Clozapine indications

Examples abound regarding the role of serendipity in the discovery of new therapeutic approaches, which on closer examination usually turned out to be the result of clinicians paying attention to unexpected clinical effects rather than discounting them. For example, lithium was tried first for hypertension, chlorpro-mazine was initially developed as an anesthetic, and imipramine was originally regarded as an antihistamine and an antipsychotic agent. Without astute clinical observations, these drugs would not have found their niche, nor would clozapine have been revived for the benefit of millions of the most difficult to treat schizophrenic patients. Other examples include the expanded indications of newer... 

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. 

The other group within this class of dibenzazepines are formed by agents which are related to clozapine. Clozapine is an atypical antipsychotic which is used for the treatment of schizophrenia. It is primarily indicated for schizophrenic patients with predominantly negative symptoms. Its indication can be extended to those patients that have shown to be refractory to the conventional neuroleptics. It can also be substituted for other antipsychotics in... 

Other newer agents were claimed to provide the benefits of clozapine without the drawback of potentially lethal agranulocytosis, but recent studies indicate that older agents like perphenazine and sulpiride when used in sensitive dose regimens provide as good an outcome as any other drugs. 

Agranulocytosis is a potentially catastrophic idiosyncratic reaction that usually appears within the first 3 months of therapy. Although the incidence is extremely low (except for clozapine), mortality is high. Thus, any fever, sore throat, or cellulitis is an indication for discontinuing the antipsychotic and immediately conducting white blood cell and differential counts. 

Anisette Doe, a 28-year old woman, went to the emergency department with abdominal bloating and inability to void her bladder she had been unable to urinate for 16 hours. A urinary catheter was inserted and 2.5 L of urine was withdrawn. Subsequent testing revealed no calculi or masses in the bladder, urethra, ureters, or kidneys. Ms. Doe s medical records indicated that she was being treated with clozapine for paranoid schizophrenia. She reported no signihcant side effects as a result of this treatment. For 2 days prior to admission to the hospital, Ms. Doe complained of a cold and was taking diphenhydramine Benadryl)... 

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. 

The main indications for atypical antipsychotics are the acute and maintenance treatment of schizophrenic disorders, with an emphasis on the treatment of refractory and chronic disorders. However, because of the lower risk of EPS and in particular of tardive dyskinesia, there is a tendency toward a wider range of indications for some of the atypical neuroleptics. Favorable effects in drug-induced psychoses have been demonstrated for olanzapine. Clozapine seems effective in the treatment and relapse prevention of manic episodes and bipolar disorders, and risperidone has been shown to have good efficacy in conduct disorders and in the pervasive developmental disorders. 

Schulz, E., Fleischhaker, C., and Remschmidt, H. (1996) Correlated changes in symptoms and neurotransmitter indices during maintenance treatment with clozapine or conventional neuroleptics in adolescence and young adulthood schizophrenia. / Child Adolesc Psychopharmacol 6 119-131. 

Risperidone, a novel benzisoxazole derivative, is an atypical antipsychotic medication that combines dopamine D2 receptor antagonism with potent 5-HT2 receptor antagonism. Risperidone has a higher affinity for dopamine D2 receptors than does clozapine. Risperidone also antagonizes dopamine Dj and D4 receptors, aj- and a2-adrenergic receptors, and histamine Hj receptors. Although the optimal dose of risperidone in North American trials was 6 mg/day, subsequent clinical experience has indicated that most patients do well at lower doses of 3-6 mg/day, and elderly patients may require doses as low as 0.5 mg/day. Unlike other atypical antipsychotics. 

Several controlled trials have shown that lithium is efficacious in the maintenance treatment of bipolar disorder, with higher serum levels (0.8 1 mol/1) being more indicative of successful prophylaxis (Keck and McElroy. 2002). Valproic acid also appears to have efficacy in maintenance therapy, specifically in bipolar patients with mixed mania and rapid cycling (Bowden et al., 1995). The results concerning carbamazepine s efficacy as a maintenance medication are controversial (Stuppaeck et al., 1994). Other potential agents with some evidence of good maintenance value include clozapine and olanzapine. A combination of lithium and carbamazepine or other anticonvulsants is recommended under certain conditions if an adequate preventive effect cannot be obtained with the substances individually (Bauer et al., 2002). 

Another use of the laboratory is for therapeutic drug monitoring (TDM) of psychotropics with defined optimal ranges, narrow therapeutic indices, or both. Although TDM is not essential for many psychotropics, it is for others, including lithium, several TCAs, valproate, and carbamazepine. It may also be helpful to optimize the use of certain antipsychotics (e.g., haloperidol, clozapine) ( 7). 

Postmortem studies of patients with idiopathic Parkinson s disease demonstrate cell loss in the striatal system (A-9), directly implicating this tract vis-a-vis the neuroleptic-induced pseudoparkinsonian side effects. The assumption that psychosis is related to the A-10 system is made by exclusion. Evidence also indicates that clozapine may differentially block DA pathways. Specifically, it seems to act on the mesolimbic dopaminergic system (A-10), while being relatively inactive in the striatal system (A-9) however, this remains controversial. Chronic administration of clozapine decreases the firing rate of A-10 mesocortical tract dopamine neurons... 

In this context, there is anecdotal clinical data indicating that risperidone and clozapine can be overlapped or used concomitantly with beneficial results and no serious adverse reactions (99,100, 101 and 102). This strategy has been used successfully for residual positive symptoms during clozapine therapy and in patients who relapsed when a neuroleptic was withdrawn from combined therapy with clozapine. Indeed, up to 60% of clozapine-treated patients receive additional medication, including a second antipsychotic. 

Clozapine, risperidone, olanzapine, quetiapine, and ziprasidone have all been approved for the treatment of schizophrenia. Data from long-term open evaluations of clozapine demonstrate that improvement is maintained over time, even when the dose is reduced. Further, patients did not develop tolerance to its antipsychotic effect. Naturalistic reports indicate that an adequate trial for acute response in some patients may be at least 6 months. Further, a small number (8 of 14) of previously refractory patients were successfully maintained on clozapine for up to 2 years ( 215). 

While there is no evidence that combining two neuroleptics is superior to comparable amounts of a single agent, the combined use of a neuroleptic plus a novel antipsychotic or, alternatively, the combination of two different novel agents (e.g., clozapine plus risperidone) may be beneficial in certain circumstances. Preliminary reports indicate that the pharmacology of novel antipsychotics may be sufficiently different that, when combined with each other or with neuroleptics, a better overall effect can be achieved in selected patients ( 100). Thus, potential scenarios include ... 

In this light, an important indication for clozapine may be for patients who develop severe EPS or TD on another antipsychotic. Not only is clozapine unlikely to produce TD, as noted earlier, a body of clinical evidence indicates that it may benefit TD. 

As noted earlier, evidence indicates that atypical antipsychotics may also produce NMS ( 488). Several patients have developed NMS after treatment with clozapine, risperidone, or olanzapine. A few of these cases are classic NMS, with symptoms such as markedly elevated temperature and CPK levels. For each drug, approximately a dozen reported cases fulfill a reasonably stringent criteria for NMS, whereas the rest can be considered borderline. The number of NMS cases, however, appears low relative to use. In addition, some of the patients on clozapine who developed NMS were also receiving neuroleptics. There are cases of patients who had NMS on clozapine alone, however, and when rechallenged with clozapine experienced another NMS episode. Similarly, rechallenge with olanzapine- or risperidone-induced NMS has resulted in either questionable or definite reemergence of NMS. 

This agent has a broad spectrum of activity encompassing several neurotransmitter systems. In this light, clozapine is similar to such phenothiazines as CPZ and thioridazine (519). It is also subject to a hepatic first-pass effect, which produces metabolites with low or unknown pharmacological activity. It has an elimination half-life ranging from 6 to 33 hours and a volume of distribution (V 5 l /kg) lower than most other antipsychotics. This last quality indicates less drug is sequestered in tissue sites. Plasma levels of the parent compound at or above 350 ng/mL may be associated with a better clinical response ( 66, 520). Plasma levels are lower in men than women, especially male smokers (329). 

Early reports found clozapine to benefit some affectively disordered patients (e.g., bipolar, schizoaffective) who had previously been treatment-refractory, but improved rapidly and significantly on this agent ( 108, 109, 278). Further, many patients were able to sustain their early gains in psychosocial functioning over a 3-5-year period. The low incidence of EPS and TD also increased interest in potentially new indications for these agents. 

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