Chronic Neuroleptic Administration Research Articles

Chronic neuroleptic exposure in bipolar outpatients.

Although the chronic use of neuroleptic medications is generally discouraged in patients with bipolar disorder, data on the actual extent of this practice are relatively scarce. All bipolar patients receiving treatment at the Connecticut Mental Health Center on September 1, 1994, were identified through a computerized administrative database; the medical record was then examined. Patients were included in the study if (1) the last two recorded diagnoses in the chart were concordant for bipolar disorder and (2) the patient had not been hospitalized in the past year. Of 49 patients meeting review criteria, 33 (67%) met criteria for chronic neuroleptic exposure. The mean +/- SD continuous neuroleptic dosage for these 33 outpatients was 416 +/- 527 mg/day chlorpromazine (CPZ) equivalents. The dosage distribution was skewed, with 17 (52%) receiving < or = 200 mg/day CPZ [corrected] equivalents. Chronic neuroleptic administration occurred frequently in our sample of nonhospitalized bipolar outpatients.

The Neurotensin Antagonist SR 48692 Fails to Modify the Behavioural Responses to a Dopamine D1 Receptor Agonist in the Rat

The effects of the neurotensin antagonist SR 48692 on the behavioural responses to the dopamine D1 receptor agonist SKF 38393 were investigated in the rat. SKF 38393 (5 mg/kg s.c.) elicited vacuous chewing movements (VCMs) and grooming, which were unaffected by SR 48692 (50 μg/kg i.p.). The dopamine D2 receptor antagonist raclopride (0.5 mg/kg s.c.) elicited a small increase in VCMs in animals treated with SR 48692 and attenuated grooming induced by SKF 38393. These effects were not otherwise modified by SR 48692.We conclude that VCMs induced by acute administration of a dopamine D1 receptor agonist are unlikely to be dependent upon enhanced release of neurotensin in the striatum or its projections. This is in contrast to the vacuous chewing response which emerges following chronic administration of neuroleptics, which is attenuated by a neurotensin receptor antagonist. Thus, inasmuch as chronic neuroleptic-induced VCMs in the rat may be analogous to tardive dyskinesia in humans, the responses induced by acute administration of a D1 agonist to the rat cannot be used as a model of this disorder. Furthermore, the behavioural effects of chronic neuroleptic administration reflect more than a simple shift in the balance of D1 versus D2 receptor stimulation. © 1997 Elsevier Science Ltd. All rights reserved.

The Dose Reduction in Schizophrenia (DORIS) study: a final report

Twenty-one medication-free chronic schizophrenics were randomly assigned to three treatment groups: 50% blockade of the bromocriptine growth hormone (GH) response, 100% blockade or 10 ng/ml haloperidol. Only seven of the 21 patients showed a significant improvement after 6 weeks in positive psychotic symptoms; six of the seven responders came from the 50 and 100% blockade groups, suggesting greater efficacy at lower doses. Fifty percent blockade was associated with an average daily haloperidol dose of 3.2 mg and plasma haloperidol levels below the limit of detection (< 1 ng/ml). 100% blockade was associated with a daily dose of 6.5 mg and a plasma haloperidol level of 1 ng/ml. Negative symptoms significantly improved in only four of the 21 patients, and three of these patients were from the 100% blockade group. Twenty-nine patients currently receiving 20 mg/day haloperidol were randomly assigned to three treatment groups: placebo, 100% blockade of the GH response and 10 ng/ml. Patients in the placebo group showed significant deterioration along both the positive and negative symptom dimensions. There were no significant symptom differences between the 100% blockade and the 10 ng/ml groups. The patients in the 100% blockade group had on average a daily dose reduction from 20 to 11 mg/day and a 65% reduction in the plasma haloperidol level. There was a 70% difference in the average daily dose for 100% blockade between the two study arms. The higher daily dose in the dose-reduction arm may reflect receptor up-regulation and/or other ‘tolerance’-like mechanisms associated with chronic neuroleptic administration.

Duration-dependent increase in striatal glutamate following prolonged fluphenazine administration in rats

Chronic neuroleptic administration has been shown to selectively increase striatal extracellular glutamate concentration. In the current study, age-matched female rats were administered chronic oral fluphenazine or no drug via their drinking water for 3 or 32 weeks. Microdialysis probes were inserted into the ventrolateral caudate putamen and the medial nucleus accumbens and dialysis samples were analyzed for glutamate and γ-aminobutyric acid (GABA) concentrations. Glutamate levels were significantly increased only in the ventrolateral caudate putamen after 32 weeks. No significant effects were seen for GABA levels. Neuroleptic-induced enhancement of striatal glutamate levels thus appears to increase with chronic exposure and this increase may relate to late onset motor side effects.

Quantitative electroencephalographic frequencies and relative neuroleptic receptor affinities in schizophrenia

Information is now available about the receptor binding properties of standard and atypical antipsychotic drugs (Kerwin 1994; Lieberman 1993; Pickar 1995). As yet there has been minimal attention to neurophysiological attributes that may correspond to receptor affinities, although Czobor and Volavka (1993) have hypothesized that changes in power spectral density and symmetry may be related to serotonergic and dopaminergic mechanisms. Sloan et al (1992) have shown that the central effects of anticholinergic drugs are reflected in increased electroencephalographic (EEG) slowing and reduced coherence. An opportunity to examine such relationships was afforded by our practice of collecting quantitative EEG data before and during chronic administration of neuroleptics in chronic schizophrenic patients.

Chronic haloperidol-induced changes in regional dopamine release and metabolism and neurotensin content in rats

Chronic neuroleptic administration has previously been shown to alter in vivo measures of dopaminergic function and lead to regionally selective increases in neurotensin levels. In the current study, female rats were administered chronic haloperidol for 6 months via subcutaneous silastic implants. After 24 weeks of administration, microdialysis probes were inserted into the lateral caudate putamen and the medial prefrontal cortex. Basal samples were collected prior to infusion of a high K + concentration (100 mM KCI). Extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid were assessed using HPLC. Chronic haloperidol-treated rats showed increased basal dopamine metabolite levels in the caudate putamen and an altered response to the effects of high K + on 3,4-dihydroxyphenylacetic acid; no significant differences were seen with other analytes in the caudate putamen. Although basal concentrations were not different between groups in the prefrontal cortex, haloperidol-treated rats showed a significant attenuation of response to the effects of high K + infusion on dopamine metabolite concentrations. Radioimmunoassay measurement of tissue neurotensin content showed highly significant elevations of neurotensin concentrations in the caudate putamen and nucleus accumbens, but not in other brain regions analyzed. These results suggest a confluence of altered dopamine and neurotensin function in the caudate putamen which may be related to motor side effects of haloperidol, whereas changes in prefrontal dopamine function are not associated with altered neurotensin levels.

Olanzapine, a novel atypical antipsychotic, has electrophysiological effects on A9 and A10 dopamine cells similar to clozapine

The role of neurotensin (NT) in a putative model of tardive dyskinesia (TD) was examined in the rat. When administered directly into the ventrolateral striatum of neuroleptic-naive animals, NT (2.5 μg/side) elicited vacuous chewing movements. This response was not seen following administration of NT into other striatal regions or the substantia nigra and was suppressed by the NT antagonist SR 48692 (100 μg/kg i.p.). Vacuous chewing movements were also seen following chronic administration of fluphenazine decanoate. These movements were likewise suppressed by SR 48692 (10–100 μg/kg i.p.), which failed to affect other behavioural responses and was without effect in neuroleptic-naive animals. Our data suggest that increased levels of endogenous NT within the ventrolateral striatum may play a critical role in the development of TD following chronic neuroleptic administration and that NT antagonists may be beneficial for the treatment of this disorder.

Effects of neurotensin in a rodent model of tardive dyskinesia

The role of neurotensin (NT) in a putative model of tardive dyskinesia (TD) was examined in the rat. When administered directly into the ventrolateral striatum of neuroleptic-naive animals, NT (2.5 μg/side) elicited vacuous chewing movements. This response was not seen following administration of NT into other striatal regions or the substantia nigra and was suppressed by the NT antagonist SR 48692 (100 μg/kg i.p.). Vacuous chewing movements were also seen following chronic administration of fluphenazine decanoate. These movements were likewise suppressed by SR 48692 (10–100 μg/kg i.p.), which failed to affect other behavioural responses and was without effect in neuroleptic-naive animals. Our data suggest that increased levels of endogenous NT within the ventrolateral striatum may play a critical role in the development of TD following chronic neuroleptic administration and that NT antagonists may be beneficial for the treatment of this disorder.

Loss of striatal cholinergic neurons as a basis for tardive and L-dopa-induced dyskinesias, neuroleptic-induced supersensitivity psychosis and refractory schizophrenia

In the first section of this paper several aspects of tardive dyskinesia (TD) (clinical, epidemiological, pharmacological) are reviewed. We propose that this syndrome is not the consequence of dopamine receptor proliferation, but results from damage or degeneration of striatal cholinergic interneurons. We suggest that this cellular damage is caused by prolonged overactivation of these neurons, which occurs when they are released from dopaminergic inhibition following neuroleptic administration. Overactivity of central cholinergic systems during akinetic and motor retarded depression could be a contributory cause. The predisposition to L-DOPA-induced peak-dose dyskinesia in Parkinson's disease may depend on the same type of striatal neuronal loss. In the second part of the paper, the subject of supersensitivity psychosis and drug-resistant schizophrenia is reviewed. These two syndromes, are commonly associated with TD, have similar predisposing factors and pharmacology to TD, and are potentially persistent. We suggest that these conditions also result from degeneration of cholinergic striatal interneurons following chronic neuroleptic administration. The efficacy of clozapine for such treatment-refractory psychoses is explained in terms of its blockade of D-1 dopamine receptors. Other drugs effective against refractory psychoses (e.g. risperidone) are predicted to reduce activation at D-1 receptors.

Chronic treatment with neuroleptics alters neutral endopeptidase 24.11 activity in rat brain regions

Chronic administration of neuroleptics has been shown to affect the endogenous levels, mRNA, posttranslational processing, and metabolism of neuropeptides in specific regions of rat brain. Neutral endopeptidase 24.11 (NEP) is known to metabolize a variety of neuropeptide substrates, including the enkephalins and neurotensin, thus modifying or terminating the bioactivity of such peptides. In the present study, chronic treatment with haloperidol (1 mg/kg/day, 12 days) increased NEP activity in nucleus accumbens, and chronic treatment with chlorpromazine (4 mg/kg/day, 12 days) increased NEP activity in caudate putamen. Higher dosages with either compound did not significantly alter NEP activity, and none of the treatments altered NEP activity in the hypothalamus. Chronic treatment with apomorphine (5 mg/kg/day, 12 days) decreased NEP activity in both nucleus accumbens and caudate putamen. These data suggest that chronic treatment with neuroleptic drugs may lead to regionally specific alterations in the metabolism of neuropeptides.

Neuroleptic-induced chewing movements in the rat are suppressed by peripherally but not centrally administered CCK and abolished by bilateral subdiaphragmatic vagotomy

We have previously demonstrated that intraperitoneal cholecystokinin (CCK-8S) suppresses the vacuous chewing mouth movements (VCM's) elicited by chronic neuroleptic administration in the rat, a possible model of tardive dyskinesia (TD) in humans. The studies described here were undertaken in order to better determine whether this effect is mediated centrally or peripherally. In the first set of experiments, CCK-8S (10, 30 or 50 ng, i.c.v.) was found to have no effect on VCM's elicited by 20 weeks treatment with fluphenazine decanoate (25 mg/kg, i.m., every 3 weeks). A second set of experiments was then performed to determine if the previously observed effects of intraperitoneal CCK-8S were vagally mediated. As previously described, CCK-8S (10, 30 or 60 μg/kg, i.p.) suppressed neuroleptic-induced VCM's in sham-operated animals without affecting the baseline VCM rate. Bilateral subdiaphragmatic vagotomy alone unexpectedly suppressed neuroleptic-induced VCM's to control levels and CCK-8S had no further effect. Vagotomy also prevented the suppressive effects of peripherally administered CCK-8S on rearing and grooming. We conclude that neuroleptic-induced VCM's may depend upon tonic activity in the vagus nerve and/or its central projections and that the effects of CCK-8S on this behavioural response are likely to be peripherally mediated.

Characterization of 8‐OH‐DPAT‐induced hypothermia in mice as a 5‐HT1A autoreceptor response and its evaluation as a model to selectively identify antidepressants

1. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) dose-dependently induced hypothermia in mice. 2. The 5-HT1A receptor partial agonists, buspirone, gepirone and ipsapirone, also dose-dependently induced hypothermia. 3. The 8-OH-DPAT temperature response was antagonized by the 5-HT1 receptor antagonists quipazine (2 mg kg-1, i.p.), (+/-)-propranolol (10 mg kg-1, i.p.). (+/-)-pindolol (5 mg kg-1, i.p.), spiroxatrine (0.5 mg kg-1, i.p.) and metitepine (0.05 mg kg-1, i.p.), but not by 5-HT2 (ketanserin) or 5-HT3 (MDL 72222, GR 38032F) receptor antagonists. 4. The response was also antagonized by the dopamine D2 receptor antagonists, haloperidol and BRL 34778. No other catecholamine or muscarinic receptors were involved in mediating the response. 5. Destruction of 5-hydroxytryptamine (5-HT)-containing neurones with the neurotoxin, 5,7-dihydroxytryptamine (75 micrograms, i.c.v.), abolished the response to 8-OH-DPAT indicating that the 5-HT1A receptors involved were located on 5-HT neurones. 6. Chronic antidepressant treatment down-regulated this 8-OH-DPAT response. In addition, chronic administration of anxiolytics and neuroleptics was also effective in this respect. Down-regulation was also observed following repeated administration of 8-OH-DPAT (0.5 mg kg-1, s.c.), (+/-)-pindolol (10 mg kg-1, i.p.) and ketanserin (0.5 mg kg-1, i.p.). 7. In conclusion, these data confirm that 8-OH-DPAT-induced hypothermia is mediated by 5-HT1A autoreceptors. They also indicate that the response involves D2 receptors.The present study also shows that a wide range of antidepressant drugs down-regulate this response although this property is not restricted to antidepressant treatments. Therefore, care should be exercised when interpreting data from this paradigm.

Chronic neuroleptic administration decreases extracellular GABA in the nucleus accumbens but not in the caudate-putamen of rats

The extracellular levels of γ-aminobutyric acid (GABA) in the caudate-putamen and the nucleus accumbens of rats following administration of haloperidol decanoate, fluphenazine decanoate, or vehicle for 8 months were assessed using intracranial microdialysis. Basal levels of extracellular GABA were significantly decreased in the nucleus accumbens of both neuroleptic-treated groups while levels of GABA in the caudate-putamen were not significantly different between groups. These results provide evidence for selective chronic neuroleptic-induced effects on in vivo GABA function in different terminal regions containing dopamine receptors.

Treatment of Alzheimer's disease by zinc compounds

AbstractAt the onset of Alzheimer's disease (AD), specific lesions occur in the hippocampus, i.e., neuropile‐capillary amyloid (AM) plaques and neuronal paired‐helical filaments (PHF)‐neurofibrillary tangles (NFT). The hippocampus is the area of brain with the highest zinc content. Chemical investigations demonstrated that in AD, the cerebral zinc decreases, especially in the hippocampus. The mechanism may be the following: The primary, genetically determined, microvascular AM (asymptomatic) disturbs the blood‐brain barrier, and metals (calcium, iron, aluminium, silicon, mercury, etc.( reach the cerebral cortex, where their levels increase and displace the zinc (whose level decreases) in some enzymes which become nonfunctional. The secondary production of PHF‐NFT and the neuronal dysfunction responsible of the clinical symptoms of dementia may be related to the functional deficiency of the following zinc‐enzymes: (1) those of DNA metabolism giving rise to abnormal DNA and therefore synthesis of abnormal proteins, constituting the NFT; (2) those involved in phosphorylating mechanisms at a post‐transcriptional (ribosomal‐mitochondrial) level, producing the abnormally phosphorylated tau protein, constituting the PHF; 3) that of glutamate (GLU) catabolism, resulting in a neurotoxic increase of GLU, producing PHF by abnormal phosphorylation of the neurofilaments; 4) those of neuronal detoxification contributing to the neuronal dysfunction. In regard to potential for therapeutic intervention, the timing needed for the AM‐induced production of NFT, in the various areas of the brain, has been estimated to be about 14–67 months. During this time it may be possible to influence the AM‐induced production of NFT: The chronic administration of neuroleptics enhances it, and the chronic administration of other drugs may reduce it. Such drugs may be zinc compounds, which will give an excess of zinc in the brain, will inhibit the above‐mentioned AM induced by zinc deficiency, mechanisms producing the NFT related to the clinical symptoms of dementia, and therefore, may prevent, stop, delay, and even improve them. Preliminary trials with zinc‐aspartate give promising results. Research is in progress to consolidate this zinc theory and to find more appropriate zinc compounds for this treatment. © 1992 Wiley‐Liss, Inc.

Neurotensin and neurotensin analogues modify the effects of chronic neuroleptic administration in the rat

The effects of intracerebroventricular neurotensin and the neurotensin analogues neuromedin N and [D-Trp 11]neurotensin on the behavioural responses to chronic neuroleptic adminstration were investigated in the rat. Chronic (18 weeks) administration of a low dose (12.5 mg/kg, i.m., every 3 weeks) of fluphenazine decanoate alone failed to elicit the vacuous chewing mouth movements (VCMs) which have previously been reported following higher doses of this drug, but VCMs were seen in neuroleptic-treated animals following the additional administration of neurotensin. A higher dose of fluphenazine (25 mg/kg, i.m., every 3 weeks) greatly increased the VCM response, and this potentiation was suppressed to control levels by [D-Trp 11]neurotensin, but unaffected by neuromedin N. These findings suggest that alterations in neurotensin may contribute to the deleterious extrapyramidal effects of long-term neuroleptic administration, and that [D-Trp 11]neurotensin may attenuate these effects by blockade of neurotensin receptors within the central nervous system.

Estimation of haloperidol concentrations in rat striatum after chronic treatment

3H-Spiroperidol association and dissociation rate constants were determined in rat striatal homogenates in the presence of known concentrations of unlabelled haloperidol. The rate of 3H-spiroperidol association was progressively decreased in the presence of increasing concentrations of haloperidol and no changes were seen in 3H-spiroperidol dissociation rate constants. Measuring changes in 3H-spiroperidol association rate constants permitted detection of 0.1 pmol/ml unlabelled haloperidol in assay homogenates. Then, male Sprague-Dawley rats received daily injections of haloperidol (1.5 mg/kg) for 1–21 days. Twenty-four hours after the last injection, 3H-spiroperidol kinetic rate constants and K d values were measured and found to be unchanged in all treatment groups. These findings suggest that, under these conditions of drug withdrawal and tissue preparation, which are widely employed in studies of chronic neuroleptic administration, residual haloperidol does not interfere with the estimation of 3H-spiroperidol binding parameters.

Sensitization versus tolerance to the dopamine turnover-elevating effects of haloperidol: the effect of regular/intermittent dosing

Recent clinical research suggests that particular patterns of changes in presynaptic dopamine (DA) turnover accompany the therapeutic response to neuroleptics. We sought to determine whether daily versus weekly dosing of haloperidol for 3 weeks produced distinct effects on DA, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) concentrations in multiple brain areas. Daily dosing favored the development of tolerance to the DA-turnover elevating effects of haloperidol in the striatum and nucleus accumbens. Weekly dosing favored the development of sensitization in the striatum, posterior olfactory tubercle, and ventral tegmental area. These results suggest that dosing schedules may determine, at least in part, the effects of chronic neuroleptic administration on presynaptic DA function.

Metabolism of enkephalins in rat brain after chronic administration of neuroleptics

This chapter presents results of studies that analyze antipsychotic and antianxiety agents. The use of long-acting fluphenazine in the management of schizophrenia and its comparison with conventional therapy was reviewed. Studies of other 6-6-6 tricyclics included several new phenothiaaine derivatives. A diazabicyclononane analog of chlorpromazine (CPZ), one of a series, presented a typical neuroleptic profile. The sulfone derived from thioridazine, that is, inofal caused improvement in two-thirds of a group of chronic schizophrenic females. A valeroylphenothiazine, M&B 18,706 was a selective and mope potent fusimotor depressant than CPZ. In SAR studies of phenothiazines, a high oil and water partition coefficient was related to toxicity in a goldfish test and to serum albumin binding. Numerous tricyclic compounds were examined for their ability to inhibit glutamate dehydrogenase; however, a clearcut correlation with antipsychotic efficacy was not observed. Metabolic studies of piperazine-bearing phenothiazine antipsychotics in rats and dogs demonstrated the formation of ethylenediamine derivatives from prochlorperazine and trifluoperazine. The distribution and metabolism of azaperone, a neuroleptic which induces rapid sedation, was studied in rats and pigs. Clorazepate dipotassium, marketed in the United States in 1972, was also studied in the clinic and in animals.

Autoradiographic analysis of regional alterations in brain receptors following chronic administration and withdrawal of typical and atypical neuroleptics in rats

Rats were administered haloperidol, clozapine, raclopride, or no drug for 28 days or 8 months. Following a 3 week withdrawal period, in vitro autoradiography was utilized to examine receptor binding for dopamine D2 ([3H]spiperone and [3H]raclopride), dopamine D 1 ([3H]SCH23390), GABA(A) ([3H]muscimol), benzodiazepine ([3H]RO15-1788), and muscarinic ACh receptors ([3H]QNB). [3H]spiperone was elevated in striatal subregions only in haloperidol-treated rats, with the largest increases seen in the 8 month duration animals. Striatal [3H]raclopride binding was increased after both short- and long-term treatment in both haloperidol and raclopride, but not clozapine-treated animals. Clozapine-treated rats showed significant increases in [3H]SCH23390 in the nucleus accumbens after 28-day administration; otherwise no changes were seen for this ligand in any other groups. Increases in [3H]muscimol binding in the substantia nigra reticulata were seen in haloperidol-treated rats after 8 month treatment. Binding of [3H]QNB and [3H]RO151788 were not significantly different from control for any of the drug-treated groups. These data suggest that persisting alterations in receptor binding are primarily seen in dopamine D2 and GABA receptors after withdrawal from chronic administration of haloperidol but not the atypical neuroleptics, clozapine and raclopride.

Neuroleptics: Effects on Neuropsychological Function in Chronic Schizophrenic Patients

We have reviewed the literature from the 1950's to the present on the effects of neuroleptics on perceptual and neuropsychological function in chronic schizophrenic patients. In contrast to previous reviews, we have delineated the acute and chronic effects of neuroleptics on individual cognitive and motor tasks by drug, dose, and length of administration. To date, studies have shown that acute administration of neuroleptics impairs performance on some, but not all, tasks requiring vigilance and attention, and on some tasks requiring motor behavior. Chronic administration of neuroleptics, however, improves performance on some tasks requiring sustained attention and visuomotor problem-solving skills depending on dose and length of administration. Moreover, there is consistent evidence to suggest that chronic administration of neuroleptics in this patient population does not impair neuropsychological function independent of motor function. These findings have direct implications regarding the risk/benefit ratio and legal ramifications for the use of neuroleptics in chronic schizophrenic patients.