Is olanzapine better than haloperidol in resistant schizophrenia? A double-blind study in partial responders.

INTRODUCTION: To compare the efficacy and safety of olanzapine and haloperidol in partial-responder paranoid schizophrenic patients. METHOD: In this multi-centre, double-blind study, 28 patients with DSM-IV paranoid schizophrenia were randomized to receive 14 weeks treatment with either olanzapine or haloperidol at flexible doses. The pre- and post-treatment assessment included the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), the CGI, the Simpson-Angus Rating Scale, and the Barnes Akathisia Rating Scale. RESULTS: The two treatment groups showed similar improvement on the BPRS positive symptoms subscale, while the improvement of BPRS negative symptoms subscale was significant only in the olanzapine group (ANOVA with repeated measures, group effect: F=5.89, P =0.023). Only the olanzapine-treated patients experienced a significant improvement of negative symptoms as rated by the SANS (ANOVA with repeated measures, group effect: F=6.81, P =0.016). No significant differences were found between the two groups on the Simpson and Angus Rating Scale scores, but a significant difference was found in the Barnes Akathisia Rating Scale scores: no patient in the olanzapine-treated group experienced akathisia, while a few patients in the haloperidol-treated group showed this side-effect, thus resulting in a significant group effect detected by the ANOVA (F=4.23, P =0.05). CONCLUSIONS: These preliminary results suggest that olanzapine is superior to haloperidol in the treatment of partial-responder paranoid schizophrenic patients, and also shows a better tolerability profile. Further investigations, including different diagnostic subgroups, are still needed to further clarify the clinical profile of olanzapine. (Int J Psych Clin Pract 2002; 6: 107-111).

Modulation of glutamate receptors in response to the novel antipsychotic olanzapine in rats.

BACKGROUND: A disturbance in glutamate neurotransmission has been hypothesized in schizophrenia. Hence, the beneficial effects of pharmacological treatment may be related to adaptive changes taking place in this neurotransmitter system. METHODS: In this study, we investigated the modulation of ionotropic and metabotropic glutamate receptors in the rat brain following acute or chronic exposure to the novel antipsychotic olanzapine. RESULTS: In accordance with the clear distinction between classical and atypical drugs, olanzapine did not alter glutamate receptor expression in striatum. Chronic, not acute, exposure to olanzapine was capable of up-regulating hippocampal mRNA levels for GluR-B and GluR-C, two alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA)-forming subunits. This effect could be relevant for the improvement of schizophrenic alterations, which are thought to depend on dysfunction of the glutamatergic transmission within the hippocampal formation. We also found that the expression of group II glutamate metabotropic receptors was up-regulated in the frontal cortex after chronic exposure to clozapine, and to a lesser extent olanzapine, but not with haloperidol. CONCLUSIONS: The adaptive mechanisms taking place in glutamatergic transmission might prove useful in ameliorating some of the dysfunction observed in the brain of schizophrenic patients.

H(2) antagonist nizatidine may control olanzapine-associated weight gain in schizophrenic patients.

BACKGROUND: Olanzapine is temporally associated, in a number of patients with schizophrenia, with weight gain. H(2) antagonists, like nizatidine, have been shown to control appetite in overweight patients. METHODS: A patient with olanzapine temporally associated weight gain was treated with nizatidine as "add-on" therapy. RESULTS: Nizatidine treatment was associated with good control and subsequent reduction of weight after 4 to 5 weeks of therapy in a patient with repetitive episodes of weight gain during olanzapine treatment. Olanzapine was otherwise well tolerated and effective in controlling psychopathology. CONCLUSIONS: H(2) antagonist treatment with olanzapine may be a valid medical strategy in preventing and/or reducing weight gain in patients with schizophrenia. Controlled studies are recommended to confirm this observation.

Pergolide monotherapy in the treatment of early PD: a randomized, controlled study. Pergolide Monotherapy Study Group.

OBJECTIVE: To determine whether pergolide monotherapy provides symptomatic relief in early PD. BACKGROUND: Early treatment with dopamine agonists may reduce the risk of motor fluctuations, which are most likely linked to levodopa therapy. Pergolide, a D1-D2 dopamine agonist, has been studied as "add on" therapy in PD, but no controlled clinical trial studying the efficacy of pergolide monotherapy is available. METHODS: The efficacy and tolerability of pergolide were evaluated in a multicenter, double-blind, randomized, parallel-group, 3-month trial versus placebo. Patients with a diagnosis of idiopathic PD, a modified Hoehn & Yahr score of 1 to 3, and a score greater than 14 points on the Unified Parkinson's Disease Rating Scale (UPDRS) part III at baseline were enrolled in the study (pergolide, n = 53; placebo, n = 52). RESULTS: Patient characteristics at study entry were comparable in the two study groups. The pergolide group showed a significantly greater percent of responders (defined as a -30% decrease in UPDRS part III score at end point) compared with placebo (57% versus 17%; p < 0.001). Pergolide-treated patients experienced a significantly greater improvement than placebo-treated patients (p < 0.001) in UPDRS (overall, part II, and part III) score, Schwab & England score, and Clinical Global Impression improvement score. By the study end the mean dose of pergolide was 2.06 mg/day. Six patients in the pergolide group versus two patients in the placebo group discontinued the study because of treatment emergent side effects. CONCLUSION: This study suggests that pergolide monotherapy may be an efficacious and well-tolerated first-line treatment in patients with early-stage PD.

Acetyl L-carnitine slows decline in younger patients with Alzheimer's disease: a reanalysis of a double-blind, placebo-controlled study using the trilinear approach.

OBJECTIVES: To assess the longitudinal effects of acety-L-carnitine (ALC) on patients diagnosed with Alzheimer's disease. DESIGN: Longitudinal, double-blind, parallel-group, placebo-controlled. SETTING: Twenty-four outpatient sites across the United States. PARTICIPANTS: A total of 334 subjects diagnosed with probable Alzheimer's disease by NINCDS-ADRDA criteria. These data were originally reported by Thal and colleagues (1996). MEASUREMENTS: Cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS) given every 3 months for 1 year. RESULTS: The average rate of change was estimated using the trilinear approach, which allows for periods of both change and stability. Both the ALC group and the placebo group exhibited the same mean rate of change on the ADAS (0.68 points/month). However, a multiple regression analysis revealed a statistically significant Age x Drug interaction characterized by younger subjects benefiting more from ALC, significant, cutpoint for ALC benefit was 61 years of age. CONCLUSIONS: ALC slows the progression of Alzheimer's disease in younger subjects, and the use of the trilinear approach to estimate the average rate of change may prove valuable in pharmacological trials.

Apomorphine responses in Parkinson's disease and the pathogenesis of motor complications.

We studied the contribution of basal ganglia circuitry downstream from the nigrostriatal dopaminergic system to the pathogenesis of levodopa associated motor complications by means of an apomorphine dose-response paradigm in 28 parkinsonian patients grouped according to their clinical response to levodopa therapy. With progression from the dopa-naive to the severely fluctuating dyskinetic state, apomorphine response duration shortened, the dose-response slope steepened, and the therapeutic window narrowed. Because apomorphine acts independently of the integrity of presynaptic dopaminergic neurons, our results suggest that postsynaptic alterations account mainly for the appearance of response complications. The present findings support the possibility, raised by animal model studies, that motor response complications arise as a consequence of altered signal transduction mechanisms in striatal medium-sized neurons.

Pergolide binds tightly to dopamine D2 short receptors and induces receptor sequestration.

Pergolide is an ergotamine derivative with potent D1 and D2 receptor activity. In this study we showed that pergolide binds tightly to dopamine D2 short receptors, as indicated by the long period of occupancy of the receptors after washing. Furthermore, pergolide induces receptor internalization to a larger extent than dopamine, seeing that no recycling of the receptors to the plasma membrane was observed for either agonist. The dissociation of pergolide from dopamine receptors occurs during the endocytotic process, leaving the receptors accessible to [3H]methylspiperone. Pergolide is a lipophilic compound that can reach and compete with [3H]methylspiperone for binding to sequestered receptors. If internalized receptors are still a target for drug action, pergolide could be a suitable compound of therapeutic interest in cases where receptor sequestration could prevent dopamine efficacy, as in levodopa therapy.

Longitudinal assessment of symptoms of depression, agitation, and psychosis in 181 patients with Alzheimer's disease.

OBJECTIVE: The goal of this study was to define the recurrence or continuation of neuropsychiatric symptoms in patients with Alzheimer's disease who were observed serially for a 1-year period. METHOD: One hundred eighty-one patients with probable Alzheimer's disease were assessed five times at 3-month intervals with a standardized neuropsychiatric rating instrument. RESULTS: Recurrence rates of neuropsychiatric symptoms during the 1-year period were 85% for depression, 93% for agitation, and 95% for psychosis. Symptom frequency at any point in time underestimated the cumulative 1-year frequency. Recurrence rates were significantly greater among patients who had multiple symptoms. Women exhibited more symptoms than men. Patients in the oldest age group (76-87 years) had more psychosis, less depression and agitation, and slower cognitive decline. Psychosis was associated with more rapid cognitive decline, and agitation was associated with more rapid functional deterioration. CONCLUSIONS: These results indicate that once psychiatric symptoms are present in patients with Alzheimer's disease, they frequently recur. These symptoms vary with age, sex, and rate of illness progression.

Is early-onset Alzheimer disease a distinct subgroup within the Alzheimer disease population?

Although patients with Alzheimer disease (AD) share major clinical and neurohistologic features regardless of age of onset, the hypothesis that early-onset AD comprises a distinct subgroup remains viable. Most studies addressing this hypothesis find quantitative differences between early- and late-onset AD patients. Early-onset AD is characterized by shorter survival, more rapid cognitive deterioration, greater frequency of language disturbance, more severe and widespread neurochemical abnormalities, and a greater density of neurohistologic lesions. In addition, both the chromosome 14 genetic abnormality and chromosome 21 amyloid precursor protein mutations appear restricted to early-onset familial AD. Age of onset of AD subjects may be relevant to the design of clinical trials. For example, the efficacy of a drug that slows disease progression may be more easily demonstrated in subjects with early-onset disease.

Motor effects of the partial dopamine agonist (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine (preclamol) in Parkinson's disease.

The motor effects of the partial dopamine agonist (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(-)-3-PPP, preclamol] were evaluated in nine patients with Parkinson's disease using a double-blind, placebo-controlled design. (-)-3-PPP monotherapy had an antiparkinsonian effect in five of nine patients at a mean dose of 37 +/- 10 mg intramuscularly. The co-administration of (-)-3-PPP and a mildly dyskinetic dose of levodopa, infused intravenously at steady-state, resulted in complete suppression of dyskinesias and reemergence of parkinsonian signs in two of seven patients. These dopamine antagonist effects of (-)-3-PPP occurred at relatively low (2.5 and 5 mg) doses. Our results suggest that partial dopamine agonists can exert agonist or antagonist activity in parkinsonian patients depending on concurrent dopaminergic tone. Although this dual action of (-)-3-PPP and other partial agonists could be therapeutically important on theoretical grounds, the small number of patients manifesting a clinically significant response and the frequently inconsistent effects could indicate that this class of agents may have relatively limited clinical utility.

Wearing-off fluctuations in Parkinson's disease: contribution of postsynaptic mechanisms.

Wearing-off phenomenon that complicates levodopa therapy of Parkinson's disease has been attributed to a reduction in striatal dopamine storage due to the progressive degeneration of presynaptic dopaminergic terminals. To determine whether postsynaptic mechanisms also contribute to these response fluctuations, the duration of the antiparkinsonian response in parkinsonian patients grouped by disease severity was compared following discontinuation of a steady-state optimal-dose infusion of apomorphine. Although the plasma half-life of this dopamine receptor agonist remained constant, its mean efficacy half-time declined from 66 minutes in early, levodopa-naive patients to 33 minutes in advanced, complicated parkinsonians (p < 0.005). Since the motor effects of apomorphine do not depend on the presence of dopaminergic terminals, changes at the postsynaptic level undoubtedly contribute to the diminished response duration. The only slightly greater attenuation of levodopa's motor effects observed previously under similar conditions suggests these postjunctional alterations, possibly involving relatively plastic striatal dopaminoceptive systems, account for most of the shortening in the duration of levodopa action that underlie wearing-off fluctuations.

Levodopa peak response time reflects severity of dopamine neuron loss in Parkinson's disease.

We measured the time to peak antiparkinson response following injection of levodopa or apomorphine in 57 patients with Parkinson's disease. The peak response time for levodopa fell from 53 +/- 6.5 minutes in patients at Hoehn and Yahr stage I-II, and 28 +/- 4.8 minutes in those at stage IV (p < 0.0005). There was a significant correlation between levodopa peak response time and symptom duration (r = 0.65; p < 0.0001), but there was no relation between apomorphine peak response time and measures of disease severity. Peak response time to levodopa appears to reflect predominantly the status of compensatory presynaptic dopaminergic mechanisms and thus may provide an index to the degree of dopamine neuron degeneration in parkinsonian patients.

D-cycloserine treatment of Alzheimer disease.

Degeneration of cortical glutamatergic projections may contribute to the cognitive decline in Alzheimer disease (AD). To evaluate whether 1glutamate system stimulation might confer symptomatic benefit, we administered D-cycloserine, a putative partial indirect agonist at certain N-methyl-D-aspartate (NMDA) glutamate receptors, to 12 patients with probable AD. The patients (seven men, five women) had a mean age of 65 +/- 8.4 years; Mini Mental State Examination scores ranged from 15 to 25. A dose escalation phase, in which cycloserine was given in daily oral doses from 25 to 500 mg (total of six dose levels, 1 week per dose), was followed by a "best dose" crossover comparison with placebo under double-blind conditions. The crossover phase consisted of 2 weeks of cycloserine and 2 weeks of placebo, separated by a 1-week washout period. We observed no significant or consistent effect on neuropsychological outcome measures. The results suggest that short-term potentiation of NMDA-mediated glutamatergic transmission may not prove useful in the symptomatic treatment of Alzheimer dementia.

Catechol-O-methyltransferase inhibitor tolcapone prolongs levodopa/carbidopa action in parkinsonian patients.

The wearing-off phenomenon frequently complicates levodopa therapy of Parkinson's disease (PD). These response fluctuations appear when intrasynaptic dopamine concentrations begin to reflect the swings in levodopa availability that attend standard dosing regimens. Drugs that prolong the biologic half-life of levodopa and dopamine should thus prove beneficial. We administered levodopa/carbidopa in combination with single oral doses of tolcapone (Ro 40-7592), an inhibitor of catechol-O-methyltransferase, under controlled conditions to 10 PD patients with the wearing-off phenomenon. Tolcapone prolonged the antiparkinson response to levodopa/carbidopa by about 67% at several doses ranging from 50 to 400 mg (p < 0.05). There was no significant change in the peak levodopa effect on parkinsonian signs or in the severity of dyskinesias. No dose-limiting adverse effects occurred. Multiple daily dosing with tolcapone would thus be expected to safely reduce the wearing-off phenomenon associated with levodopa/carbidopa therapy.

End-of-dose dystonia in Parkinson's disease.

To evaluate the pathogenesis of end-of-dose dystonia in levodopa-treated patients with Parkinson's disease, we discontinued a steady-state optimal-dose levodopa infusion either abruptly or slowly. Although dystonic signs appeared sooner after sudden levodopa termination, in both situations dystonia emerged only when circulating drug levels had fallen to the same concentration and parkinsonian scores had declined by the same amount. Dystonia onset thus appears to reflect the degree, rather than the rate, of reduction in dopaminergic stimulation, and may involve the preferential interaction of dopamine with a receptor subpopulation that does not mediate its antiparkinsonian efficacy.

Acetyl-L-carnitine and Alzheimer's disease: pharmacological considerations beyond the cholinergic sphere.

Since ALCAR and L-carnitine are "shuttles" of long chain fatty acids between the cytosol and the mitochondria to undergo beta-oxidation, they play an essential role in energy production and in clearing toxic accumulations of fatty acids in the mitochondria. ALCAR has been considered of potential use in senile dementia of the Alzheimer type (SDAT) because of its ability to serve as a precursor for acetylcholine. However, pharmacological studies with ALCAR in animals have demonstrated its facility to maximize energy production and promote cellular membrane stability, particularly its ability to restore membranal changes that are age-related. Since recent investigations have implicated abnormal energy processing leading to cell death, and severity-dependent membrane disruption in the pathology of Alzheimer's disease, we speculate that the beneficial effects associated with ALCAR administration in Alzheimer patients are due not only to its cholinergic properties, but also to its ability to support physiological cellular functioning at the mitochondrial level. This hypothetical mechanism of action is discussed with respect to compelling supportive animal studies and recent observations of significant decrease of carnitine acetyltransferase (the catalyst of L-carnitine acylation to acetyl-L-carnitine) in autopsied Alzheimer brains.

No evidence for altered muscle mitochondrial function in Parkinson's disease.

Recent reports indicate that reductions in mitochondrial respiratory chain function occur in substantia nigra, platelets, and muscle from patients with Parkinson's disease. To confirm and further characterise the presence of a generally distributed mitochondrial defect, mitochondrial metabolism was evaluated in muscle obtained from subjects with Parkinson's disease and from normal controls. Oxygen consumption rates in muscle mitochondria represented by complex I, complexes II-III, or complex IV did not differ between the two groups. Likewise, activities of rotenone sensitive NADH cytochrome c reductase, succinate cytochrome c reductase, or cytochrome oxidase in muscle mitochondria were not significantly different between Parkinsonian and control subjects. These findings fail to provide support for a generalised defect in mitochondrial function in Parkinson's disease but do not exclude an abnormality in respiratory function confined to the substantia nigra.

Treatment of Parkinson's disease with the partial dopamine agonist EMD 49980.

The motor effects of the partial dopamine agonist EMD 49980 were evaluated in parkinsonian patients under controlled conditions. EMD 49980 monotherapy resulted in a mild improvement in parkinsonian symptoms, but when co-administered with levodopa, had no significant effect on dyskinesias or on the antiparkinsonian effect of the dopamine precursor. These results suggest that EMD 49980 exerts a net weak dopamine agonist effect but fails to ameliorate levodopa-induced dyskinesias.

Effect of aging and dopaminomimetic therapy on mitochondrial respiratory function in Parkinson's disease.

Oxygen consumption and enzyme activity were evaluated in platelet mitochondria from 17 patients with Parkinson's disease. In comparison with age-matched controls, no consistent abnormality could be discerned in complex I, complex II-III, or complex IV oxygen consumption, or in the enzyme activity of these respiratory chain complexes. Neither chronic therapy with levodopa/carbidopa alone nor in combination with deprenyl significantly affected any measure of mitochondrial respiratory function. There was no discernible relationship between patient age or disease severity and any parameter of mitochondrial respiration. Moreover, blood lactate levels following glucose loading were not different in patients and controls. These results fail to support the occurrence of a generalized defect in any mitochondrial respiratory function in Parkinson's disease.

A pharmacological study of dopaminergic receptors in planaria.

The dopaminergic receptors of planaria have been studied with pharmacological and biochemical criteria. Dopamine D1 selective agonists (CY 208243 (10 micrograms/ml) and SKF 38393 (10 micrograms/ml] induced in planaria typical screw-like hyperkinesias, that were inhibited by a D1 antagonist (SCH 23390 (10 micrograms/ml], but not by a D2 antagonist (sulpiride (1000 micrograms/ml]. Dopamine D2 selective agonists (PHNO (5 micrograms/ml), lisuride (5 micrograms/ml] on the contrary induced a typical "C" like curling, that was inhibited by pretreatment with D2 selective blocking agents, but not by D1 selective blocking agents. With agonists with a D1/D2 mixed action (apomorphine 60 micrograms/ml) or with amphetamine (100 micrograms/ml), the D1 type movements appeared to be more evident. Dopamine D1-selective agonists, mixed action agonists or D2-selective agonists, all induced a significant increase in levels of cAMP, that was prevented by pretreatment with the specific DA blocking agent.