cerebrospinal fluid of patients with chronic schizophrenia ... homovanillic acid (HVA), the principal metabolites of norepinephrine, serotonin, and dopamine,.
Effect of propranolol on monoamine metabolites in
cerebrospinal fluid of patients with chronic schizophrenia Large doses (960 to 3200 mg/day) of propranolol were taken by eight patients with chronic schizophrenia in a double-blind therapeutic trial. To investigate the effects of such treatment on central monoaminergic processes, samples of cerebrospinal fluid (CSF) were drawn before starting the study and after 31 to 63 days (X = 49 days) on propranolol. Concentrations in CSF of 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA), the principal metabolites of norepinephrine, serotonin, and dopamine, were determined by HPLC with electrochemical detection. The level of HVA did not change. CSF 5-HIM levels decreased an average of 34%, which indicates reduced turnover of serotonin in the central nervous system (CNS). There was a strong correlation between duration of treatment with propranolol and change in CSF 5-HIM levels. The concentration of MHPG in CSF increased an average of 39%; this could have resulted from increased turnover of CNS norepinephrine as a consequence of the blockade of central P-adrenoceptors or of altered metabolism and clearance of peripheral MHPG. Psychotic symptoms of the patients, as indicated by the 3-day average score on the Bunney-Hamburg scale, were not affected by treatment.
Mika Scheinin, M.D.,* Daniel P. van Kammen, M.D., Ph.D.,** Philip T. Ninan, M.D.,*** and Markku Linnoila, M.D., Ph.D.**** Bethesda, Md. Clinical Psychobiology Branch and Biological Psychiatry Branch, National Institute of Mental Health
Large doses of propranolol have been reported to be beneficial in organic and manic psychoses as well as acute and chronic schizophrenia. In
Received for publication Jan. 3, 1984; accepted Feb. 15, 1984. Reprint requests to: Markku Linnoila, M.D., Ph.D., Clinical Director, DICBR, National Institute on Alcohol Abuse and Alcoholism, Building 10, Room 3B-23, 9000 Rockville Pike, Bethesda, MD 20205. *Present address: Department of Pharmacology, University of Turku, SF-20520 Turku 52, Finland. **Present address: Department of Psychiatry, VA Medical Center, Highland Drive, Pittsburg, PA. ***Present address: Department of Psychiatry, Emory University, Atlanta, GA 30322. ****Present address: Laboratory of Clinical Studies, National Institute of Alcohol Abuse and Alcoholism, Bethesda, MD 20205.
chronic schizophrenia, however, therapeutic efficacy has been uncertain. Some positive results have been reported, especially with propranolol as an adjunct to conventional neuroleptic drugs, and with propranolol alone. 1 4,6,13 15,20,28,37,42,43 The benefits from a combination of neuroleptics and propranolol may stem from the inhibition of the biotransformation of phenothiazines by propranolo1.29. 30 Our aims were to evaluate the therapeutic efficacy of large doses of D,L-propranolol in chronic schizophrenia with a doubleblind design and to investigate the mechanisms of action of such treatment by measuring concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (533
34 Scheinin et al.
Clin. Pharmacol. Ther. July 1984
Table I. Patient and treatment variables Patient No. 1
2 3
4 5
6
Sex
Age (yr) 25 27 28 29 23 23
24
7 8
9 10
total group X subjects 1, TC
25 30 22
25.6 25.4
No. of yr ill
RDC subtype
5 8 2
UND UND PAR UND SA SA UND UND UND PAR
10 2
4 0.5 3
12 5
Premorbid* adjustment score
Days on placebo
Days on
Daily dose
propranolol
(mg)
50
17 17 19
20 27
24
18
9 22
210 42 27
21
103
12
120
24
56 29
63
57.8 61.4
38.0 48.7
960 1920 1436 1829
11
12
5.2 5.4
46
60 33 7
63 41
20 31
960 1920 1920 160 1920
3200 1280
2,3,5,6,9, 10 M
= male; F = female; UND = undifferentiated; PAR = paranoid; SA = schizoaffective.
*Phillips
scale: A
value of 15 or less indicates a good level of premorbid adjustment.
HIAA), and homovanillic acid (HVA), the principal metabolites of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), in cerebrospinal fluid (C SF). The effects of propranolol on monoamine metabolites in CSF have been reported in two small studies. In the study of Belmaker et al.3 in 10 patients, the short washout period (9 days) after cessation of treatment with neuroleptics may have partly invalidated the results. In the study of King et al. ,13 propranolol, 1 gm/day, had been given to five patients for only 1 to 2 wk after a 4-wk washout. While our manuscript was in preparation, another study of 11 patients was published by the same group'4 in which the washout period was 4 wk but the dose of propranolol was lower and the duration of treatment was shorter than in our experiment. Methods
Our subjects were 10 patients with chronic schizophrenia (Table I). All met the Research Diagnostic Criteria (RDC) and the Diagnostic and Statistical Manual (DSM) III requirements for the diagnosis of schizophrenia. Patients with somatic illness, organic brain syndrome, or alcohol or drug dependence were excluded. Subjects received placebo for an average of 58 days (range 18 to 210 days) before starting.
None had been receiving depot neuroleptics. After the first lumbar puncture, treatment with D,L-propranolol was started and the dose was increased in a stepwise fashion, while signs of over-medication, such as toxic psychosis and reduction of the heart rate to less than 50 bpm and reduction of blood pressure to under 90/40 mm Hg, were carefully monitored. A second lumbar puncture was performed during treatment with propranolol. In eight subjects, the second CSF sample was drawn during maintenance treatment of a daily dose of 960 to 3200 mg. In two subjects, the second sample was drawn after less than 2 wk on low doses of propranolol; a third CSF sample had been scheduled during subsequent high-dose therapy, but the subjects withdrew their consent (Table I). Lumbar punctures were performed in the lateral decubitus position between 8:30 and 9:30 A.M. after an overnight fast and bed rest. Twelve milliliters of CSF were drawn, mixed, and placed on ice at bedside. Aliquots were taken and frozen at 60° until assayed. Concentrations of MHPG, 5-HIAA, and HVA in CSF were determined by HPLC with electrochemical detection (HPLC-EC).34 NE in CSF was assayed by a modification of an HPLC-EC method for catecholamines in plasma.10, 36 In one patient (No. 7), lumbar punctures
Propranolol and monoamine metabolites in CSF of chronic schizophrenics
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Number
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Table II. Effect of high-dose propranolol on psychotic symptoms and concentrations of NE, MHPG, 5-HIM, and HVA in CSF Concentration (nmo111) Psychosis rating* (n = 8) Before propranolol During propranolol P valuet
7.8 ± 0.57 7.6 ± 0.48 NS
NE (n
= 6) 0.20
36.1
-±
1.12 ± 0.26 NS
50.3
-±
0.79
5-HIM (n = 7)
MHPG (n = 7)
154.8 -± 24.3 102.1 ± 12.7
3.7 1.5
