Growth hormone response to sodium valproate in chronic schizophrenia

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Growth Hormone Response to Sodium Va lproate in Chronic Schizophrenia Palmiero Monteieone,

Mario Maj, Michele Iovino, and

Luca Steardo

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Introduction A role for GABA in the pathophysiology of schizophrenia was first suggested by Roberta in 1972. Since then, several studies have assessed this hypothesis. A decrease of GABA content has been reported (Perry et al. 1979; Spokes et al. 1980) as well as a decrease of glutamic acid decarboxylase (GAD) activity (Bird et al. 1977; McGeer and McGeer. 1979) in postmortem brains from schizophrenics and a reduction of GABA levels in the cerebrospinal fluid of drug-free psychotic patients (Hare et al. 1980; van Kammen et al. 1980). These findings. however, have not been replicated by other groups (Lichtshtein et al. 1978; Cross et al. 1979; Gold et al. 1980; Gemer and Hare 1981). Clinical trials with GABAergic agents (such as baclofen or dipropylacetic acid) have also yielded conflicting results: therapeutic efficacy of these drugs was claimed by some investigators (Frederiksen 1975: Linnoila et al. 1976), but not confirmed by others (Davis et al. 1976:

From the Mental School, IM

I.):

General

Health

Unwersity

Service.

and the Department Hospital,

Boston.

Address reprmt requests to Dr X0145 Napoli. Rcwved

Octohcr

USL 41 Regione Campania.

of Naples.

Italy

(M.M.);

of Neurology, MA

(L.S

Harvard

Medical

Italy (P.M.).

the Department

of Endocrinology.

General

ofP\ych~atry,

Hospital

School and Neuropharmacology

Fuat McJJ~~I

of Eboli,

Laboratory.

Eboh,

Ital)

Massachux%\

I.

P. Mont&one,

Mental

Health

Ital) 16. 19x5. rolwd

Naples.

the Department

December

2. 1’9x5

Serwce.

USL 41 Re@one Campan~a,

bia Emdio

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iW

GH Response to Valproate in Schizophrenia

BIOL PSYCHIATRY 1986;21:588-594

589

Simpson et al, 1978; Lautin et al. 1980). Thus, at present, evidence supporting an involvement of GABAergic disorder in schizophrenia is far from conclusive. To help clarify the issue, a neuroendocrine strategy could be adopted. Psychoneuroendocrinological considerations suggest that neurotransmitter and/or receptor abnormalities in limbic regions of psychotic subjects might extend to, or influence, the hypothalamus, which, in turn, modulates pituitary hormone secretion. Thus, an assessment of adenohypophyseal hormone levels in the blood may give us some indication of central neurotransmitter function. On the other hand, GABA has been shown to play a role in the neural modulation of certain pituitary hormones via a tuberoinfundibular-GABA (TI-GABA) system whose neural networks are located in the mediobasal hypothalamus (Elias et al. 1982; Racagni et al. 1982). It therefore seems feasible to record the activity of this system to see whether or not a defect in GABA transmission can be identified in schizophrenic patients. More specifically, a modulatory role for GABA on anterior pituitary GH secretion has been largely documented both in animal and in humans (Elias et al. 1982; Racagni et al. 1982). Studies carried out in humans show a dual action of this neurotransmitter on GH release. In fact, GABA itself and some GABAergic compounds are able both to enhance basal GH secretion (Takahara et al. 1977; Fioretti et al. 1978; Cavagnini et al. 1980a) and inhibit the stimulated GH release (Koulu et al. 1980; Steardo et al. 1985). Moreover, in a very recent report (Steardo et al. 1985a,b) we have shown that sodium valproate also stimulates basal GH secretion and blunts the exercise-induced GH rise in healthy male volunteers. The aim of this study is to test the activity of the TI-GABA system by observing the basal GH response to the GABAergic drug sodium valproate (SV) in chronic schizophrenic subjects compared to controls.

Methcads The patient group consisted of 13 male patients in a large psychiatric hospital, aged 28-49 years, who fulfilled the Research Diagnostic Criteria (Spitzer et al. 1978) for the diagnosis of chronic schizophrenia, who had never been treated with electroconvulsive therapy, and who agreed to participate in the study. The schizophrenic group comprised eight paranoid, three disorganized, and two undifferentiated schizophrenics; the mean duration of their illness was 14.5 + 3.7 years. All patients had been drug-free for at least 2 months, and seven of them for more than 6 months. The control subjects were 10 healthy men, matched to the patients for age, who gave their informed consent to participate in the study. They were not hospitalized, and none presented any medical or psychiatric symptoms or had used any drug for at least 30 days before the study. Both schizophrenic and healthy men were nonobese, had normal endocrine and metabolic function, and had no family history of diabetes. In a double-blind design, all subjects received placebo or SV (800 mg po) on two different occasions. The placebo consisted of tablets (supplied by Sigma-Tau, Rome, Italy) lacking SV but similar to those containing the drug with respect to size, color, and taste. The experiments were performed in the morning. After an overnight fast, a butterfly cannula was inserted into a forearm vein at approximately 9:00 AM and was kept open with dilute heparinized saline, which was discarded prior to sampling. Thirty (T = - 15) and 45 (T = 0) min later, baseline blood samples were taken; then each subject received the drug or the placebo (T = 0). Further blood samples were collected 30, 60, 90, 120, 180, and 240 min after administration. Plasma was separated by centrifugation at 4000 t-pm and stored at - 20°C until assayed. Plasma GH levels were determined by radioim-

munoaasay measured

using ccnnmcr~~ai I\IIX suppl~cd by Uiodata (Milan. by the Enzyme

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Italy).

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Co t Palo Alto. CA I; the measurements wert: performed with %I 111 spectophc,tunletcr (Oberim. OH) and w’erc zornputed on a CP 5OCiCl

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computer

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(Syva

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Results MANOVA performed in normal healthy male volunteers for drug (F‘ = 49.225; 17 e. 0.01). for time (F = 30.725; drug-time interaction (F = 30.324; [’ c. 0.01). In fact. in clear-cut rise in plasma GH levels, reaching a statistical

disclosed a significant effect p *c 0.01). and a significant these sub.jects, SV induced ;I significance of 17 < 0.05 al

Figure I. PlasmaGH levels in normal (bottom) and chronic schizophrenic sodium Ltalproate (800 mg po) or placebo administration. from 10 healthy male volunteers and 13 schizophrenic

subjects (upper) followmp Data represent mean k SEM averaged patients. **p ~c[0.05 (Dunnett’s text)

*p -C 0.01 (Dunnett’a test). SCHIZOPHRENICS

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GH Response to Valproate in Schizophrenia

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BIOL PSYCHIATRY 1986;21:588-594

591

test) and p < 0.01 at each time point from T = 60 min to

T = 240min (Figure 1). No significant variation of plasma GH occurred after placebo administration (Figure I). In chronic schizophrenics, neither SV nor placebo induced any significant change in plasma GH levels (Figure 1). SV plasma levels were not statistically different in the two groups (Table 1) and were in the thera~utic ~ticonvulsant range (So-100 pglml) from T = 30 min until the end of the experiment.

Discussion SV is a very active anticonvulsant drug, normally used in the human therapy of epilepsy. It easily crosses the blood-brain barrier and penetrates the brain tissue. The present data and previous reports by us (Monteleone et al. 1984; Steardo et al. 1985a,b) and other investigators (Melis et al. 1982) show that this GABAergic compound is able to affect the release of anterior pituitary hormones. The mechanism through which SV exerts its neuroendoc~ne effect is at present only speculative. Although this drug is classically believed to influence GABA metabolism, resulting in increased levels of the neurotransmitter in various brain areas (Godin et al. 1969; Van der Laan et al. 1979), it is still controversial as to whether or not this is its primary mechanism of action. Recent studies suggest that SV may increase GABA release from nerve terminals (Lkcher and Siemes 1984) or may directly affect the postsynaptic GABA-benzodiazepine receptor ionophore complex (Liljequist and Engel 1984). In summary, SV is able to enhance central GABAergic transmission, and, more probably, this effect may lead to its neuroendocrine action. Evidence has accumulated to suggest that the hypothalamus is the main site of action of GABA on GH secretion, as GABA affects neither basal nor stimulated GH secretion on rat anterior pituita~ lobes in vitro (NegroVilar et al. 1980). In addition, Cavagnini et al. (1980b) reported that acute oral administration of 5 g GABA to healthy volunteers induced a clear-cut rise of basal GH secretion, whereas a 4-day daily treatment with 18 g GABA blunted the GH response to insulin hypoglycemia. Although GABA does not easily cross the blood-brain barrier, the study seemed justified, as the basal hypothalamus lies partly outside this brain stmcture. On the other hand, a direct action on somatotropes cannot be excluded, as systemic administration of muscimol, the potent GABA agonist that crosses the blood-brain barrier quite poorly, induces a clear-cut reduction of plasma GH in the rat (Cocchi et al. 1980). Thus, at present, it seems confirmed that GABA affects human GH release, but the site of action and the mechanism through which it exerts this effect remain to be established, The present results confirm our previous observation (Steardo et al. 1985) that SV enhances

Table 1. Sodium Vafproate Plasma Levels (pgimf) after an Oral Dose of 800 mg Time (min) 30 60 90 120 180 240 Data represent mean

t

Schizophrenics 80 72 70 65 63 58

+ 4 t- 6 -t_ 5 t 8 ‘- 4 2 7

Controls 73 -c 83 -c 69 I 6027 70 t 67 2

8 7 5 4 6

SEM averaged from 13 chronic schizophrenics and IO healthy controls.

s92

HIOI. PSY(‘HIA I Kl !YXh.ZI

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basal GH release in healthy subjects; in contrast, the drug did not affect basal plastl~;~ levels of this hormone in chronic schizophrenic patients. In a previous report (Monteleone et al. 19X5 ). we showed a failure of the GABAcrglc compound to affect basal prolactin secretion in chronic schizophrenic 4ubjects. Then data. taken together with the present results. may suggest a lack of activation of the I‘i (;ABA system by SV in chronic schizophrenia. The intrinsic significance of this obser vation is very difficult to explain at this time. We can certainly exclude the possibilit! that the reduced responsiveness observed IS chronic schitophren1c.s nught be due icI differing pharmacokinetics oi‘ SV in patients and controls. as SV plasma levels were not statistically different in the two groups. It I\ conceivable that the failure of SV to at‘te~! basal GH secretion in chrome schizophrenics reported here results from long-term ncli roleptic treatment. All our patients. in fact. had a history ot many years of’ antipsychotrc therapy; it is well known that these drugs profoundly alter many neurotransmitter system% and that 4ome of these changes may persist long after the drug is discontinued. To th1, purpose, two groups of investigators (Cleghorn et al. 1983a.b) reported that the (.;I i response to apomorphinc hydrocloride in acute schizophrenics who had never been treated was different from that of’ chronic schizophrenics who had been drug-free for 3 monthor more, indicating that their responsivenes\ difi’ers, due either to evolution of the disea>c or to the previous therapy. In addition. studies carried out in rats (Gunne and Haggstron-; 1983; Itoh 1983) showed Y decrease of GAD activity in certain brain regions 01’ T~IX\ chronically treated with neuroleptics that persisted after several months of drug wrth drawal, suggesting that it may be irreversible. Moreover, Freed and coworkers (1%0; showed that chronic administration of haloperidol profoundly affects central GABA tran\ mission in rats. Thus, It ma) be hypothesized that chronic neuroleptic treatment Induccx which, in turn. may account for rhc marked changes in centrai tiABA transmission. differences in GH release observed here. On the other hand. as it is generally believcci that the modulatory role ot’ GABA on human CiH release IS mediated by dopaminergic (C’avagnini et al. I%()) and/or noradrenerglc (Laakman et al. 1982) hypothalamic path ways. we cannel rule out the possibility that primary or secondary changea in the\< neurotransmitter systems may be responsible for the present results, Finally. it is conceivable that the abnormalities in GH secretion reported here arc’
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BIOL PSYCHIATRY 1986;21:588-594

GH Response to Valproate in Schizophrenia

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to graded

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activity in discrete brain areas of

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Br

J

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acid I” (‘SF of epilcptrl

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to

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Gamma-aminobutyric

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EE (1982):

acrd detictcncy

GABAcrgic

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htr .I

P.~vchiutr\~

R. Branchey

M (1978): Baclofen Bull 14: 16-18.

control

in brain (it of anterror

system in schrzo

m the treatment

of tardivc

P.vyc~hophurmucd

J. Robins E (1978): 35:773- 782

Research Diagnostic

Criteria:

Rationale

and reliability

Spokes EGS. Garret NJ. Kosaor MN, Iversen LL (1980): Distribution of GABA in post-mortem brain tissue from control. psychotic and Huntington’s chorca subjects. J Neurd Sci 48:303-3 13

Steardo I.. lovino

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A dual effect of the GABAergrc

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Low spinal

flud