A meta-analysis of the response to chronic l-dopa in patients with schizophrenia: therapeutic and heuristic implications

Jaskiw, George E.; Popli, Anand P.

doi:10.1007/s00213-003-1672-y

Cited by 22 publications

(11 citation statements)

References 77 publications

(99 reference statements)

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“…The increased availability of dopamine in the prefrontal cortex may not only contribute to improve the effect on cognitive symptoms, but can probably also, in the presence of a D 2 antagonist, contribute to enhance the antipsychotic effect per se. Previous clinical studies show that low doses of L-dopa used as adjunct treatment to conventional APDs may enhance their therapeutic effect in schizophrenic patients (see Jaskiw and Popli, 2004), and experimental data reveal that adding low doses of L-dopa to raclopride not only caused a preferentially increased prefrontal cortical dopamine output, but also potentiated the antipsychotic-like effect of the D 2/3 antagonist (Eltayb et al, 2005). Therefore, addition of drugs that are able to increase the availability of cortical monoamines, for example, reboxetine and idazoxan, to APDs may both enhance the antipsychotic effect, as well as improve negative or depressive symptoms and certain aspects of cognitive impairment.…”

Section: Discussionmentioning

confidence: 99%

Reboxetine Enhances the Olanzapine-Induced Antipsychotic-Like Effect, Cortical Dopamine Outflow and NMDA Receptor-Mediated Transmission

Marcus¹,

Jardemark²,

Malmerfelt³

et al. 2010

Neuropsychopharmacol

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Preclinical data have shown that addition of the selective norepinephrine transporter (NET) inhibitor reboxetine increases the antipsychotic-like effect of the D 2/3 antagonist raclopride and, in parallel, enhances cortical dopamine output. Subsequent clinical results suggested that adding reboxetine to stable treatments with various antipsychotic drugs (APDs) may improve positive, negative and depressive symptoms in schizophrenia. In this study, we investigated in rats the effects of adding reboxetine to the second-generation APD olanzapine on: (i) antipsychotic efficacy, using the conditioned avoidance response (CAR) test, (ii) extrapyramidal side effect (EPS) liability, using a catalepsy test, (iii) dopamine efflux in the medial prefrontal cortex and the nucleus accumbens, using in vivo microdialysis in freely moving animals and (iv) cortical N-methyl-D-aspartate (NMDA) receptor-mediated transmission, using intracellular electrophysiological recording in vitro. Reboxetine (6 mg/kg) enhanced the suppression of CAR induced by a suboptimal dose (1.25 mg/kg), but not an optimal (2.5 mg/kg) dose of olanzapine without any concomitant catalepsy. Addition of reboxetine to the low dose of olanzapine also markedly increased cortical dopamine outflow and facilitated prefrontal NMDA receptor-mediated transmission. Our data suggest that adjunctive treatment with a NET inhibitor may enhance the therapeutic effect of low-dose olanzapine in schizophrenia without increasing EPS liability and add an antidepressant action, thus in principle allowing for a dose reduction of olanzapine with a concomitant reduction of dose-related side effects, such as EPS and weight gain.

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Section: Discussionmentioning

confidence: 99%

Reboxetine Enhances the Olanzapine-Induced Antipsychotic-Like Effect, Cortical Dopamine Outflow and NMDA Receptor-Mediated Transmission

Marcus¹,

Jardemark²,

Malmerfelt³

et al. 2010

Neuropsychopharmacol

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“…The authors concluded that add-on levodopa may be beneficial in patients already on antipsychotics [93]. It is noteworthy that the beneficial effects of levodopa prevailed over its negative effects even though high doses of levodopa, associated with a peripheral decarboxylase inhibitor, were given.…”

Section: Overcoming the Metabolic And Cardiovascular Side Effects Of mentioning

confidence: 99%

Antipsychotic-Induced Metabolic and Cardiovascular Side Effects in Schizophrenia: A Novel Mechanistic Hypothesis

Scigliano

Ronchetti

2013

CNS Drugs

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The use of antipsychotics is hindered by the frequent occurrence of metabolic and cardiovascular side effects, resulting in worsened quality of life and greater mortality as a result of cardiovascular and cerebrovascular disorders in schizophrenia patients than the comparable general population. The various antipsychotics induce extrapyramidal symptoms, impaired glucose and lipid metabolism, weight gain, hypertension and arrhythmias, with variable frequency. Second-generation antipsychotics appear to have several advantages over first-generation antipsychotics, including a claimed better action on cognitive function and the negative symptoms of schizophrenia, and lower frequency of extrapyramidal side effects; however, their use is associated with a greater frequency of metabolic and cardiovascular disturbances. The mechanisms of these important side effects are not well understood, and generic approaches (psychoeducational programmes and symptomatic therapies) have been proposed to limit their severity. Extensive data from the literature indicate that autonomic nervous system dysfunction—intrinsic to schizophrenia and strongly exacerbated by antipsychotic treatment—is the cause of the pervasive metabolic and vascular dysfunctions associated with schizophrenia. In this article, we marshal further literature data to argue that the metabolic and cardiovascular side effects of antipsychotics are primarily mediated by their ability to block peripheral dopamine receptors, which physiologically modulate sympathetic activity. We also propose that these effects might be overcome by providing peripheral dopaminergic stimulation.

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“…In these studies no exacerbation of psychotic symptoms was reported. Levodopa has also been used as add-on in 5 placebo-controlled studies in patients with schizophrenia and a meta-analysis of these studies found a beneficial overall effect (because of the variety of outcome measures used in these studies, patients were divided in two response groups on the basis of their response in the scale used in the individual studies for the purposes of the meta-analysis: poor response = no change or worsening and good response = improved) with a medium-large ES (Cohen's d= 0.71) and no worsening of any symptoms of schizophrenia (Jaskiw and Popli, 2004). There was however clinical worsening in 38% of the patients who received high doses of levodopa without concomitant antipsychotics.…”

Section: Which Cognitive-enhancing Drugs?mentioning

confidence: 99%

Treating impaired cognition in schizophrenia: The case for combining cognitive-enhancing drugs with cognitive remediation

Michalopoulou

Lewis

Wykes

et al. 2013

European Neuropsychopharmacology

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A meta-analysis of the response to chronic l-dopa in patients with schizophrenia: therapeutic and heuristic implications

Abstract: . In patients already on antipsychotic drugs, the addition of L-dopa can be beneficial. Dopamine agonists merit further consideration as adjuncts to antipsychotic drugs in the treatment of schizophrenia.

Cited by 22 publications

References 77 publications

Reboxetine Enhances the Olanzapine-Induced Antipsychotic-Like Effect, Cortical Dopamine Outflow and NMDA Receptor-Mediated Transmission

Reboxetine Enhances the Olanzapine-Induced Antipsychotic-Like Effect, Cortical Dopamine Outflow and NMDA Receptor-Mediated Transmission

Antipsychotic-Induced Metabolic and Cardiovascular Side Effects in Schizophrenia: A Novel Mechanistic Hypothesis

Treating impaired cognition in schizophrenia: The case for combining cognitive-enhancing drugs with cognitive remediation

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