Mazindol Treatment of Negative Symptoms William T. Carpenter, Jr., M.D., Alan Breier, M.D., Robert W. Buchanan, M.D., Brian Kirkpatrick, M.D., Paul Shepard, Ph.D., and Elaine Weiner, M.D. Hypodopaminergic and hyponoradrenergic pathophysiology subjects were similar, and were not affected by whether may be a basis for primary and/or secondary negative concurrent the antipsychotic drug treatment was clozapine, symptoms in schizophrenia. The hypothesis that enhanced fluphenazine, or haloperidol. The efficacy hypothesis was neurotransmission in these systems would be therapeutic not supported for either primary or secondary negative for negative symptoms was tested by comparing mazindol symptoms. [Neuropsychopharmacology 23:365–374, and placebo in a double-blind, cross-over design trial. 2000] © 2000 American College of Outcome following mazindol supplementation was Neuropsychopharmacology. Published by Elsevier comparable to placebo supplementation (F(1,30) ϭ 0.9; p ϭ Science Inc. .57). Results for deficit and non-deficit schizophrenia KEY WORDS: Schizophrenia; Mazindol; Negative symptoms; Negative symptoms of schizophrenia are defined Clinical trial; Dopamine more broadly than anhedonia, but the core features of reduced social drive, restricted emotional experience Many mental and physical states can temporarily re- and expression, alogia, and a diminished capacity for duce an individual’s ability to experience pleasure, the experience of pleasure are hypothesized to emerge gratification, and reinforcement. However, when Rado from pathophysiology in the neural circuits concerned (1956) described anhedonia as a core feature of schizo- with drive, emotion, and reward. Dopaminergic and phrenia, he referred to an enduring or trait reduction in noradrenergic neurons are central to the mediation of capacity rather than a transitory or state impairment. these experiences (Schultz 1997). Meehl (1962) elaborated this concept in the context of a These considerations suggest a therapeutic hypothe- trait neurointegrative disability associated with schizo- sis, that enhanced neurotransmission in noradrenergic phrenia. Stein and Wise (1971) subsequently introduced and/or dopaminergic systems would be therapeutic for the hypothesis that neurotoxic damage to the noradren- negative symptoms. In particular, the dopaminergic ergic reward system was present in schizophrenia. This mesocortical projections and noradrenergic circuitry in- latter theory, while not capable of accounting for the volved with reward are seen as possible neural sub- broad range of clinical manifestations of the disease, strates for the negative symptoms of schizophrenia seemed a highly cogent hypothesis for anhedonia per se (Weinberger 1987; Davis et al. 1991). Developing a (Strauss and Carpenter 1972). treatment based on either of these presumptions is not straightforward, however, since the hyperdopaminer- From the Maryland Psychiatric Research Center, Department of gic mesolimbic hypothesis would predict that a drug Psychiatry, University of Maryland, Baltimore, MD. A.B. current that reduces negative symptoms would have the poten- affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indi- anapolis, IN. tial liability of increasing positive symptoms. Address correspondence to: William T. Carpenter, Jr., M.D., An approach to enhancing mesocortical dopaminer- Maryland Psychiatric Research Center, P.O. Box 21247, Baltimore, gic activity, while having little effect on other projec- MD 21228. Received March 8, 2000; revised March 8, 2000; accepted March tions, is the use of dopamine reuptake inhibitors. This 14, 2000. approach is based on the observation that dopamine NEUROPSYCHOPHARMACOLOGY 2000–VOL. 23, NO. 4 © 2000 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/00/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(00)00115-9 366 W.T. Carpenter, Jr. et al. NEUROPSYCHOPHARMACOLOGY 2000–VOL. 23, NO. 4 turnover rates in the mesocortical projection are two to a direct effect on negative symptoms, or are exerting four fold higher than in the mesolimbic or nigrostriatal their therapeutic effect through their anti-parkinsonian systems (Agnati et al. 1980; Bannon et al. 1981; Thierry and/or antidepressant properties. In the present study et al. 1976). Accordingly, a reuptake blocker should re- we examine whether mazindol is effective for either sult in a faster accumulation and higher concentration primary and/or secondary negative symptoms when of synaptic dopamine in cortical regions than in other added to a conventional antipsychotic, or when added dopamine terminal fields. Direct support for this hy- to clozapine. Mazindol is a potent antagonist of both pothesis is provided by preclinical studies in which DA and NE transporters (Heikkila et al. 1977) and is se- drugs that block amine transporters increase dopamine lected for testing on the basis of preliminary reports of levels in the prefrontal cortex but not in the nucleus ac- its efficacy in the treatment of negative symptoms cumbens (Carboni et al. 1990; Tanda et al. 1994). Block- (Seibyl et al. 1991). ade of the noradrenergic transporter contributes directly to the selective increase in mesocortical dopamine lev- els, presumably by preventing heterologous uptake METHODS into norepinephrine-containing nerve terminals in the Subjects cortex (Tanda et al. 1997). The rationale for this strategy has received support Thirty-nine patients meeting DSM-III-R criteria for from previous clinical trials. Previous studies have sug- schizophrenia or schizoaffective disorder were selected gested that drugs which enhance the release of DA and from the Maryland Psychiatric Research Center Outpa- other monoamines may be effective in reducing nega- tient Research Program for entry into the study. Pa- tive symptoms (Angrist et al. 1980, 1982; Cesarec and tients were diagnosed using a best estimate diagnostic Nyman 1985; Van Kammen and Boronow 1988; approach that utilized all available information from a Mathew and Wilson 1989; Goldberg et al. 1991; Sanfil- structured diagnostic interview (Structured Clinical In- ipo et al. 1996). The negative symptom advantage terview for DSM-III-R), direct assessment, family infor- sometimes reported with antipsychotic drugs that have mants, and past medical records. Patients with concur- robust serotonin antagonism may be an indirect effect rent drug abuse or alcoholism, organic brain disorders, of diminishing inhibition of dopamine neurons mental retardation, or a medical condition that con- (Schmidt and Fadayel 1995; Kapur and Remington traindicated any study medication were excluded from 1996). A similar advantage has been associated with se- the study. All patients provided written informed con- lective serotonin reuptake inhibitors (Silver and Nassar sent prior to participating in the study. 1992; Spina et al. 1994; Goff et al. 1995a; see also Bucha- Patients were relatively chronic and stable outpa- nan et al. 1996). These seemingly paradoxical findings tients and were required to exhibit a minimum level of could be resolved if one considers that SSRIs adminis- negative symptoms. The minimum negative symptom tered in the presence of antipsychotic drugs with affin- level was a total score of at least 20 on the Scale for the ity for 5-HT2 receptors could indirectly increase DA Assessment of Negative Symptoms, or SANS (An- levels in the prefrontal cortex via activation of inhibi- dreasen 1984), or a score of at least 2 on at least one tory serotonergic autoreceptors. Alternatively, it has SANS global item. been suggested that the ability of both SSRIs and 5-HT antagonists to improve negative symptoms could re- Study Design flect a differential effect of these drugs on the depres- sive (SSRI-sensitive) and extrapyramidal (5-HT2 an- Patients were randomly assigned to placebo or mazin- tagonists-sensitive) components of these symptoms dol in an all-blind, balanced-order, cross-over design, (Kapur and Remington 1996). Finally, it should also be with a four-week washout at cross-over and admission noted that noradrenergic reuptake inhibitors have also to the second condition only if baseline criteria were been used to successfully to treat negative symptoms met again. Each treatment phase was eight weeks. Pa- (Yamagami and Soejima 1989; Siris et al. 1987) and that tients randomized to mazindol received three 1-mg tab- clozapine, sometimes observed to be superior in the lets in the morning. If a patient could not tolerate this treatment of negative symptoms (Lieberman et al. 1994) dose, then downward dose adjustments were permit- is associated with a substantial increase in norepineph- ted. Patients randomized to placebo also received three rine concentrations (Breier et al. 1994). tablets in the morning. Patients were continued on their However, in all of these studies, there is usually current dose of oral fluphenazine, haloperidol, or cloza- no effort made to take into account the effect of the pine throughout the study. The mean daily dose (oral) putative therapeutic agents on sources of secondary is given in Table 1. Compliance was assessed by a negative symptoms. The failure to control for potential weekly pill count and weekly medication review. In ad- effects on secondary negative symptoms leaves unan- dition, all patients had a compliance plan that consisted swered the question of whether these agents are having of medication checks by family and/or mental health NEUROPSYCHOPHARMACOLOGY 2000–VOL. 23, NO. 4 Mazindol