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Fluphenazine treatment reduces CSF somatostatin in patients with schizophrenia: Correlations with CSF HVA
BIOL PSYCHIATRY 1989;25:431439
431
Fluphenazine Treatment Reduces CSF Somatostatin in Patients with Schizophrenia: Correlations with CSF HVA Allen R. Doran, David R. Rubinow, Owen M. Wolkowitz, Alec Roy, Alan Breier, and David Pickar
CSF somatostatin and homovanillic acid (HVA) were measured in 14 schizophrenic patients while they were drug-free and during chronic jiuphenazine treatment. CSF somatostatin was signi$cantly reduced and CSF HVA was significantly elevated (p c 0.002) during jluphenazine treatment. There was a trend toward correlation between CSF somatostatin and CSF HVA in the 14 schizophrenic patients when drug-free (r = 0.49, p < 0.07) and fluphenazine-treated (r = 0.47, p C 0.08). When examined in a larger group (n = 46) of drug-free schizophrenics, this relationship was highly significant (r = 0.59, p < 0.001). These clinical data are consistent with preclinical evidence indicating a junctional interaction between CNS somatostatin and dopamine systems.
Introduction Somatostatin is a tetradecapeptide distributed abundantly throughout the central nervous system (CNS) with significant concentrations in cortex, including prefrontal cortex, and notably high concentrations in subcortical regions, such as striatum, amygdala, and nucleus accumbens (Finley et al. 1981; Reichlin 1983). Somatostatin has been shown to exert a number of behavioral actions following direct CNS administration in animal models, including alterations in sleep, locomotion, memory, learning, and eating behavior (Rubinow et al. 1987). Clinically, decreased concentrations of CSF somatostatin immunoreactivity have been found in patients with depression (Rubinow et al. 1983), Parkinson’s disease (DuPont et al. 1982), Alzheimer’s disease (Oran et al. 1981), and multiple sclerosis (Sorensen et al. 1980). Two controlled postmortem studies have suggested abnormal concentrations of brain somatostatin in schizophrenia. Ferrier et al. (1983) observed lower concentrations of somatostatin in the hippocampus of schizophrenic patients, and Nemeroff et al. (1983) reported lower concentrations of somatostatin in one frontal cortical region in schizophrenic patients. In addition to these findings, somatostatin has been linked to CNS dopaminergic systems. Somatostatin stimulates the release of dopamine from the striatum
From the Section on Clinical Studies, Clinical Neuroscience Branch, National Institute of Mental Health, Bethesda, MD. Address reprint requests to Dr. David P&u, Section on Clinical Studies. Clinical Neuroscience Branch, NIMH, NIH Bldg. 10, Rm. 4N212,9WO Rockville Pike, Bethesda, MD 20892. Received December 28, 1981; revised April 27, 1988.
This article is in the Public Domain.
ooo6-3223/89/$00.1X1
432
BIOL PSYCHIATRY 1989;25:43 l-439
Table 1. ~rno~~~c
A.K.
Doran et al
and Clinical Data for Patient Croups n =
14
n = 46
Sex Male
Female Age (mean + SD) Weight, kg (mean * SD) Drug-free days before LP (mean 2 SD) Fluphenazine days before LP (mean 2 SD) Fluphenazine dose (LP day) (mean 2 SD) Bunney-Hamburg Rating Scale (I-15) Placebo Psychosis (mean i SD) Depression (mean + SD) Ftuphenazine Psychosis (mean T SD) Depression (mean d SD)
7
25
7 28.0
64.2 31.9 32.9 18.4
9,6 rt Et.6 rt 9.6 z?z8.6 1: 12.3 2
7.3 + 2.4 t 1.7
5.4
21 25.7 + 7.0 66.7 % 13.4 31.4 2 15.8
8.0 Y!T 2.9 4.9 r 2.3
5.6 rt 1.8 4.9 ‘-c 1.2
in animals (Chesselet and Reisine 1983; Beal and Martin 1984a) and is reduced in brain by neuroleptics in a time-dependent fashion (Beal and Martin 1984b). Furthermore, dopamine stimulates the release of somatostatin from several brain regions (Negro-Vilar et al. 1978). We have previously reported decreased concentrations of CSF somatostatin in depressed patients and in depressed and sch~op~eni~ patients who showed abno~~ activation of the hypo~alamus-pi~it~-adrenal (HPA) axis in comparison with normal controls (Doran et al. 1986). In this article, we report the results of further studies of CSF somatostatin in patients with schizophrenia. We have examined the effect of neuroleptic treatment on CSF somatostatin concentrations and the relationship between CSF somatostatin and CSF concentrations of the dopamine metabolite homovanillic acid (HVA).
Methods Fourteen inpatients of the 4-East NIMH research ward granted written informed consent to participate in this prospective study of the reIationship among CSF somatostatin, CSF dopamine, and neuroleptic ~atment. All patients met DSM-III criteria for schizop~enia (subtypes: 9 paranoid, 3 undifferentiat~, 1 disorganized, 1 catatonic). Patients received a lumbar puncture (LP) after at least 3 weeks of both fluphenazine (mean ‘_ SD days was 32.9 ?z 8.6) and placebo (31.9 2 9.6) treatment (Table 1). CSF obtained from a research LP in an additional 32 drug-free inpatients on placebo with DSM-III diagnosed schizophrenia (11 paranoid, 14 undifferentiated, 1 disorganized, 1 catatonic) and in 6 patients with sch~o~f~tive disorder was assayed for CSF soma~statin and HVA to further examine this relationship and to diseem any possible differences according to subtype of schizophrenia (Table 2). Concentrations of CSF somatostatin of some of the patients from the additional group have already been reported (Doran et al. 1986). All patients were kept on a low monoamine, alcohol-free, and caffeine-restricted diet, and daily ratings were performed by nurses who were blind to treatment and were skilled in the use of the Bunney-Hamburg rating scale (Bunney and Hamburg, 1983). All LPs
BIOI,. I?aTmmRY 1989;25:43 1-439
433
434
BIOL PSYCHIATRY 1989;25:431-439
A.R.Doran et al
were performed with patients in the lateral decubitus position between 8:00 and 9:00 AM after an overnight fast and at lease 8 hr of bedrest. The first 10 ml of CSF for HVA determination was collected as a pool and was placed on ice at the bedside, subsequently divided into aliquots, and then frozen at - 80°C. CSF HVA was assayed using high-pressure liquid chromatography with electrochemical detection (HPLC-EC) (Scheinin et al. 1983; Sepala et al. 1984). Intraassay and interassay coefficients of variation of HVA were 4% and 8%, respectively. CSF somatostatin was assayed from the 28th milliliter of CSF, collected in a tube containing 100 1.~1of 1 N acetic acid, placed immediately on dry ice, and kept frozen at - 80°C. CSF somatostatin was assayed using a previously described radioimmunoassay technique employing TyPI’*‘-somatostatin (Carlsson 1959), synthetic somatostatin standards, rabbit antisomatostatin antiserum, and charcoal separation (Pate1 and Reichlin 1979). Intraassay and interassay coefficients of variation of somatostatin were 10% and 12%, respectively. Student’s r-test and simple linear regression were used for statistical analysis.
Results Fluphenazine treatment was associated with a significant reduction in CSF concentrations of somatostatin (paired f = 3.78, p < 0.002); 10 of 14 patients showed fluphenazineinduced decreases in somatostatin concentrations (Figure 1). Concentrations of somatostatin during the drug-free and fluphenazine treatment periods were significantly correlated (r = 0.66, p < 0.01). Fluphenazine increased CSF HVA in 11 of 14 patients (paired t = - 3.84, p < 0.002) (Figure 2). Concentrations of CSF HVA during the drug-free and fluphenazine treatment periods were significantly correlated (r = 0.69, p < 0.006). There was a trend toward correlation between CSF somatostatin and CSF HVA when dtug-free (I = 0.49, p < 0.07) and during fluphenazine treatment (r = 0.47, p < 0.08). However, when the additional drug-free group (n = 32) was added to the 14 drug-free patients (total 46), the relationship was highly significant (r = 0.59, p < 0.001) (Figure 3). Fluphenazine-induced changes in somatostatin and HVA were not significantly correlated (r = -0.29, NS); moreover, neither change was significantly correlated with change in psychosis or depression ratings (Table 1). There were no significant relationships between drug-free or fluphenazine-treated concentrations of CSF somatostatin and age, sex, or subtype of schizophrenia (Table 2).
Discussion We have shown that treatment with the neuroleptic fluphenazine significantly decreased concentrations of CSF somatostatin in patients with schizophrenia. This decrease in CSF somatostatin paralleled the fluphenazine-induced increase in CSF HVA. In addition to this robust neuroleptic effect, a significant correlation was found between CSF somatostatin and HVA concentrations in a larger group of drug-free patients with schizophrenia. Thus, our study supports the idea that CNS somatostatin and dopamine systems are physiologically linked. No significant relationship between fluphenazine-induced change in CSF somatostatin and clinical response to medication was observed. To our knowledge, there has been only one previous report of the effect of neuroleptic treatment on CSF somatostatin concentrations. Gattaz et al. (1985) reported a trend for increase in CSF somatostatin concentrations in schizophrenic patients treated with halo-
BIOL PSYCHIATRY 1989$5:431-439
Fluphenazine and CSF Somatostatin
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Figure 1. CSF somatostatin in patients with schiiophrenia (n = 14) while drug-free and during fluphenazine treatment (r = 3.78, p < 0.002).
peridol for several weeks. In that study, the greatest increase in CSF somatostatin was found in patients treated for the least amount of time and who received the lowest cumulative haloperidol dose, suggesting that the observed increase may not have been a drug effect or may not be seen with chronic treatment. No correlation between haloperidolinduced change in somatostatin and clinical response to medication was found. Bissette et al. (1986) reported lower concentrations of CSF somatostatin in schizophrenic patients in comparison with controls, but noted that a relatively short drug-free period (2 weeks) may have ~n~but~ to these findings. Black et al. (1986) reported decreased concentrations of CSF somatostatin in 18 depressed patients, 11 of whom were treated with neuroleptics. In our previous study (Doran et al. 1986), we found concentrations of CSF somatostatin in schizophrenic patients who had been maintained drug-free for at least 3 weeks to be similar to controls. Those ~hizop~~~ patients who showed abnormal activation of the I-IPAaxis, as reflected by the Dexamethasone Suppression Test, however, showed diminished concentrations comparable to those found in depressed patients. Our observations are consistent with the study of Beal and Martin (1984b), who observed that h~o~~dol, ~uphen~e, and c~o~~rn~i~ each decreased concentra-
436
BIOL PSYCHIATRY 1989;25:431A39
A.K.
Doran et al
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260
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220 200 180 160
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Figure 3. Linear correlation between CSF scmatostatin and CSF HVA in 46 drug-free patients with schizophrenia (r = 0.59, p < 0.001).
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(n = 14) while drug-free and during fluphen-
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CSF SOMATOSTATIN(pglml)
Fluphenazineand CSF Somatostatin
BK% PSYcHlATRY 1989;25:431-439
437
tions of so~tos~tin in key brain regions, idling the striatum, the amygdala, and nucleus accmrhns. Moreover, these investigators reported that this neuroleptic effect was time-dependent, with peak decreases occurring only after 2 weeks of treatment. Our finding of a significant correlation between CSF somatostatin and HVA supports a functional interaction between these neurotransmitter systems. Although the basis for the fluphen~~e-induct decrease in somatostatin is not completely understood, it likely results from fishy unctions activity of do~rgic systems due to dopamine receptor blockade. Fluphenazine-induced increase in CSF HVA is consistent with an extensive literature regarding neuroleptic effects on CSF dopamine metabolites (Pickar 1988) and is thought to reflect feedback activation of presynaptic dopamine neurons in response to receptor blockade. Other drug treatments have been shown to reduce CSF concen~tions of somatostatin. Rubinow et al. (1984) reported that carbamazepine si~i~c~~y reduced CSF ~matos~tin in affectively ill patients, and Steardo et al. (1986) demonstrated the same in patients with temporal lobe epilepsy. Wolkowitz et al. (1987) found that prednisone administration to normal volunteers was associated with significant decreases in CSF somatostatin concentrations. Thus, our findings with regard to fluphenazine’s effects on CSF somatostatin are not specific to this drug event. However, this is not surprising in light of the diverse localizations of somatostatin systems in brain and its important inhibitory function in the CNS. It is also possible that these common effects indicate shared interactions with CNS dopamine systems. Whereas the link between CNS dopamine and somatostatin is well supported, our ability to interpret the significance of our findings is limited. For exampie, we have recently suggested that ~oncen~tions of CSF HVA may, under some conditions, be prominently influenced by the mesocortical dopamine system, which innervates the prefrontal cortex (Doran et al. 1987; Pickar 1988). It is unknown whether the observed correlation between CSF somatostatin and HVA is accounted for by functional relationships in specific brain regions or is general&able to all dopaminergically innervated brain regions in humans. Postmortem studies of schizophrenic patients suggest decreased brain somatostatin concen~ations in both prefrontal cortical and s&cortical sites. The lack of relationship between CSF somatostatin concentrations and their fluphenazine-induced change and clinical symptomatology, although providing little direction for interpretation, should not necessarily suggest that somatostatin has no role in influencing dopaminergic function, particularly in response to neuroleptic treatment. Somatostatin and other peptide modulators of CNS dopamine system activity, including cholecystokinin (Nair et al. 1985), neu~tensin (Govoni et al. 1980), beta-endorphin (Schmauss and Emrich 1985), and met-enkephalm (Hong et al. 1978), may prove to be useful targets for enhancing neuroleptic response or for improved pharmacotherapeutic strategies for schizophrenia.
References Beal MI?, Martin JB (1984a):The effect of somatostatinon stiatal catecholamines.Neurosci Lett #:271. Beal MF, Martin JB (1984b): Effects of neuroleptic drugs on brain somatostatin-likeimmunoreactivity. Neurosci L&t 44~125. Bissette G, Widerlijv E, Wall&s H, KarIsson I, Eklund K, Forsrnan A, Nemeroff CB (1986): Alterationsin cerebrospinalfluid ~ncen~tio~s of somatostatin-like~uno~~ti~~ in neuropsychiatric disorders. Arch Gen Psychiatry 43: 1148.
438
BIOL PSYCHIATRY 1989;25:431-439
A.R Doran et ai.
Black PM, Ballantine HT, Carr DB, BeaJ MF, Martin JB (1986): Beta-endorphin and somatostatin concentrations in the ventricular cerebrospinal fluid of patients with affective disorder. Bid/ Psychiatry 21: 1077. Bunney W Jr, Hamburg DA (1983): Methods for reliable longitudinal observation of behavior: Development of a method for systemic observation of emotional behavior on psychiatric wards. Arch Gen Psychiatry 9:280.
Carlsson A (1959): The occurrence, distribution, and physiological role of catecholamines in the nervous system. Pharmacol Rev 11:490. Chesselet MF, Reisine TD (1983): Somatostatin regulates dopamine release in rat striatal slices and cat caudate nuclei. J Neurosci 3:232. Doran AR, Rubinow DR, Roy A, Pickar D (1986): CSF somatostatin and abnormal response to dexamethasone administration in schizophrenic and depressed patients. Arch Gen Psychiatry 43:365.
Doran AR, Boronow J, Weinberger DR, Wolkowitz OM, Breier A, Pickar D (1987): Structural brain pathology in schizophrenia revisited: Prefrontal cortex pathology is inversely correlated with cerebrospinal fluid levels of homovanillic acid. Neuropsychopharmacology 1:25. DuPont E, Christensen SE, Hansen AP, DeFine-Olivarius B, Orskov H (1982): Low cerebrospinal fluid somatostatin in Parkinson disease: An irreversible abnormality. Neurology 32:312. Ferrier NI, Roberts GW, Crow TJ, Johnstone EC, Owens DGC, Lee YC, O’Shaughnessy D, Adrian TE, Polak JM, Bloom SR (1983): Reduced cholecystokinin-like and somatostatin-like immunoreactivity in limbic lobe is associated with negative symptoms in schiozphrenia. Life Sci 33:475. Finley JLW, Maderdrutt JL, Rogers LT, Petrusz P (198 1): The immunocytochemical localization of somatostatin-containing neurons in the rat central nervous system. Neuroscience 6:2173. Gattaz WF, Rissler K, Gattaz D, Cramer H (1985): Effects of haloperidol on somatostatin-like immunoreactivity in the CSF of schozphrenic patients. Psychiatry Res 17: 1. Govoni S, Hong JS, Yang HYT, Costa E (1980): Increase of neurotensin content elicited by neuroleptics in nucleus accumbens. J Phurmucol Exp Ther 2 15413. Hong HS, Yang HYT, Fratta W, Costa E (1978): Rat striatal methionine-enkephalin content after chronic treatment with cataloptogenic and noncateloptogenic antischizophrenic drugs. J Pharrnacol Exp Ther 205: 141. Nair NPV, La1 S, Bloom DM (1985): Cholecystokinin peptides, dopamine and schizophrenia: A review, Prog Neuro-Psychophartnacol Biol Psychiatry 91515. Negro-Viler A, Ojeda SR, Arimura A, McCann SM (1978): Dopamine and norepinephrine stimulate somatostatin release by median eminence fragments in vitro. Life Sci 23: 1493. Nemeroff CB, Youngblood WW, Manberg PJ, Prange AJ, Kizer JA (1983): Regional brain concentrations of neuropeptides in Huntington’s chorea and schizophrenia. Science 221:972. Oran JJ, Edwardson J, Millard PH (1981): Investigation of cerebrospinal fluid neuropeptides in idiopathic senile dementia. Gerontology 27:2 17. Pate1 YC, Reichlin S (1979): Somatostatin. In Jaffe BM, Beheman HR (eds), Methods of Hormone Radioimmunoassay, ed 2. Orlando, FL: Academic Press, pp 77-100. Pickar D (1988): Perspectives on a time-dependent model of neuroleptic action. Schizophr Bull, 14:255-268.
Reichlin S (1983): Somatostatin. In Krieger DT, Brownstein MJ, Martin JB (eds), Bruin Peptides. New York: John Wiley & Sons, pp 71 l-752. Rubinow DR, Gold PW, Post RM, Ballenger JC, Cowdry R, Bollinger J, Reichlin S (1983): CSF somatostatin in affective illness. Arch Gen Psychiatry 40:409. Rubinow DR, Gold PW, Post RM, Ballenger JC, Cowdry R (1984): Somatostatin in patients With affective illness and normal volunteers. In Post RM, Ballenger JC (eds), Neurobiology of Mood Disorders, vol 1. Baltimore: William & Wilkins, pp 369-387. Rubinow DR, Post RM, Davis CL, Doran AR (1987): Somatostatin and GHRH: mood and behavior
Fluphenazine and CSF Somatostatin
BIOL PSYCHIATRY 1989;23:431-439
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regulation. In Nerozxi D, Goodwin FK, Costa E (eds), Hypothalamic Dysfunction in Neuropsychiatric Disorders. New York: Raven Press, pp 137-152.
Scheinin M, Chang W, Kirk M, Lhmoila M (1983): Simultaneous determination of 3-methoxy-4hydroxyphenylglycol,5-hydroxyindoleacetic acid, and homovanillic acid in cerebrospinal fluid with high performance liquid chromatography using electrochemical detection. Anal Biochem 131:246. Schmauss C, Emrich MH (1985): Dopamine and the action of opiates: A reevaluation of the dopamine hypothesis of schizophrenia. Biol Psychiatry 20: 1211. Sepala T, Scheinin M, Capone A, Linnoila M (1984): Liquid chromatographic assay for CSF catecholamines using electrochemical detection. ACM Phamucol Toxic01 55:81. Sorensen KV, Christensen SE, DuPont E, Hansen AP, Pederson E, Grskov H (1980): Low somatostatin content in cembrospinal fluid in multiple sclerosis: An indicator of disease activity. Acta Neural Stand 61:186. Steardo L, Barone P, Hunnicutt E (1986): Carbamazepine lowering effect on CSF somatostatinlike immunoreactivity in temporal lobe epileptics. Acta New-01 Stand 74:140. Wolkowitz OM, Rubinow DR, Breier A, Doran AR, Davis C, Pickar D (1987): Prednisone decreases CSF somatostatin in healthy humans: Implications for neuropsychiatric illness. Life Sci 41: 1929.
431
Fluphenazine Treatment Reduces CSF Somatostatin in Patients with Schizophrenia: Correlations with CSF HVA Allen R. Doran, David R. Rubinow, Owen M. Wolkowitz, Alec Roy, Alan Breier, and David Pickar
CSF somatostatin and homovanillic acid (HVA) were measured in 14 schizophrenic patients while they were drug-free and during chronic jiuphenazine treatment. CSF somatostatin was signi$cantly reduced and CSF HVA was significantly elevated (p c 0.002) during jluphenazine treatment. There was a trend toward correlation between CSF somatostatin and CSF HVA in the 14 schizophrenic patients when drug-free (r = 0.49, p < 0.07) and fluphenazine-treated (r = 0.47, p C 0.08). When examined in a larger group (n = 46) of drug-free schizophrenics, this relationship was highly significant (r = 0.59, p < 0.001). These clinical data are consistent with preclinical evidence indicating a junctional interaction between CNS somatostatin and dopamine systems.
Introduction Somatostatin is a tetradecapeptide distributed abundantly throughout the central nervous system (CNS) with significant concentrations in cortex, including prefrontal cortex, and notably high concentrations in subcortical regions, such as striatum, amygdala, and nucleus accumbens (Finley et al. 1981; Reichlin 1983). Somatostatin has been shown to exert a number of behavioral actions following direct CNS administration in animal models, including alterations in sleep, locomotion, memory, learning, and eating behavior (Rubinow et al. 1987). Clinically, decreased concentrations of CSF somatostatin immunoreactivity have been found in patients with depression (Rubinow et al. 1983), Parkinson’s disease (DuPont et al. 1982), Alzheimer’s disease (Oran et al. 1981), and multiple sclerosis (Sorensen et al. 1980). Two controlled postmortem studies have suggested abnormal concentrations of brain somatostatin in schizophrenia. Ferrier et al. (1983) observed lower concentrations of somatostatin in the hippocampus of schizophrenic patients, and Nemeroff et al. (1983) reported lower concentrations of somatostatin in one frontal cortical region in schizophrenic patients. In addition to these findings, somatostatin has been linked to CNS dopaminergic systems. Somatostatin stimulates the release of dopamine from the striatum
From the Section on Clinical Studies, Clinical Neuroscience Branch, National Institute of Mental Health, Bethesda, MD. Address reprint requests to Dr. David P&u, Section on Clinical Studies. Clinical Neuroscience Branch, NIMH, NIH Bldg. 10, Rm. 4N212,9WO Rockville Pike, Bethesda, MD 20892. Received December 28, 1981; revised April 27, 1988.
This article is in the Public Domain.
ooo6-3223/89/$00.1X1
432
BIOL PSYCHIATRY 1989;25:43 l-439
Table 1. ~rno~~~c
A.K.
Doran et al
and Clinical Data for Patient Croups n =
14
n = 46
Sex Male
Female Age (mean + SD) Weight, kg (mean * SD) Drug-free days before LP (mean 2 SD) Fluphenazine days before LP (mean 2 SD) Fluphenazine dose (LP day) (mean 2 SD) Bunney-Hamburg Rating Scale (I-15) Placebo Psychosis (mean i SD) Depression (mean + SD) Ftuphenazine Psychosis (mean T SD) Depression (mean d SD)
7
25
7 28.0
64.2 31.9 32.9 18.4
9,6 rt Et.6 rt 9.6 z?z8.6 1: 12.3 2
7.3 + 2.4 t 1.7
5.4
21 25.7 + 7.0 66.7 % 13.4 31.4 2 15.8
8.0 Y!T 2.9 4.9 r 2.3
5.6 rt 1.8 4.9 ‘-c 1.2
in animals (Chesselet and Reisine 1983; Beal and Martin 1984a) and is reduced in brain by neuroleptics in a time-dependent fashion (Beal and Martin 1984b). Furthermore, dopamine stimulates the release of somatostatin from several brain regions (Negro-Vilar et al. 1978). We have previously reported decreased concentrations of CSF somatostatin in depressed patients and in depressed and sch~op~eni~ patients who showed abno~~ activation of the hypo~alamus-pi~it~-adrenal (HPA) axis in comparison with normal controls (Doran et al. 1986). In this article, we report the results of further studies of CSF somatostatin in patients with schizophrenia. We have examined the effect of neuroleptic treatment on CSF somatostatin concentrations and the relationship between CSF somatostatin and CSF concentrations of the dopamine metabolite homovanillic acid (HVA).
Methods Fourteen inpatients of the 4-East NIMH research ward granted written informed consent to participate in this prospective study of the reIationship among CSF somatostatin, CSF dopamine, and neuroleptic ~atment. All patients met DSM-III criteria for schizop~enia (subtypes: 9 paranoid, 3 undifferentiat~, 1 disorganized, 1 catatonic). Patients received a lumbar puncture (LP) after at least 3 weeks of both fluphenazine (mean ‘_ SD days was 32.9 ?z 8.6) and placebo (31.9 2 9.6) treatment (Table 1). CSF obtained from a research LP in an additional 32 drug-free inpatients on placebo with DSM-III diagnosed schizophrenia (11 paranoid, 14 undifferentiated, 1 disorganized, 1 catatonic) and in 6 patients with sch~o~f~tive disorder was assayed for CSF soma~statin and HVA to further examine this relationship and to diseem any possible differences according to subtype of schizophrenia (Table 2). Concentrations of CSF somatostatin of some of the patients from the additional group have already been reported (Doran et al. 1986). All patients were kept on a low monoamine, alcohol-free, and caffeine-restricted diet, and daily ratings were performed by nurses who were blind to treatment and were skilled in the use of the Bunney-Hamburg rating scale (Bunney and Hamburg, 1983). All LPs
BIOI,. I?aTmmRY 1989;25:43 1-439
433
434
BIOL PSYCHIATRY 1989;25:431-439
A.R.Doran et al
were performed with patients in the lateral decubitus position between 8:00 and 9:00 AM after an overnight fast and at lease 8 hr of bedrest. The first 10 ml of CSF for HVA determination was collected as a pool and was placed on ice at the bedside, subsequently divided into aliquots, and then frozen at - 80°C. CSF HVA was assayed using high-pressure liquid chromatography with electrochemical detection (HPLC-EC) (Scheinin et al. 1983; Sepala et al. 1984). Intraassay and interassay coefficients of variation of HVA were 4% and 8%, respectively. CSF somatostatin was assayed from the 28th milliliter of CSF, collected in a tube containing 100 1.~1of 1 N acetic acid, placed immediately on dry ice, and kept frozen at - 80°C. CSF somatostatin was assayed using a previously described radioimmunoassay technique employing TyPI’*‘-somatostatin (Carlsson 1959), synthetic somatostatin standards, rabbit antisomatostatin antiserum, and charcoal separation (Pate1 and Reichlin 1979). Intraassay and interassay coefficients of variation of somatostatin were 10% and 12%, respectively. Student’s r-test and simple linear regression were used for statistical analysis.
Results Fluphenazine treatment was associated with a significant reduction in CSF concentrations of somatostatin (paired f = 3.78, p < 0.002); 10 of 14 patients showed fluphenazineinduced decreases in somatostatin concentrations (Figure 1). Concentrations of somatostatin during the drug-free and fluphenazine treatment periods were significantly correlated (r = 0.66, p < 0.01). Fluphenazine increased CSF HVA in 11 of 14 patients (paired t = - 3.84, p < 0.002) (Figure 2). Concentrations of CSF HVA during the drug-free and fluphenazine treatment periods were significantly correlated (r = 0.69, p < 0.006). There was a trend toward correlation between CSF somatostatin and CSF HVA when dtug-free (I = 0.49, p < 0.07) and during fluphenazine treatment (r = 0.47, p < 0.08). However, when the additional drug-free group (n = 32) was added to the 14 drug-free patients (total 46), the relationship was highly significant (r = 0.59, p < 0.001) (Figure 3). Fluphenazine-induced changes in somatostatin and HVA were not significantly correlated (r = -0.29, NS); moreover, neither change was significantly correlated with change in psychosis or depression ratings (Table 1). There were no significant relationships between drug-free or fluphenazine-treated concentrations of CSF somatostatin and age, sex, or subtype of schizophrenia (Table 2).
Discussion We have shown that treatment with the neuroleptic fluphenazine significantly decreased concentrations of CSF somatostatin in patients with schizophrenia. This decrease in CSF somatostatin paralleled the fluphenazine-induced increase in CSF HVA. In addition to this robust neuroleptic effect, a significant correlation was found between CSF somatostatin and HVA concentrations in a larger group of drug-free patients with schizophrenia. Thus, our study supports the idea that CNS somatostatin and dopamine systems are physiologically linked. No significant relationship between fluphenazine-induced change in CSF somatostatin and clinical response to medication was observed. To our knowledge, there has been only one previous report of the effect of neuroleptic treatment on CSF somatostatin concentrations. Gattaz et al. (1985) reported a trend for increase in CSF somatostatin concentrations in schizophrenic patients treated with halo-
BIOL PSYCHIATRY 1989$5:431-439
Fluphenazine and CSF Somatostatin
95
435
r PAIRED t = 3.78
90
p<.oO2
85 80 75
$
60
;f
55-
ts $
50-
$
45
u,
40-
3
k i4, \
s
/-
46.0 f
35 30 25
-
2ot 15 t PLACEBO
FLUPHENAZINE
Figure 1. CSF somatostatin in patients with schiiophrenia (n = 14) while drug-free and during fluphenazine treatment (r = 3.78, p < 0.002).
peridol for several weeks. In that study, the greatest increase in CSF somatostatin was found in patients treated for the least amount of time and who received the lowest cumulative haloperidol dose, suggesting that the observed increase may not have been a drug effect or may not be seen with chronic treatment. No correlation between haloperidolinduced change in somatostatin and clinical response to medication was found. Bissette et al. (1986) reported lower concentrations of CSF somatostatin in schizophrenic patients in comparison with controls, but noted that a relatively short drug-free period (2 weeks) may have ~n~but~ to these findings. Black et al. (1986) reported decreased concentrations of CSF somatostatin in 18 depressed patients, 11 of whom were treated with neuroleptics. In our previous study (Doran et al. 1986), we found concentrations of CSF somatostatin in schizophrenic patients who had been maintained drug-free for at least 3 weeks to be similar to controls. Those ~hizop~~~ patients who showed abnormal activation of the I-IPAaxis, as reflected by the Dexamethasone Suppression Test, however, showed diminished concentrations comparable to those found in depressed patients. Our observations are consistent with the study of Beal and Martin (1984b), who observed that h~o~~dol, ~uphen~e, and c~o~~rn~i~ each decreased concentra-
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Figure 3. Linear correlation between CSF scmatostatin and CSF HVA in 46 drug-free patients with schizophrenia (r = 0.59, p < 0.001).
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Fluphenazineand CSF Somatostatin
BK% PSYcHlATRY 1989;25:431-439
437
tions of so~tos~tin in key brain regions, idling the striatum, the amygdala, and nucleus accmrhns. Moreover, these investigators reported that this neuroleptic effect was time-dependent, with peak decreases occurring only after 2 weeks of treatment. Our finding of a significant correlation between CSF somatostatin and HVA supports a functional interaction between these neurotransmitter systems. Although the basis for the fluphen~~e-induct decrease in somatostatin is not completely understood, it likely results from fishy unctions activity of do~rgic systems due to dopamine receptor blockade. Fluphenazine-induced increase in CSF HVA is consistent with an extensive literature regarding neuroleptic effects on CSF dopamine metabolites (Pickar 1988) and is thought to reflect feedback activation of presynaptic dopamine neurons in response to receptor blockade. Other drug treatments have been shown to reduce CSF concen~tions of somatostatin. Rubinow et al. (1984) reported that carbamazepine si~i~c~~y reduced CSF ~matos~tin in affectively ill patients, and Steardo et al. (1986) demonstrated the same in patients with temporal lobe epilepsy. Wolkowitz et al. (1987) found that prednisone administration to normal volunteers was associated with significant decreases in CSF somatostatin concentrations. Thus, our findings with regard to fluphenazine’s effects on CSF somatostatin are not specific to this drug event. However, this is not surprising in light of the diverse localizations of somatostatin systems in brain and its important inhibitory function in the CNS. It is also possible that these common effects indicate shared interactions with CNS dopamine systems. Whereas the link between CNS dopamine and somatostatin is well supported, our ability to interpret the significance of our findings is limited. For exampie, we have recently suggested that ~oncen~tions of CSF HVA may, under some conditions, be prominently influenced by the mesocortical dopamine system, which innervates the prefrontal cortex (Doran et al. 1987; Pickar 1988). It is unknown whether the observed correlation between CSF somatostatin and HVA is accounted for by functional relationships in specific brain regions or is general&able to all dopaminergically innervated brain regions in humans. Postmortem studies of schizophrenic patients suggest decreased brain somatostatin concen~ations in both prefrontal cortical and s&cortical sites. The lack of relationship between CSF somatostatin concentrations and their fluphenazine-induced change and clinical symptomatology, although providing little direction for interpretation, should not necessarily suggest that somatostatin has no role in influencing dopaminergic function, particularly in response to neuroleptic treatment. Somatostatin and other peptide modulators of CNS dopamine system activity, including cholecystokinin (Nair et al. 1985), neu~tensin (Govoni et al. 1980), beta-endorphin (Schmauss and Emrich 1985), and met-enkephalm (Hong et al. 1978), may prove to be useful targets for enhancing neuroleptic response or for improved pharmacotherapeutic strategies for schizophrenia.
References Beal MI?, Martin JB (1984a):The effect of somatostatinon stiatal catecholamines.Neurosci Lett #:271. Beal MF, Martin JB (1984b): Effects of neuroleptic drugs on brain somatostatin-likeimmunoreactivity. Neurosci L&t 44~125. Bissette G, Widerlijv E, Wall&s H, KarIsson I, Eklund K, Forsrnan A, Nemeroff CB (1986): Alterationsin cerebrospinalfluid ~ncen~tio~s of somatostatin-like~uno~~ti~~ in neuropsychiatric disorders. Arch Gen Psychiatry 43: 1148.
438
BIOL PSYCHIATRY 1989;25:431-439
A.R Doran et ai.
Black PM, Ballantine HT, Carr DB, BeaJ MF, Martin JB (1986): Beta-endorphin and somatostatin concentrations in the ventricular cerebrospinal fluid of patients with affective disorder. Bid/ Psychiatry 21: 1077. Bunney W Jr, Hamburg DA (1983): Methods for reliable longitudinal observation of behavior: Development of a method for systemic observation of emotional behavior on psychiatric wards. Arch Gen Psychiatry 9:280.
Carlsson A (1959): The occurrence, distribution, and physiological role of catecholamines in the nervous system. Pharmacol Rev 11:490. Chesselet MF, Reisine TD (1983): Somatostatin regulates dopamine release in rat striatal slices and cat caudate nuclei. J Neurosci 3:232. Doran AR, Rubinow DR, Roy A, Pickar D (1986): CSF somatostatin and abnormal response to dexamethasone administration in schizophrenic and depressed patients. Arch Gen Psychiatry 43:365.
Doran AR, Boronow J, Weinberger DR, Wolkowitz OM, Breier A, Pickar D (1987): Structural brain pathology in schizophrenia revisited: Prefrontal cortex pathology is inversely correlated with cerebrospinal fluid levels of homovanillic acid. Neuropsychopharmacology 1:25. DuPont E, Christensen SE, Hansen AP, DeFine-Olivarius B, Orskov H (1982): Low cerebrospinal fluid somatostatin in Parkinson disease: An irreversible abnormality. Neurology 32:312. Ferrier NI, Roberts GW, Crow TJ, Johnstone EC, Owens DGC, Lee YC, O’Shaughnessy D, Adrian TE, Polak JM, Bloom SR (1983): Reduced cholecystokinin-like and somatostatin-like immunoreactivity in limbic lobe is associated with negative symptoms in schiozphrenia. Life Sci 33:475. Finley JLW, Maderdrutt JL, Rogers LT, Petrusz P (198 1): The immunocytochemical localization of somatostatin-containing neurons in the rat central nervous system. Neuroscience 6:2173. Gattaz WF, Rissler K, Gattaz D, Cramer H (1985): Effects of haloperidol on somatostatin-like immunoreactivity in the CSF of schozphrenic patients. Psychiatry Res 17: 1. Govoni S, Hong JS, Yang HYT, Costa E (1980): Increase of neurotensin content elicited by neuroleptics in nucleus accumbens. J Phurmucol Exp Ther 2 15413. Hong HS, Yang HYT, Fratta W, Costa E (1978): Rat striatal methionine-enkephalin content after chronic treatment with cataloptogenic and noncateloptogenic antischizophrenic drugs. J Pharrnacol Exp Ther 205: 141. Nair NPV, La1 S, Bloom DM (1985): Cholecystokinin peptides, dopamine and schizophrenia: A review, Prog Neuro-Psychophartnacol Biol Psychiatry 91515. Negro-Viler A, Ojeda SR, Arimura A, McCann SM (1978): Dopamine and norepinephrine stimulate somatostatin release by median eminence fragments in vitro. Life Sci 23: 1493. Nemeroff CB, Youngblood WW, Manberg PJ, Prange AJ, Kizer JA (1983): Regional brain concentrations of neuropeptides in Huntington’s chorea and schizophrenia. Science 221:972. Oran JJ, Edwardson J, Millard PH (1981): Investigation of cerebrospinal fluid neuropeptides in idiopathic senile dementia. Gerontology 27:2 17. Pate1 YC, Reichlin S (1979): Somatostatin. In Jaffe BM, Beheman HR (eds), Methods of Hormone Radioimmunoassay, ed 2. Orlando, FL: Academic Press, pp 77-100. Pickar D (1988): Perspectives on a time-dependent model of neuroleptic action. Schizophr Bull, 14:255-268.
Reichlin S (1983): Somatostatin. In Krieger DT, Brownstein MJ, Martin JB (eds), Bruin Peptides. New York: John Wiley & Sons, pp 71 l-752. Rubinow DR, Gold PW, Post RM, Ballenger JC, Cowdry R, Bollinger J, Reichlin S (1983): CSF somatostatin in affective illness. Arch Gen Psychiatry 40:409. Rubinow DR, Gold PW, Post RM, Ballenger JC, Cowdry R (1984): Somatostatin in patients With affective illness and normal volunteers. In Post RM, Ballenger JC (eds), Neurobiology of Mood Disorders, vol 1. Baltimore: William & Wilkins, pp 369-387. Rubinow DR, Post RM, Davis CL, Doran AR (1987): Somatostatin and GHRH: mood and behavior
Fluphenazine and CSF Somatostatin
BIOL PSYCHIATRY 1989;23:431-439
439
regulation. In Nerozxi D, Goodwin FK, Costa E (eds), Hypothalamic Dysfunction in Neuropsychiatric Disorders. New York: Raven Press, pp 137-152.
Scheinin M, Chang W, Kirk M, Lhmoila M (1983): Simultaneous determination of 3-methoxy-4hydroxyphenylglycol,5-hydroxyindoleacetic acid, and homovanillic acid in cerebrospinal fluid with high performance liquid chromatography using electrochemical detection. Anal Biochem 131:246. Schmauss C, Emrich MH (1985): Dopamine and the action of opiates: A reevaluation of the dopamine hypothesis of schizophrenia. Biol Psychiatry 20: 1211. Sepala T, Scheinin M, Capone A, Linnoila M (1984): Liquid chromatographic assay for CSF catecholamines using electrochemical detection. ACM Phamucol Toxic01 55:81. Sorensen KV, Christensen SE, DuPont E, Hansen AP, Pederson E, Grskov H (1980): Low somatostatin content in cembrospinal fluid in multiple sclerosis: An indicator of disease activity. Acta Neural Stand 61:186. Steardo L, Barone P, Hunnicutt E (1986): Carbamazepine lowering effect on CSF somatostatinlike immunoreactivity in temporal lobe epileptics. Acta New-01 Stand 74:140. Wolkowitz OM, Rubinow DR, Breier A, Doran AR, Davis C, Pickar D (1987): Prednisone decreases CSF somatostatin in healthy humans: Implications for neuropsychiatric illness. Life Sci 41: 1929.