Plasma homovanillic acid in neuroleptic responsive and nonresponsive schizophrenics

BIOL PSYCHIATRY 1993;34:523-528

523

Plasma Homovanillic Acid in Neuroleptic Responsive and Nonresponsive Schizophrenics Erica Duncan, Adam Wolkin, Burton Angrist, Michael Sanfilipo, Susan Wieland, Thomas B. Cooper, and John Rotrosen

Changes in plasma homovanillic acid (HVA) were investigated in neuroleptic responsive and nonresponsive schizophrenics in order to delineate parameters of dopamine regulation, which may underlie differences in neuroleptic responsivity. Nineteen schizophrenics were treated with haloperidol for 6 weeks. HVA was sampled at baseline, 24 hr after initial neuroleptic dose, and after 6 weeks of treatment. Subjects were pretreated with debrisoquin in order to reduce the peripheral production of HVA. The responders had an initial rise in HVA at 24 hr after first neuroleptic dose, followed by a decline back to baseline over the 6 weeks of treatment. The nonrespmlders' HVA failed to rise at 24 hr after first neuroleptic dose. At 6 weeks of treatment their HVA had fallen to significantly below baseline. Thus, a rise in HVA 24 hr after the first dose of neuroleptic predicted treatment response; a fall in HVA at 6 weeks to below pretreatment values was associated with neuroleptic nonresponse. Key Words: Homovanillic acid, schizophrenia, dopamine, neuroleptic, debrisoquin

Introduction The blockade of dopamine (DA) receptors by neuroleptics leads to an initial sharp increase and subsequent decrease in DA release and metabolism, as indicated by changes in plasma homovanUlic acid (HVA) (Kendler and Davis 1984; Chang et al 1986; Bacopoulos et al 1979; Davila et al 1987, 1988; Davidson et al 1987a, 1987c; Pickar et al 1984, 1986; Bowers et al 1989; Harris et al 1984). A number of studies suggest that the late-phase decrease in DA release is associated with clinical response in schizophrenics (Pickaxet al 1984, 1986; Chang et al 1988; Sharma et ai 1989; Davila et al 1988; Davidson et al 1991a; Bowers From the Psychiatry Service, Department of Veteraas Affairs Medical Center, New York, NY (ED, AW, BA, MS, SW, TBC, JR), the Department of Psychiatry, New York University Medical Center tED, AN, BA, JR), and the Nathan Kline Institute, Orangeburg, NY (TBC). Address reprint requests to Erica Duncan, MD, Psychiatry Service (I 16A), DVA Me~:."~ Ccnte-. 423 Eas! 23 S!~e!, New York, NY I0010, Received December 31. 1992; revised July 1:5, 1993. © 1993 Society of Biological Psychiatry

et al 1984, 1989; Mazure et al 1991). The purpose of this study was to assess the effects of acute (24 hr) and long term (6 weeks) neuroleptic treatment in schizophrenics rigorously defined as clinical responders (n ~- 10) and nonresponders (n = 9), using plasma HVA as an index of dopamine turnover, in order to inhibit peripheral production of HVA, subjects were pretreated with debrisoquin (DBQ) (Maas et al 1985, lo~8; Davidson et al 1987a 1987c, 1987d; Kendler et al 1981; Swann et al 1980).

Subjects and Methods Written informed consent was obtained from 19 men who were schizophrenic inpatients at the New York Department of Veterans Affairs Medical Center (mean years ill --13.2 -4- 6.5; mean age ~ 36.3 ± 5.4). All subjects fulfilled DSM-III-R criteria for schizophrenia, and diagnosis was confirmed by the Scheduled Clinical Interview for Diagnosis (SCID) (Spitzer et al 1988). Potential subjects 0006-3223/93/$06.00

524

BIOL PSYCHIATRY 1993;34:523-528

E. D u n c a n et al

were excluded if there was significant medical illness requiring treatment, a history of head trauma, neurological disease, mental retardation, or significant recent drug or alcohol abuse. Subjects were selected who were either acutely decompensated or persistently symptomatic. To ensure that subjects had at least a moderate level of psychopathology to allow the potential for neuroleptic response, subjects were required to have a minimum total score of 22 on the Brief Psychiatric Rating Scale (BPRS, 0---6 scale)(Guy 1976) as well as a minimum global score of 6 on the Schedule for Assessment of Positive Symptoms (SAPS)(Andreasen 19841. Patient characteristics are presented in Table 1. In an attempt to select equal numbers of neuroleptic responsive and nonresponsive subjects, approximately half those subjects entered were selected as probable nonre-

sponders on the basis of their having documented failure of prior adequate neuroleptic trials. In addition, they had to have been persistently psychotic for the previous 2.5 years. Three of the subjects in this group had failed a trial of clozapine. All of the nine subjects who were entered into the study as presumptive nonresponders did indeed fail to respond to the haloperidol treatment, which was a part of this study. Prior to beginning the protocol, all subjects were off oral neuroleptics for at least 5 weeks (mean = 99 -+ 103 days excluding three patients who were neuroleptic naive) and off depot neuroleptic for at last 6 months. These criteria were chosen because previous work (Pickar et al 1986; Davidson et al 1991b) has shown that plasma HVA takes at least 5 weeks to reach drug-free baseline after neuroleptic withdrawal. During neuroleptic washout lor-

Table I. Patient Characteristics Responders (n = 10)

Nonresponders (n = 9)

All subjects (n = 19)

t(17)

Demographics Age(yrs) Height (in.) Weight (Ibs.) Years III No. hospitalizations No. hospitalizations per Years III Race White Black Hispanic Schiz. subtype Undifferentiated Paranoid Disorganized Days of Washour Psychiatric ratings

34.3 71,0 171,8 I0. I 5.0 0.7

Total BPRS(base.) Total BPRS (6 Wks) Total BPRS % change BPRSSchiz. (base.) BPRS Schiz. (6 Wks) BPRSSchiz. %change Haloperidol levels (6 Weeks)

36.1 14.7 58.4 11.3 2.7 76.3

Plasma Halop. (ng/mL) Haloperidol Dose(ms) HVA plasma levels

15 3 ± 6.8 29.3 "*- 14.3

HVA Baseline(ng/mLI HVA Acute (ng/mL) HVA 6-Weeks (ng/mlA Acute-Base(ng/mL) 6-Week-Base (ng/mL)

_-,2 5.1 ± 2.2 ± 25.5 ± 5.3 ± 3.1 ± 0.5

38.6 69.2 158.7 16,8 10.6 0.6

_-'n 5.1 ± 3.5 ± 23,7 ± 6,0 ± 6.5 "," 0.3

36,3 70,2 165,6 13.2 7.6 0.7

± ± ± ± ± _

5.4 2.9 24,9 6.5 5.6 0.4

5 5 0

3 5 I

8 I0 I

7 2 I 121 ± 119

7 0 2 82 ± 92

14 2 3 99 -4- 103

3,7 4.8 3.7 I.I 0.0

~p ~ 0.05; ~p <~ O.OI; 'p <~ 0.001; ap ~ O.000l. 'Washout does not include three neuroleptic-naive patients. rSee analysis of variance (ANOVA) results.

± ± _ ± ± ±

8.8 8.3 23.2 1.8 2.1 17.3

± 1,0 ± 0.8 ":t" I.n ± I.I ± 0.6

36.7 30.7 16.3 10.9 10.4 4.0

± 9.7 ± 9.5 ± 20.0 ± 3.4 _-4- 3.7 ± 20.5

15.4 ± 4.6 36.3 --- 12.4 4,7 4.5 3.6 -0.2 -1.1

_ 1.8 ± 1.6 ± !.0 ± 0.9 ± 1.0

36.4 22.3 38.5 I1.1 6.4 42.1

± ± ± ± ",__.

--

9.0 11.9 30.2 2.6 4.9 41.4

15.4 _-&- 5.6 32.8 ± 13.5 4,2 4.6 3.6 0.5 -0.6

± ± ± ± ±

1.8 1.4 1,2 2.6" 2.4" 0.6

1.5 1.2 1.0 1.2 i.O

-0.7 0.1 3.9" 4.2" 0.3 5.7 a 8.3 a 0.1 !.1 / / : a "

Plasma HVA in Schizophrenics

azepam or chloral hydrate was used on a PRN basis to control agitation. After entry into the study, subjects were placed on a low monoamine diet. They were treated with debrisoquin I0 nag BID for 5 days prior to and throughout all days of HVA sampling (Davidson et al 1987d). Blood for plasma HVA was drawn between 8:50 AM and 9:10 AM, after overnight fast and bedrest. Three baseline 9 AM samples were drawn on three successive days. Immediately after the blood drawing on the third morning, subjects received haloperidol 0.1 mg/kg IM, and then started that evening on a dose of 5 mg PO TID. The following morning blood was drawn for HVA after overnight fast and before the AM doses of haloperidoi and debrisoquin. Debrisoquin and diet were discontinued and subjects were then treated for 6 weeks with haloperidol. Concomitant treatment with benztropine or propranolol was allowed as needed to control Parkinsonian side effects or akathisia respectively. Fifteen subjects needed concomitant treatment with lorazepam or choral hydrate during the early haloperidol phase to control agitation. Doses of haioperidol were increased to produce a targeted plasma haloperidol level of 15 + 5 ng/ml. Positron emission tomography (PET) studies have demonstrated this to be an adequate plasma level to achieve virtually maximal DA receptor blockade (Wolkin et al 1989), and clinical studies to date suggest that this plasma level is adequate for clinical response (Midha et al 1987). After 2 weeks of treatment, haloperidol trough levels were measured weekly at 9 AM. All subjects achieved a plasma level within the target range by at least week 5 of the study. The mean haloperidol level at 6 weeks of treatment was 15.4 --. 5.6 ng/ml, achieved with a mean dose of haloperidol of 32.8 -+ 13.5 rag/day. Five days before the 6 weeks' treatment with haloperidol was completed, low monoamine diet and debrisoquin 10 mg BID were restarted and continued to the end of the study. Blood was drawn for plasma HVA and haloperidol levels at 9 AM on the final 3 days of the study as previously described. Subjects were rated by the same rater at baseline and weekly throughout the study. Psychopathology was rated with the BPRS, SAPS, Clinical Global Impression Scale (CGI) (Guy 1976), and Abrams and Taylor Scale for Emotional Blunting (Abrams and Taylor 1978). Movements and side effects were rated by means of the Simpson-Angus (Hillside modification) (Simpson and Angus 1970), Akathisia Subjective Rating Scale Assessment (Adler et al 1986), and Abnormal Involuntary Movement Scale (AIMS) (Guy 1976). Side effect data will be reported elsewhere. Ten patients were classified as responders in this prospective baloperidol treatment trial. They had a percentage of change in the BPRS schizophrenia symptoms subscale

BIOLPSYCHIATRY 1993;34:523-528

525

of 35% or greater (mean = 76.3 + 17.3; range 45.4 to 100). Nine patients were classified as nonresponders, based on a percentage of change in the BPRS schizophrenia symptoms subscale of less than 35% (mean = 4.0 _+ 20.5; range 45.4 to 23.5). Changes in BPRS scores (total and schizophrenia factor) in the two groups are shown in Table 1.

HVA Determination Plasma HVA was measured by means of the gas chromatography-mass spectroscopy method adapted from Fri et al (1974). Using pentadeuterated HVA as an internal standard, 0.5 ml of plasma is diluted with aqueous buffer (pH 4,0) and extracted with ethyl acetate. The ethyl acetate is then placed in a tapered tip glass tube containing 50 ttl of pentafluoropropionic anhydride (PFPA) and taken to dryness via a vacuum centrifuge at 40° C. PFPA and trifluoroethanol (4: l) are then added and incubated at 75 ° C for 15 rain and again taken to dryness. The residue is redissolved in 30 ~1 cyclohexane. One microliter is then injected into a capillary gas chromatograph-mass spectrometer using the cold trapping procedure with the mass spectrometer operated in the electron impact mode utilizing simultaneous ion monitoring of the molecular ion 410 m/z and the internal standard molecular ion 415 m/z. Secondary ions at 283 m/z and 288 m/z are also monitored for additional specificity. In our hands the method has an intra-assay and interassay coefficient of variation of 4.2% and 6.1%. Standard curves are linear through 50 ng/ml with negligible intercept and a lower limit of sensitivity of 0.5 ng/ml.

Haloperidol Levels Plasma haloperidol levels were measured using the gas chromatography method of Bianchetti and MorseUi (1978). Results For all subjects the mean coefficient of variation (CV) for the three baseline plasma HVA levels was 14.94% -+ 9,18. The CV for the three endpoint plasma HVA levels was 11.88% - 6.57. Data were analyzed using a two-factor analysis of variance (ANOVA) design. Post hoc t-tests were used to determine significant interactions; Newman-Keuls tests were used to determine main effects. For the group-as-a-whole plasma HVA rose significantly from 4.2 ± 1.5 at baseline (mean of three baseline values drawn at 9 AM Off 3 consecutive days) to 4.6 -+ 1.2 at 24 hr after the first neuroleptic dose. After 6 weeks of treatment HVA (mean of three endpoint values drawn at 9 AM on 3 consecutive

526

BIOL PSYCHIATRY 1993:34:523-528

E. Duncan et al

days) declined to 3.6 -+ 1.0, which was significantly lower than baseline or acute treatment conditions. These results are shown in Table I. The ANOVA and post-hoe analysis revealed significant differences in the pattern of plasma HVA changes between the responders and nonresponders. The responders had a robust rise in HVA from baseline to 24 hr after first haloperidol dose (p < 0.001). By 6 weeks of treatment their HVA had fallen to baseline values. The nonresponder group had a higher baseline HVA, which failed to rise at 24 hr after first neuroleptic dose. At 6 weeks their HVA had fallen to significantly below their baseline value (p < 0.001). These results are shown on Table I and in Figure I. HVA change scores were analyzed by t-tests for differences between the two patient groups. As shown in "Fable I, Acute HVA - Baseline HVA differed between responders and nonresponders at the p = 0.013 level; Endpoint HVA - Baseline HVA differed between the responders and nonresponders at the p = 0.014 level. The plasma HVA of the responders was nonsignilicantly lower at baseline (3.7 - 1.0) than that of responders (4.7 _ !.8; p = 0.148 by t-test). There were no significant differences between responders and nonresponders with

Discussion The baseline values of HVA and the magnitudes of change that we found in the present study were comparable to values reported in the literature for subjects pretreated with

HVA Level (ng!mL) ...............................................................

7

.....

5

respect to their absolute HVA levels at 24 hr and 6 weeks after neuroleptic treatment. There were no significant correlations between baseline HVA and baseline or treated psychopathology. The responder and nonresponder groups did not differ significantly with respect to age (in years, responder = 34.3 - 5.1; nonresponder = 38.6 _ 5.1), height (in inches, responder = 71.0 _ 2.2; nonresponder = 69.2 +- 3.5), weight (in pounds, responder = 171.8 -+ 25.5; nonresponder = 158.7 - 23.7), length of neuroleptic washout (responder = 121 _ l l9; nonresponder = 82 _ 92), total daily dose of haloperidol (in mg, responder = 29.3 - 14.3; nonresponder = 36.3 _+ 12.4), or final plasma level achieved (in ng/ml, responder = 15.3 -+ 6.8; nonresponder = 15.4 -+ 4.6). The two groups did not differ significantly in the number of days treated with haloperidol at the target plasma range (responder = 23.8 - 5.3; nonresponder = 27.2 _ 8.2). These results are shown in Table I.

t

....

............................

I

I

.

J

.... l.....

Figure I. Absolute values of plasma HVA at baseline, after 24 hr of neuroleptic treatment, and after 6 weeks of treatment, for rcsponders and nonresponders. Two-factor ANOVA interaction was signilicant. p = 0,01 I. Post hoc tests: for the responder group--Baseline versus Acute Tx, p < O.OOl; Acute Tx versus Endpoint, p < O.OOI. For the nonresponder group, Baseline versus Endpoint, p < 0.01; Acute versus Endpoint p < 0.01.

4

2

Base Acute

End

Responders

Base

Acute

End

Non-Responders

Plasma HVA in Schizophrenics

debrisoquin. For our subjects analyzed as a whole we observed an initial rise in HVA at 24 hr after the first dose of neuroleptic, followed by a decline essentially to baseline values after 6 weeks of treatment. This pattern of change is similar to what has been reported in prior studies (Davila et al 1987; Davidson et al 1987a, 1987c; Pickar et al 1984, 1986). With respect to the differences between our responders and nonresponders, we found that only the subjects who went on to respond to our prospective haloperidol trial had an initial rise in HVA at 24 hr after beginning treatment. In our hands this acute rise in HVA served to predict clinical response to neuroleptic. This finding is in accord with what has been reported in prior studies (Davila et al 1987, 1988). After the initial 24 hr of treatment our responders had a subsequent fall in HVA, back to but not below baseline levels. It was our nonresponders who demonstrated a decline in HVA over 6 weeks' treatment to significantly below pretreatment values. This result differs from some previous reports, in which those patients who had better clinical response had the greatest decline in HVA from baseline to treated conditions (Bowers et al 1984, 1989; Chang et al 1988; Davila et al 1988; Davidson et al 1991a; Pickar et al 1984, 1986). There are several factors that could account for this difference between our study and the above-cited studies. Our subjects were washed out of neuroleptic for an extended period, in light of Pickar's (1986) and Davidson's (1991b) reported rise in HVA for as long as 5-6 weeks off neuroleptic, the length of washout appears to be an important factor in determining baseline levels. We titrated haloperidol dose to a target plasma level (15 - 5 ng/ml) rather than using a fixed-dose design. Our protocol defined patient groups by means of the schizophrenia factor of the BPRS, which specifically relates to core schizophrenia symptoms. We used percentage of change in this factor to differentiate responders from nonresponders. Our responders had a quite robust decline

References Abrams R, Taylor MA (1978): A rating scale for emotional blunting. Am J Psychiatry 135:226-229. Adler L, Angrist B, Peselow E, Corwin J, Maslansky R, Rotrosen J (1986): A controlled assessment of propranolol in the treatment of neuroleptic-induced akathisia. Br J Psychiatry 149:42-45. Andreasen NC ( 1984): The Scale for the Assessment of Positive Symptoms (SAPS). Iowa City, Iowa: University of Iowa. Bacopoulos NG, Hattox SE, Roth RH (1979): 3,4-Dihydroxyphenylaeetic acid and homovanillic acid in rat plasma: Possible indications of central dopaminergic activity. Eur J Pharmacol 56:225-236.

BIOLPSYCHIATRY 1993;34:523-528

527

in symptoms (76.3 -+ 17.3 percentage of decrease in BPRS schizophrenia factor), whereas our nonresponders had very minimal change in symptomatology during treatment (4.0 _+ 20.5 percentage of decrease in BPRS schizophrenia factor). The schizophrenia factor of the BPRS does not include less specific BPRS items such as agitation or anxiety. These nonspecific items could be expected to rise or fall with poripberal adrenergic activity, therefore causing plasma HVA to rise or fall because of changes in its peripheral adrenergic component (Kopin e~ al 1988). Other studies looking at HVA changes after neuroleptic treatment in patients of differing responsivity did not use dehrisoquin. Because peripheral nondopaminergic sources account for a large percentage of measured plasma HVA in the absence of debrisoquin, it is possible that the robust fall in HVA from baseline to treated conditions observed in neuroleptic responsive subjects occurred partly as a result of diminution in peripheral adrenergic activity. Changes in peripheral adrenergic sources of plasma HVA would not be as prominent in our study as our subjects received dehrisoquin. Finally, it is possible that differences in patient populations across sites could account for differences between our findings and previously reported results. The between-group differences in HVA change scores could be viewed as being caused by the difference in E ~'A between the two groups at baseline. From this perspective both the act:t.e and long-term change score differences could be interpreted as a regression to the mean. However, it must be emphasized that baseline HVA differed nonsignificantly between the two groups. This study provides support to the idea that an early rise in plasma HVA in response to neuroleptics can predict eventual clinical response to treatment. Further study is required in order to better characterize the changes in dopamine turnover in subgroups of schizophrenics. This material is based on work supported by the Office of Research and Development of the Department of Veterans Affairs.

Bianchetti G, Morselli PL (1978): Rapid and sensitive method for determination of haloperidol in human samples using hydrogen phosphorus selective detection. J Chromatogr 153:203209. Bowers MB Jr, Swigar ME, Jatlow PI, Goicoechea N (1984): Plasma catecholamine metabolites and early response to haloperidol. J C/in Psychiatry 45(6):249-251. Bowers MB, Swigar ME, Jatlow PI, Hoffman FJ (1989): Plasma catecholamine metabolites and treatment response at neuroleptic steady state. Biol Psychiatry 25:734738. Bunney BS (1988): Effects of acute and chronic neuroleptic

528

BIOL PSYCHIATRY 1993:34:523-528

treatment on the activity of midbrain dopamine neurons. Ann NY Acad Sci 537:77-85. Chang WH, Chen TY, Lee CF, Hung JC, Hu WH, Yeh EK (1988): Plasma homovanillic acid levels and subtyping of schizophrenia. Psychiatry Res 23:239-244. Chang WH, Yeh EK, Hu WH, Tseng YT, Chung MC, Chang HF (! 986): Acute and chronic effects of haloperidol on plasma and brain homovanillicacid in the rat. Biol Psychiatry 21:374381. Davidson M, Giordani AB, Mohs RC, et al (1987a): Short-term haloperidol administration acutely elevates human plasma homovanillic acid concentration. Arch Gen Psychiatry 44:189190 Davidson M. Giordani AB, Mobs RC, et al (1987b): Control of exogenous factors affecting plasma homovanillic acid concentration. Psychiatry Res 20:307-312. Davidson M, Kahn RS, Knott P, et al (1991a): Effects of neuroleptic treatment on symptoms of schizophrenia and plasma homovanillicacid concentrations. Arch Gen Psychiatry 48:910-913. Davidson M, Kahn RS, Powchik P, et al (1991b): Changes in plasma homovanillic acid concentrations in schizophrenic patients following neuroleptic discontinuation. Arch Gen Psychiatry 48:73-76. Davidson M, Losonczy MF, Mohs RC, et al (1987c): Effects of debrisoquin and haloperidol on plasma homovanillic acid concentration in schizophrenic patients. Neuropsychopharma. cology I: 17-23. Davidson M, Losonczy MF, Mohs RC, et al (1987d): Methodologies for assessing central dopaminergic function: Plasma and urinary homovanillic acid following debrisoquin administration. Psychopharm Bull 23:407-410. Davila R (1989): Plasma HVA, ncuroleptics, and dopaminergic plasticity. Biol Psychiatry 25: I-3. Davila R, Manero E, Zumarraga M, Andia I, Schweitzer JW, Friedhoff AJ ( 1988): Plasma homovanillic acid as a predictor of response to neuroleptics. Arch Gen Psychiatry 45:564567. Davila R, Zumarraga M, Perea K, Andia 1, Friedhoff AJ (1987): Elevation of plasma homovanillic acid level can be detected within four hours after initiation of haloperidol treatment. Arch Gen Psychiatry 44:837-838. Fri CG, Wiesel FA, Sedvall G (1974): Simultaneous quantification of homovanillic acid and 5-hydroxyindoleacetic acid in cerebrospinal fluid by mass fragmentugraphy. Life Sci 14:2469-2480. Guy W (1976): ECDEU Assessment Manual for Psychopharmacology. Washington, DC: US Department of Health, Education and Welfare (publication number ADM76-338). Harris PQ, Brown Sl, Friedman MJ, Bacopoulos NG (1984): Plasma drug and homovanillic acid levels in psychotic patients receiving ncuroleptics. Biol Psychiatry. 19:849-860. Kendler KS, Davis KL (1984): Acute and chronic effects of

E. Duncan et al

neuroleptic drugs on plasma and brain homovanillic acid in the rat. Psychiatry Res 13:51-58. Kendler KS, Heninger GR, Roth RH (1981): Brain contribution to the haloperidol-induced increase in plasma homovanillic acid. Ear J Pharmacol 71:321-326. Kendler KS, Hsieh JY, Davis KL (1982): Studies of plasma homovanillic acid as an index of brain dopamine function. Psychopharmacol Bull 18:152-155. Kopin U, White JH, Bankiewicz K (1988): A new approach to biochemical evaluation of brain dopamine metabolism. Cell Mol Neurobiol 8(2): 171-179. Maas JW, Contreras SA, Seleshi E, Bowden CL (1988): Dopamine metabolism and disposition in schizophrenic patients. Arch Gen Psychiatry 45:553-559. Maas JW, Contreras SA, Bowden CL, Weintranb SE (1985): Effects of debrisoquin on CSF and plasma HVA concentrations in man. Life Sci 36:2163-2170. Mazure CM, Nelson JC, Jatlow Pl, Bowers MB (1991): Plasma free homovanillic acid (HVA) as a predictor of clinical response in acute psychosis. Biol Psychiatry 30:475-482. Midha KK, Hawes EM, Hubbard JW, Korchinski ED, McKay G (1987): The search for correlations between neuroleptic plasma levels and clinical outcome: A critical review, in HY Meltzer (ed), Psychopharmacology: The Third Generation of Progress. New York: Raven Press, pp 1341-1351. Pickax D, Lahaxca R, Doran AR, et al (1986): Longitudinal measurement of plasma homovanillic acid levels in schizophrenic patients. Arch Gen Psychiatry 43:669-676. Pickax D, Labarea R, Linnoila M, et al (1984): Neurolepticinduced decrease in plasma homovanillic acid and antipsychotic activity in schizophrenic patients. Science 225:954957. Riddle MA, Leckman JF, Cohen DJ, et al (1986a): Assessment of central dopaminergic function using plasma-free homovanillic acid after debrisoquin administration. J Neural Transm 67:31-43. Riddle MA, Shaywitz BA, Leckman JF, et al (1986b): Brief debrisoquin administration to assess central dopaminergic function in children. Life Sci 38:1041-1048. Sharma R, Javaid Jl, Janicak P, Faull K, Comaty J, Davis JM (1989): Plasma and CSF HVA before and after pharmacological treatment. Psychiatry Res 28:97-104. Simpson GM, Angus JWS (1970): A rating scale for extrapyramidal side effects. Acta Psychiatr Scand (suppl) 212:! 119, Spitzer RL, Williams JBW, Gibbon M, First MB 0988): Stractared Clinical interviewfor DSM-IlI-R . Patient Version(SCIDP, 411/88). New York: Biometrics Research Department, New York State Psychiatric Institute, Swann AC, Maas JW, Hattox SE, Landis H (1980): Catecholamine metabolites in human plasma as indices of brain function: effects of debrisoquin. Life Sci 27:1857-1862. Wolkin A, Brodie JD. Barouche F, et al (1989): Dopamine receptor occupancy and plasma haloperidol levels. Arch Gen Psychiatry 46:482-3.