Mazindol Treatment of Negative Symptoms

Abstract

Hypodopaminergic and hyponoradrenergic pathophysiology may be a basis for primary and/or secondary negative symptoms in schizophrenia. The hypothesis that enhanced neurotransmission in these systems would be therapeutic for negative symptoms was tested by comparing mazindol and placebo in a double-blind, cross-over design trial. Outcome following mazindol supplementation was comparable to placebo supplementation (F(1,30) Many mental and physical states can temporarily reduce an individual's ability to experience pleasure, gratification, and reinforcement. However, when Rado (1956) described anhedonia as a core feature of schizophrenia, he referred to an enduring or trait reduction in capacity rather than a transitory or state impairment. Meehl (1962) elaborated this concept in the context of a trait neurointegrative disability associated with schizophrenia. Stein and Wise (1971) subsequently introduced the hypothesis that neurotoxic damage to the noradrenergic reward system was present in schizophrenia. This latter theory, while not capable of accounting for the broad range of clinical manifestations of the disease, seemed a highly cogent hypothesis for anhedonia per se (Strauss and Carpenter 1972).Negative symptoms of schizophrenia are defined more broadly than anhedonia, but the core features of reduced social drive, restricted emotional experience and expression, alogia, and a diminished capacity for the experience of pleasure are hypothesized to emerge from pathophysiology in the neural circuits concerned with drive, emotion, and reward. Dopaminergic and noradrenergic neurons are central to the mediation of these experiences (Schultz 1997).These considerations suggest a therapeutic hypothesis, that enhanced neurotransmission in noradrenergic and/or dopaminergic systems would be therapeutic for negative symptoms. In particular, the dopaminergic mesocortical projections and noradrenergic circuitry involved with reward are seen as possible neural substrates for the negative symptoms of schizophrenia (Weinberger 1987;Davis et al. 1991). Developing a treatment based on either of these presumptions is not straightforward, however, since the hyperdopaminergic mesolimbic hypothesis would predict that a drug that reduces negative symptoms would have the potential liability of increasing positive symptoms.An approach to enhancing mesocortical dopaminergic activity, while having little effect on other projections, is the use of dopamine reuptake inhibitors. This approach is based on the observation that dopamine NO . 4 turnover rates in the mesocortical projection are two to four fold higher than in the mesolimbic or nigrostriatal systems (Agnati et al. 1980;Bannon et al. 1981;Thierry et al. 1976). Accordingly, a reuptake blocker should result in a faster accumulation and higher concentration of synaptic dopamine in cortical regions than in other dopamine terminal fields. Direct support for this hypothesis is provided by preclinical studies in which drugs that block amine transporters increase dopamine levels in ...

Neurobiological background of negative symptoms

“…These findings were contradicted by Nibuya et al [143], who found higher pHVA concentrations in DS as compared to NDS subjects; the identification of patients with DS in this study has been criticized [8,142]. Two blind, placebo-controlled trials of MAO inhibitors also reported mixed results [144,145].…”

Pharmacological Augmentation Strategies for Schizophrenia Patients With Insufficient Response to Clozapine: A Quantitative Literature Review

“…Augmentation with conventional or atypical antipsychotics, 22,23 various antidepressants, 24,25 lithium, 26 sodium valproate, 27 carbamazepine, 28 novel anticonvulsants, 29 dopamine agonists, 30 glutamate receptor agonists, 31 mazindol, 32 and omega-3 fatty acids 33 have all been described as clozapine adjuncts in the treatment of resistant symptoms. The available literature addressing different augmentation strategies in clozapine-resistant patients seems promising at first glance because most reports suggest that therapeutic benefits can be gained.…”

Augmentation Strategies in the Treatment of Schizophrenia

“…56 ' 59 A single dose of amphetamine was found to improve some aspects of cognitive function 60 and to improve prefrontal cortical hypoactivity observed during performance of the Wisconsin Card Sorting Test/' 1 However, Casey and colleagues 62 found no improvement in negative symptoms when amphetamine was added to chlorpromazine in a 20-week outpatient trial. More recently, Carpenter and colleagues 63 failed to detect any benefit from augmentation of antipsychotics with mazindol, a dopamine and norepinephrine reuptake blocker, administered in a double-blind, placebo-controlled crossover trial involving an 8-week treatment phase in 39 patients with schizophrenia or schizoaffective disorder.…”