Chronic Neuroleptic Therapy Research Articles

Chronic nicotine use blocks haloperidol-induced increase in striatal D 2-dopamine receptor density

Epidemiologic studies have suggested a positive association in man between nicotine use and the incidence of tardive dyskinesia, a disease characterized by dopaminergic supersensitivity after chronic neuroleptic therapy. In rats, repeated administration of neuroleptics results into dopaminergic supersensitivity and increased density of striatal D 2-dopamine receptors. We investigated the effects of 6-week continuous nicotine intake on the neuroleptic (haloperidol)-induced increase in murine striatal D 2-dopamine receptor density. Contrary to expectations, our data show that nicotine blocked the increase in D 2-dopamine receptor density after neuroleptic administration.

Drug levels and antiparkinsonian drugs in neuroleptic-treated schizophrenic patients.

The limitations of antiparkinsonian treatment strategy when using anticholinergic drugs are determined by their side effects induced through excessive inhibition of parasympathetic functions. In the present study we have investigated the peripheral effects of antiparkinsonian agents on blood levels of concomitantly administered neuroleptic drugs. We have compared the anticholinergic and a dopamine mimetic antiparkinsonian agent in their effects on serum neuroleptic activity (SNA) and serum anticholinergic activity (SAA). Sixteen schizophrenic patients on chronic neuroleptic therapy with steady state neuroleptic levels were receiving either amantadine, 200 mg/day, or anticholinergic drugs (trihexyphenidyl, 10 mg/day, or benztropine, 6 mg/day) for the first 2 weeks, after which the amantadine group was crossed over to anticholinergic and the anticholinergic group to amantadine for the following 2 weeks. Blood samples were obtained once a week along with clinical testing. The results indicate that SAA was fivefold higher with benztropine than with trihexyphenidyl and that amantadine had no effect on SAA. Moreover, SNA was not altered either by anticholinergics or amantadine coadministration, indicating that the therapeutic blood neuroleptic levels are not compromised by antiparkinsonian administration.

Clonidine-induced growth hormone secretion in chronic schizophrenia.

Clonidine (0.15 mg intravenously), an alpha-adrenergic receptor agonist, was administered to 13 male chronic schizophrenics, who had been withdrawn from chronic neuroleptic therapy, and to 18 normal male controls. There was no significant difference in growth hormone (GH) response between the two groups. There was no significant correlation between duration of psychosis, duration of neuroleptic therapy or length of neuroleptic withdrawal and GH response. These results suggest that postsynaptic alpha-adrenergic receptor function in the hypothalamic-pituitary axis is unaltered in chronic schizophrenia or by prior chronic neuroleptic therapy.

The effect of chronic neuroleptic administration on cerebral dopamine receptor function

Acute administration of neuroleptic drugs causes blockade of cerebral dopamine receptors. It has been discovered that chronic administration of neuroleptic drugs may have different effects on cerebral dopamine systems. Initial antagonism of dopamine mediated behaviour, such as stereotypy, disappears and may be replaced by supersensitivity to dopamine agonists. Changes also occur in biochemical indices of dopamine receptors, such as in the number and affinity of specific binding sites identified by 3H-ligands labelling D-2 receptors, and in dopamine-stimulated adenylate cyclase activity. All these changes occur obviously in the striatum in response to chronic administration of a range of neuroleptic drugs. Lesser changes take place in the mesolimbic dopamine system. What happens in the mesocortical dopamine pathways is unknown. The consequence of such adaptive responses to chronic neuroleptic therapy may be of importance to understanding of tardive dyskinesia and schizophrenia.

Reproductive parameters in prolactinaemic men.

The sexual behavior, hypothalamic-pituitary-testicular axis and seminal fluid parameters in three different models of hyperprolactinaemia were studied: patients with prolactin secreting pituitary adenomas, normal volunteers before and during metoclopramide, and psychotic patients on chronic neuroleptic therapy. Hyperprolactinaemia is always accompanied by a reduced seminal volume but there is no clearcut evidence that it can induce spermatogenesis modifications. Impotence is constantly present in the hyperprolactinaemic syndromes. The mildly impaired androgen production by the Leydig cells during hyperprolactinaemia does not seem to explain the impotence. Hypotheses on the pathogenesis of this symptom are suggested.

Increased central 5-hydroxytryptamine receptor mechanisms in rats after chronic neuroleptic treatment.

1 The behavioural responses of drugs known to act through central 5-hydroxytryptamine (5-HT) mechanisms have been investigated in rats receiving a neuroleptic (trifluoperazine) in their drinking water for 4 to 6 months.2 5-Hydroxytryptophan (5-HTP) induced 5-HT-dependent behaviours including head bobbing and lateral head weaving, reciprocal forepaw treading, tremor, backward walking, body writhing and ;wet-dog' shakes. In doses of 50 to 150 mg/kg, 5-HTP induced more intense behavioural effects in neuroleptic-treated rats than in the control animals.3 Similarly the putative 5-HT agonist, quipazine (1 to 20 mg/kg) and the 5-HT releasing drug, fenfluramine (5 to 20 mg/kg), both induced significantly greater motor responses in the chronically neuroleptic-treated rats.4 A 5-HT uptake inhibitor (femoxetine, 2.5 to 10 mg/kg) had little behavioural effect in either control or trifluoperazine-treated rats.5 Total specific high-affinity binding of radiolabelled 5-HT was significantly increased in crude membrane fractions prepared from the cortex, striatum and substantia nigra of neuroleptic-treated rats compared to control animals.6 High-affinity uptake of radiolabelled 5-HT into striatal slices was similar in experimental and control animals.7 Behavioural and biochemical data would indicate that postsynaptic 5-HT mechanisms are enhanced in rats treated chronically with trifluoperazine. Chronic neuroleptic therapy may thereby induce cerebral 5-HT receptor supersensitivity in addition to the well-documented cerebral dopamine receptor supersensitivity.

Effects of chronic neuroleptic therapy on human PRL secretion and testicular function.

Correlation between secretion of testicular steroids and plasma prolactin (PRL) levels, before and during bromocriptin treatment, was studied in 20 psychiatric patients under neuroleptic therapy for two years or longer. Eleven of them were under additional treatment with antiparkinson drugs (AP group). Plasma PRL, testosterone (T), 5 alpha dihydrotestostérone (DHT), 17 beta-estradiol (E2), 17 alpha OH-progestérone (17 alpha OHP), and dehydroepiandrosterone-sulfate (D-S) were measured by specific RIA both at basal level and in response to testicular stimulation by hCG. Mean basal PRL levels were normal in the patients under neuroleptic treatment along (Ne group), and slightly elevated in the AP group. In the Ne group, an unexpected, significant increase occurred in mean plasma PRL during the hCG stimulation, before bromocriptine treatment. Mean basal steroid levels were normal in both groups. The testicular responses to hCG, as reflected by the T, E2, 17 alpha OHP, and DHT mean plasma levels, were within the normal ranges in the AP group; in the Ne group, however, T and DHT displayed a subnormal mean increase, while E2 and 17 alpha OHP responses were within the normal range. These results suggest that some modifications of the enzymatic activity for testicular steroidogenesis could be induced in the patients under neuroleptic treatment alone. Moreover, a significant reverse correlation was found between PRL and T basal in both group; this correlation disappeared during the bromocriptine treatment.

Gilles de la Tourette syndrome after long‐term chlorpromazine therapy

Following 6 years of continuous chlorpromazine therapy for schizophrenia, a young woman developed multifocal tics and vocalizations characteristic of Tourette syndrome. The symptoms first appeared when chlorpromazine was withdrawn. They were permanent, although partially ameliorated by chronic haloperidol therapy. Because of her age and past history, these symptoms were attributed to chronic neuroleptic therapy analogous to neuroleptic-induced tardive dyskinesia, rather than to Tourette syndrome per se. These symptoms suggest that chronic receptor-site blockade can result in hypersensitivity of dopamine receptor sites, and that this may play a role in the pathophysiology of Gilles de la Tourette syndrome. This is the first evidence that hypersensitivity of dopamine receptors is involved in the pathophysiology of Tourette syndrome.

Neuroendocrine effects of chronic neuroleptic therapy in male psychiatric patients

(1) Hypogonadism with impotence, decreased libido and oligospermia is known to occur in patients with prolactin (PRL) secreting tumors and in patients receiving neuroleptics. The present study deals with male psychiatric patients under chronic treatment with neuroleptics. (2) Testosterone levels were within the normal range. (3) Prolactin levels were only elevated in patients also receiving anticholinergic agents. (4) A significant inverse relationship was found between the PRL and testosterone levels. (5) Human chorionic gonadotrophin (HCG) produced a net increase in prolactin and testosterone. (6) The same treatment did not affect the prolactin levels when the patients were treated with bromocriptine (7.5 mg b.d). a dopamine agonist. (7) Bromocriptine did not affect the PRL and testosterone levels.

Neurochemistry of withdrawal emergent symptoms in children.

The probenecid procedure was used to study the metabolite accumulations of dopamine (DA) and serotonin (5-HT) in the cerebrospinal fluid (CSF) of 11 children receiving chronic neuroleptic therapy. Specimens were obtained while the children were being given chronically prescribed medication (Condition 1) and again 3–4 weeks later, following the discontinuation of drugs (Condition 2). At that time, five children showed typical dyskinetic withdrawal emergent symptoms (WES) and six were free of symptoms. CSF specimens were also obtained from eight drug-free children, diagnosed as having ‘chronic organic brain disease,’ who served as a contrast population against which the findings were evaluated. CSF accumulations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) did not differentiate the drug-treated children who showed WES from those who did not manifest these symptoms. A significant decrease in 5-HIAA was found in Condition 2, suggesting that chronic treatment with neuroleptics may effect 5-HT metabolism in children. The contrast population was found to have lower CSF concentrations of probenecid and were consequently of little help in clarifying the nature of the 5-HIAA decrement. A number of serious deficiences were noted regarding the use of the probenecid procedure, and it is felt that the use of spinal taps for studying neuroleptic effects on brain metabolism in children is unlikely to provide important information with regard to either CNS drug actions or toxicity.

Effect of apomorphine on growth hormone and prolactin secretion in schizophrenic patients, with or without oral dyskinesia, withdrawn from chronic neuroleptic therapy.

Serum growth hormone (GH) and prolactin (PRL) concentrations were measured after administration of the dopamine receptor agonist, apomorphine HC1 (0.75 mg subcutaneously), to 17 chronic schizophrenic patients, four of whom had an oral dyskinesia, who were withdrawn from chronic neuroleptic therapy for periods of two to 15 weeks, and in 21 control subjects (normal volunteers or physically healthy alcoholics not exposed to neuroleptics). Six of the schizophrenic patients, but none of the controls, had raised baseline levels of GH (greater than 6 ng/ml). After apomorphine all controls showed an increase in serum GH with a peak concentration of 9 ng/ml or more, whereas eight subjects withdrawn from neuroleptics showed an inadequate response (peak less than 6 ng/ml) and in two others an inadequate response was obtained on one of two trials. The peak GH concentration was significantly less after apomorphine in patients withdrawn from neuroleptics (11.90 +/- 3.19 ng/ml) compared with controls (20.80 +/- 2.11 ng/ml) (P less than 0.05). Among patients withdrawn from neuroleptics, those with an oral dyskinesia had significantly lower peak GH concentration 2.46 +/- 0.93 ng/ml) after apomorphine compared with those without (14.85 +/- 3.83 ng/ml) (P less than 0.05). There were no differences in serum PRL concentrations, before or after apomorphine administration, between patients withdrawn from neuroleptics and controls. In uncontrolled observations none of the four patients with an oral dyskinesia showed any worsening of the movement disorder after apomorphine. These data provide no evidence for supersensitivity of dopamine receptors in chronic schizophrenic patients withdrawn from chronic neuroleptic therapy.

Cholinergic and anticholinergic influences on amphetamine-induced stereotyped behavior

The effect of cholinergic and anticholinergic agents on the threshold dosage of amphetamine required to produce stereotyped behavior in guinea pigs was investigated. The anticholinergic agent scopolamine lowered the threshold dosage of amphetamine required to produce stereotyped behavior. The cholinergic agent physostigmine strongly antagonized the onset of amphetamine-induced stereotyped behavior. The effect of altering cholinergic activity in human movement disorders which have as their basis alterations in the dopaminergic system is discussed. On the basis of this investigation it is suggested that centrally acting cholinergic agents may be of value in the treatment of Huntington's chorea, levodopa-induced dyskinesia, and tardive dyskinesias. It is further suggested that the use of anticholinergic drugs in patients receiving chronic neuroleptic therapy may predispose them to the development of tardive dyskinesias and should be avoided.