The use of the atypical antipsychotic clozapine in the treatment of schizophrenia
I submitted the following term paper for graduate credit in my neuropsychopharmacology course.

The atypical antipsychotic clozapine is an important drug in the treatment of schizophrenia.  Unlike traditional antipsychotics, clozapine does not produce Parkinson’s like (extrapyramidal) symptoms.  However, because of its potentially fatal side effects due to agranulocytosis, it is best suited for only those patients who have proven to be unresponsive or resistant to other pharmacological interventions.  The unique pharmacological profile of clozapine may indicate future treatments of schizophrenia as well as possible causes of the disorder.

A brief history of clozapine
Clozapine is a drug with a promising outlook for the treatment of schizophrenia.  Although it now has an established reputation for dealing with even those patients who were unresponsive to other medications, clozapine has a lengthy history and some persistent negative consequences.

Clozapine was first synthesized in 1958, and first clinical trials were carried out in the 1960s.  Whereas previously tested and more widely prescribed anti-psychotic medications were notable for side-effects on the motor systems (as will be discussed later), these trials demonstrated that such effects did not occur under clozapine treatment (Naber, 2000).

The antipsychotic effect of clozapine was recognized early in its history, the manufacturer was reluctant to introduce it for clinical use because it did not meet the "psychopharmacologic dogma" established with previous medications that an antipsychotic effect could not be achieved without negatively affecting the motor systems (Naber, 2000).

In 1972 clozapine was introduced in Austria, Switzerland, and Germany, and, within the following five years, in 30 other countries.  By this time more than 100,000 schizophrenic patients had been treated with clozapine, and its antipsychotic effect had been demonstrated in numerous double-blind controlled studies (Naber, 2000).

However, the rapid increase in the distribution of clozapine stopped abruptly in 1974, when sixteen patients developed agranulocytosis due to clozapine treatment.  Eight of these patients died.  In many countries clozapine was withdrawn from the market.  An exception was to this was German speaking countries, where the intervention of several renowned psychiatrists allowed it to continue to be prescribed although now under precautionary restrictions (Naber, 2000).

Only after the unique effect of clozapine on was demonstrated in schizophrenic patients resistant to other treatments, did clinical research into the effectiveness of clozapine being to dramatically increase.   That study and its resulting interest led to the (re-)introduction of clozapine in most countries (Naber, 2000).

Clozapine finally received approval from the U. S. Food and Drug Administration for clinical use in the United States in 1990; however, it has been extensively used in the United States since the 1970s (Owens & Risch, 2001).

Since that time other antipsychotic drugs with chemical structures somewhat related to clozapine have been developed: olanzipine, loxapine, zotepine, and quetiapine, all of which lack clozapine’s propensity to cause agranulocytosis (Stahl, 2000).

Mechanism of action
Whereas traditional or “typical” antipsychotic agents act on primarily dopamine receptors, clozapine has a much more broad, complex pharmacological profile, acting on dopaminergic, serotonergic, and other receptors.  An increased understanding of brain biology has led to the development of newer hypotheses regarding the pathology of psychosis and innovations in the approaches to psychopharmacological treatments.

Much work has been performed in laboratory settings to assess the pharmacological properties of clozapine, while other researchers have begun to employ various brain scanning techniques to determine anatomically how and where the drug produces its therapeutic effect.

When the dopamine D1- and D2-receptor occupancy in the basal ganglia was measured in schizophrenic patients, those under traditional antipsychotic treatment had a D2-receptor or occupancy of 70-90%, while those under clozapine treatment had only 18-80%.  , without evidence for a critical degree of D2-receptor occupancy required to sustain clozapine's therapeutic effects.  Those patients with acute extrapyramidal motor side-effects (Naber, 2000).

These results were replicated by another group who demonstrated through PET results that clozapine patients, treated with 125-600 mg/day, showed a D2-receptor occupancy of 20-67% and a D1-receptor the relatively high occupancy of 36-59%, whereas under typical antipsychotics the occupancy was 0-44%).  Further, the 5-HT-receptor occupancy even under a low clozapine dose was very high (84-94%).  Although the clozapine plasma level varied greatly (105-2121 ng/ml), the D2-receptor occupancy was low or below 60% for all patients and did not correlate with the plasma level or the dose.

Clozapine produces its greatest effect in the treatment of the positive symptoms of schizophrenia (e.g. thought disorders, delusions, and hallucinations), but has also been associated with relatively greater effectiveness in the treatment of negative symptoms (e.g. blunted affect, apathy, and social withdrawal).  Owens and Risch (2001) point out that many investigators have noted the association of prominent negative symptoms with relative reductions in prefrontal cortical blood flow and glucose metabolism seen during PET or single photon emission computerized tomography (SPECT) scanning of schizophrenic patients.  Clozapine apparently improves (or at least does not worsen) this relative "hypofrontality" when compared with traditional antipsychotic medications (Owens & Risch, 2001).

The dopamine hypothesis
For many year researchers attempted to elucidate the links between medication, dopamine, and schizophrenia. However, the results of pharmacological interventions did not permit the formation of any simple picture of dopamine “causing” schizophrenia.  In fact, researchers noted that the "atypical" drug clozapine produced the same kind of clinical benefits as other neuroleptics, yet affected different neurochemical receptors in the brain (as will be discussed in more detail later).

Further, it was realized that that patients with schizophrenia may suffer from excess and depressed dopamine activity in different regions of their brains.  Thus, it was determined that any simple equation of "antischizophrenic" with "dopamine inhibiting" (as antipsychotic medications did in whole or in part) was impossible (Gelman, 1999).

To complicate matters, Caliguri et al. (1993) found mild Parkinson's disease-like symptoms in 30% of people with schizophrenia who had never been medicated. The dopamine hypothesis attempted to link schizophrenia to an increase in dopamine activity.  However, these symptoms were usually associated with decreased dopamine activity in a particular brain system (Gelman, 1999).

Efficacy, quality of life
Most studies indicate that the degree of compliance (how well a given medication is working) for schizophrenics receiving long-term treatment with clozapine.  For typical or “traditional” antipsychotics, compliance is 20-50%.  For clozapine (depending on length of treatment and the sample population) compliance is between 50-70% and about 90% (Naber, 2000).

Perhaps the most important property of clozapine is that it offers the possibility of treatment to patients for whom no other medication produced a significant effect; as much as 27% patients who did not respond to other antipsychotics benefited from clozapine (Gelman, 1999). The superior antipsychotic efficacy of clozapine in many studies has been confirmed for both the positive and negative symptoms of psychosis.  Other preliminary studies suggest that an additional 15% - 30% of patients who are unresponsive to clozapine in the first few months may show significant improvement after six months to two years of continued clozapine pharmacotherapy (Meltzer, 1992).

Many schizophrenics under long-term treatment with a typical antipsychotic report affective and cognitive deficits, which are difficult to show objectively.  Typical complaints such as and anhedonia and lack of drive are difficult to distinguish from negative symptoms or extrapyramidal side-effects, have long been known and labeled "pharmacogenic depression, akinetic depression, or neuroleptic-induced deficits syndrome."

The quality of life of schizophrenic patients under treatment with traditional antipsychotics was scientifically neglected for a long time.  The first study of that area was conducted by Meltzer et al (1995) who showed that the quality of life of 38 chronic patients increased significantly within six months of clozapine treatment.  Recently, a double-lined controlled study compared haloperidol and clozapine, both in rather high dosages, confirmed with this result.  Within one year of treatment, compliance as well as quality of life were significantly after under therapy with the atypical neuroleptic (Rosenheck et al., 1997, cited in Naber, 2000).

Extrapyramidal side effects
Clozapine and the other, newer antipsychotic medications are frequently classified as “atypical” because they produce their therapeutic effect without affecting the extrapyramidal motor systems.  Conventional (“typical”) antipsychotics produce Parkinson’s-like symptoms.  For this reasons they are often referred to as neuroleptics.  Although others such as Marder (2001) prefer terms such as “traditional” or “conventional” to describe drugs that were previously termed neuroleptic to denote these symptoms.

Baldessarini (1988) suggested another reason for clozapine's apparent advantage against negative symptoms, one that it not arise from the drug's effects on illness. Psychiatrists "easily confused" the side effects of medication with negative symptoms of schizophrenia. His implication was again obvious: clozapine did not necessarily affect negative symptoms any differently; it simply failed to produce the same impairments from side effects that other medication did (Gelman, 1999).

In spite of its advantages in treating schizophrenia without producing extrapyramidal symptoms, clozapine is also the only antipsychotic drug associated with the risk of a life-threatening and occasionally fatal complication called agranulocytosis. This condition typically occurs in 0.5% to 2% of patients.  Because of this, patients must have their blood counts monitored weekly for the first six months of treatment and then every two weeks for as long as they are being treated with the medication (Stahl, 2000).  Several ongoing studies are attempting to elucidate both the mechanisms and the predictors of clozapine-associated agranulocytosis in attempts to reduce or eliminate this potentially fatal side effect (Owens & Risch, 2001).  Because of this relatively high risk/benefit ratio, clozapine is not generally considered a first-line agent for the treatment.  Instead it is prescribed only when several other agents have failed, especially with violent or otherwise difficult patients (Stahl, 2000).

Side effects and toxicology
Although clozapine lacks the extrapyramidal symptoms that plagued the first generation of antipsychotic medications, it is prone to produce some notable side effects.  For example, profound and often prolonged sedation, hypersalivation, and anti-cholinergic side effects (e.g. dry mouth, blurred vision, urinary retention, and constipation).  These side effects are usually temporary although they may persist for several months.  These symptoms are often related to the dosage taken and may respond to a temporary reduction in dose or to treatment by taking (or co-ingesting) other agents with pharmacological properties that do not cause the problematic side effects (Owens & Risch, 2001).

Clozapine also entails an increased risk of seizures, especially at high doses.  As stated above, it can be very sedating and is associated with the greatest degree of weight gain among the antipsychotics.  Goldberg and Weinberger (1994) also found that clozapine could worsen memory in some patients. Thus, clozapine may simultaneously have the greatest efficacy, but the most side effects among the atypical antipsychotics (Stahl, 2000).

The occurrence of seizures appears to be dose related, possibly bow covering at a rate of 0.7% per 100 mg does.  Patients experiencing seizures may be treated concurrently with anticonvulsants or the clozapine therapy may be reduced or stopped entirely.  When therapeutic levels of anticonvulsants are achieved, clozapine may be titrated upward to its previously therapeutic levels (Owens & Risch, 2001).

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.  Clozapine’s antagonism of serotonin and dopamine receptors does not explain its side effects of weight gain, sedation, seizures, and agranulocytosis.  In fact, while the mechanism of clozapine's induction of agranulocytosis remains unknown, no other atypical antipsychotic drug appears to produce this effect.

Clozapine’s ability to cause seizures are also poorly understood but are not a serious problem for any other atypical antipsychotic. Among all of the atypical antipsychotics, clozapine appears to cause the greatest problems with weight gain.  This correlates best with its antihistaminic properties, and is probably made worse by its antagonism of serotonin 2C receptors.  Sedation may be also by caused by its antihistaminic and anticholinergic actions (Stahl, 2000).

It is also possible to overdose on clozapine.  An overdose or intoxication with a dose of 2000 mg leads to a mortality of 12%, according to the manufacturer.  The reason of death is usually cardiac failure or aspiration pneumonia.  However, there are also reports of patients who recuperated without complications from doses as high as 10,000 mg.  Also notable is that for adult patients, who have never consumed clozapine, a dose of 400 mg can lead to coma or death (Naber, 2000).

Clinical Use
Because of its infrequent but potentially fatal adverse side effects, clozapine is rarely prescribed as the first means of treatment for psychotic patients.  However, if indicated, clozapine therapy is typically begun at 12.5-25 mg/day and increased in 25 mg increments each day, as tolerated by the patient.  As patients began to show appreciable clinical improvement, their previous antipsychotic therapy is titrated downward and eventually discontinued (Owens & Risch, 2001).

Patients apparently rarely need or benefit from continued combined treatment with clozapine and a high-potency typical antipsychotic medication (e.g. haloperidol, etc.).  In fact, the continued use of "combination therapy" puts the patients in increased and continued risk for the extrapyramidal symptoms associated with the traditional “neuroleptic” medications (Owens & Risch, 2001).

Although clozapine has been employed clinically for decades, and despite its increasingly widespread use, there is still a dangerous practice in the method of its prescription.  Specifically, when clozapine was first introduced, it was recommended that candidates for clozapine have antipsychotic medication "washouts" for up to one week prior to the initiation of clozapine.  This is dangerous because the withdrawal of a typical antipsychotic prior to treatment with clozapine may sometimes be associated with significant clinical deterioration.  It is recommended that withdrawal be individualized according to patient indications (Owens & Risch, 2001).

There is no universal agreement as to the "optimal" daily dose of clozapine that would produce the greatest therapeutic effect while avoiding the more serious side effects.  Although doses in the range of 200-400 mg/day have occasionally been associated with significant improvement and efficacy, greater improvement in otherwise unresponsive or partially responsive patients may occur with doses in the range of 500-900 mg/day (Stahl, 2000).

Confounding the determination of a particular patients' most defective daily does is the observation that some patients appear to need increased time taking medication, rather than increased doses of medication, for an optimal therapeutic response.  Thus, some patients who experienced little or no improvement during the first 3-4 months of therapy will go on to improve significantly after six months to two years of continued pharmacotherapy.  However, approximately one-third of patients will not experience significant benefits from clozapine pharmacotherapy, regardless of the dose or the duration of trial (Owens & Risch, 2001).

Economic implications
Morris et al. (1998) surveyed the economic aspects and cost-effectiveness of clozapine treatments. Patients require regular, expensive blood monitoring for agranulocytosis, causing out-patient treatment to cost far more for those patients than with typical antipsychotics.  However, costs of in-patient treatment are diminished due to a much lower rate of hospitalization.  Two U.S. studies (cited in the following results) showed a savings per patients of $20,000-41,500 per year. Meltzer et al (1993) showed a decrease in costs of 23%. Reed et al. (1994) found similar results, where clozapine treatment significantly reduced the number of in-patient days for a savings of $33,000 to $50,000 per patient per year (Naber, 2000).

Chronic treatment with clozapine has also been associated with improvements in "functionality," including increased vocational, social, and interpersonal adaptation in otherwise chronically compared, treatment-refractory patients.  The results of this include diminished frequency and duration of hospitalizations and an increased ability of patients to increase their educational level and to re-enter the workplace. Meltzer et al. (1992) and several other studies throughout the world have indicated that the therapeutic use of clozapine, in spite of its higher costs, has resulted in significant savings to society.  These savings comprise reduced hospital costs, and in potentially improved economic productivity of otherwise chronically ill patients (Owens & Risch, 2001).

Because of the dramatic efficacy of clozapine, some such as Meltzer (1993) suggested that patients be shifted to atypicals entirely.  However, Most psychiatrists have not gone nearly that far because of the expensive blood monitoring and the potential risks of agranulocytosis. The typical annual cost for clozapine and the necessary blood monitoring equaled $5500 according to one estimate, which was more than 10 times the cost of standard medication.  Consequently, psychiatrists largely have confined the use of clozapine to treatment-resistance cases (Gelman, 1999).

While clozapine possesses some notable drawbacks, its use will likely continue to expand throughout the population of schizophrenic patients as therapists are increasingly educated into this treatment option.  Further, as research clarifies the mechanisms of action for both clozapine’s therapeutic effect as well as its side effects, mechanisms for newer therapies and even the etiology of schizophrenia may be uncovered.

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