Clozapine treatment-resistant

Revicki DA, Luce BR, Weschler JM et al (1990). Cost-effectiveness of clozapine for treatment-resistant schizophrenic patients. Hosp Community Psychiatry 850-69. 

Kane), Honigfeld G, Singer), et al (1988). Clozapine for the treatment resistant schizophrenic. A double blind comparison with chlorpromazine. Arch Gen Psychiatry h hy 766-71. 

To date, clozapine remains the only drug with proven and superior efficacy in treatment-resistant patients, and it is currently the only drug approved for the treatment-resistant schizophrenic. Studies have shown a response of approximately 30% to 50% in these well-defined treatment-resistant patients. Clinical trials have consistently found clozapine to be superior to traditional antipsychotics for treatment-refractory patients, and it is efficacious even after nonresponse to other SGAs and in partially responsive patients. It is often rapidly effective even in those who have had a poor response to other medication for years. Recent studies have demonstrated that it has a beneficial effect for aggression and suicidality, which led to the Food and Drug Administration (FDA) approval for the treatment of suicidal behavior in people with psychosis.41... 

Only clozapine has shown superiority over other antipsychotics in randomized clinical trials for the management of treatment-resistant schizophrenia. 

Clozapine (Clozaril). Clozapine was introduced over 30 years ago but has only been available in the United States since 1990. It remains the medication of choice for treatment-resistant schizophrenia. Since its introduction, it has been used to treat acute mania with excellent results. Furthermore, it avoids the potential for tardive dyskinesia posed by haloperidol and the other typical antipsychotics. 

In addition to being effective in the treatment of schizophrenia, clozapine also is effective in the treatment of the manic phase of bipolar disorder. Although not a first-line treatment for mania, clozapine is useful for patients who are not responding well to more traditional treatments. Finally, clozapine is the one antipsychotic proven to help treatment-resistant schizophrenia. Fully one-third of patients who do not respond to other antipsychotics will respond to clozapine. 

Clozapine can certainly be a difficult and expensive medication to take. However, for the treatment-resistant patient with schizophrenia, clozapine is often well worth the trouble. 

Only after a patient has failed two adequate antipsychotic trials should clozapine or augmentation with a second medication be considered. Refer to Section 4.7 for more information on handling treatment resistance. 

Of all these treatments, the only consistent improvement is seen with the atypical antipsychotic clozapine (Clozaril). Treatment-resistant TD is in fact one generally accepted indication for nsing clozapine. However, becanse of the expense of this drug, the risk for granulocytopenia, and the reqnirement for biweekly blood draws, other measures should hrst be tried. 

Clozapine was the first atypical antipsychotic released in the United States. However, clozapine is associated with the risk of leukopenia and, potentially, lethal agranulocytosis. Because of these concerns, hematological monitoring during clozapine pharmacotherapy is required (Alphs and Anand, 1999). Due to these hematological risks, clozapine is indicated only for patients with treatment-resistant schizophrenia. The other atypical antipsychotics, risperidone, olanzapine, quetiapine, and ziprasidone, that are marketed in the United States can be used as first-line treatments for adults with schizophrenia. 

Clozapine Dibenzodiazepine 25-900 Low 100 Treatment-resistant illnesses Schizophrenia Bipolar disorder Autistic disorder Kumra et ah, 1996 Kowatch et ah, 1995 Zuddas et ah, 1996... 

Utman RE, Su TP, Potter WZ, et al Idazoxan and response to typical neuroleptics in treatment-resistant schizophrenia comparison with the atypical neuroleptic, clozapine. Br J Psychiatry 168 571-579, 1996 Uttle A, Levy R, Chuaqui-Kidd P, et al A double-blind placebo-controlled trial of high-dose lecithin in Alzheimer s disease. J Neurol Neurosurg Psychiatry 12 110-118, 1985... 

Suppes T, Webb A, Paul B, et al Clinical outcome in a randomized 1-year trial of clozapine versus treatment as usual for patients with treatment-resistant illness and a history of mania. Am J Psychiatry 156 1164— 1169, 1999... 

The previous course of a disorder and its resolution with treatment can be a key element of patient selection. Investigation of the effects of a drug in de novo diagnosed, first-episode patients will lead to different conclusions than a trial in mainly chronic, multitreatment-exposed patients. Some key inclusion criteria can be defined according to the treatment response history of patients a study with clozapine in treatment resistant schizophrenic patients (Kane et ah. 1988 see Chapter 2) is an example for this. 

Kane, J. M., Honigfeld, G., Singer, J.. Meltzer, H. Clozapine for the treatment-resistant schizophrenic a double-blind comparison with chloipromazine. Arch. Gen. Psychiatry 45, 789-796, 1988. 

Honigfeld G, Patin J, Singer J. Clozapine antipsychotic activity in treatment-resistant schizophrenics. Adv Ther 1984 1 77-97. 

Buckley P, Thompson P, Way L, et al. Substance abuse among patients with treatment-resistant schizophrenia characteristics and implications for clozapine theory. Am J Psychiatry 1994 151 385-389. 

Yovell Y, Opier LA. Clozapine reverses cocaine craving in a treatment-resistant mentally ill chemical abuser a case report and a hypothesis. J Nerv Ment Dis 1994 182 591-592. 

Bondolfi G, Baumann P, Paths M, et al. A randomized double-blind trial of risperidone versus clozapine for treatment-resistant chronic schizophrenia. Presented at the 148th Annual Meeting of the American Psychiatric Association, Miami, May 1995. 

Potkin SG, Bera R, Gulasekaram B, et al. Plasma clozapine concentrations predict clinical response in treatment resistant schizophrenia. J Clin Psychiatry 1994 55(9, suppi B) 117-121. 

Clozapine Longitudinal Trials. In a naturalistic study design, Banov et al. (300) found clozapine was an effective long-term treatment in mood disorders, particularly nondepressed affective patients. After a chart review, the authors identified 193 treatment-resistant patients, including the following ... 

Dibenzodiazepine Clozapine May benefit treatment-resistant patients little extrapyramidal toxicity May cause agranulocytosis in up to 2% of patients dose-related lowering of seizure threshold... 

Benzodiazepines are used as hypnotics because they have the ability to increase total sleep time. They demonstrate minimal cardiovascular effects, but do have the ability to increase heart rate and decrease cardiac output. Most CNS depressants, including the benzodiazepines, exhibit the ability to relax skeletal muscles. Clozapine, a dibenzodiazepine, is used in the treatment of schizophrenia. It has both sedative and antipsychotic actions, and is the only FDA-approved medication indicated for treatment-resistant schizophrenia, and for reducing the risk of suicidal behavior in patients with schizophrenia. This drug can have potentially life-threatening side effects, but appears to have no abuse potential and will not be considered further. 

Pharmacologists have been attempting to define what it is about clozapine s biochemical mechanism of action that accounts for its special efficacy as well as its side effects. As discussed extensively in this chapter, SDA properties may account in part for reducing EPS, for reducing tardive dyskinesia, and perhaps even for lack of prolactin elevation SDA properties may even help explain improvement in negative symptoms of schizophrenia. However, the concept of SDA does not appear to explain the therapeutic actions of clozapine in treatment-resistant cases because clozapine is superior to other agents that share this property. 

Ozdemir V, Kalow W, Okey AB, Lam MS, Albers LJ, Reist C, Fourie J, Posner P, Collins EJ, Roy R. Treatment-resistance to clozapine in association with ultrarapid CYP1A2 activity and the C A polymorphism in intron 1 of the CYP1A2 gene effect of grapefruit juice and low-dose fluvoxamine. J Clin Psychopharmacol 2001 21 603-607. 

The concept of treatment-resistant schizophrenia, which was developed to delineate a market for the relaunch of clozapine, has lead to public acknowledgment of the extent of non-response to treatment with other neuroleptic drugs. It is now widely admitted that at least 25% of patients do not show any significant clinical improvement with drug treatment. A recent comparison of two of the newer neuroleptic drugs, risperidone and olanzapine, found that 46% and 56% of patients, respectively, did not respond after four months of treatment (Robinson et al. 2006). In addition, the majority of inpatients with psychosis are treated with other sedative drugs in addition to... 

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