.

Abstract. Dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and homo- vanillic acid (HVA) were measured in cerebrospinal fluid (CSF) of 14 schizo- phrenic inpatients before and 2 weeks after withdrawal of long-term neuroleptic medication. Total neuroleptic-like activity (NLA) in serum was determined at the same times. DA and its metabolites (DOPAC and HVA) were significantly reduced after neuroleptic discontinuation. NLA was substantially diminished. The decrease in DA and DOPAC was positively correlated with positive symptoms of postwithdrawal deterioration, and low prewithdrawal DOPAC level predicted severe relapse. These results are compatible with the hypothesis linking an overregulated central DA system to the positive symptoms of schizophrenia.

Key Words. Schizophrenia, neuroleptics, withdrawal, biochemical changes, psychopathology.

Two syndromes can be distinguished in disorders currently described as schizo- phrenic, and each may be associated with a specific pathological process. One of them-approximating acute schizophrenia-is characterized by positive symptoms, e.g., delusions, hallucinations, and thought disorder (Type I syndrome), and may reflect altered dopaminergic transmission. On the other hand, the defect state, marked by negative symptoms, e.g., affective flattening, poverty of speech, and loss of volition (Type II syndrome), is presumably unrelated to dopaminergic activity (Crow, 1980).

In vivo studies published thus far have not revealed disturbances in central dopaminergic function of schizophrenic patients (Pearlson and Coyle, 1983). To date, an increase in numbers of dopamine (DA) receptors is the most commonly mentioned abnormality of dopaminergic transmission detected in post-mortem brain of schizophrenics and is correlated to positive symptoms rated in life. A case can be made that this change is not solely a consequence of the neuroleptic medication patients have received. Rather, it may be related to the disease process and imply an increased, perhaps maladaptive reactivity of the central DA system (Crow, 1980, 1982). The psychotogenic response to dextroamphetamine in schizophrenia could reflect not only DA receptor supersensitivity but also an instability in DA regulatory mechanisms (Van Kammen et al., 1982). King et al. (1982) propose an excessive feedback

Ede Frecska, M.D.. is Psychiatrist; And& Pertnyi, M.D., is Psychiatrist; Gyorgy Bagdy, Ph.D.. is Research Pharmacologist: and Katalin Revai, M.D., is Psychiatrist, National Institute for Nervous and Mental Diseases. 1281 Budapest Pf. I. Hungary. (Reprint requests to Dr. E. Frecska.)

0165-1781~85/$03.30 0 1985 Elsevier Science Publishers B.V.

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regulation of DA as the basis for this instability. Linnoila et al. (1983) reported that there is a considerable fluctuation in cerebrospinal fluid (CSF) monoamine turnover of drug-free schizophrenic individuals over time, and these authors also hypothesized inadequate regulation of transmitter release.

The present study was designed to investigate the regulation of DA in schizophrenic subjects by the change of CSF DA turnover after withdrawal of long-term neuroleptic treatment, and to compare this change with psychopathology. The hypothesis tested was that patients with increasing severity of positive symptoms would show greater change and that positive symptoms would prove to be mainly responsible for the inter-individual and intra-individual variation in the concentration of DA and its metabolites within the schizophrenic group.

Methods

Patients. The sample consisted of 14 chronic schizophrenic inpatients, 11 males and 3 females, with a median age of 43 years (range 35-55 years), who met Research Diagnostic Criteria for schizophrenia (Spitzer et al., 1977). Leading symptoms were emotional instability and loss of motivation, and these were responsible for chronic hospitalization. Positive symptoms, such as paranoid-hallucinatory syndromes, were also apparent and showed a satisfactory response to continuous neuroleptic medication during hospitalization (median 11 years; range 5-15 years). The patients received the following neuroleptics, some of them in combination: haloperidol(6) chlorpromazine (4), levomepromazine (4) thioridazine (3) and methofenazine (2). Ten of them also received promethazine, which was not discontinued. The mean dose in chlorpromazine (CPZ) equivalents (Davis, 1976) was 485 (range 100-963) mg/24 hours.

Procedures. Before and in the period of withdrawal (days 0 and 14, respectively), venous and lumbar punctures, and psychiatric ratings were performed. Psychopathology in the drug-free period was rated biweekly through 12 weeks, unless the patient relapsed and needed readministration of the neuroleptic. In exacerbated cases, clinical state was scored before resumption of the drug.

All lumbar punctures were obtained between 8 a.m and 9 a.m. with the patient in a sitting position, after a IO-hour fast and bed rest. CSF, 5 ml, was collected in plastic tubes, mixed, and immediately frozen in dry ice. Blood samples for neuroleptic assay were taken at the same time. CSF DA and dihydroxyphenylacetic acid (DOPAC) levels were determined by a radio- enzymatic method described by Fekete et al. (1978) with some modification (Bagdy et al., 1983). Homovanillic acid (HVA) was measured by the method of Westerink and Korf (1975). Neuroleptic radioreceptor assay was modified by Bagdy et al. (1985) from the technique of Cohen et al. (1979). Total neuroleptic-like activity (NLA) is expressed as a concentration of haloperidol in the serum (nM/l) causing the same inhibition on a standard curve. All samples were measured in one assay.

The following psychopathological variables were determined from the Brief Psychiatric Rating Scale (BPRS) (Overall et al., 1967): total score, factors of positive schizophrenic symptomatology (No. 3 thought disturbance, No. 4 activation, and No. 5 hostile suspiciousness) and withdrawal-retardation factor for negative schizophrenic symptomatology (Angrist et al., 1980).

Clinical and biochemical assessments were made in a blind fashion.

Statistics. Statistical analysis was performed with paired Student’s t test (two-tailed), and Spearman’s rank correlations were calculated.

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Results

The mean (k SD) serum NLA before neuroleptic withdrawal was 253 f 238 nM/l, which fell to 11 * 7.3 r&/l at day 14. Both DA and its metabolites significantly decreased in CSF after discontinuation of neuroleptics (Table 1).

Table 1. CSF concentrations (ng/ml) and O/O changes in DA, DOPAC, and HVA before and 2 weeks after withdrawal of long-term neuroleptics

Day 0 Day 14 % Change

Mean SD Mean SD Mean SD

DA 4.0 2.90 3.1 0.85 121 20.9

DOPAC 2.7 1.16 2.2 1.29 222 23.4

HVA 31 18.8 23 9.4 161 25.1

1.p 5 0.05.

2. p <O.Ol.

Table 2 contains the correlations between the biochemical parameters (i.e., serum NLA, CSF DA, DOPAC, and HVA levels) and indices of clinical state (i.e., total BPRS scores, ratings of positive and negative symptom cluster) on day 0 and 14. Among them, only the total BPRS scores and the ratings of the positive symptom cluster on day 0 showed a significant negative correlation to the concentrations of DOPAC in the CSF samples obtained on the same day.

Neither CPZ equivalents nor prewithdrawal serum NLA showed any substantial correlation with amine and metabolite levels and changes (r,values were between -0.52 and 0.42).

Table 2. Spearman’s rank correlation coefficients between prewithdrawal and oostwithdrawal biochemical data and clinical state

CSF values of CSF values of

Day 0 DA DOPAC HVA Day 14 DA DOPAC HVA

BPRS scores BPRS scores

Total 0.46 -0.601 0.24 Total 0.20 -0.44 -0.07

Positive symptom 0.29 -0.591 -0.04 Positive symptom 0.30 -0.34 -0.12

Negative symptom -0.04 -0.05 0.20 Negative symptom -0.07 0.07 0.24

Serum NLA 0.42 -0.05 0.29 Serum NLA -0.22 0.40 0.27

1. p < 0.05

In an analysis of the statistical relationship between the highest ratings of the positive symptom cluster assessed during the drug-free period (i.e., indices of the most florid states developed in the drug pause) and the prewithdrawal and postwithdrawal DOPAC levels, a stronger negative correlation emerged (Table 3). The maximal ratings of positive symptoms correlated positively to the individual decrease of

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DOPAC and DA that occurred between day 0 and day 14. As Table 3 indicates, within the positive symptom cluster, the activation factor was mainly responsible for this relationship. No significant correlations were observed between the highest total BPRS scores and any parameters of DA, or between the ratings of negative symptoms and the DA data. The effects were unrelated to age and length of hospitalization (r, values of correlations of DA and DOPAC data vs. age and length of hospitalization were between -0.36 and 0.15). No patients relapsed before day 14.

Table 3. Spearman’s rank correlation coefficients between prewithdrawal and oostwithdrawal biochemical data and oostwithdrawal deterioration

CSF DA CSF DOPAC CSF HVA

Day Day Day Day Day Day BPRS scores 0 14 Decrease 0 14 Decrease 0 14 Decrease

Total1 0.19 -0.03 0.47 -0.48 -0.37 0.24 0.35 0.32 -0.04

Positive

symptom1 0.29 0 0.644 -0.845 -0.795 0.664 0.38 -0.04 0.35

Factor No. 32 0.23 0.14 0.47 -0.634 -0.48 0.23 0.22 0.02 0.19

Factor No. 42 0.28 -0.07 0.563 -0.573 -0.644 0.715 0.40 -0.10 0.37

Factor No. 52 0 -0.32 0.18 -0.07 -0.18 0.36 0.20 0.23 -0.28

Negative

symptom1 0.19 0.11 0.06 0.05 0.08 -0.08 0.17 0.10 0.15

1. The highest scores of drug-free period were calculated. 2. The factors of the highest positive symptom scores were calculated. 3. p < 0.05. 4. p < 0.02. 5. p < 0.01.

Discussion

The paradigm used in the present study differed from previous CSF studies (Bowers, 1974; Post et al., 1975) but the conclusions are compatible in refuting the simplest form of the DA hypothesis, i.e., that overactivity of dopaminergic neurons is inherent in schizophrenia. The present results support Crow’s (1980) formulation in that positive symptoms were associated with increased dopaminergic responsivity. The reduction in DA turnover after withdrawal of long-term neuroleptic medication may be due to a rebound effect of cessation of receptor blockade and shows great variance between individuals, presumably caused by individual differences in rate and/or intensity. Probably the size of this rebound reflects vulnerability to severe relapse and in the majority of cases the rebound takes its course in 1 month, because Zander et al. (198 1) failed to detect any change in CSF HVA levels by day 30 of withdrawal. It seems that as the basis of florid psychotic symptoms there is an overregulation of the dopaminergic system, leading to an instability of function as proposed by King et al. (1982) in their dynamic model. This excessive regulatory pattern may be evident, for example, during long-term neuroleptic therapy or after its discontinuation. Lower prewithdrawal DOPAC level (indicating quiescent firing of DA neurons) and marked postwithdrawal decrease in those patients whose symptoms became more “productive”

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may reflect strong short-loop and/ or long-loop down-regulation offsetting the consequences of postsynaptic DA receptor up-regulation induced by chronic neuroleptic administration (Roth, 1983; Rupniak et al., 1983). The latter is more pronounced in Type I syndrome (Owen et al., 1981), which also represents an overregulation.

Both hypersensitive DA autoreceptors and hypersensitive postsynaptic DA receptors could give rise to the decrease in presynaptic DA activity. Because of the long-loop feedback for DA function, supersensitive postsynaptic DA receptors might lead to a decrease in DA neuronal firing, and thus to the observed decrease in released DA and DOPAC. Under such conditions, presynaptic DA synthesis might be increased, decreased, or unchanged, in view of the paradoxical increase in DA synthesis at low firing rates demonstrated by Walters et al. (1973). Thus, the inability to find a correlation with HVA could be due either to paradoxical changes in presynaptic synthesis as a function of firing rate or to the low specificity of the fluorimetric assay for HVA. Therefore, these data would be supportive of work by researchers such as Crow (1982) and Seeman et al. (1984) on the elevated postsynaptic DA receptors found in post-mortem studies of schizophrenics.

We are, of course, aware that the small sample size and lack of pretreatment biochemical data allow only limited interpretation. Firmer conclusions require a more direct and extensive study, so these findings must be regarded as tentative.

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