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Schizophrenia is a terrible illness, and a substantial percentage of its victims fail to achieve a good therapeutic response to standard antipsychotic treatment. Clozapine has been shown, in multiple studies, to offer additional therapeutic benefi t to otherwise treatment-unresponsive patients. Clozapine has distinctive advantages for reducing aggressive and suicidal behaviors, for treating compulsive water drinking, and, perhaps, for reducing co-morbid substance use. Much attention has been paid to clozapine’s dramatically dangerous side effects: agranulocytosis and myocarditis. Weight gain and metabolic side effects caused by clozapine have been considered annoying. It is now vividly clear that weight gain and metabolic side effects are slowly and surreptitiously lethal to far more patients treated with clozapine than agranulocytosis or myocarditis. Patients started on clozapine in the 1990s are now dying in their 40s and 50s of accelerated cardiovascular disease. Given that the treatment of schizophrenia is increasingly more effective, it is worrisome to see that the mortality gap is in fact widening (ie. Schizophrenics are dying even earlier than the general population). This is not necessary. Worldwide increases in obesity and associated cardiovascular disease in the general population have provoked medical practitioners to develop strategies to manage this risk. These strategies now must be applied to patients treated with clozapine. Clozapine-induced insulin resistance, dyslipidemia, and infl ammation proceed quietly for years to decades before pancreatic beta cells fail (diabetes mellitus) or cardiovascular events (myocardial infarction or stroke) occur. It makes no sense to wait until damage has been done to intervene. Pre-emptive interventions should be initiated as clozapine is started. Metformin can greatly reduce the weight gain associated with starting atypical antipsychotic treatmen, and help patients who have already gained weight to lose it. Metformin reverses insulin resistance, thereby delaying the failure of pancreatic beta cells by years if not decades. There is no reason to delay starting metformin when starting clozapine. The initial dose is 850 mg daily, to be increased to 850 mg BID with breakfast and dinner. Metformin is usually well-tolerated, but must be used cautiously in patients with renal failure. Fasting lipids should be checked 6-8 weeks after starting clozapine. Elevated low-density lipoproteins (LDL) enter vascular epithelium in areas of non-laminar fl ow, e.g. where the coronary or carotid arteries branch steeply off the aorta. LDL lipids are oxidized, becoming irritants causing local infl ammation and attracting macrophages that burrow under the epithelium and ingest the lipids. Some of these lipid-gorged macrophages (foam cells) die. Soft, fragile, inflamed DROP lets of lipid and necrotic macrophages bulge the epithelium. Efforts to cover the bulges with connective tissue are usually flawed. These atheromatous plaques may rupture and spill their contents into the arterial lumen, provoking platelet adhesion and the clotting factors cascade. A thrombus forms and downstream tissues die. Statins lower low-density lipoprotein levels, and raise high-density lipoprotein (HDL) levels; fewer lipids are delivered to arterial cell walls by LDL, and more are removed by HDL. Statins reduce infl ammation; the reaction to oxidized lipids is attenuated. Statins have been shown to significantly reduce the risk for myocardial infarction, stroke, and other cardiovascular events in high-risk populations. In clozapine-treated patients with elevated LDL levels, simvastatin can be started at 20mg QHS. Plaque formation will slow; already present plaques will stabilize as the lipid levels in them decline and infl ammation is reduces. Side effects of statins such as muscle damage or elevation of liver function tests are dose-related and relatively rare in the low dose range used for prevention. A single aspirin daily reduces platelet aggregation and thrombus formation around unstable plaques. The better brain function that only clozapine brings to many patients is well worth the efforts that we psychiatrists, working with primary-care colleagues, must expend in managing clozapine’s liabilities. If we do this well, out patients will have longer lives as well as lives with less psychopathology. Carolina Aponte Urdaneta Joseph P. McEvoy Duke University Medical Center, Department of Psychiatry Durham, NC, Estados Unidos carolina.aponteurdaneta@duke.edu

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2008-09-22   |   1,865 visitas   |   Evalua este artículo 0 valoraciones

Vol. 37 Núm.2. Junio 2008 Pags. Rev Col Psiqui 2008; XXXVII(2)